Chemistry creates its subject. This creative ability, similar to that of art, essentially distinguishes Chemistry among the natural sciences. Berthelot, J. 1860

The ultimate goal of Organic Synthesis is to assemble a given organic compound (target molecule) from readily available starting materials and reagents in the most efficient way. This process usually begins with the design of a synthetic plan (strategy) which calls upon various synthetic reactions to address individual synthetic objectives in a certain sequence. If a transformation or a strategic maneuver required by the synthetic plan has to be demonstrated before, the plan must rely on the development of a suitable synthetic method or tactic to solve the particular problem at hand. Thus, the science of organic synthesis is constantly enriched by new inventions and discoveries pursued deliberately for their own sake or as subgoals within a program directed towards the synthesis of a target molecule. Nicolaou, K. C. Classics in Total Synthesis

Name Reaction !!!!

Organic Synthesis
The Practice of Total Synthesis With its share of glorious moments, setbacks, and frustrations Total Synthesis can be compared to the game of chess. The object of this game is to capture the opponent's king by a series of allowed moves played out in such a combination and order as outmaneuver the opponent. Similarly, in total synthesis the object is to reach the target molecule by a series of reactions which have to be carried out in the right sequence to outmaneuver natural barriers. Studying and applying the moves (reactions) to capture the king (make the molecule) then becomes the object of total synthesis. The practice and elegance of total synthesis involves and depends of the following stages: 1. Selection of the target: natural product or designed molecule 2. DESIGN OF THE SYNTHETIC STRATEGY: RETROSYNTHETIC ANALYSIS 3. Selection of the reagents and conditions 4. Experimental execution Design is a term that refers to a creative activity within the realm of technology, an activity that, to be sure, can ascend into the domain of great art. The design of a chemical synthesis is not science a priori: it is a fruit of science; its prerequisite is comprehensive matured, and approved scientific knowledge.
Robert Burns Woodward. Architect and Artist in the World of Molecules

Serratosa defined Synthesis as a heuristic activity "According to the Oxford Dictionary, the word heuristic derives from the Greek heurisko ("I find') and it is used as an adjective to describe activities directed towards the act of discovering , including all those reasonings and arguments that are persuasive and plausible without being logically rigorous... The heuristic principles, in contrast with the mathematical theorems and the rules of proof, do not pretend to be laws, an only suggest lines of activities“
Serratosa, F. Organic Chemistry in Action.

Organic Synthesis: The targets can be Natural Products ...
Brevetoxin B marine neurotoxin associated with the red tide catastrophes [Nicolaou 1995]

Vancomycin antibiotic of last resort against anti-drug resistant bacteria Evans 1995]

Swinholide A cytotoxic potent activity against multi-drug-resistant (MDR) carcinoma cell lines [Paterson 1994]

Organic Synthesis: The targets can be compounds with interesting activities...

Acetylsalicilic acid (Aspirin, Bayer)

Fluoxetine (Prozac, Eli Lilly) depressions

Allura red AC (Allied Chem) red pigment

Parathion insecticide

Crivixan (Merck) anti AIDS

Sildenafil (Viagra, Pfizer) male erection disfunction

Organic Synthesis: The targets can be compounds with artistic or anthropomorphic attributes...

NanoPutians Tour, J. M. JOC 2003, 8750

Classifications of Synthesis: The Power of "Convergent Synthesis " The first principle of retrosynthetic planning: convergent strategies are the most efficient strategies for the assembly of complex molecules .

In one strategy divergent synthesis aims to generate a library of chemical compounds by first reacting a molecule with a set of reactants. This methodology quickly diverges to large numbers of new compounds . It is often an alternative to convergent synthesis or linear synthesis.Classifications of Synthesis Divergent synthesis : • A divergent synthesis is a strategy with the aim to improve the efficiency of chemical synthesis.

Classifications of Synthesis Combinatorial synthesis : The characteristic of combinatorial synthesis is that different compounds are generated simultaneously under identical reaction conditions in a systematic manner. . so that ideally the products of all possible combinations of a given set of starting materials (termed building blocks) will be obtained at once.

Each structure derived antithetically from a TGT then itself becomes a TGT for a further analysis. to a target structure. a different and more systematic approach was developed: Retrosynthetic Analysis Retrosynthetic (or antithetic) analysis is a problem solving technique for transforming the structure of a synthetic target (TGT) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic precursor is accomplished by the application of a transform. . the planning syntheses were initially based on the availability of starting materials that contained a major portion of the final atomic framework and on the knowledge of reaction suitable for forming polycyclic molecules By the mid 1960's. Repetition of this process eventually produces a tree of intermediates having chemical structures as nodes and pathways from bottom to top corresponding to possible synthetic routes to the TGT.e. associative thinking or thinking by analogy was sufficient) With the exception of a minor proportion which clearly depended on a more subtle way to thinking about.Organic Synthesis In the beginning until Second World War organic synthesis was based on the Direct Associative Approach (i. the exact reverse of a synthetic reaction.

Organic Synthesis In The Direct Associative Approach. the realization of the synthesis in the laboratory may be one of the most arduous tasks which the synthetic organic chemist faces . recognition of the constituent aminoacids is almost immediate. However. the chemist directly recognizes within the structure of the target molecule a number of readily available structural subunits. which can be properly joined by using standard reactions with which he is familiar In the synthesis of peptides.

. but people do not practice it much. That is a very useful accomplishment. otherwise the success will be ardous and unspectacular . Eliot ". although the demarcation between certain tactics and strategies is difficult to make.. However thoroughly proficient the strategy formulation (the retrosynthetic analysis) .-L. . and a very easy one.. . Tactics of Organic Synthesis In pursuit a total synthesis. the grand thing is to be able to reason backwards. a chemist tries to foresee the key disconnections which will allow him to reach the target. still needs tactical coordination to smooth the progression..Strategies and Tactics in Organic Synthesis Retrosynthetic Analysis: The key to the design of efficient syntheses "The end is where we start from... T. . S..“ Sherlock Holmes Strategy 1 overall plan to achieve the ultimate synthetic target 2 Intellectual 3 retrosynthetic planning 4 TRANSFORMS Tactics 1 means by which plan is implemented 2 experimental 3 synthetic execution 4 REACTIONS Synthetic versus retrosynthetic analysis tactic Strategy Strategy and Tactic Ho. The set of these main disconnections defines and establishes the strategy..“T.

-M. The exact reverse of a synthetic reaction. .. or joined by known or conceivable synthetic operations..“ from E. the term "synthon" is suggested. Transform Imaginary retrosynthetic operation transforming a target molecule into a precursor molecule in a manner such that bond(s) can be reformed (or cleaved) by known or reasonable synthetic reactions. Corey. "The Logic of Chemical Synthesis". Chem.Strategies and Tactics in Organic Synthesis "Retron: The minimal substructural element in a target structure which keys the direct application of a transform to generate a synthetic is convenient to have a term for such units. the chemist must make use of a particular form of analysis which depends on the interplay between structural features that exist in the target molecule and the types of reactions or synthetic operations available from organic chemistry for the modification or assemblage of structural units. J. The synthetic chemist has learned by experience to recognize within a target molecule certain units which can be synthesized. 1989 For instance... the same atoms within a molecule may be constituents of several overlapping synthons. J. Cheng. Corey retron ". is 6-membered ring with a π-bond: E. 14. These are defined as structural units within a molecule which are related to possible synthetic operations.even in the earliest stages of the process of simplification of a synthetic problem. Corey and X.. a synthon may be almost as large as the molecule or as small as a single hydrogen. 19 Retron Structural unit that signals the application of a particular strategy algorithm during retrosynthetic analysis. Pure Appl. Strategy Algorithm Step-by-step instructions for performing a retrosynthetic operation. modified. a minimal keying element.. the formation of starting materials from a single product. in Diels-Alder reaction the retron... 1969.“ from "General Methods for the Construction of Complex Molecules“ E. J.

is a rational and penetrating analysis of the structure of TGT. Such analysis leads to a limited logical set of intermediate structures which can be transformed into the original in just one reaction or synthetic step. One should avoid excessive branching and proliferation of useless pathways. By this process a set of possible alternative synthetic pathways is generated which correspond to sequences of synthetic intermdiates structures that go from possible starting materials to TGT: it is the so-called "synthesis tree". . · Functional Group Interconversion (FGI): is the process of the transformation of one functional group to another to help synthetic planning and to allow disconnections corresponding to appropriate reactions. The converting process transform one functional group into another by substitution.Strategies and Tactics in Organic Synthesis Retrosynthesis analysis is a problem solving technique for transforming the structure of synthetic target molecule (TM) to a sequence of progressively simpler structures along the pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The process is repeated for every intermediate until a "tree“ of such intermediate structure is obtained. there are other factors which must be addressed including the control of regiochemistry and stereochemistry.J Corey) The transformation of a molecule to a synthetic precursor is accomplished by: · Disconnection: the reverse operation to a synthetic reaction. Every structure generated is then carefully analysed as before to give another set of structures. In planning a synthetic strategy. (E. Synthetic Strategies: Choosing the way along the retrosynthetic tree or the synthetic planning. apart from devising means of constructing the carbon skeleton with the required functionality. Synthetic Tactics: How a specific bond or set of bonds at a given site can be efficiently created. which can be transformed into the preceding structures in one step. reduction. Repetition of the process eventually produces a tree of intermediates having chemical structures in the nodes and possible chemical transformations as pathways from bottom to TM. or oxidation. elimination. The retrosynthetic step involving the breaking of bond(s) to form two (or more) synthons is referred to as a disconnection. Strategies for control and guidance are of the utmost importance. The central point in this methodology Each structure thus derived from TM then itself becomes a TM for further analysis. addition.

usually a cation. the manipulation of functional groups. and the introduction of stereochemistry must be considered simultaneously. either real or potential. 2. All the synthetic routes can be derived through a rational and penetrating analysis of the structure of TGT. Problems associated to the construction of the skeleton. The best route is the most simple. 5. It is desirable that disconnections correspond to known and reliable reactions. resulting from a disconnection Reagent: a real chemical compound used as the equivalent of a synthon Some Useful Guidelines 1. There are many approaches to the synthesis of a TGT. This repeating analysis produces the synthesis tree. and efficient. i) consider alternative disconnections and choose routes that avoid chemo. the synthetic possibilities derive from the identification of retrons and the application of transforms. ii) functional group relationships (it is imperative to remove or modify the highly unstable groups) iii) carbon skeleton: chains. anion or radical. which should consider i) symmetry. Then. Synthesis tree: set of all the possible disconnections and synthons leading from the target to the starting materials of a synthesis . which permit the generation of synthons. flexible.Strategies and Tactics in Organic Synthesis Some Useful Definitions Target molecule: the molecule to be synthetized Retrosynthetic analysis or retrosynthesis the process of menthally breaking down a molecule into starting material Transform: the exact reverse of a synthetic reaction Retron: structural subunit on the target that enables a transform to operate Disconnection: an imaginary bond cleavage corresponding to the reverse of a real reaction Synthon: idealized fragments. 4. It is worth identifying the most difficult steps and to provide alternative routes (flexibility) 6. These synthons are next evaluated.and regioselectivity problems ii) use two-group disconnections wherever possible. rings and appendages iv) stereochemistry 3.

In order for a transform to operate on a target structure to generate a synthetic predecessor.Strategies and Tactics in Organic Synthesis Transform & Retron The transformation of a molecule into a synthetic precursor is accomplished by application of a transform (antithesis process). It is possible to have partial Diels-Alder retron as in the case of cyclohexane unit . the exact reverse of a synthetic reaction. to a target structures.the enabling structural subunit or retron for that transform must be present in the target.

One feature of major significance is the overall effect of transform application on molecular complexity.. Molecular complexity elements are: (1) Molecular size (2) Cyclic connectivity or topology moderate complexity (3) Element or functional group content (4) Stereocenter content/density (5) Centers of high chemical reactivity (6) Kinetic (thermal) stability high complexity ..Strategies and Tactics in Organic Synthesis Transforms & Molecular Complexity There are many thousands of transforms which are potentially useful in retrosynthetic analysis just as there are very many known and useful chemical reactions .

functional group interchange (FGI). 2. They include rearrangements of molecular skeleton. Structurally simplifying transforms effect molecular simplification by disconnecting molecular skeleton.Strategies and Tactics in Organic Synthesis Types of Transforms 1.. . and/or functional groups and/or stereocenters. There are transforms which bring about no essentially no change in molecular complexity. and inversion/transfer of stereocenters. structurally increasing complexity transforms includes addition of rings or stereocenters and addition functional groups (FGA). Opposite to 1. 3. but which can be useful because they modify a TGT to allow the subsequent application of simplifying transforms.

Structurally simplifying transforms by disconnecting molecular skeleton and by disconnecting functional groups or stereocenters. ..Strategies and Tactics in Organic Synthesis Types of Transforms 1.

by rearrangements of molecular skeleton.. or functional group interchange (FGI) ..Strategies and Tactics in Organic Synthesis Types of Transforms 2. Structurally "neutral" transforms .

Strategies and Tactics in Organic Synthesis Types of Transforms 3. . functional groups (FGA). Structurally increasing complexity transforms includes addition of rings. or stereocenters.

JACS 1994. 2167. 2615. 1994. Otherwise. I. 1096 . Chem. Res. may be disconnected to give either a symmetrical structure or two synthetically equivalent structures. Scripta 1987. Chem. The recognition of symmetry in the structure of the TGT may be of paramount importance in the choices of disconnections to simplify the molecular complexity regioselective esterification Paterson. Ed 2003. 9. Chem. although asymmetrical molecule. Int. Tetrahedron 1995. 9391 Tetrahedron 1995. 9393–9437 See: Two-directional Chain Synthesis. plane or centre. Angew. 563.Strategies and Tactics in Organic Synthesis Guidelines in action: Symmetry A TGT molecule is said to have real symmetry if the structure possesses symmetry elements: axis. Acc. it is said to have potential symmetry when.

Chem. Am. 1917. R.Strategies and Tactics in Organic Synthesis Guidelines in action: Symmetry Robinson. I. Commun. 1984. 5304 Fleming. Soc. J. 2285 . Chem. J. Soc. 1994. J. Chem. 762 Bartlett. R. Chem. Soc.

Chem. S. O. Soc. Am. 114. Soc. Chem. J.L. Am. L. 6696 Schreiber. Chem&Ind 1955. D. J. Soc. 1971. J.Strategies and Tactics in Organic Synthesis Guidelines in action: Symmetry See also these works Barton. 1992. H. 1039. 1956. 530 Chapman. 93. 2525 . R. Chem.

Strategies and Tactics in Organic Synthesis Guidelines in action: Unstable functional groups? It is imperative to remove or modify the highly unstable groups: Early strategic disconnections must address this type of problems. D. At the outset of the project. preliminary studies are often required. no NMR spectroscopic or chemical stability data are available for the natural product. both spectroscopic and chemical studies have to be undertaken. Evans. JACS 1990 7001. A. Since such information is invaluable in the design stages of any complex synthesis plan. If this information is not available. .

R. and in this synthesis the authors decide to pursue a synthetic strategy in which this stereocenter would be introduced at an early stage or the synthetic plan and carried throughout most of the synthesis in the absence of the C-9 carbonyl group Taxol Holton. J. A. Am. 116. Soc. 1597 . 1994.Strategies and Tactics in Organic Synthesis Guidelines in action: Unstable functional groups? The facile epimerization of taxol at C-7 is well documented. Chem.

and acceptor. d. whose origin relies on the presence of functional groups. synthons. a bond forming process (and the corresponding transform) can be viewed as a combination of donor. Then.Strategies and Tactics in Organic Synthesis Guidelines in action: functional groups relationships Taking into account that most common synthetic reactions are polar. Following this idea. Evans suggested an heuristic (from the Greek heurisko: "I find') classification of functional groups (Attention: only the heteroatom is considered as the functional group) . it might be useful to consider the carbon framework of any molecule as an ionic aggregate. a.

Strategies and Tactics in Organic Synthesis Guidelines in action: functional groups relationships .

Angew.Strategies and Tactics in Organic Synthesis Guidelines in action: stereochemical issues The selective removal of stereocenters depends on the availability of stereosimplifying transforms.. 1985.. Remember that stereocontrol can rely on the same molecule (substrate control) or on external reagents (reacting control) and that just one or several elements can play a crucial role (single or double asymmetric reactions. S. D. Chem Rev. 1 Evans. E. The most powerful transforms produce an overall simplification on the stereochemistry. the establishment of the required retrons (complete with defined stereocenter relationships) and the presence of a favorable spatial environment in the precursor generated by application of such a transform. matched and mismatched cases) Corey. Eng. Int. A. J. Ed. The Logic of Chemical Synthesis Masamune. the functional group and the skeleton of the target molecules. Chem. 1993.1307 .

d. but later. . or electron donor. 19...) with respect to the relative positions of a functional group (FG) and the reacting site . they can be viewed as combination of a negatively polarized (electronegative) carbon atom. Additionally. he avoids this term and uses synthetic precursor instead. Eng. or a0. The Logic . Taking into account that the most common synthetic reactions are polar.Strategies and Tactics in Organic Synthesis Synthon Corey defined synthon in 1967 as: structural units within a molecule which are related to possible synthetic operations or units which can be formed and/or assembled by known or conceivable synthetic operations" Corey. Chem. Synthons are numbered (d0.. a.. d1. Int. J. Corey.. polar synthons have been classified. Angew.. . this concept easily rooted in the synthetic language and nowadays is commonly used. 1967. of one synthon and a positively polarized (electropositive) carbon atom. E.. E. a2. of another synthon. J.. 1990. a1. or electon acceptor. Ed. Chem. d2. 1320 However.. 14..... Pure&Appl.

Strategies and Tactics in Organic Synthesis Synthon .

Donor Synthons .

Acceptor Synthons .

Strategies and Tactics in Organic Synthesis Synthon .

Strategies and Tactics in Organic Synthesis Synthon .

Strategies and Tactics in Organic Synthesis Some “natural Synthons” .

Strategies and Tactics in Organic Synthesis Some “Unnatural Synthons” .

. The synthesis must be short.e. It is better to use convergent approach rather than divergent for many complex molecules. 2. This is pretty much inevitable. or very close to functional groups in the target molecule (i. The focus is on the removal of stereocentres under stereocontrol. 6. 4.Strategies and Tactics in Organic Synthesis Disconnections Other guidelines for retrosynthesis are given below: 1. Disconnect to readily recognizable synthons by using only known reactions (transform). Use only disconnections corresponding to disconnect C–C bonds and C–X bonds wherever possible. 5. Where should I choose to disconnect? Disconnections very often take place immediately adjacent to. Stereocontrol can be achieved through either mechanistic control or substrate control. 3. given that functionality almost invariably arises from the forward reaction. It is better to use those reactions which do not form mixtures. the one being disconnected).

Otherwise. and you’ve most likely gone a long way to identifying the synthetic equivalent! . the synthesis challenge doesn’t get any easier! How do I decide which synthon carries which charge? A good trick here is to consider whether you can draw a resonance form of the synthon which looks more like a real reactive intermediate… If it does.Strategies and Tactics in Organic Synthesis Disconnections How do I recognize a good disconnection? A good disconnection visibly simplifies the target molecule. you’ve clearly made a good choice of polarity.

Grignard BenzylGrignard and propyne-halide. choose disconnection corresponding to the highest yielding reaction.Strategies and Tactics in Organic Synthesis Disconnections Basic Guidelines: 1. Use disconnections corresponding to known reliable reactions. . Diazonium salt and propargylic Grignard phenylGrignard and propargylic halide synthons reagents Benzyl-halide and propyne.

Allylic C-C bond d. Disconnect C-C bond according to the present FGs in the molecule: a. C-C bond with two oxygen substituents in positions 1. C-C bond with no neighbouring functional groups b. C-C bond with one oxygen substituent c.Strategies and Tactics in Organic Synthesis Disconnections 2.3 .

Strategies and Tactics in Organic Synthesis Disconnections 2. 3. Disconnect C-C bond according to the present FGs in the molecule: e. Umpolung methods.4. Aim for simplification: a) Disconnect C-X bond (RCO-X) . C-C bond with two heteroatom substituents in positions 1.2 or 1.

Strategies and Tactics in Organic Synthesis Disconnections 3. Aim for simplification: b) disconnect in the middle of the molecule Tetrahedron Lett. 761 . 1981. 5001 c) disconnect at a branch point d) use symmetry K. 2001. Int.C. 40.Nicolaou Angew. Chem. 22. Ed.

Aim for simplification: e) disconnect rings from chain f) use rearrangements Org. 2001.Strategies and Tactics in Organic Synthesis Disconnections 3. Lett. 115 . 3.

Carbocyclic Rings: If one or more 6-membered carbocyclic unit present in the molecule consider a set of disconnection available for construction of 6-membered rings: Diels-Alder. Robinson annulation. Dieckmann. internal SN2. Some types of Diels-Alder disconnections: . Birch reduction.Strategies and Tactics in Organic Synthesis f) use rearrangements Disconnections HO HO O Oxy-Cope 4. etc. aldol.

Examples of cleavage of C-C bond as a retrosynthetic reconnection TM TM TM Via retro [2+2] and ketene formation TM More electronrich double bond ozonolysis TM TM TM .Strategies and Tactics in Organic Synthesis Disconnections 5.

. aryl. S). C=C disconnections are used to be strategic.. is embodied in the carbon framework. the C–X bond disconnection uses to be strategic C–C disconnections far from functional groups or stereocentres are not favored. .Strategies and Tactics in Organic Synthesis Disconnections Those disconnections leading to two fragments of similar complexity are specially appealing. Alkyl.. O. subunits may be considered as building blocks and they should not be disconnected When an heteroatom (X = N.

. But in the case of a monocyclic system .Strategies and Tactics in Organic Synthesis Disconnections In the case of cyclic systems it is more difficult to elaborate general trends because of the different shapes present in these systems.. .

Strategies and Tactics in Organic Synthesis Disconnections Disconnection of molecules according to the present FGs in the molecule: The potential of carbonyl functionality .

However. Sticking to latent polarity usually gives the best choice of synthons. this is not always possible! Willis p.Latent Polarity Latent polarity is the imaginary pattern of alternating positive and negative charges used to assist in the choice of disconnections and synthons. 15 .

3-difunctional consonant relationship 1. it is possible to identify difunctional relationships (consonant or dissonant) among the functional groups in a TGT 1. However. radical or perycyclic reactions .2-difunctional dissonant relationship 1. dissonant relationships often require to introduce umpolung tactics.Strategies and Tactics in Organic Synthesis Disconnections Guidelines in action: functional groups relationships According to these ideas.4-difunctional dissonant relationship 1.5-difunctional consonant relationship Consonant relationships usually permit to devise easy disconnections.

Strategies and Tactics in Organic Synthesis Disconnections Guidelines in action: dissonant disconnection examples + -+ Masked acylanion: unpolung H .

1.2-Difunctional Compounds .

2-Difunctional Compounds .1.

Strategies and Tactics in Organic Synthesis Disconnections Guidelines in action: consonant disconnection examples + .+ 1.5-difunctionalised compounds + -+ -+ .

1.3-Difunctional Compounds .

4-Difunctional Compounds .1.

4-Difunctional Compounds .1.

1.4-Difunctional Compounds .

1.5-Difunctional Compounds .

1.5-Difunctional Compounds .

1.6-Difunctional Compounds .

1.6-Difunctional Compounds .

6-Difunctional Compounds .1.

Disconnection Guidelines Warren. p. 86-92 .

Disconnection Guidelines .

Disconnection Guidelines

Available Starting Materials A list of starting materials Warren p.90

Available Starting Materials Chiral and enanthiopure compounds

Summary of Useful Reactions

Summary of Useful Reactions

Regioselective Enolate Formation

Regioselective Enolate Formation

Regioselective Enolate Formation

Strategies and Tactics in Organic Synthesis
Functional Group Interconversion (FGI):

Classification of functional groups by oxidation state of carbon atoms:
Oxidation state of carbon in alkanes (cycloalkanes ) is usually negative, the carbon in the fragment C-H is approximated as carbanion. The replacement of the hydrogen with a higher electronegative atom (C and heteroatoms) is equivalent to oxidation

+2 0 oxidation +2+2 0 Very difficult simple +2 0 reduction . Isohypsic transformations with no change to the oxidation level of carbon Type 2. where carbon atom is either reduced or oxidised. transformations between levels can be achieved only on certain derivatives. Non-isohypsic transformations. on the same oxidation level any functional group interconversion can be performed in more or less easy way.Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): FGI can be divided into two groups: Type 1. However. In general.

Level 1. . In addition. partial hydrogention) synthons Conclusion: in practice all functions of oxidation level 1 are synthetically equivalent as they can be easily transformed into each other. The most common functions resulting from C-C bond construction are alcohol (Grignard addition to carbonyl compounds. aldol reaction.Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Type 1 (no change in oxidation state). croton condensation. etc). olefin methathesis. etc) and olefin (Wittig and related processes. FGI of type 2 often lead to alcohols and olefins (reduction of carbonyl compounds.

In organic synthesis vinyl halides can play a dual role: as electrophiles in reaction with organocuprates and as nucleophiles when transformed themselves into organometallic derivatives. . Level 2.Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Type 1 (no change in oxidation state). The main functional groups are carbonyl compounds (aldehydes and ketones) and alkynes. Formation of synthetic equivalents of carbanions: Formation of vinyl derivatives.

2-disubstituted compounds. oxiranes.Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Compounds having two functional groups of level 1 which react as a whole belong to level 2 (1. allylic systems) Formation of epoxides in a C-C bond forming procedure (apart from epoxidation of olefines): Formation of allylic systems: .

This is a typical electrophile used to make derivatives of carboxylic acids and in Friedel-Crafts C-C bond forming reactions. Polyfunctional compounds of level 3 are α. Level 3. The main functional group that allows formation of any other derivative on the same level is acid halide.Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Type 1 (no change in oxidation state).β-unsaturated aldehydes and ketones – good Michael acceptors: .

.Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Type 2 transformations (change in oxidation state). 2. carbonyl and carboxyl functions synthetically equivalent. Many functional groups. As any functional group can be removed. Other important kind of transformations – interconversion of nitrogen containing functions. especially on the same level of oxidation. Unfortunately. Availability of methods to go from alcohol to carboxylic acid derivatives and back makes alcohol. can be considered as synthetically equivalent so their retrosynthetic interconversions can be planned. Conclusions: 1. reverse is not achievable as yet. retrosynthetically we can put a functional group in any position of alkane or cycloalkane chain and that would allow assembly of a given C-C fragment.

Strategies and Tactics in Organic Synthesis Example of FGI and FGA approach FGA= functional group addition .

. M. Trost which deals with chemical reactions that do not waste atoms. This can be done by taking the ratio of the mass of the utilized atoms to the total mass of the atoms of all the reactants and multiplying by 100. M. with 55. Engl. Trost’s concept of atom economy is to calculate the percentage atom economy. Atom economy describes the conversion efficiency of a chemical process in terms of all atoms involved.86% of the reactant atoms ending up as unwanted by-products. Ed. Trost.. 1995. Trost. It is widely used to focus on the need to improve the efficiency of chemical reactions.. Science. B. 34. Chem. M. Angew.Strategies and Tactics in Organic Synthesis Atom economy The concept of atom economy was developed by B. Even if the reaction were to proceed with 100% yield. 259. only 44.. 254. B. M. . 1991.14% (by weight) of the atoms of the reactants are incorporated into the desired product. 1471. Int. A logical extension10 of B.

5 (C20H42NO10ClN9) and the total MFW of atoms utilized is 206 (ibuprofen. new three stage process with an atom economy of 77.4%. C13H18O2).Strategies and Tactics in Organic Synthesis Atom economy Other examples: Boots and Hoechst Celanese Corporation synthesis of ibuprofen The total MFW of all the reactants used is 514. .

Efficiency and Selectivity in Organic Synthesis Selectivity: Stereoselectivity: Formation of one stereoisomer over others Efficiency Tactical Efficiency: High Yield Atom Economy Regioselectivity: Formation of one regioisomer over others Chemoselectivity: Reaction of one functional groups over others Strategic Efficiency: Minimum of Steps Convergence Specificity : complete selectivity . regio-.chemo-. stereo .

polyfunctional molecules. 8) Participation of the protecting group in any reaction should be either complete or absent. T.g.M Synthetic Organic Chemistry Michael B. 6) It must confer solubility. Of course.. Smith.. but may also be a question of which functional groups in the molecule are transformed preferentially: the so called chemoselectivity. Wuts. mild reagent. An ideal protecting group has the following properties: 1) It must be introduced selectively in the first instance in high yield. Carey.. 629-672. in order to avoid the formation of diastereomers. Sometimes it simply isn't possible to devise a reaction which carries out a desired transformation whilst leaving other functional groups in the molecule untouched. 2) It must be stable to a wide range of reaction conditions.and regiochemistry. 6. 7) It must stabilize the whole molecule (e. This is often the case in multi-stage syntheses of complex.W. it is necessary to mask or protect functional groups temporarily. 3) It must be readily removed by a specific. avoids racemisation or epimerisation). pp. Advanced Organic Chemistry part B: Reactions and Synthesis. Greene. few protecting groups meet all of these criteria. P. in order that they are not affected by reactions transforming functions in other parts of the molecule. and facilitate purification. the selectivity may concern stereo. 631-701. A very smart discussion. to regenerate the starting functional group. 4) It must itself possess a minimum of functionality to avoid the possibility of side reactions. 9) It must be small compared to the mass of what you are trying to make.G. capter 13. When this happens. using reagents which are readily available. 677-92 . and generally a compromise must be found Comprehensive Synthetic Organic Chemistry. Properties of protecting groups. 5) It must be achiral.Protecting groups in organic synthesis As seen. Protective Groups in Organic Synthesis 2nd ed. although it is not always necessary for them to do so. stable and easily handled.J. The functional group used to effect this protection is called a protecting group (PG).

Substrate Control .Protecting groups in organic synthesis Strategies For Protection 1. Protecting groups which block more than one functional group. . .use of chelation control. via dianions. .Orthogonal Protection (a set of PG whose removal can be accomplished in any order with reagents and conditions which do not affect other PG).Graded Protection (deprotection relies upon differences in relative rates of reaction of various PG under the same reaction conditions). 3.Uniform Protection ( use of PG which are all removed under the same conditions) .g. None This could be achieved with selective reagents (so called Reagent Control).Convert protecting groups to other functionality 4. . The next best thing is the use of transient protection. but is limited by the availability of such reagents. Multiple protection .use of steric bulk to block reactivity.use of negative electron density to repel reagents e. . 2.

2) Don’t just protect a group because you have to go through x number of steps. These aspects are often against the efficiency in terms of Tactical Efficiency (i. Strategic Efficiency: Minimum of Steps: each PG introduces at least two extra steps to the synthesis Convergence . Atom Economy) and Strategic Efficiency (i.e.e. 4) If you can avoid protection of a group in a synthesis. Minimum of Steps) Remember the Efficiency: Tactical Efficiency: High Yield Atom Economy: the atom of PGs are not included in the final product.Protecting groups in organic synthesis Some things to consider before you use protecting groups 1) Know why and when do you need to protect a functional group. 3) One must use protecting groups when the functionality (you wish to preserve) and the reaction conditions necessary to accomplish a desired transformation are incompatible (non-orthogonal). you should 5) It is much better to plan ahead and avoid protection 6) Protecting groups add extra steps to your synthesis more steps cost time and money.

-other conditions – 1) Reductive . i. F3) Organometallic: Pd(0).hydrogenolytically labile 1) H2 and catalyst 2) catalytic transfer hydrogenation (NH4 + HCOO-) and catalyst. 5) Oxidative 6) Photolytic Protecting groups for a variety of functional groups heteroatom functional groups.unsaturated carbon-carbon bonds . RNH2 and RSH .carbonyls .acid labile -base labile .Protecting groups in organic synthesis Types of protecting groups (by method of cleavage) . ROH. Nu-. 2) SN2-type cleavage PhSe-. 4) Lewis acid: ZnCl2.phosphate . carboxylic acid and derivatives.Zn/HOAc.α-methylene groups of ketones .e.

THF. Org. IV 1963.. Chem. 42. Soc. NaH. PhCH2Cl.CH2N2 . Li / NH3 .0]nonane. Perkin Trans. F3CSO3H J.or Ph2PMe3SiI (J. EtS. 836). THF (Org Synth.3.Protecting groups in organic synthesis Hydroxyl Protecting Groups Ethers Methyl ethers R-OH → R-OMe difficult to remove except for on phenols Formation: .. 1977. 1977. Chem. 42.KH. 2619). 1 1996. Collect. PhSe. Vol. Chem. MeI. 9-Bromo-9-borabicyclo[3. Chem. 1978. Soc. silica or HBF4. (J.(J. Org. Organomet. 3761). stable to acid and base Formation: . Cleavage: . 2247 Cleavage: H2 / PtO2.AlBr3 /EtSH. PhCH2OC(=NH)CCl3. 221 Benzyl Ethers (R-OBn) R-OH → R-OCH2Ph. Chem. P1 1985. J.156. 1228).

Li / NH3. 63. F3CSO3H Tetrahedron Letters 1988. 54. DDQ. 1 1985. Chem. For base-sensitive substrates. J. Chem. Org. Pd(Ph3P)4. 4172 cleavage: hydrogenolysis H2 / PtO2 p.. H+. J. CH2Cl2. 4139 Cleavage: H2 / PtO2. p-MeOPhCH2Cl p-MeOPhCH2OC(=NH)CCl3. 2247 and Tetrahedron 1998. RSO2Na. 1998. electrochemically Allyl ether Formation CH2=CHCH2OC(=NH)CCl3.Methoxybenzyl Ethers (PMB) Formation: . KH. 8932 . THF. J. Soc. Ce(NH4)2(NO3)6 (CAN). 62. Chem.KH. 1997. 2967.Protecting groups in organic synthesis Hydroxyl Protecting Groups 2-Napthylmethyl Ethers (NAP) O-R formation: 2-chloromethylnapthalene. Perkin Trans. Org. 29 .

1987.photolysis at 320 nm p-Nitrobenzyl Ether Tetrahedron Letters 1990. n-BuLi. 70. catalytic hydrogenation. 389 -selective removal with DDQ. 225 Cleavage: . and lead tetraacetate. Chem. 20% piperidine–CH2Cl2.Protecting groups in organic synthesis Hydroxyl Protecting Groups t-Butyldiphenylsilylethyl (TBDPSE) ether formation: The TBDPSE group is stable to 5% TFA/CH2Cl2. 40 ° C. J. Org. hydrogenolysis or electrochemically . 9 . 2005. overnight) or 50% TFA/CH2Cl2. 31 . The TBDPSE group has been cleaved using TBAF (2. 1. 1467. o-Nitrobenzyl ethers Review: Synthesis 1980. Organic Photochemistry.0 equiv.

Tetrahedron Letters 1998.Protecting groups in organic synthesis Hydroxyl Protecting Groups 9-Phenylxanthyl.(pixyl. 39. 1653 . px) .

Protecting groups in organic synthesis Hydroxyl Protecting Groups Trityl Ethers -CPh3 = Tr R-OH → R-OCPh3 .mild acid Methoxytrityl Ethers. JACS 1962.selective for 1°alcohols removed with mild acid. pyridine. base stable formation: .Ph3C-Cl. 430. 84 . methoxy group(s) make it easier to remove Tr-OR < MMTr-OR < DMTr-OR << TMTr-OR . DMAP or Ph3C+ BF4Cleavage: .

O . Bromocatechol borane. 24 .Me2BBr2 Tetrahedron Letters 1983. Sometimes a source of iodide ion is added to enhance the reactivity of the alkylating O reagent. or NaI. B Br Cleavage . NaH. Typical sources include Bu4N+ I– LiI.Protecting groups in organic synthesis Hydroxyl Protecting Groups Acetals Methoxymethyl ether MOM R-OH → R-OCH2OMe stable to base and mild acid Formation: MeOCH2Cl. CH2Cl2. MeOCH2Cl. 3969. THF (on the corresponding Na-alcoholate). iPr2EtN.

Protecting groups in organic synthesis Application to Oligonucleotide Synthesis (phosphoramidite method .Lessinger) Tetrahedron 1992. 48 . 2223 .

CH2Cl2. NaH. 1411. H2O . THF. NaH. Can also be cleaved in the presence of THP ethers Protecting groups in organic synthesis Hydroxyl Protecting Groups Acetals Methyl Thiomethyl Ethers (MTM) R-OH → R-OCH2SMe Stable to base and mild acid Formation: MeSCH2Cl.Methoxyethoxymethyl ethers (MEM) R-OH → R-OCH2OCH2CH2OMe stable to base and mild acid Formation: MeOCH2CH2OCH2Cl. 26. Na/ NH3. EtOH Bromocatechol borane. Tetrahedron Lett. TiCl4. base Benzyloxymethyl Ethers (BOM) R-OH → R-OCH2OCH2Ph.MeOCH2CH2OCH2Cl. iPr2EtN Cleavage: H2/ PtO2 . This reagent cleaves a number of protective groups in approximately the following order: MOMOR ≈ MEMOR > t-BuO2CNHR > BnO2CNHR ≈ tBuOR > BnOR > allylOR > t-BuO2CR ≈ 2° alkylOR > BnO2CR > 1°alkylOR >> alkylO2CR. 1985. Stable to acid and base Formation: PhOCH2Cl. CH2Cl2. THF( on Na-alcoholate) Cleavage: HgCl2. THF (on Na-alcoholate) . iPr2EtN Tetrahedron Letters 1976. CH3CN/H2O AgNO3. 809 Cleavage : Lewis acids such as ZnBr2. Me2BBr2 . .

Protecting groups in organic synthesis Hydroxyl Protecting Groups Acetals Tetrahydropyranyl Ether (THP)

Stable to base, acid labile Formation: dihydropyran (DHP), pTSA, PhH (azeotropic water removing) Cleavage: AcOH, THF, H2O; Amberlyst H-15, MeOH

Ethoxyethyl ethers (EE)
J. Am. Chem. Soc 1979, 101 , 7104; JACS 1974, 96 , 4745.

base stable, acid labile

Protecting groups in organic synthesis Hydroxyl Protecting Groups Silyl Ethers R-OH → R-O-SiR3 Synthesis 1985, 817; 1993, 11; 1996, 1031 formation: - R3Si-Cl, pyridine, DMAP; J. Am. Chem. Soc. 1972, 94, 6190 R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAP R3Si-OTf, iPr2EtN, CH2Cl2 Tetrahedron Lett. 1981, 22, 3455 Trimethylsilyl ethers Me3Si-OR TMS-OR - very acid and water labile -useful for transiant protection Triethylsilyl ethers Et3Si-OR TES-OR -considerably more stable that TMS can be selectively removed in the presence of more robust silyl ethers with with For mild acid

Protecting groups in organic synthesis
Silyl Ethers Triisopropylsilyl ethers iPr3Si-OR TIPS-OR - more stabile to hydrolysis than TMS Phenyldimethylsilyl ethers, J. Org. Chem. 1987, 52 , 165 t-Butyldimethylsilyl Ether tBuMe2Si-OR TBS-OR TBDMS-OR; JACS 1972, 94 , 6190 - Stable to base and mild acid - under controlled condition is selective for 1°alco hols t-butyldimethylsilyl triflate tBuMe2Si-OTf; TL 1981, 22 , 3455 - very reactive silylating reagent, will silylate 2°al cohols cleavage: acid; F- (HF, nBu4NF, CsF, KF) t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR - stable to acid and base - selective for 1°alcohols - Me3Si- and iPr3Si groups can be selectively removed in the presence of TBS or TBDPS groups. - TBS can be selectively removed in the presence of TBDPS by acid hydrolysis. TL 1989, 30 , 19 Cleavage: F-, Fluoride sources: - nBu4NF (TBAF basic reagent), HF / H2O /CH3CN TL 1979, 3981. HF•pyridine Synthesis 1986, 453; other fluoride sources: Triethylamine trihydrofluoride, Et3N•3HF; Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF); H4N+F–

JOC 1981, 46 ,1506 TL 1989, 30 , 19.

JACS 1984, 106 , 3748

Protecting groups in organic synthesis Silyl Ethers: stability • In general, the stability of silyl ethers towards acidic media increases as indicated: TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000) • In general, stability towards basic media increases in the following order: TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000)

J.Chem. Soc., Perkin Trans . 1 1992, 3043. J. Org. Chem. 1988, 53, 2602

Protecting groups in organic synthesis Silyl Ethers Monosilylation of symmetrical diols is possible, and useful
J. Org. Chem. 1986, 51, 3388.

Tetrahedron Lett. 2000, 41, 4281

J. Org. Chem. 1983, 49, 4674

Selective deprotection of silyl ethers is also important, and is also subject to empirical determination

J. Am. Chem. Soc. 1995, 117, 8106

J. Am. Chem. Soc., 1994, 116, 1599.

Protecting groups in organic synthesis Esters and Carbonates:

Protecting groups in organic synthesis Ester formation with activated carboxylic functions


Carbonate formation

Protecting groups in organic synthesis Activated esters. These activated esters can be used as acyl transfer agents to alcohols or amines (Nu)

Mukaiyama's Reagent, Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575

Corey Reagent

The DMTC group is stable to a variety of reagents and reaction conditions (PCC oxidations, Swern oxidations, chromium reagents, Grignard and alkyllithium reagents, phosphorous ylides, LAH, HF, TBAF, and borane). The protecting group is introduced using imid2CS followed by treatment with dimethylamine, or by reaction with commercially available ClCSN(CH3)2.

Protecting groups in organic synthesis Esters are stable to acid and mild base, not compatible with strong base or strong nucleophiles such as organometallic reagents In general, the susceptibility of esters to base catalyzed hydrolysis increases with the acidity of the product acid.

Trifluoroacetates Formation: trifluoroacetic anhydride or trifluoroacetyl chloride Cleavage: - K2CO3, MeOH Pivaloate (t-butyl ester), Fairly selective for primary alcohols Formation: - tbutylacetyl chloride or t-butylacetic anhydride Cleavage: - removed with mild base Benzoate (Bz) more stable to hydrolysis than acetates. Formation: benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) , benzoyl tetrazole (TL 1997, 38, 8811) Cleavage: mild base; - KCN, MeOH, reflux

Chem. reflux. 27. 1255. NH3. Meso compounds Tetrahedron Lett. Chloroacetate: can be selectively cleaved with Zn dust. 1998. thiourea or primary amines NH H2N SH J. 1986. The enantioselective hydrolysis of meso diesters is an important synthetic transformation and racemic esters have been kinetically resolved using lipases. 5319 . Lipases can often be used for the enantioselective hydrolysis of acetate esters (the same enzimes are emploied for forming acetates). K2CO3. MeOH. Chem. EtOH. 1026 J. Am. H2O and enzymatic hydrolysis. THF.Protecting groups in organic synthesis Ester function cleavage Acetate Esters: Several methods cleaving acetate esters have been developed. 120. LiOH. reflux. Soc. KCN. CC 1987. Soc. MeOH.

Am. Chem. 1978. Soc. 969. 22. 1981. Comm. 672 Tetrahedron Lett. 5. 1982. 19. 1988. 2227. 3328 Org. 1375 Synlett 1993. 61. 29. 4755 . Chem.Protecting groups in organic synthesis Carbonate function cleavage Methyl Carbonate Allyl Carbonate Tetrahedron Lett. Lett. Chem. Trichloroethyl Carbonate: Benzyl Carbonate: Tetrahedron Lett. 680.. 1939. 9-Fuorenylmethyl Carbonate: 2-(Trimethylsilyl)ethyl Carbonate: J. Dimethylthiocarbamate (DMTC) Carbamate J. Soc. 2003.

HF•pyridine). cleaved with fluoride (HF. Et3N. CH3CN. will not fuctionalize a 3° -alcohol TL 1988. 29 . 1561 Formation iPr2Si(Cl)-O-Si(Cl)iPr2 pyridine TL 1981. 4999 formation (t-Bu)2SiCl2.Diols acetals Synthesis 1981. 74.3. Rev. HOBT .Protecting groups in organic synthesis Protection of 1. 581 Silylethers. 501 Chem.and 1.Bu4NF -or. CH3CN -or. 1974.2. 22 .

1. 501 Chem.2-Oalkylidene-a-glucofuranoses have been studied. 1977. 581 Cycloalkylidene Ketals . Rev.2-acetonide formation is usually favored .3-diols. 58.Protecting groups in organic synthesis General methods used to form acetals and ketals.Cyclohexylidenes are slightly harder to cleave than acetonides The relative rates of hydrolysis of 1.cleaved with mild aqueous acid Synthesis 1981. 337 . Res. Acetonides: in competition between 1.2. 74. 1974.Cyclopentylidene are slightly easier to cleave than acetonides .and 1. Carbohydr.

Chem.3-triol. 1 1997. 2. 913 Selective Protection: thermodynamic control Selective Protection: kinetic control Methods Carbohydr. 54. 1963. then the alternative. 87 .. Chem. Chem. less substituted acetonide may be favored. In the case of a 1. J. Org. 1989. The more substituted acetonide will be favored in cases where the substituents on the resultant five-membered ring will be trans. Chem. 108. 1984. 35. If the substituents on the five-membered ring would be oriented cis. careful analysis must be performed to accurately predict the site of acetonide formation. 1974. J.Protecting groups in organic synthesis Examples of selectivity in acetal and ketal formation. 318 Carbohydr. 915. Soc. Perkin Trans. 2949 J. Res. Am.2. Soc.

Chim. 1995. 78. Acta. 1.and 1.Protecting groups in organic synthesis General methods used to form Benzylidenes. .benzylidenes can be removed by acid hydrolysis or hydrogenolysis . Benzylidene Acetals in competition between 1.benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins Selectivity in benzylidenes formation Helv.3-benzylidene formation for is usually favored .3-diols. 1837.2.

cis-fused 5. Chem. 518.6-systems No cis Acta. 1972. trans Note the preference for 1. Carbohydr. in an equatorial orientation. The phenyl group is oriented exclusively as shown. 1972. 473 . 26. In general. Res.6-systems are formed faster than trans-fused 5.3-diol protection with the benzylidene acetal. 21. Scand.Protecting groups in organic synthesis Examples of selectivity in benzylidenes formation.

3897 J. Chem. 1 1997. .Protecting groups in organic synthesis Special diol protection groups Formation of dispiroacetals as a protective group for vicinal trans diequatorial diols Tetrahedron Lett. Chem. Org.. Soc. 1992. 4767 A cheaper alternative has also been developed: J. 1996. 61. Perkins Trans. 2023.

1963. 45. 1978. 181 . 318.Protecting groups in organic synthesis Generalities concerning the selective removal of acetals and ketals: Hydrolysis of the less substituted dioxane or dioxolane ring occurs preferentially in substrates bearing two such groups. Carbohydr. 1996. Tetrahedron Lett. 37. Res. Chem. 2. 8643 Methods Carbohydr.

1962. Am. substitution of the ring of a benzylidene acetal with a p-methoxy substituent increases the rate of hydrolysis by about an order of magnitude J. 430. Soc. 84. Can be oxidatively removed with Ce(NH4)2(NO3)6 (CAN) Benzylidene acetals can also be cleaved from the diol reductive .Protecting groups in organic synthesis Generalities concerning the selective removal of benzylidenes: In general. Chem.

1993. 845. Chem. 3480 . This reaction has been extensively studied in the context of carbohydrate chemistry Tetrahedron Lett. J. Tetrahedron Lett. 58.Protecting groups in organic synthesis Selective removal of benzylidenes Methods have also been developed to cleave only one carbon-oxygen bond resulting in the formation of a benzyl ether. Chem. Org. Appl.. 1998. 669. 355 Pure. 1995. 5. 56. 39. 1984.

Protecting groups in organic synthesis Other examples of selective removal of benzylidenes .

1987. Org. 1969. Syn. Org.Protecting groups in organic synthesis Selective removal of benzylidenes Oxidation of benzylidene and substituted benzylidene acetals: J. 34. 65. 1045. 243 mechanism . Chem. 1035. and 1053.

1996. 49. Org.Protecting groups in organic synthesis Selective removal of benzylidenes Oxidation of benzylidene and substituted benzylidene acetals: Ozonolysis also cleaves acetals to hydroxy esters efficiently. Chem. 992 J. 3651. 1974. 52. J. 2394 . This reaction has been reviewed: Can. 1984. Chem. Org. Chem. 61. J.

J. Org. 54. 4037 . 24.Protecting groups in organic synthesis 2. A useful extension of this reaction has been developed to protect diols directly Tetrahedron Lett. Chem. 17. 1989.electron oxidation of 4-methoxybenzyl groups with DDQ is a general reaction. 1983.

1953. Chem. LaCl3. J. acetone.β-unsaturated ketones ≈ α. Cleavage of dimethyl acetals and ketals: TFA. Cl3CCO2H. Synlett 1996. Acetals are formed efficiently.. 839 Other dialkyl acetals are formed similarly. Soc. Chem. toluene. Me3SiOTf. 4187. 858. 2.α disubstituted ketones >> aromatic ketones. Tetrahedron Lett. CHCl3. Tetrahedron Lett. 2. Preparation of dimethyl acetals and ketals: 1. 3. J. 499. 1979. Trans-ketalization 3. (MeO)3CH. 1993. Tetrahedron Lett. J. 1975.Protecting groups in organic synthesis Carbonyl protective groups General order of reactivity of carbonyl groups towards nucleophiles: aldehydes (aliphatic > aromatic) > acylic ketones ≈ cyclohexanones > cyclopentanones > α. CH2Cl2. . MeOH. 5609. 3864. Commun. Sc(OTf)3. H2O. Soc. Chem. Chem. 44. 995. MeOH. These conditions cleaved a dimethyl acetal in the presence of a 1. Org. TsOH. (MeO)3CH. 29. 34. 4. t-BuOH. 1971.3-dithiane and a dioxolane acetal. 0 ° C. Me3SiOCH3. but ketalization is unpredictable. –78 ° C. dimethyl sulfide. CH2Cl2. dry HCl. 1988. 70% H2O2.

3-dioxanes J. 1357. Recl. methods used for formation of 1. 92.Protecting groups in organic synthesis Cyclic acetals and ketals: Relative rates of ketalization with common diols: In general. olefin isomerization is common. Chem.3-dioxolanes are also useful for formation of 1. 1986.ß-unsaturated ketones. saturated ketones can be selectively protected in the presence of α.β-unsaturated ketones. . 51. Org. 1973. Trav. Chim. 1980. 1047. Generally. In protecting α. Pays-Bas. 773 Tetrahedron Lett. 21.

CeCl3•7H2O. 1967. PPTS. 4178. acetone. Tetrahedron Lett. Chem. –78 ° C. Chem. 1M HCl. Rev. 1983.ß-unsaturated ketones over ketals of saturated ketones. This reagent also cleaves MEM and MOM ethe rs. J. NaI. 3969. 67 . 1997. Org. 1977. heat. Me2BBr. Soc.3-dioxolanes (Chem. 1987. 4. 43. 1351. 2. H2O. CH2Cl2. Basic cleavage Using fluoride Using organic bases . Chem. THF. 24. Chem.. J. CH3CN. J. This method is selective for cleavage of ketals in the presence of acetals. 427) 1. Soc. Commun. 62. 3. 4183. Am. It is also selective for ketals of α.3-dioxanes and 1.Protecting groups in organic synthesis Cleavage of 1.

reflux. 1978. General methods of cleavage of S. 6. 30.S''-dialkyl acetals. 3. MeOH. Chem. A variety of methods has been developed for the cleavage of S... Belletire. 1977. 2. J. Soc. 83. RSH. Et3N Ac2O.S''-dialkyl acetals. H2O. Tetrahedron Lett. 6490. 5009. 1971. Am. 43. Collect. acetone. 20 ° C. J.15. 1. Tetrahedron Lett. with any of the above mentioned conditions conjugate addition is a concern. Soc. (CF3CO2)2IPh. 1973. Vol. 275. L. 871. Synth. Org. 99.95. Ber. 4. CH2Cl2. A. See also J. m-CPBA.β-Unsaturated ketones are reported not to isomerize under these conditions. Marshall. Org. α. 1989.Protecting groups in organic synthesis Dithioacetals General methods of formation of S. 1989.S''-dialkyl acetals 1. RSSi(CH3)3. RSH. ZnI2. 2. HCl. CH3CN. H2O. Tetrahedron Lett. J. 3. CHCl3. 109. Hg(ClO4)2. 1988. Et2O. 287. Chem. CuO. . Am. J. Chem. 30. CuCl2. 4172. 1950. largelydue to the fact that these functional groups are often difficult to remove. However. Chem. BF3•Et2O.

. Lett. S. S'-dialkyl acetals serve as an umpolung synthon (acyl anion equivalent) in the construction the of carbon-carbon bonds.Protecting groups in organic synthesis Dithioacetals as useful synthons In addition to serving as a protective group. Org. 3127. 2000. 2.

100. 261. 1977. MeOH. 3529. benzene. 32. 25 ° DMAP. Vol. 2557. 34. Pig liver esterase. Soc. 1963. Et2O. 2513 . 1982. 1991. t-butyl esters: Isobutylene. Cleavage: CF3CO2H. This enzyme is often effective for the enantioselective cleavage of a meso diester Tetrahedron Lett. methyl esters: MeOH. Am. 99. 1993. CH2Cl2. LiOH. H2SO4. MeOH. 4239). pyridine C. 6536. 1981. i-PrN=C(O-tBu)NH-i-Pr. Am. 1985. IV. reflux (Tetrahedron Lett. 30. Pharm. 1411. Chem. PhH. toluene. Chem. Bull. Collect. Tetrahedron Lett. 1962. 29. J. J. 975. 5 ° C. 26.Fisher esterification (RCOOH +R'OH + H+). 25. J. Tetrahedron Lett. 47. 1978.Protecting groups in organic synthesis Carboxylic Acid Protective Groups: Alkyl Esters Formation: . 2353. diazomethane. Chem. TMSCHN2. Bromocatechol borane. 1475. Org. Soc.. Synth. Tetrahedron Lett. 1989. t-BuOH. This is considered a safe alternative to using diazomethane. Org. Tetrahedron Lett. H2SO4. or Acid Chloride + R-OH. 1984. EDC•HCl. 1977. Chem. CH2Cl2. Bu2SnO. 60 ° C.

2967. 26. Org. 54. They have have the advantage of being cleaved under mild. benzene. but is less susceptible to nucleophilic attack at the acyl carbon. Cs2CO3. 1983. H2O. Synthesis. 62. Org. Chem. NH3 Phenyl esters: Phenyl esters typically prepared by the methods outlined in the general methods section. Pd(Ph3P)4. 2005. J. 1972. basic conditions Cleavage: H2O2. Formation: Allyl bromide. 1953. Chem. 294. 493. J. 3. Benzyl ester: benzyl esters are typically prepared by the methods outlined in the general methods section cleavage: 1. 1998. The 1. 3259. Pept. (–H2O). CH2Cl2. 263. 2. 7.1-dimethylallyl ester is removed under the same conditions as an allyl ester. H2. 1712 Cleavage: The use of allyl esters in synthesis has been reviewed: Tetrahedron. TsOH. Chem.Protecting groups in organic synthesis Allyl esters.5. 1473. pH = 10. 1985. Na. Liebigs Ann. Am.. Soc. CH2Cl2. React. DMF. . BCl3. 1991. 7. DMF. Allyl alcohol. Protein Res. Org. Lett. 1997. 8932. J. Int. 94. Pd–C. RSO2Na.

1980. 547. Acta 1977. 1984. Cleavage: . Cleaved with Bu4NF in DMF. 2Trimethylsilyl)ethoxymethyl Ester (SEM).mild H3O+. 60 . BF3•OEt2 o-Nitrobenzyl Esters: selective removed by photolysis . Soc. 3030 . 2-(Trimethylsilyl)ethyl Esters J. MgBr2•OEt2 Tetrahedron Lett. 106 . 32. Chim. 2711. 3099 SEM ester Diphenylmethyl Esters. Helv. Am.cleaved with Fluoride ion. 1991.Protecting groups in organic synthesis Other carboxylic acid activation systems for mild esterification Synthesis. Chem. H2. Pd/C.

839. 1986. Stable to base. α-Hydroxy and ß-Hydroxy: Formation: 1. 1983. 66. Acta. CH2Cl2. Ketone or aldehyde. 1983. 153. Pivaldehyde. Chem.70. MgSO4. cleaved with mild acid Tetrahedron Lett.Protecting groups in organic synthesis Special protecting groups Ortho Esters: The synthesis of simple ortho esters has been reviewed: Synthesis. Chim. Soc. ortho esters can be prepared from a nitrile: Helv. Sc(NTf2)3. 1974. Rev. Synlett 1996. . Special Carboxylates. Acta. 2294. 1987. 24. Chim. acid catalyst. 5571 Alternatively. 448. Helv. 75.

Protecting groups in organic synthesis Protection of amines: Amides Removable alkyl groups formamides acetamides Benzylamine Allylamine Tritylamine Trifluoroacetamide Carbamates Methyl Carbamate Benzyl carbamate (Cbz) Allyl Carbamate (Alloc) 2. Res. Chem. 20 . 401 .2.2-Trichloroethyl Carbamate (Troc) t-Butyl Carbamate (Boc) 2-(Trimethylsilyl)ethyl Carbamate (Teoc) 9-Fluorenylmethyl Carbamate (Fmoc) Acc. 1987.

Removal: Pd(Ph3P)4. Tetrahedron Lett. 1996. Org. dibenzylamines are the products 1209.2% TFA. 198. HCO2NH4.Protecting groups in organic synthesis Formation of benzylamines: If primary amines are the starting materials. including allyl ethers and esters. J. Na. . Most allyl groups are cleaved by this method. Formation of allylamines: If primary amines are the starting materials. 6109. Comm. CH2Cl2. Formation of tritylamines: Synthesis 1989. 515. J. 1997. 8932. Chem. Org. RSO2Na. NH3. 58. Tetrahedron Lett. 20. Chem. Synth. 1990. diallylamines are the products. 37. CH2Cl2. 1987. 1993. 28. Monobenzylated derivatives Removal : Pd–C. 4195. Cleavage: 0. 1% H2O. 62. ROH.

Protecting groups in organic synthesis General preparation of carbamates: Bases that are typically employed are tertiary amines or aqueous hydroxide. 3753 Tetrahedron Lett. 1985. 26 . 27 . 1986. Tetrahedron Lett. 1411 .

1987. MeLi. THF. 114 . CH2Cl2. p. 1993. Sheppard R. Tetrahedron Lett.. C. Soc. 5959 9-Fluorenylmethyl Carbamate: Acc. Chem. Soc. Am. 1992. Other removal methods: Bu4N+F–.. Udenfriend. 1. Res. Thiols can be used to scavenge liberated fulvene. Am. 1987. in The Peptides. 442. 109. 1987.Protecting groups in organic synthesis Cleavage of carbamates Methyl Carbamate: TMSI. E. 401 Amine base. 28. 9. Vol. Bu4N+F–. 721. Chem. 20 . Chem. DMF. n-C8H17SH. . The half-lives for the deprotection of Fmoc-ValOH have been studied Atherton. S. Lett. Chem. J. 1987. and Meienhefer Eds. Academic Press: New York. 6617. J.

1986. Tetrahedron Lett.Protecting groups in organic synthesis Cleavage of carbamates 2. Synthesis. 49. 50 ° C. 249. Am. 101. AcOH. 1982. 358. DMF. 457. Tetrahedron Lett. J. electrochemically.. 514. 4687 2-Trimethylsilylethyl Carbamate: Bu4N+F–. 1978. 1979.2-Trichloroethyl Carbamate: Zn. KF•H2O. Cd. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF). Chem. Soc. THF. CF3COOH. Chem.2. 1997. Commun. J. 2325. 7104 . Soc. Chem. J. 23. CH3CN.2. 0 ° C. Chem. pH = 4. Soc. 27 .. 1976. H2O. Commun. JACS 1979. Chem.

70 – 100% yield. 3753 . 1411. TMS-I Allyl Carbamate 1. 89 – 100% yield. Org. 2413. Pd(Ph3P)4. 52. Tetrahedron Lett. PhSH. 1987. Thiophenol is used to scavenge t-butyl cations. (CH3)2NTMS. Bu3SnH. Bromocatecholborane.Protecting groups in organic synthesis Cleavage of carbamates t-Butyl carbamate CF3COOH. 27 . Chem. Chem. 1996. J . 1411and Tetrahedron Lett 1985. Tetrahedron Lett 1986. J. 33. Org. 61. 477. Pd(Ph3P)4. AcOH. TBS and TBDMS ethers are reported to be stable under these conditions. 26. 26 . 4984. 1985. 1992. Tetrahedron Lett.

1974. 65. Bromocatecholborane. 39 . hν (254 nm). 1427. Ber. BBr3. Chem. 3108). Tetrahedron Lett. Org. J. NH3. 1985. Org. 53. MeOH. Chem. H2/Pd–C. 26. Na/ NH3 removed by photolysis J. 1932. 1411. 192 Cleavage of Amides Formamides or Ac2O/HCOOH removed with strong acid Acetamides removed with strong acid Trifuoroacetamides base (K2CO3. CH2Cl2. Chem. 1192. 3465. Tetrahedron Lett. Org. 1974. 1988. This reagent is reported to cleave benzyl carbamates in the presence of benzyl ethers and TBS ethers. MeOH . Chem. These conditions cleave the benzyl carbamate in the presence of a benzylether. NH3. 1995. J.Protecting groups in organic synthesis Cleavage of carbamates Benzyl Carbamate: H2/Pd–C. reflux. 39. 36.

1989. Org. 2992 Trifluoromethanesulfonyl (introduced using (CF3SO2)2O) J. 54 .Protecting groups in organic synthesis Sulfonamides p-Toluenesulfonyl (Ts) Cleavage: .Strong acid. Org. Chem. sodium Naphthalide. 33. 5505 . Na(Hg) J. 1992. Chem.

1986. J. 62. 2990. 4143. 1997. Chem.Protecting groups in organic synthesis Other amine protecting groups Trimethylsilylethanesulfonamide (SES) Tetrahedron Lett. Many silyl acetylenes are commercially available. TIPS. and TBDMS. Org. removed with CsF. General preparation of silyl acetylenes: Silyl chorides are suitable for smaller silyl groups. and are useful acetylene equivalents. 1988. but the preparation of more hindered silylacetylenes may require the use of the more reactive silyl triflate. TBS. 95° C tert-Butylsulfonyl (Bus) J. 8604 Alkyne protecting groups Typical silyl groups include TMS. 54 . . DMF. Chem. Org. 53. TES.

Chim. milder conditions can be used. Cleavage of trimethysilylalkynes: KF. 8106. Acta. 78. Ed. Int. 2732. Helv. Chem Soc. Alternatively to trialkylsilyl groups. propargylic alcohol can be considered as alkyne protecting group. 1995. MeOH. Engl. These are formed by reacting acetilides with ketones (acetone or benzophenones) and removed by treatment with NaOH in MeOH R O HO R + Na OH R H R1 R1 R1 R1 = Me or Ph R1 MeOH . Am. J. 2. a strong fluoride source such as TBAF is used to cleave silylalkynes. Soc. 117.6-lutidine. Angew. Chem. 694. 2000. J. MeOH. 113. 50 ° C. 15. K2CO3. Am. AgNO3.Protecting groups in organic synthesis In general. 1995. Chem. 732. 1991.. In the case of trimethylsilylalkynes.

A. computer-assisted synthetic analysis The computer-assisted synthetic analysis designated OCSS (organic chemical simulation of synthesis) and LHASA (logic and heuristics applied to synthetic analysis) were designed to assist chemists in synthetic analysis by Corey et al. 421. Use protecting groups to resolve these problems. Wipke. Write the synthetic sequence. 4. Corey.infochem. Chem.Strategies and Tactics in Organic Synthesis Synthesis plan guide line 1. 1974. Other programs: WODCA. Chem.. T... J. including reagents. J. removal of protecting groups.W. J. 6. Corey. E. J.. 2. Howe. Check compatibility between FGs and reagents. 1972.. Soc. J.spresi. size of rings. 94. nature and position of FGs.. Check for mutually incompatible FGs. Soc. W. 7724 . D. position of substituents. Take into account problems of regioselectivity and chemoselectivity. III and Howe. E. 5. Cramer. Am. LHASA generates trees of synthetic intermediates from a target molecule by analysis in the retrosynthetic direction. SYNGEN (Hendrickson) AIPHOS (Sasaki). Am.W. J. D. and Pensak.. www. www. Make sure you make the right TM: check for length of carbon chain. EROS (Gasteiger).. info@infochem. R.

E. The Logic of Chemical Synthesis . Stereochemical-based strategies remove stereocenters and stereorelationships under control. Functional group-based strategies identify functional groups as key structural subunits. J. Structure-based strategies rely on the recognition of possible starting materials or key intermediates for a synthesis. Corey. Topological-based strategies depend on the identification of one or more individual bond disconnections or correlated bond-pair disconnections as strategic.Strategies and Tactics in Organic Synthesis Basic Concepts of Retrosynthetic Analysis There are some useful general strategies which do not depend on molecular complexity: Transform-based strategies rely on the application of powerfully simplifying transforms.

Such a strategy relies on synthetic and mechanistic knowledge. which can inspire the recognition of a hidden retron (partial retron) . The required retron may be not present in a complex TGT and a number of antithetic (retrosynthetic) steps may be needed to establish it.Strategies and Tactics in Organic Synthesis Transform-based strategies Transform-based strategies consist on the identification of a powerful simplifying transform leading to a TGT with certain keying features.

. Yes..Strategies and Tactics in Organic Synthesis Transform-based Strategies A case: six-membered cyclic motif Is it possible to envisage any simple transform in these cyclic structures? The answer could be . .

1258 For a similar retrosynthetic analysis based on a SN2 process. 5672 and Synlett 2003. 1997.Strategies and Tactics in Organic Synthesis Transform-based Strategies In the case of tetrahydropyran a straightforward disconnection.Chem. Chem. 2003. based on SN2 or SN1 processes. can be easily envisaged Angew. see J. Ed. Org. Int. 1817 .

in the sense that one or more functional gruop is added to individuate the retron retron for Diels-Alder cycloaddition or Robinson annulation retron for Diels-Alder cycloaddition or Birch reduction of a benzene ring with Li 1 x FGA retron for Diels-Alder cycloaddition.Strategies and Tactics in Organic Synthesis Transform-based Strategies It becomes more difficult to identify a similar transform in the cyclohexane case and often FGA transforms are required. Metathesis and Cationic ring formation In all these case a Diels-Alder reaction can be envisage .

Strategies and Tactics in Organic Synthesis Transform-based Strategies The venerable Diels-Alder reaction: a [4π + 2π] cycloaddition Otto Diels Remember that an alkyne can also partecipate in Diels.Alder process Kurt Alder Otto Diels and Kurt Alder Justus Liebigs Annalen der Chemie 460. 98 (1928) .

Strategies and Tactics in Organic Synthesis Transform-based Strategies It can be rationalized through Frontier Orbital analysis which permits to predict the regio-. siteand the relative stereochemistry .

Strategies and Tactics in Organic Synthesis Transform-based Strategies Regioselectivity: orto-para rule The coefficients of AO of the monosubstituted diene and of the mono-substituted dienophile are not equal at each end .

4800 .Strategies and Tactics in Organic Synthesis Transform-based Strategies Site-selectivity For a siteselectivity analysis in unsymmetrical quinones. see JACS 2004.

Strategies and Tactics in Organic Synthesis Transform-based Strategies Relative stereochemistry: endo rule .

increasing the regioselectivity and makes the secondary interaction greater that in the uncatalysed case which accounts for the greater endo selectivity Fleming.Strategies and Tactics in Organic Synthesis Transform-based Strategies Lewis acid catalysed DA reactions are faster and more stereo and regioselective. The Lewis acid coordination with the dienophile lowers the energy of the LUMO. modifies the LUMO coefficient. which increases the rate. I. All these features can be explained by the effect the Lewis acid has on the LUMO of the dienophile. Frontier Orbitals and Organic Chemical Reactions .

Strategies and Tactics in Organic Synthesis Transform-based Strategies A classic example: the synthesis of reserpine by Woodward .

6696 .Strategies and Tactics in Organic Synthesis Other examples Carpanone JACS 1971.

Strategies and Tactics in Organic Synthesis Transform-based Strategies The power of tactic combinations: estrone by Vollhardt J. Am. 5253 . Chem. 1980. Soc.

Chem. 2482 . 2001. Int.Strategies and Tactics in Organic Synthesis An asymmetric Diels Alder reaction: colombiasin A synthesis by Nicolaou Angew. Eng.

Chem. With the evolution of new catalysts. Olefin metathesis can be formally described as the intermolecular mutual exchange of alkylidene fragments between two olefins promoted by metal-carbene complexes Katz 1976 Tebbe 1978 Schrock 1990 Grubbs 1995 Grubbs 1999 .Strategies and Tactics in Organic Synthesis Olefinic Metathesis: an alternative to Diels-Alder cyclohexene retron Metathesis = Meta (change) & thesis (position) AB Blechert. olefin metathesis is now widely considered as one of the most powerful synthetic tools in organic chemistry. the selectivity.. Ed. S. C. 2004.. Int. Angew. A. 4490 – 4527 + CD AC + BD Olefin metathesis has come to the fore in recent years owing to the wide range of transformations that are possible with commercially available and easily handled catalysts. Int. Hoveyda.. Angew. Ed. Nicolaou. Int. H. Chem. 4592. 1900 Schrock. Ed. R. 44. 2003.. These advances together with a better understanding of the mechanism have brought us to a stage where more and more researchers are employing cross-metathesis reactions in multistep procedures and in the synthesis of natural products. efficiency. K. and functional-group compatibility of this reaction have improved to a level that was unimaginable just a few years ago. R. Consequently. 2005. Angew. Chem.

Strategies and Tactics in Organic Synthesis Olefinic Metathesis: The perfect reaction: The process is catalytic (1–5 mol%) High yields under mild conditions High levels of chemo-. regio-.and stereoselectivity The reaction is reversible The starting materials are easily prepared The olefinic products are suitable for further structural elaboration Three main variations on the metathesis theme a) Cross–Metathesis b) Ring-Closing & Ring-Opening Metathesis (RCM & ROM) c) Enyne metathesis .

Strategies and Tactics in Organic Synthesis Olefinic Metathesis Diels-Alder and Ring-Closing-Metathesis (RCM): two transforms for cyclohexene retron (Catalytic) process Inter or intramolecular process Reversible Up to four new stereocenters Carbon.and hetero-Diels-Alder are possible Catalytic process Intramolecular process Reversible No new stereocenters Carbon.and hetero-RCM are possible .

573 . Chem. 2002. Org.Strategies and Tactics in Organic Synthesis Olefinic Metathesis The power of RCM: laulimalide by Ghosh and Mulzer Laulimalide Ghosh. 8973 Mulzer. A. 2001. K. Adv. Synth. J. Catal. J.

A. Am. Soc. 10302 Double bonds Zirconium-Catalyzed Asymmetric Carbomagnesation Hoveyda. 1997. 6997 . Am.Strategies and Tactics in Organic Synthesis Olefinic Metathesis Pioneering catalytic transforms: Sch38516 by Hoveyda Sch38516 J. Chem. Chem. J. Soc. 1993.

Strategies and Tactics in Organic Synthesis Olefinic Metathesis The hidden retron: halosaline by Blechert (–)-Halosaline Tetrahedron 1999. 817 Expected metathesis disconnection >78% Combined ROM & RCM metathesis .

J. Chem. Org. R. H.Strategies and Tactics in Organic Synthesis Olefinic Metathesis Domino cyclization mediated by metathesis: Grubbs Grubbs. 4291 . 1998.

Nicolaou. K. C. Tietze. Rev.. and in which the subsequent reactions result as a consequence of the functionality formed in the previous step. L.will require increasingly precise mechanistic and kinetic understanding of organic transformations combined with a large dose of intellectual flexibility and creativity.. Classics in Total Synthesis II . cascade reactions are destined to become an integral design aspiration of most synthetic endeavors.Strategies and Tactics in Organic Synthesis Domino reactions A domino reaction is a process involving two or more bond-forming transformations (usually C–C bonds) which take place under the same reaction conditions without adding additional reagents and catalysts. 1996. In order to push the state-of the art of these sequences . 115 With ever-increasing pressure to fashion diverse molecular architectures rapidly through efficient and atom-economical processes with high degrees of selectivity. Chem.

4.Exo forbidden b) 5. Rule 1.7-Endo allowed Rule 2.7-Exo allowed b) 5 i 6-Endo forbidden Rule 2.7-Exo allowed c) 3.Exo allowed b) 3.5.7.Strategies and Tactics in Organic Synthesis Domino reaction: Isolated rings The Baldwin rules often constitute a good starting point to analyze the synthetic possibilities . Dig a) 3- allowed .5.6.4. Tetr a) 3. Trig a) 3.5.5-Endo forbidden c) 6.4.6.

the retron for the radical π-cyclization transform can be defined as a radical with electron β to a ring bond which is to be cleaved. but . The retron for the cation π-cyclization transform can be defined as a carbocation with charge β to a ring bond which is to be cleaved.. ..Strategies and Tactics in Organic Synthesis Cation π-cyclization. Radical π-cyclization In a similar way.

Strategies and Tactics in Organic Synthesis Domino reaction: a classic of cation π-cyclization: progesterone by Johnson Progesterone. Three rings and six contiguous stereocenters are created simultaneously . 4332 K2CO3 72% Stereochemical course of the process relies on stereoelectronic issues. according to the StorkEschenmoser hypothesis. JACS 1971.

Soc.Strategies and Tactics in Organic Synthesis Domino reaction: a nice solution to a daunting problem: aspidophytine by Corey Aspidophytine J. 1999. Chem. 6771 . Am.

Strategies and Tactics in Organic Synthesis Apparently similar radical π-cyclization .

Strategies and Tactics in Organic Synthesis Just two classics of radical π-cyclization: hirsutene and ∆9(12)-capnellene by Curran Hirsutene JACS 1985. 4991 . 1448 ∆9(12)-Capnellene TL 1985.

Strategies and Tactics in Organic Synthesis Functional group-based Strategies Functional groups The concept of functional group provides a valuable framework for understanding reactivity and an useful tool to go deeply into retrosynthetic analysis .

or combination of more fundamental group They can also be associated into super-set or super-families depending on their electronic behaviour EWG: CO. SOR. NO2 or EDG: OR.Strategies and Tactics in Organic Synthesis Functional group-based Strategies Corey classifies the functional groups. which are associated with useful reagents providing activation or control in chemical processes. in three families: 1st Level: the most important FG 2nd Level: less important FG 3rd Level: peripheral. CN. NR . FG.

many retrons contain only a single FG. while others consist of a pair of FG's separated by a specific carbon chain path or connection .Strategies and Tactics in Organic Synthesis Functional group-based Strategies Furthermore.

obvious rules can apply to arrangement of functionality in the product. and acceptor. Then. Single FG's or pairs of FG's. and the interconnecting atom path. synthons. For a molecule containing n FG's there are n(n–1)/2 possible pairs … Consonant relationschip . break strategic bonds or join proximate atoms to form rings. FG's may key transforms which stereoselectively remove stereocenters. As mentioned early. d. a. taking into account that most common synthetic reactions are polar. FGI is a commonly used tactic for generating from a TGT retrons which allow the application of simplifying transforms. a bond forming process (and the corresponding transform) can be viewed as a combination of donor. can key directly the disconnection of a TGT skeleton to form simpler molecules or signal the application of transforms which replace functional by hydrogen.Strategies and Tactics in Organic Synthesis Functional group-based Strategies Functional group-based strategies The use of functional group to guide retrosynthetic reduction of molecular complexity.

Strategies and Tactics in Organic Synthesis Functional group-based Strategies Remember! .

N.2-Difunctional systems: a1 + d1 combination Moss.Strategies and Tactics in Organic Synthesis 1. 32 . Synthesis 1997.

enolate and synthetic equivalents 2 a1synthons: aldehydes.Strategies and Tactics in Organic Synthesis 1.3-Difunctional systems: a1 + d2 combination d synthons: enol. ketones and esters .

5728 .Strategies and Tactics in Organic Synthesis A benchmark: helminthosporal by Corey Helminthosporal JACS 1965.

Strategies and Tactics in Organic Synthesis Experimental condition and final result Attention: this 1.5-difunctional relationship can evolve through two different pathways .

Strategies and Tactics in Organic Synthesis Helminthosporal: synthetic protocol .

Lett. 2002. 859 .Strategies and Tactics in Organic Synthesis A polifunctional target: 18-epi-tricyclic core of garsubellin A by Shibasaki Applying the n(n–1)/2 Org.

Strategies and Tactics in Organic Synthesis Retrosynthesis garsubellin A core .

but tactics accounts for the success: regiocontrol of enolate formation Kinetic trap of the resulting enolate avoids regioselective problems Me3Si N K SiMe3 KHDMS OK OTBS More accessible site for derotonation with potassium hexamethyldisilylamide (KHDMS) a bulky base more stagle but not formes by steric inderance .Strategies and Tactics in Organic Synthesis Garsubellin A core: synthetic protocol Strategy leads the way.

Strategies and Tactics in Organic Synthesis Garsubellin A core: synthetic protocol .

Strategies and Tactics in Organic Synthesis Garsubellin A core: synthetic protocol Retrosynthetic strategy is based on the following disconnections .

Strategies and Tactics in Organic Synthesis Garsubellin A core: final steps .

C. Nicolaou. Angew.Strategies and Tactics in Organic Synthesis TRANSITION METAL-MEDIATED PROCESSES: Cross-Coupling reactions Tsuji Palladium Reagents & Catalysts Wiley 2004 and van Leeuwen Homogenous Catalysis Kluwer 2004. Int. 4442 – 4489 . K. 44. Chem. Ed. 2005.

Kluwer 2004 . ed.Strategies and Tactics in Organic Synthesis TRANSITION METAL-MEDIATED PROCESSES LG:leaving group LG Pd0 Nu Pd Tsuji: Palladium Reagents & Catalysts. ed. Wiley 2004. van Leeuwen: Homogenous Catalysis.

Strategies and Tactics in Organic Synthesis Palladium mediated cross coupling reaction mechamism Reductive elimination Oxidative addition Boronic or other organometallic reagent .

239 Johnson.Strategies and Tactics in Organic Synthesis What should be the analysis in the case of dissonant relationships? Remember of considering the opportunity of: Seebach. 2004. Angew. Eng 1979. Int. Angew. D. Chem. . Ed. Ed. 1326. Int. Chem. S. J.

Strategies and Tactics in Organic Synthesis Remember. in a retrosynthetic sense. the replacement of that group by an equivalent which allows or actuates becomes a subgoal objective. from acceptor to donor or from donor to acceptor . Obviously. if a disconnection is identified as strategic but is not permitted by the particular core functional group present. such an operation requires a synthetic step that permits to invert (umpolung) the type of synthon.

Strategies and Tactics in Organic Synthesis Carbonyl Umpolung: acylanion .

Strategies and Tactics in Organic Synthesis Enolate Umpolung: α−carbonyl cation .

Strategies and Tactics in Organic Synthesis Michael acceptor Umpolung: β−carbonyl anion .

195. 783 . 191. OL 2002.Strategies and Tactics in Organic Synthesis The Spongistatins: architecturally Complex Natural Products through umpolung concept ACIE 2001.

Strategies and Tactics in Organic Synthesis Fragment A–B 1. but it was envisioned another disconnection .3-Consonant relationships: Aldol reaction could be the answer? It could be.

Strategies and Tactics in Organic Synthesis Fragment C–D .

Strategies and Tactics in Organic Synthesis Fragment A–B HMPA: hexamethylphosphorotriamide. strong lithium coordinating agent. Me2N Me2N P O Me2N HMPA . It is used to disaggregate lithium organometallic reagents improving nucleophilicity and basicity.

It was not until much later (1951–1952) that the correct structure of Zeise's compound was reported in connection with the structure of a metallocene compound known as ferrocene . according to most definitions. and high reactivity. oxidizability. The first metal complex identified as an organometallic compound was a salt. Compounds containing metal to hydrogen bonds as well as some compounds containing nonmetallic ( metalloid ) elements bonded to carbon are sometimes included in this class of compounds.Strategies and Tactics in Organic Synthesis Organometallic Compounds Organometallic compounds have at least one carbon to metal bond. obtained from reaction of ethylene with platinum (II) chloride by William Zeise in 1825. insolubility in water. toxicity. This bond can be either a direct carbon to metal bond ( σ bond or sigma bond) or a metal complex bond ( π bond or pi bond). solubility in ether and related solvents. Some common properties of organometallic compounds are relatively low melting points. It is presently banned from use in the United States. K(C 2 H 4 )PtCl 3 . An example of an organometallic compound of importance years ago is tetraethyllead (Et 4 4Pb) which is an antiknock agent for gasoline.

Look at the electronegativities of the metals Li. O2 etc.0 He Ne Ar K0.0 Na0. e.9 Be1. H 2. the higher the electron density and the more blue an area is. The more red an area is.5 Si1.0 Cl3. CH3MgBr = methyl magnesium bromide.0 Sc Ti V Cr Mn Fe Co Ni Cu Zn Partial Periodic Table with Pauling Electronegativities B2.Strategies and Tactics in Organic Synthesis Organometallic Compounds Nomenclature: Organometallic compounds are normally named as substituted metals. Physical Properties: Organometallic are usually kept in solution in organic solvents due to their very high reactivity (especially with H2O.1 Li1. K and Mg compared to C and the other atoms we have seen so far (e. F.1 O3. O.) Structure: Organosodium and organopotassium compounds are essentially ionic compounds. 2 Ca1.g. See how C is more electronegative than the metal.g.5 Mg1. N. the lower the electron density . covalent bonds due to the electropositive character of the metals.8 Kr methyl chloride methyl lithium methyl magnesium bromide The images show the electrostatic potentials for methyl chloride. Organolithiums and organomagnesiums have a s bond between a C atom and the metal: C-M These are very polar. 5 Ga C2. Cl etc). Na.5 S2. methyl lithium and methyl magnesium bromide. Examples: CH3Li = methyl lithium. alkyl metal or alkyl metal halide.8 Ge As Se Br2.0 Al1.0 P2.8 N3. Organomagnesium compounds are generally referred to as Grignard reagents.5 F4.

organometallic compounds react as electron rich or anionic carbon atoms i.M+ Basicity: The following equation represents the loss of a proton from a generic hydrocarbon forming a carbanion: Organolithium and organomagnesium compounds are strong bases since the negative charge is on carbon. (see pKa's below) since the C is not very electronegative (compared to N or O).e. NH or -SH units. It is reasonable to think of these organometallic compounds as R. In the presence of weak acids. RLi and RMgX protonate giving the hydrocarbon. the methyl group is less electron rich that methyl lithium. and is an electrophile. In methyl lithium. the methyl group has higher electron density (red) and is a nucleophile. Simple carbanions are strong bases. as carbanions. Therefore. . In methyl magnesium bromide. the methyl group has lower electron density (blue).Strategies and Tactics in Organic Synthesis Organometallic Compounds In the alkyl halide. which means they will function as either bases or nucleophiles. Implications: RLi or RMgX CANNOT be used in the presence of acidic hydrogens such as -OH.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Compound 2methylpropane ethane methane ethene Structure pKa 71 62 60 45 Benzene 43 The table shows the pKa's of a selection of representative systems.7 . Note that the hydrocarbons are very weak acids. ammonia ethyne Ethanol water 36 25 16 15. implying that the carbanions will be strong bases.

vinyl or aryl Other Group I metals (Na. K) can be used instead of Li.reduction Summary Organolithiums are formed by the reaction of alkyl halides with lithium metal. secondary or tertiary. Halide reactivity : I > Br > Cl R can be alkyl. Typical solvents are normally anhydrous diethyl ether but pentane or hexane can also be used.Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Organolithium Reagents Reaction type: oxidation . The alkyl group can be primary. .

secondary or tertiary. . The alkyl group can be primary. vinyl or aryl.Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Organomagnesium Reagents Reaction type: oxidation – reduction Summary Organomagesiums are formed by the reaction of alkyl halides with magnesium metal. Halide reactivity : I > Br > Cl R can be alkyl. Typical solvents are normally anhydrous diethyl ether or tetrahydrofuran.

R can be alkyl. Lithium dialkylcuprates are formed by the reaction of 2 equivalents of an organolithium with a copper (I) halide. The alkyl group is usually primary. .Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Organocopper Reagents Summary The most useful organocopper reagents are lithium dialkylcuprates. Typical solvents are normally anhydrous diethyl ether or tetrahydrofuran. R2CuLi. Secondary and tertiary are prone to decomposition. vinyl or aryl.

They are much less reactive than either RLi or RMgX to aldehydes and ketones. are prepared in a fashion analogous to that of organomagnesium reagents RMgX.Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Organozinc Reagents Reaction type: oxidation – reduction Summary Organozinc reagents. RZnX. The most common application of organozinc reagents is in the Simmons Smith reaction .

NaNH2 Acetylenic Grignard reagents. . RC=CMgX. Rather than starting from the acetylenic halides. can also be prepared. Acetylenic Grignards react in a similar fashion to other Grignard reagents. they are prepared by an acid-base reaction of the terminal acetylene with a second Grignard reagent.Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Acetylenic Reagents Reaction type: acid-base Summary terminal acetylenes can be deprotonated using sodium amide.

Organocuprates. . ketones or esters but can be reacted with alkyl halides or tosylates to give alkanes without elimination. RLi. and organomagnesium. In principle there are 3 important groups of reactions where nucleophiles attack electrophilic C atoms. Nucleophilic Substitution: R2CuLi with alkyl halides or tosylates to give alkanes 2. R2CuLi. reagents are most commonly used with esters. so it reacts as a carbanion. RMgX. the carbon attached to the metal is anionic in character. Nucleophilic acyl substitution (3) reactions of organolithium. Nucleophilic Acyl Substitution: RLi or RMgX with esters to give 3o alcohols Limitations: Organolithium. a nucleophilic carbon. Nucleophilic Addition: RLi or RMgX with aldehydes or ketones to give 2o or 3o alcohols 3. RMgX. reagents are less reactive and do not react with aldehydes. reagents are typically too basic to be used in nucleophilic substitution reactions (1) with alkyl halides or tosylates where they tend to cause elimination reactions or other side reactions. For the organometallic reagents these types of reactions will result in the formation of new C-C bonds. RLi. and organomagnesium.Strategies and Tactics in Organic Synthesis Organometallic Compounds Reactivity of Organometallics As previously said. 1.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Overview of Grignard Reactions: Here is a preview of Grignard reactions. from the original Grignard reagent is indicated in blue and the electrophilic portion in black. In each case the alkyl group. . R'.

Reaction usually in Et2O followed by H3O+ work-up Reactions of RLi and RMgX with Esters. Reactions performed usually in Et2O or THF followed by H3O+ work-ups Reactions of RC=CM with Aldehydes and Ketones. First step Nucleophilic Acyl Substitution then Nucleophilic Addition .Strategies and Tactics in Organic Synthesis Organometallic Compounds Reactions of RLi and RMgX with Aldehydes and Ketones. Reaction usually in Et2O followed by H3O+ work-up.

it is more complex and is currently not well understood.2. Primary alkyl iodides make the best substrates otherwise elimination can be a problem.and 1.Strategies and Tactics in Organic Synthesis Organometallic Compounds Alkane synthesis using R2CuLi Organolithium cuprates. giving alkanes. The R' group in the halide can also be aryl or vinyl. Although the mechanism looks like a SN2. . Conjugate Addition with Organocopper reagents Other organometallics reagents such as alkyl lithiums tend to undergo direct or 1. react with alkyl halides forming a new C-C. while Grignard reagents may give mixtures of 1. The R group of the cuprate can also be aryl or vinyl.2-addition. R2CuLi.4-addition depending on the system.

The iodomethyl zinc iodide reacts with an alkene to give a cyclopropane.Strategies and Tactics in Organic Synthesis Organometallic Compounds Synthesis of Cyclopropanes using RZnX (The Simmons-Smith reaction) The iodomethyl zinc iodide is usually prepared using Zn activated with Cu. Substituents that are trans in the alkene are trans in the cyclopropane . The reaction is stereospecific with respect to to the alkene (mechanism is concerted).

mercury compounds are generally quite toxic Regioselectivity predicted by Markovnikov’s rule (most highly substituted alcohol) The reaction is not stereoselective Reaction proceeds via the formation of a cyclic mercurinium ion (compare with bromination of alkenes) Nu + Hg Nu NaBH4 Nu HgOAc OAc H . Hg(OAc)2 in aqueous THF Unfortunately.Strategies and Tactics in Organic Synthesis Organometallic Compounds Oxymercuration-Demercuration of Alkenes Overall transformation C=C to H-C-C-OH This is an alternative method for hydrating alkenes to give alcohols Typical reagents are mercury acetate.

In other words. retron–containing element or initiating chiral element. building block. In many synthetic problems the presence of a certain type of subunit in the target molecule coupled with information on the commercial availability of compounds containing that unit can suggest potential starting materials .Strategies and Tactics in Organic Synthesis Structure-goal strategies Structure-goal strategies are based on the identification of a potential starting material. the retrosynthetic analysis is guided by the use of a particular structure corresponding to a potentially available starting material or synthetic intermediate.

1993. α-amino aldehyde. Such molecules normally contain one to five or six stereogenic centers and can originate from Nature (terpenes... of stereochemical features. Chem. The chiron approach to synthesis involves disconnection of strategic bonds in a target molecule with minimum pertubation of existing stereogenic centers. Hanessian.. generally D sequential functionality α-hydroxy aldehyde. carbohydrates. polyols. … . and of carbon framework with the target molecule (or a given substructure). from asymmetric reactions on achiral is the type of chiral substructure present in the molecules that will dictate the strategy. Total Synthesis of Natural Products: The Chiron Approach Pure & Appl. amino alcohols. The main issue now deal with proceeding in the forward direction using the inherent or newly-created chirality and building from there. α-amino acids. the scenario for a synthesis plan is established In the chiron approach.Strategies and Tactics in Organic Synthesis Chiron approach: synthesis of enantiomerically pure compounds. .. αhydroxy acids. This generates chirons with a maximum overlap of functional groups. 1189 Sugars carbon framework Acyclic Cyclic combination 3–7 carbon atoms asymmetric centres 1–5 (or 6 includes anomeric center) sense of chirality 2n permutations. and from enzymatic and related sources.. .. By relating a TGT to chiral starting materials as the outset. from resolution of racemates. S.)..

Strategies and Tactics in Organic Synthesis Sugars as starting chiral materials: some example of retrosynthesis approach Elaboration of glucose in the synthesis of thromboxane B2 Can. Chem. 562. Chem. 1981. J. Can. 1977. 870 . J.

Strategies and Tactics in Organic Synthesis .

1984. 1853 D-Mannose .Strategies and Tactics in Organic Synthesis Tetrahedron Lett.

231 D-Glucose It is evident that all the hydroxyl groups in D-glucose must be destroyed en route to the construction of the carbon skeleton of (+)-meroquinone. Chem. the D-glucose framework is efficiently used to install the two vicinal C-substituents by a sequential stereocontrolled one-step conjugate addition and enolate trapping protocol on a readily available enone Pure & Appl. Tetrahedron 1990. 1189 . However.Strategies and Tactics in Organic Synthesis (+)-Meroquinone by Hanessian (+)-Meriquenone . which can be regarded as a stereochemically wasteful procedure. 1993.

terpenes . hydroxy acids.Strategies and Tactics in Organic Synthesis Other chiral starting materials: Amino acids.

Strategies and Tactics in Organic Synthesis Some examples of retrosynthesis individuating aminoacids. terpenes and hydroxyacids .

852 .Strategies and Tactics in Organic Synthesis A brilliant performance: cephalosporin C by Woodward JACS 1966.

Strategies and Tactics in Organic Synthesis .

– Cycloalkyl subunits bound to the carbon skeleton should not be disconnected – Several options should be considered. or subunit as eligible for disconnection to guide retrosynthetic analysis. Conversely. . the designation of bonds or cyclic subunits as ineligible for disconnection.Strategies and Tactics in Organic Synthesis Topological-based strategies The existence of alternative bond paths through a molecular skeleton as a consequence of the presence of cyclic subunits gives rise to a topological complexity which is proportional to the degree of internal connectivity. Then. The disconnection of a strategic bond simplifies the topological complexity of a TGT Guidelines – It is not worth disconnecting aromatic or heteroaromatic systems. pair of bonds. topological strategies are based on the use of a particular bond. set of bonds.

1800 . ACIE 2003.Strategies and Tactics in Organic Synthesis Metathesis Cannon & Blechert. 1900 Pauson-Khand Gibson&Stevenazzi ACIE 2003.

Strategies and Tactics in Organic Synthesis Fused and Bridged systems Primary rings are those that can not be constructed by the sum of two or more smaller rings Secondary rings are those that are not primary rings Synthetically significant rings are 3-7 membered primary or secondary rings .

Strategies and Tactics in Organic Synthesis .

Strategies and Tactics in Organic Synthesis .

Strategies and Tactics in Organic Synthesis .

Strategies and Tactics in Organic Synthesis .

Angew. Mukaiyama. 1995. Chem. Chem. Engl. Corey. 166. W-D. 2002. de la Torre. Rev. M. S.. Angew. Architect and Artist in the World of Molecules.. Q. Nicolaou. Int. S. 40 . Vourloumis.. 62. M. 1971. T. K. Robert Burns Woodward. Chem.. Frontiers in Organic Synthesis. U.. J. 41. Int. 1. J.Chem. Science 2000. C. 1993. Nicolaou. Rev. Franco. 259. 96. Pure&Appl. Arya. Ed. 1990. 2613. Int. J. Baran. L. Angew. E. B. C. K. Winssinger. CIBA of India . 44. 55. Engl. 2004. L. Gasteiger. 1967. Angew. Angew. Int. 39. Sierra. Hanessian. 1996. Chem. E. Ed. E. C. 1995.Chem. Corey. 8609. T. Angew. T. Chem. T. N. M. Chem.. Chem. Chou. Angew. Philadelphia. Ed. 2678. K. 1991. Ed. 2000. Chem. 75.. 34. 2003. Angew. Pure&Appl. S. D. Trost. N. 65. Engl. Benfey. 43 .1963 Corey. 1990. J. Morris. P. 29. 1887... 19. 25. Int. Sierra. Chemical Heritage Foundation. Schreiber. L. Chem. Ed. 43 . D. Int. Diverses autors. 46. Nicolaou. Ed. Ed. Tetrahedron 1999. B. 160. Baek. H.Strategies and Tactics in Organic Synthesis Further readings Woodward. Wipke. Chem. J. 1993.. Ihlenfeldt. A. T.. 2004. Ed. Art and Science in the Synthesis of Organic Compounds: Retrospect and Prospect. Burke. Ed. Larouche. Schreiber. J. 455.. Sorensen. Int. Tietze.Chem. . 2001. Vol. J. Science 1969. 1998. W. 14. Chem. S. Seebach. D. S. Int. Ed. Beifuss. F. 2000. Angew.. Ed. J. Soc. O. 39. S. 455. In Pointers and Pathways in Research. de la Torre. 1964. Hanessian. 339.. Int. Winssinger. Int. Corey. J. 131.Angew. Chem. Chem. Engl. C. P. Chem. C. E. A. 178. Int. P. R. Pure&Appl. 1320. 1226.. Ed. Angew.-G. Baran. P. 34. B. D. 32.. 1538. 287. Engl. M. 30. M. M.. 1189. E.

an asymmetric process or by relying on the "chiral pool" 3) through an asymmetric synthesis . and it is estimated that this fraction will increase. as the development of active compounds continues to be improved . Chem. Enantiomerically pure compounds are also being used increasingly in the agrochemicals industry... About 80% of the active compounds that pharmaceutical companies have in the pipeline are chiral. Ed. 1993. The authorities responsible for the registration of new active compounds increasingly demand the targeted synthesis of one stereoisomer. The targeted synthesis of the active enantiomer can improve the economics of the process and lead to reduced quantities applied and thus to reduced environmental impact. Hauer. 1189. it is now common practice to plan synthesis in such a way so as to produce an enantiomerically pure (or enriched) TGT.Strategies and Tactics in Organic Synthesis Stereochemical-based Strategies Why should we consider stereochemistry? For practical and aesthetic reasons. Int. Hanessian. 2004. Angew. This has become a virtual necessity in pharmaceuthical research laboratories since stereochemistry is the common denominator between chemistry and biology. Chem. B. 788 There are basically three main strategies to adopt when the synthesis of an enantiomerically pure molecule is considered: 1) resolution of a racemic final compound or an intermediate 2) use of an enantiomerically pure starting material. Pure & Appl.. S.. which can be obtained by resolution.

A system chiral in a dimension is achiral or prochiral in a higher order dimension. Achiral or prochiral in tridimensional systems Chiral object in tridimensional system. Rouhi. Chem. properties and uses We must control stereochemistry Roughly 1/3 of pharmaceuticals are chiral. M. Achiral in bi or tridimensional systems prochiral in higher dimensional systems The importance of chirality A Nature yields an enormous variety of chiral compounds Each enantiomer often have very different effects . Object can be chiral in one. Achiral or Chiral object in monodimensional system. June 14. 2004. 41 . mirror mirror mirror A C D B B C D A A B B A A A B B Chiral object in bidimensional system. two and three dimensional system.Strategies and Tactics in Organic Synthesis The chirality is a dimensional property in the sense that it is referred to the order of dimension. 47 and Sept. News. 6. Eng. 90% of the top 10 selling drugs the active ingredient is chiral A.

Strategies and Tactics in Organic Synthesis .

Strategies and Tactics in Organic Synthesis Atrovastin or atorvastin Simvastatin Olanzapine stereocentre Clopidogrel Lansoprazole Amlodipine Sertaline Flutucasone .

1 and 2) attached to an atom in such a molecule leads to a different stereisomer. Stereogenic element is the origin of stereoisomerism (stereogenic center. Stereocomplexity depends on the number of stereogenic elements present in a molecule and their spatial and topological locations relative to one another. In a tetrahedral (Xabcd) or trigonal pyramidal (Xabc) structure.the origin of stereoisomerism.. respectively) substituents abc(d) are attached. Most obvious example is our hands.simply a molecule (or object) that cannot be superimposed upon its mirror image. axis. Lone pairs a re considered as sustituents with the lowest priority stereocentre . The chirality is a property of the whole object and not of a part of it.Strategies and Tactics in Organic Synthesis The direct goal of stereochemical strategies is the reduction of stereochemical complexity by the retrosynthetic elimination of stereogenic elements in a TGT.e.Isomers that differ only by the arrangement of substituents in space Stereogenic element . within the molecule such that the change of two substituents about this element leads to different stereoisomers Chiral compound . or plane) in a molecule such that interchange of two ligands (i. be it a stereogenic centre. Molecule with a single stereocentre or stereounit. Terminology Stereoisomers . axis or plane.. it is tolerated the old definition of chiral centre. the atom X to which the four (or three.

. but due to the rapid pyramidal inversion normally prevents isolation of either enantiomer.Strategies and Tactics in Organic Synthesis Stereogenic units other than carbon: Nitrogen. Sulfur and Phosphorous Defining absolute configuration: Define priorities according to CIP Point lowest priority (4) away from viewer Draw line from 1 to 3 If the way from 1 to 3 is anti-clockwise. If substituents are constrained in a ring then rigid structure prevents inversion as in the case of Troger’s base. the descriptor is (S) (S)-(4methoxyphenyl)methyl phenyl-phosphine oxide Nitrogen / amines have the potential to be chiral.

can cause racemisation (interconversion of the enantiomers) . certain anions (chloride ).Strategies and Tactics in Organic Synthesis Trigonal pyramidal phosphorus(III) is configurationally stable below 200° C Tetrahedral phosphorus (V) is configurationally stable Sulfoxides thiosulfinic esters and sulfinamided have a tetrahedral sulfur atom which possesses a lone pair as substituent! Are configurationally stable at room temperature but.

Strategies and Tactics in Organic Synthesis Chiral molecules with only first order symmetry elements (simple rotation axis) Molecules with C2 symmetry. with only C2 symmetry axis Spiro-compounds C2 axis Chiral axis in CIP definitions C2 axis atropoisomerism (S)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene .e. i.

Strategies and Tactics in Organic Synthesis Other chiral systems Helical system: twisted molecules (like a cork-screw) Right-handed helix is denoted P (clockwise as you travel away from viewer) and M for Left-handed Helical chirality in CIP definitions Chiral organometallics compounds: chirality resulting from the arrangement of out-of-plane groups with respect to a plane Planar chirality in CIP definitions .

The observed rotation is proportional to the amount of each enantiomer present .Strategies and Tactics in Organic Synthesis Enantiomers and optical rotation Each enantiomer has identical physical & chemical properties (in an achiral environment) Only differ by how they rotate plane polarised light (rotate in opposite directions) Enantiomers are said to be optically active Enantiomeric excess: Optical purity . the maximum rotation is outdated measurement of the enantiomeric excess (amount of two enantiomers) in a solution / mixture. If a solution contains only one enantiomer.

e.) .Strategies and Tactics in Organic Synthesis Enantiomeric excess Racemate (racemic mixture) .1 to 1 mixture of enantiomers (50% of each) Racemisation converting 1 enantiomer to a 1:1 mixture of enantiomers Polarimeter measures difference in the amount of each enantiomer. New methods more reliable & purity measured in terms of enantiomeric excess (e.

1g/100ml EtOH meso solubility 3.defines configuration with respect to any other stereogeneic element within the molecule but does NOT differentiate enantiomers A molecule can only have one enantiomer but any number of diastereoisomers.Strategies and Tactics in Organic Synthesis Molecules with more than one stereogenic unit A molecule with 1 stereogenic centre exists as 2 stereoisomers or enantiomers Enantiomers have identical physical properties in an achiral environment) A molecule with 2 or more stereogenic units can exist as 4 or 2 n stereoisomers Enantiomers (mirror images) still have identical physical properties Diastereoisomers (non-mirror images) have different properties chiral solubility 0. The different physical properties of diastereoisomers allow us to purify them .3g/100ml EtOH Enantiomers differ only by their absolute stereochemistry (R or S etc) and Diastereoisomers differ by their relative stereochemistry. Relative stereochemistry .

Strategies and Tactics in Organic Synthesis Meso Compounds The rule 2n gives the maximum number of stereoisomers but in special case as in the case of meso compounds the number of possible stereoisomers is lower A meso compound is .a molecule that contains at least one stereogenic unit but has a second order symmetry element (plane of symmetry) and is thus achiral • Meso compounds have a plane of symmetry which split up the molecule in two subunit (each ones are stereocentres) which are one the mirror image of the other with (R) configuration on one side and (S) on the other C2 axis mirror R Tartaric acid chiral no plane of symmetry non-superimposable on mirror image but due to the presence of a C2 symmetry axis it is asymmetric molecule achiral plane of symmetry superimposable on mirror image (meso) S .an achiral member of a set of diastereoisomers that also includes at least one chiral member. Simplistically .

Strategies and Tactics in Organic Synthesis Difference in diastereomers allows chiral derivatising agents to resolve enantiomers Remember a good chiral derivatising agent should: Be enantiomerically pure (or it is pointless or useless) Coupling reaction of both enantiomers must reach 100% (if you are measuring ee) Coupling conditions should not epimerize stereogenic centres Enantiomers must contain point of attachment Above list probably influenced depending whether you are measuring %ee or preparatively separating enantiomers .

Strategies and Tactics in Organic Synthesis Chiral derivatising agent: Mosher’s acid Popular derivatising agent for alcohols and amines is α-methoxy-αtrifluoromethylphenylacetic acid (MTPA) or Mosher’s acid Typical difference in chemical shifts in 1H NMR 0.17 (CF3) .15 ppm and 19F NMR gives one signal for each diastereoisomer No α-hydrogen so configurationally stable Diastereoisomers can frequently be separated In many cases use of both enantiomers of MTPA can be used to determine the absolute configuration of a stereocentre (JACS. 2143 and JACS 1991.08 (Me). 1973. 4092) Difference in NMR signals between diastereoisomers : 1H NMR ∆δ = 0. 512. 19F NMR ∆δ = 0. JOC 1973.

normally easier to recover and reuse reagent Use of non-covalent interactions allows other methods of resolving enantiomers .Strategies and Tactics in Organic Synthesis Diastereoisomeric ionic salt formation No need to covalently attach chiral derivatising group Benefit .

the separation of enantiomers from either a racemic mixture or enantiomerically enriched mixture Chiral chromatography . each complex has a different stability allowing separation .Normally HPLC or GC A racemic solution is passed over a chiral stationary phase Compound has rapid and reversible diastereotopic interaction with stationary phase Hopefully.Strategies and Tactics in Organic Synthesis Resolution of enantiomers: chiral column chromatogaphy Resolution .

Strategies and Tactics in Organic Synthesis Resolution of enantiomers: chiral column chromatogaphy Measurements of ee by HPLC or GC are quick and accurate (±0.05%) Chiral stationary phase may only work for limited types of compounds Columns are expensive (>€1500) Need both enantiomers to set-up an accurate method .

these may have different NMR signal Problems . CO2H etc). Compound must contain Lewis basic lone pair (OH. Accuracy is only ±2% . C=O. NH2. Coordination process faster than NMR timescale and normally observe a downfield shift (higher ppm) Two diastereomeric complexes are formed on complexes are paramagnetic. line broadening is observed (especially on high field machines).Strategies and Tactics in Organic Synthesis NMR spectroscopy: chiral shift reagents Chiral paramagnetic lanthanide complexes can bind reversibly to certain chiral molecules via the metal centre.

85 experimental . [D]/[L] = 1/2. Extimated ratio D/L: 1/ 3.85) in D O at pH 9.06 M.4 and in the 2 presence of samarium complex Signal show no paramagnitic broadening.02 vs 1/2.Strategies and Tactics in Organic Synthesis NMR spectroscopy: chiral shift reagents New reagents are being developed all that time that can overcome some y of these problems 1H NMR spectra (400 MHz) of valine (0.

Symmetric object containing II order symmetry element (plane containing 1. but also by selective modification or replacement of stereoheterotopic ligands. 2.Strategies and Tactics in Organic Synthesis Desymmetrisation: process that transforms a symmetric or prochiral object into a non symmetric one or in a chiral one From a synthetic point of view. the introduction of new stereogenic centers into a TGT is normally achieved by means of two fundamentally distinct processes: most commonly through addition to one or other stereoheterotopic (enantio. 3 and carbon Chiral in a bidimentional system or prochiral in a tridimentional one Chiral in tridimentional system Chiral in a bidimentional system or prochiral in a tridimentional one .2 and carbon carbon carbon Symmetric object containing II order symmetry element (plane containing 1.or diastereotopic) faces of a double bond.

In acyclic systems. high stereocontrol can be achieved if the molecule adopts a definite reactive conformation in which one of the two diastereofaces is efficiently shielded by steric effects of the substituents: 1) Passively by steric shielding of one or two diastereotopic faces on the reactive center. 2) Actively by binding the reagent in form of non-covalent interactions and directing it towards one of the diastereotopic faces Steric and stereoelectronic effects play a crucial role to devise powerful retrosynthetic analysis. The generation of a new stereocenter can be controlled by the steric bias of preexisting stereocenters. conformationally no flexibles. Otherwise. This kind of stereocontrol is frequent in cyclic structures. it depends on the structure of the substrate or reagent. the situation is much more complicated Given that the new stereocenters are usually created by addition to a sp2 carbon.Strategies and Tactics in Organic Synthesis Substrate: stereocontrol due to a stereochemical bias in the substrate The stereochemical outcome of a wide range of reactions is not contolled by mechanistic issues. Conformational issues must be considered Acyclic systems Cyclic systems .

Deslongchamps. must be also considered Stereoelectronic effect: is any effect determining the properties or reactivity of a species that depends on the orientation of filled or unfilled electron orbitals in space. hydrogen-bonding. coordination (chelation). P. Stereoelectronic Effects in Organic Chemistry O O O O O O weak lone pair repulsion More stable medium lone pair repulsion strong lone pair repulsion Less stable .Strategies and Tactics in Organic Synthesis What conformation is the most stable? And the most reactive? Lewis acid – Lewis base considerations.

OsO4 oxidation of alkenes ect. E. JOC 1991. 4031 . hydroboration.Strategies and Tactics in Organic Synthesis Mechanism: intrinsically stereocontrolled transforms There are reactions which show stereoselectivity primarily because of mechanism: SN2 processes. 1476 Ireland. ACIEE 1990. J. R. epoxidation. Those disconnections involving C–C bonds are specially important The stereochemistry of bis-epoxide controls the final stereochemical outcome Mulzer..

a reaction where one stereoisomer of a product is formed preferentially over another. Diastereoselective reactions .a reaction that produces two enantiomers of a product in unequal amounts .a stereogenic centre is introduced into a molecule in such a way that diastereoisomers are produced in unequal amounts Enantioselective reactions . Diastereospecific reaction permits only one diastereoisomer to be formed control relative stereochemistry not absolute stereochemistry for example Iodolactonisation Proceeds via an iodonium species followed by intramolecular ring-opening Geometry of alkene controls relative stereochemistry If there is a pre-existing stereogenic centre then reaction can be stereoselective. In such reactions two diastereoisomers could be formed but one is favoured I2 Stereoselective reactions .g. there is no choice! e. The mechanism does not prevent the formation of two or more stereoisomers but one predominates.Strategies and Tactics in Organic Synthesis Stereoselectivity in Organic Synthesis Stereospecific reactions .a reaction where the mechanism and the stereochemistry of the starting material determine the stereochemistry of the product. SN2 reactions.

Strategies and Tactics in Organic Synthesis Stereoselective reactions Nucleophilic addition to C=O and Prochiral Nomenclature Trigonal carbons that are not stereogenic units but can be transformed into them are called prochiral. Reaction is stereoselective if one diastereoisomer predominates . Reaction of a nucleophile with a carbonyl in a substrate where other sterecentre are present. to each carbonyl face is assigned the label Si or Re based on the CIP rules. gives two possible diastereoisomers. If the carbonyl function is in a chiral molecule is called prostereogenic unit and the faces are said to be diastereotopic In the case of achiral molecules the carbonyl faces are named enantiotopic and the addition of nucleophiles to the carbonyl function can occur with enantioselection or the reaction is enantioselective if one prochiral face is attached preferentially over the other.

Strategies and Tactics in Organic Synthesis Possible models proposed along the time for nucleophile apprach to the carbonyl function with a stereocentre in α Models proposed with a perpendicular approach of Nu to the carbonyl function Nucleophiles attack the carbonyl group along the Bürghi-Dunitz angle of ~107° the Bürghi-Dunitz (107° ) angle is the compromise between electrostatic interaction and optimised orbital overlaps Later on other models have been proposed with Bürghi-Dunitz trajectory of Nu to the carbonyl function .

Strategies and Tactics in Organic Synthesis Importance of conformational analysis Newman projection: two substituents (C=O & Ph) are eclipsed .unfavoured Other possible conformers: Two favoured as largest substituent (Ph) furthest from O and H Re face One of the more stable conformer largest substituent (Ph) furthest from O&H Si face One of the more stable conformer largest substituent (Ph) furthest from O&H Explained using Felkin-Ahn model in most stable conformation the favoured approach is close to the smallest substituent (H) when molecule .

Nucleophile (Nu) will attack along the Bürghi-Dunitz trajectory passed the least sterically demanding (smallest. Should be noted that larger substituents normally result in a slower rate of reaction . use the Felkin-Ahn model: Draw Newman projection with the largest substituent (L) perpendicular to the C=O. it does not give any information about the degree of selectivity but only whose will be the predominant stereoisomer The size of the nucleophile greatly effects the diastereoselectivity of addition: Larger nucleophiles generally give rise to greater diastereoselectivities. Choice of metal effects the selectivity as well. although this may just be a steric effect. Again. draw the Newman projection of the product. larger groups result in greater selectivity.Strategies and Tactics in Organic Synthesis General features for the addition to a carbonyl with a α stereocentre: Felkin-Ahn Model To explain or predict the stereoselectivity of nuclophilic addition to a carbonyl group with an adjacent stereogenic centre. S) substituent. The size of substituents on the substrate will also effect the diastereoselectivity. Whilst the Felkin-Ahn model predicts the orientation of attack. redraw the molecule in the normal representation.

more susceptible to nucleophilic attack. . C=O is more reactive. can play an important rule as in the case of αdibenzylamino substituted aldehydes.Strategies and Tactics in Organic Synthesis The effect of electronegative atom in α to carbonyl function Steric hinderance is not the only factor that justify the high observed stereoselectivity and faster reaction in the addition of ester enolates to α-amino substituted aldehydes. such as electronic factors. Other factors. The Bn2N group must be perpendicular to C=O since in this way there is a better interaction between the C-N and the carbonyl double bond. Fenkin-Ahn approach When an electronegative group is perpendicular to the C=O it is possible to get an overlap of the π* orbital and the σ* orbital which results in a new. the approach of enolate is favoured from the opposite site to Bn2N (electronic repulsion between two electron rich group namely enolate and Bn2N). lower energy orbital. thus if electronegative group perpendicular. Applying the Fenkin-Ahn model.

The chelating metal acts as a Lewis acid and activates the carbonyl group to attack.Strategies and Tactics in Organic Synthesis The effect of electronegative atom and chelation control Other example of electronic effect control If heteroatom (Z) is capable of coordination and a metal capable of chelating 2 heteroatoms is present we observe chelation control. Chelation controlled additions are easy to predict and normally do not need to draw Newman projection! . Chelation can reverse selectivity. Metal chelates carbonyl and heteroatom together fixing their conformation affording greater selectivity and faster reaction.

Strategies and Tactics in Organic Synthesis Chelation control in the nucleophilc addition to α carbonyl: other examples The following example shows normal Felkin-Ahn selectivity gives one diastereoisomer Electronegative and bulky phosphorus group in perpendicular position. Chelation control gives opposite diastereoisomer and occurs through 6-membered ring. Lower reaction temperatures are typical in activated chelated carbonyl systems .

9437 . 1995.Strategies and Tactics in Organic Synthesis Application of Fenkin-Ahn model in total synthesis An example of the Sakurai reaction (addition of allylsilane to carbonyl) from the synthesis of preswinholide A which is effectively the monomer of swinholide A (the dimmer. isolated from a Red Sea sponge). 51. Tetrahedron. a compound displaying potent cytotoxic activity Total synthesis by Ian Paterson.

62. Tetrahderon.Strategies and Tactics in Organic Synthesis The synthesis of canadensolide. 9713 . a fungicidal agent is another example of the Mukaiyama aldol reaction (addition of ester silylenolether to carbonyls • Yung-Son Hon & Cheng-Han Hsieh. 2006.

R2 and frequently on the geometry of the enolate (but not always) Geometry of the enolate: The terms cis and trans in relation of the disposition group with highest priority on the α-carbon atom to O–M bond C-α re face C-α si face MO R1 R2 α MO R1 H α H R2 C-α si face C-α re face .Strategies and Tactics in Organic Synthesis Stereoselctive reaction of enolates The stereoselectivity of reactions of enolates is dependent on: Presence of stereogenic centres on R1.

σ C–H orbital ultimately becomes p orbital at C-α of the enolate π bond Deprotonation process and geometry of the enolate Two possible conformations which allow this: Little steric interaction between R1 and R2 Initial conformation (Newman projection) similar to transition state results in the formation of cis enolate . this is favoured when the C–H bond is perpendicular to C=O bond as this allows σ orbital to overlap π orbital.Strategies and Tactics in Organic Synthesis Enolate formation and geometry Enolate normally formed by deprotonation.

Strategies and Tactics in Organic Synthesis Enolate formation and geometry Deprotonation process and geometry of the enolate Second conformation: C–H perpendicular to C=O which differs by relative position of R1 and R2 and gives trans-enolate The steric interaction of R1 and R2 results in the cis-enolate normally predominating but the stereoselectivity is influenced by the size of R .

Strategies and Tactics in Organic Synthesis Enolate formation and geometry The selectivity observed can be explained via chair-like transition state of deprotonation step In ketones cis-enolate favoured if R is large but trans-enolate favoured if R is small With esters the R vs OMe interaction is alleviated and 1. hence trans-enolate predominates .3-diaxial interaction controls the geometry of the enolate.

Use of the additive HMPA (hexamethylphosphoric triamide) reduces coordination and favours the thermodynamically more stable enolate In ester the reverse is observed . The previous arguments are good generalisations.Strategies and Tactics in Organic Synthesis Enolate formation and geometry Amides invariably give the cis-enolate. many factors effect geometry. remember restricted rotation of C–N bond.

new bond is formed more or less perpendicular to carbonyl group The example shows a simple SN2 reaction with X = leaving group .Strategies and Tactics in Organic Synthesis Addition electrophile to an enolate: Alkylation It is important to know the trajectory of approach of the enolate and electrophile Reaction is the overlap of the enolate HOMO and electrophile LUMO Therefore.

e. Cis. 9361.e. enantiopure aminoalcohol) or imides (Evans approach enantiopure oxazolidinones) Evans approach From phenylalanine Chelation is important for enolate geometry and for the approach of the electrophile. 116. 8215) d. 117. 104. The alkylation of prochiral enolates of acid is normally preformed using chiral derivatives such as chiral amides (Meyer approach. 112.enolate Myers approach d. M= Li (JACS 1982. 1737 ) or TiCl3 (JACS 1990.>95 to 100%. yields >80% JACS 1994.e. After removing the chiral auxiliary the final acid is obatin with high e. >94%. 1995.Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) alkylation of prochiral enolates. 8488 Cis-enolate .

So its dimension play and important role in determining diastereoselectivity. Larger the substituent.Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) alkylation of chiral enolates Simple alkylation of a chiral enolate usually occurs with very high diastereoselectivity Since the cis-enolate is usually formed with high diastereoselectivity the reactive conformer considering the alkenes A(1.3) strain. greater the selectivity The geometry of enolate is not important Cis-enolate minor diastereoisomer probably arises from electrophile approaching from R group site and not reacting with the trans enolate. R. It is possible to change the diastereoselectivity simply using the proton as electrophile in quenching the enolate of the alkylated final product .

the enolate geometry effects diastereoselectivity syn aldol . chair-like transition state. Contrary to alkylation. In addition it can form two new stereogenic centres in a diastereoselective manner.Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) aldol reaction The aldol reaction is a valuable C–C forming reaction. Most aldol reactions take place via a highly order transition state know as the Zimmerman–Traxler transition state which is a 6-membered.

Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) aldol reaction: Zimmerman–Traxler transition state Zimmerman–Traxler transition state for cis-enolate Enolate substituents are fixed due to the double bond thus the orientation of the aldehyde in relation to the enolate is crucial in determining the final stereoselectivity (diatereo and enantio selectivity) in the aldol reaction Bulky aldehyde substituent should be arranged in pseudoequatorial position in the Zimmerman–Traxler transition state in order to avoid 1.3-diaxial interactions Enantiomeric TS Me and OH point towards the observer si face of enolate attacks re face of aldehyde re face of enolate attacks si face of aldehyde to ‘see’ relative stereochemistry consider the blue carbon sequence on a plane and see which groups are above and which below. Thus in this case Me and OH are farer from observer Attack via the enantiomeric transition state (re face of aldehyde) gives the enantiomeric aldol product. This differs only by the absolute stereochemistry but the relative stereochemistry is the same Me and OH on the same site .

Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) aldol reaction: Zimmerman–Traxler transition state Trans-enolate: The opposite stereochemistry of enolate gives opposite relative stereochemistry In this case the two hydrogens must axial .

Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) aldol reaction: enolate geometry In the lithium enolates of ketones the size of the non-enolised substituent. is important Geometry of the enol in ketones is determined by the dimension of R With boron enolates we can select the geometry by altering the boron reagent used The bulky groups on boron force enolate to adopt trans geometry 9-BBN (9-borabicyclononane) looks bulky. but most of it is ‘tied-back’ behind boron thus allowing formation of the cis-enolate . R.

Strategies and Tactics in Organic Synthesis Substrate control in the total synthesis of oleandomycin aglycon Cram chelation control .

116. 11287 . Am. 1994.Strategies and Tactics in Organic Synthesis Aldon reaction: Substrate control in the total synthesis of oleandomycin aglycon the opportunities offered by the aldol reaction. Chem...Soc. Ian Paterson. J. It creates 1 C–C bond and 2 stereogenic centres per reaction.

9393–9467 fragment A fragment B .Strategies and Tactics in Organic Synthesis Aldon reaction: Substrate control in the total synthesis of swinholide A by Paterson Tetrahedron 1995.

Strategies and Tactics in Organic Synthesis

fragment A

fragment B

Strategies and Tactics in Organic Synthesis Stereoselective Synthesis; Chiral auxiliary
Chiral auxiliary - allows enantioselective synthesis via diastereoselective reaction Add chiral unit to substrate to control stereoselective reaction. Can act as a built in resolving agent (if reaction not diastereoselective). Problems - need point of attachment, adds additional steps (atom economy),.cleavage conditions must not damage product!

An ideal chiral auxiliary has to fulfil several criteria: i) it should be cheap, and both enantiomers should be readily available; ii) attachment of the substrate to the auxiliary should proceed in high yield by simple methods, applicable to a broad variety of substrates; iii) there should be many different types of reactions to be carried out; iv) the auxiliary must be stable under the conditions of the diastereoselective reaction; v) there must be a high degree of diastereoselection vi) the derivatives of the chiral auxiliary should preferably be crystalline, allowing easier purification, and removal of diastereoisomeric ans other impurities by simple crystallization; vii) the cleavage of the auxiliary must be possible with high yield under mild conditions, and the procedures should be generally applicable viii) the auxiliary should not be destroyed under the conditions applied for cleavage, thus allowing for recycling ix) isolation of the enantiomerically pure product and recovery of the auxiliary should be possible by simple methods. Seebach, D. Helvetica Chimica Acta 1998, 2093

Strategies and Tactics in Organic Synthesis Chiral auxiliary and addition to the carbonyl group
We have seen many examples of substrate control in nucleophilic addition to the carbonyl group (Felkin-Ahn & chelation control). If molecule does not contain a stereogenic centre then we can use a chiral auxiliary. The chiral auxiliary can be removed at a later stage

Opposite diastereoisomer can be obtained from reduction of the ketone with lower diastereoselectivity...‘H–’ is smaller

Strategies and Tactics in Organic Synthesis

Chiral auxiliary in synthesis The chiral auxiliary, 8-phenylmenthol, has been utilised to form the pheromone, frontalin Aggregation pheromone of the Southern Pine Beetle - the most destructive beetle to pine forests in southeastern united states

Strategies and Tactics in Organic Synthesis
Stereoselective synthesis: chiral reagents Chiral reagents Chiral reagent - stereochemistry initially resides on the reagent • Advantages - No coupling / cleavage steps required ....................... .Often override substrate control ....................... .Can be far milder than chiral auxiliaries • Disadvantages - Need a stoichiometric quantity (not atom economic) .............................Frequently expensive .............................Problematic work-ups

Strategies and Tactics in Organic Synthesis
Chiral reagents Clearly, chiral reagents are preferable to chiral auxiliaries in that they function independent of the substrate’s chirality or on prochiral substrates A large number have been developed for the reduction of carbonyls Most involve the addition of a chiral element to one of our standard reagents

selectivity governed by 1,3-diaxial interactions

Strategies and Tactics in Organic Synthesis

Binol derivative of LiAlH4
Reducing reagent based on BINOL and lithium aluminium hydride • Selectivity is thought to arise from a 6-membered transition state (surprise!!) • Largest substituent (RL) adopts the pseudo-equatorial position and the small substituent (RS) is axial to minimise 1,3-diaxial interactions

Transition state

Strategies and Tactics in Organic Synthesis
Chiral reagent in total synthesis (+)-Ipc2BCl is a more reactive, Lewis acidic version of Alpine-borane • Might want to revise the Mitsunobu reaction (step 2)

• M. Srebnik, P.V. Ramachandran & H.C. Brown, J. Org. Chem., 1988, 53, 2916

Strategies and Tactics in Organic Synthesis
Chiral allyl boron reagents Allyl boron reagents have been used extensively in the synthesis of homoallylic alcohols • Reaction always proceeds via coordination of Lewis basic carbonyl and Lewis acidic boron

• This activates carbonyl as it is more electrophilic and weakens B–C bond, making
the reagent more nucleophilic • Funnily enough, reaction proceeds by a 6-membered transition state

Aldehyde will place substituent in pseudo-equatorial position (1,3-diaxail strain) • Therefore alkene geometry controls the relative stereochemistry (like aldol rct)

Strategies and Tactics in Organic Synthesis Chiral allyl boron reagents II Reagent is synthesized from pinene in two steps • Gives excellent selectivity but can be hard to handle (make prior to reaction) • Remember pinene controls absolute configuration Geometry of alkene controls relative stereochemistry .

chiral reagents are wasteful .Strategies and Tactics in Organic Synthesis Other boron reagents A number of alternative boron reagents have been developed for the synthesis of homoallylic alcohols • These either give improved enantiomeric excess. diastereoselectivity or ease of handling / practicality • Ultimately.they need at least one mole of reagent for each mole of substrate • End by looking at chiral catalysts .

Org. Leighton • Used in the synthesis of (+)-SCH 351448. Lett. L. 3809 . 2005. a reagent for the activation of low-density lipoprotein receptor (LDLR) promoter.. 7.Strategies and Tactics in Organic Synthesis Chiral reagent in total synthesis Silicon reagent developed by J. Leighton.

Strategies and Tactics in Organic Synthesis Stereoselective synthesis: chiral catalysis Chiral catalysis .ideally a reagent that accelerates a reaction (without being destroyed) in a chiral environment thus permitting one chiral molecule to generate millions of new chiral molecule The reaction is often perfomed on achiral substrates or prochiral ones (as for example carbonyl functions). .

Prochiral carbonyl function . The reaction utilises ~10% heterocycle and a stoichiometric amount of borane and works most effectively if there is a big difference between each of the substituents on the ketone.Strategies and Tactics in Organic Synthesis Catalytic enantioselective reduction An efficient catalyst for the reduction of ketones is Corey-Bakshi-Shibata catalyst (CBS): The reagent is prepared from a proline derivative: diphenylprolinol. Enantioselection is deternated by the nature of chiral reagent and occurs by the formation of diastereoisomeric transition states with different energies.

The mechanism is quite elegant: This catalyst brings a ketone and borane together in a chiral environment Boron Lewis acidic center that coordinates carbonyl oxygen .

Simple amino alcohols are known to catalyse the addition of dialkylzinc reagents to aldehydes with a mechanism involving a bifunctional zinc species where one zinc becomes the Lewis acidic centre and activates the aldehyde and the second equivalent of the zinc reagent actually attacks the aldehyde.Strategies and Tactics in Organic Synthesis Catalytic enantioselective nucleophilic addition There are now many different methods for catalytic enantioselective reactions. Some few examples.3-diaxial interaction . Once again a 6-membered ring is involved and 1.3-diaxial interactions govern the observed selectivity 1.

e the differences between the dimention RE and RZ.e. . C-Sn Bond is enough polarized and this makes the gamma position particularly nucleophilic nucleophilc site RE Rz δ− Sn δ+ The E or Z nature of stannyl derivative has no influence on diatereoselection but are important the dimention of the group in gamma position to the Sn i. However the control of diastereoselectivity is often difficult to achieve.Strategies and Tactics in Organic Synthesis Lewis acid catalysed allylation / crotylation Chiral Lewis acids can be used to activate carbonyl group with impressive results and in the case of allylation works very well with high e. In this reaction the reaction proceeds via an open transition state and this partially explain the relative difficulty in controlling the diastereoselection.

Strategies and Tactics in Organic Synthesis Catalytic chiral Lewis base mediated allylation with allyl silicon reagents
Alternatively allylsilyl reagents are emploied in allylation of carbonyls. In this case the use of chiral Lewis bases, which activate the crotyl reagent, higher diatereoselection are obeserved. The reaction proceeds via the activation of the allylsilicon reagent by coordination of chiral base and with the generation a hypervalent silicon species This species coordinates and activate the carbonyl function allowing the reaction to proceed by a highly ordered by a closed transition state. As a result good diastereoselectivities are observed and the geometry of nucleophile controls the relative stereochemistry.

RE and RZ = Me or H Example of base catalysts used in this reaction

Strategies and Tactics in Organic Synthesis

Reactions of alkenes: Stereospecific reactions
Alkenes are versatile functional groups that present plenty of opportunity for the introduction of stereocenters. One possibility is by Hydroboration (the reaction that allows to transform alkenes in alcohols) that permits the stereo-selective introduction of boron. The corresponding borane can undergo a wide-range of stereospecific reactions

The two compounds formed previously, mono& diisopinocampheylborane are common reagents for the stereoselective hydroboration of alkenes. Ipc2BH is very effective for cisalkenes but less effective for trans. IpcBH2 gives higher enantiomeric excess with trans and trisubstituted alkenes

Strategies and Tactics in Organic Synthesis
Hydrogenation: is another important reaction that can be carried out enantioselectively under metal catalysis condition. One well known example for its huge importance from industrial point of view, is the catalytic hydrogenation of dehydroaminoacid derivatives (prepared by Knovenagel like reaction on glycine). Diphosphines are used as Rutenium ligand and it is essential that there is a second coordinating group (the amide in the dehydroaminoacid).

On coordination, two diastereoisomeric complexes are formed. The stability / ratio of each of these complexes is unimportant in determining the final stereoselection but the rate of hydrogen coordination.

Si face Re face

Strategies and Tactics in Organic Synthesis
Mechanism proposed for catalytic hydrogenation

Hydrogen oxidative addition

Hydrogen transfer

Strategies and Tactics in Organic Synthesis
Other systems can be hydrogenated with the same chiral catalyst: industrial synthesis of candoxatril

Used in the synthesis of candoxatril, a potent atrial natriuretic factor (ANF) potentiator (cardiovascular drug developed by Pfizer). Process used on ton-scale
Org.Process Res. Dev., 2001, 5, 438

Strategies and Tactics in Organic Synthesis
Reactions of alkenes: epoxidation diastereospecific reaction
Diastereospecific - reaction permits only one diastereoisomer to be formed control relative stereochemistry not absolute stereochemistry Electrophilic epoxidation via a concerted process is a good example

Concerted oxygen transfer

Epoxidation is irreversible and the reaction is under kinetic control.

Strategies and Tactics in Organic Synthesis
Conformation are important in determining the observed stereoselection: the lowest energy conformations have greatest separation of bulky substituents. The control of conformation in allyl systems is called allylic strain or A(1,3) strain

allylic strain or A(1,3) strain

Strategies and Tactics in Organic Synthesis

In the trans alkene the differences in energy between the two conformers is sensibly lower and the d.e. is minor (61/39)

Strategies and Tactics in Organic Synthesis
Hydroxyl group can direct epoxidation in acyclic compounds as well • Once again, major product formed from the most stable conformation

• Thus the cis methyl group is very important
• The minor product is formed either via non-directed attack or via the less favoured


get low selectivity .Strategies and Tactics in Organic Synthesis Directed epoxidation: effect of C-2 substituent The presence of a substituent in the C-2 position (Me) facilitates a highly diastereoselective reaction • The preferred conformation minimises the interaction between the two Me (& Me) groups • With C-2 substituent (H) there is little energy difference between conformations • Therefore.

118. Chem. Am. 1996. Evans and Annette S. Kim. 11323 . J. Soc.Strategies and Tactics in Organic Synthesis Substrate control in total synthesis Directed epoxidation from the synthesis of oleandomycin aglcon • Glycosylated version (R=sugar) is a potent antibiotic from streptomyces antibioticus • David A.

such as m-CPBA. is directed by hydrogen bonding and favours attack from the same face as hydroxyl group • The reaction with a vanadyl reagent results in higher stereoselectivity as it bonds / chelates to the oxygen .Strategies and Tactics in Organic Synthesis A hydroxyl group can reverse normal selectivity and direct epoxidation • Epoxidation with a peracid.

5974 • Sharpless asymmetric epoxidation was the first general asymmetric catalyst. B. To understand where this comes from we must look at the mechanism .Strategies and Tactics in Organic Synthesis Sharpless Asymmetric Epoxidation (SAE) of allylic alcohols Sharpless. Compounds must be allylic alcohols as shown by epoxidation of the diolefin SAE is highly predictable . There are a large number of practical considerations that we will not discuss. Suffice to say it works for a wide range of compounds in a very predictable manner. JACS 1980. K.

Strategies and Tactics in Organic Synthesis Mechanism of SAE Active species thought to be 2 x Ti bridged by 2 x tartrate Reagents normally left to ‘age’ before addition of substrate thus allowing clean formation of dimer .

Furthermore. Only cis di-substituted alkenes show lesser enantioselection SAE can over-ride (have the priority) the inherent selectivity of a substrate.Strategies and Tactics in Organic Synthesis SAE works for a wide range of allylic alcohols. it demonstrates the concept of matched & mismatched. When the catalyst & substrate reinforce each other spectacular (or matched) results are achieved .

Barry Sharpless. J. Hiroko Masamune. 1988. Hanson.Strategies and Tactics in Organic Synthesis Use of SAE in synthesis Fluoxetine is a commercial anti-depressant (better known as Sarafem® or Prozac®). 4081. 109. Chem. Klunder.. 53. Yun Gao. Robert M. Sharpless.. Am. Soc. Gao and K. and K. J.. Y. B. Ko.. 5165 . Janice M. Chem. Soo Y. Can be synthesized in a number of methods • One involves the use of the SAE reaction. Org. 1987.

45eq TBHP Using the same diethyltartrate. but rate of epoxidation is different and the differences are sufficient to epoxidise only one enantiomer if the reaction is stopped at 50% conversion. both enantiomers should be epoxidised from same face. if reaction goes to 100% completion a 1:1 mixture of diastereoisomers is obtained .6eq TBHP if epoxy alcohol is desired: use 0.Strategies and Tactics in Organic Synthesis Kinetic resolution as racemic mixture if allylic alcohol is desired: use 0.

1990. Am. 4793. and J. a key component of the cell wall lipopolysaccharide (LPS) of Gramnegative bacteria forming the necessary linkage between the polysaccharide and lipid A regions.e. Chem. 109. the same as two kinetic resolutions. 1525 .1987. Tetrahedron. Effectively. Desymmetrisation of a meso compound allows 100% yield. of desired product increases with the reaction time (84% ee 3hrs ➔ >97% 140hrs) Desymmetrisation has been used in many elegant syntheses. Soc. As an example in the synthesis of KDO. but the problem with kinetic resolution is that is can only give a maximum yield of 50% in epoxide. first desymmetrises compound second removes unwanted enantiomer.. E.Strategies and Tactics in Organic Synthesis Kinetic resolution Kinetic resolution normally works efficiently. 46.

an HIV protease inhibitor marketed by Merck as Crixivan®. Chem. 2811 . 106. 2006. represent an example that demonstrates the industrial potential of such catalytic systems.. The Industrial Syntheses of the Central Core Molecules of Indinavir.Strategies and Tactics in Organic Synthesis Jacobsen-Katsuki epoxidation SAE is a marvelous reaction but suffers certain limitations: substrate must be an allylic alcohol and cisdisubstituted alkenes are poor substrates. Rev. Alternatively (salen)Mn catalysts with bleach (NaOCl) are good in the epoxidation of many olefins.

Coordinate to the metal via the green nitrogen. K3Fe(CN)6 is the stoichiometric oxidant K2CO3 & MeSO2NH2 accelerate the reaction Normally use a biphasic solvent system And the two ligands are Ligands are pseudo-enantiomers (only blue centres are inverted.. . catalytic. oxidant is K2OsO2(OH)4 .Strategies and Tactics in Organic Synthesis Sharpless Asymmetric Dihydroxylations (SAD) The active. red are not).. OsO4 is too volatile & toxic.

. Tetrahedron Lett. 5031 . endo-brevicomin inhibits the aggregation of the southern pine beetle. 34. Interestingly. 1993.Strategies and Tactics in Organic Synthesis Sharpless Asymmetric Dihydroxylation Reaction works on virtually all alkenes • Exact mechanism not known but it is relatively predictable (but not as predictable as the SAE) The example shows the power of the SAD reaction in synthesis: exo-Brevicomin is the aggregation pheromone of several timber beetles.

1996. Scand. 50.Strategies and Tactics in Organic Synthesis The Sharpless aminohydroxylation reaction A variant has now been developed that permits aminohydrodroxylation. 649 . Acta Chem.. an anti-carcinogen. It has been employed in the semi-synthesis of paclitaxel (Taxol®).

The reaction is known as 1. for example have been utilised to prevent and treat peptic ulcers.initial nucleophile addition to the least hindered face of enone. After the addition of the nucleophile an enolate is formed this open to the possibility of forming two stereogenic centres. Chem. 1988. the electrophile addition normally occurs from opposite face Second stereocentre First stereocentre Application to the synthesis of PGE2 This stereocentre control the addition to the double bond Prostaglandins are technically hormones with very strong physiological effects. as a vasodilator. Substrate control . to treat pulmonary hypertension and induce childbirth / abortion R. 4718 .4-addition or conjugate Michael addition. Am. Soc. Noyori.Strategies and Tactics in Organic Synthesis Stereoselective Conjugate (1.4-) addition Nucleophilic attack on C=C bond normally requires electron deficient alkene as in the case of α−β unsaturated carbonyl derivaties. J. 110.

Strategies and Tactics in Organic Synthesis Diastereoselective conjugate additions Possible to use chiral auxiliary to control 1. the nucleophile (Et) addition occurs from most sterically accessible side. The chelation of amide and sultam oxygens to Mg restricts rotation and favours cis conformation.4-nucleophilic addition. Chiral auxiliary readily cleaved (& reused) to give enantiomerically pure compound via diastereoselective reaction .

The enolate can then be trapped by an appropriate electrophile.4-addition to introduce two stereogenic centres. The first addition (BuMgBr) occurs as before to generate an enolate. Once again the sultam chiral auxiliary controls the face of addition (of Me) .Strategies and Tactics in Organic Synthesis Chiral auxiliary to control two stereocentres It possible to utilise 1.

It can be prepared from carboxylic acids (normally in 3 steps) or from condensation of the amino alcohol and a nitrile. As can be seen excellent enantiomeric excesses can be achieved via a highly diastereoselective reaction .Strategies and Tactics in Organic Synthesis Alternative chiral auxiliaries A second chiral auxiliary is the oxazoline (5-membered ring) of Meyers.

Strategies and Tactics in Organic Synthesis Chiral auxiliary and radical conjugate addition Radicals once thought to be too reactive to allow diastereoselective reactions. Use of Et3B & O2 as radical initiator allows the use of low temperatures . Rare-earth Lewis acids give superior results.oxazolidinone auxiliary. But this is not always true .

Sulfoxide substituent blocks the bottom face & is readily removed. Simple substrate control instals aryl group on opposite face to substituent (–)-Podorhizon is a member of the anticancer podophyllotoxin family of compounds. 2627 . not only does it introduce a stereocentre but it activates the alkene by addition of an extra electron-withdrawing group.Strategies and Tactics in Organic Synthesis Sulfoxide-based chiral auxiliary (& total synthesis) Sulfoxide is a good chiral auxiliary. 1984. Tetrahedron Lett. 25.

one of the five basic human tastes. it is thought to be involved in cognitive functions like learning and memory in the brain and possibly with umami. Org.Strategies and Tactics in Organic Synthesis Chiral auxiliaries and total synthesis L-CCG-I (L-carboxycyclopropylglycine-I) is a conformationally restrained analogue of L-glutamic acid (there are four possible stereoisomers of L-CCG). 6817 . 68. J. Chem. 2003. L-Glutamic acid is the most abundant excitatory neurotransmitter in our bodies.

few are capable of acting on a wide range of compounds.Strategies and Tactics in Organic Synthesis Enantioselective catalytic conjugate addition Much effort has been expended trying to develop enantioselective catalysts for conjugate addition. The system above gives excellent enantioselectivities for cyclohexenone but no selectivity for cyclopentenone . Whilst many are very successful for certain substrates.

Strategies and Tactics in Organic Synthesis Enantioselective radical conjugate addition Once stereoselective conjugate radical additions with auxiliaries had been developed. the enantioselective catalytic variant rapidly has been proposed. Most work in this area has been pioneered by Sibi C2 symmetry axis . The following chiral Lewis acid catalysed reaction.

b.d .c.3]-Sigmatropic rearrangements A class of pericyclic reactions whose stereochemical outcome is governed by the geometric requirements of the cyclic transition state. 4n + 2 electrons. The type of activation (thermal or photochemical) and the stereochemistry can often be predicted by the Woodward-Hoffmann rules which are based on the total number of electrons (those in the π-system + those of single bonds) involved in the rearrangement process: 4n electrons. depend on the nature of a. Absolute stereochemistry . is photochemically allowed from excited state.controlled by alkene / enolate geometry Both are potential stereogenic unit or prochiral. the migration thermally allowed. Many similarities to the aldol reaction.Strategies and Tactics in Organic Synthesis [3.Relative stereochemistry .3-diaxial interactions are minimised. Reactions generally proceed via a chair-like transition state in which 1.controlled by existing stereocentre (destroyed in rct).

3-diaxial interactions phenyl group is pseudo-equatorial.Strategies and Tactics in Organic Synthesis Cope rearrangement A very simple example of a substrate controlled [3.3]-sigmatropic rearrangement is the Cope rearrangement. This process is often called ‘chirality transfer’ . To minimise 1. Note: the original stereocentre is destroyed as the new centre is formed.

Strategies and Tactics in Organic Synthesis Claisen rearrangements One of the most useful sigmatropic rearrangements is the Claisen rearrangement and all it’s variants. . In blue the new formed C-C bond.

Strategies and Tactics in Organic Synthesis Enantioconvergent’ synthesis Both enantiomers of initial alcohol can be converted into the same enantiomer of product. This process (Eschenmoser-Claisen) shows the importance of alkene geometry in [3+3] sigmatropic rearrangement Same configuration .

the enolisation step controls the stereochemistry of the final product. therefore. As we have seen it is relatively easy to control enolate geometry and consequently the final stereochemistry .Strategies and Tactics in Organic Synthesis Ireland-Claisen reaction Enolate geometry controls relative stereochemistry.

the Ireland-Claisen rearrangement occurs with ‘chirality transfer’. the relative stereochemistry between the two new stereocentres is governed by the geometry of the enolate . Initial stereogenic centre governs the conformation of the chair-like transition state: Largest substituent will adopt the pseudo-equatorial position. Once again.Strategies and Tactics in Organic Synthesis Substrate control in Ireland-Claisen rearrangement In a similar fashion to the Cope rearrangement.

This synthesis utilises Enders' RAMP hydrazone as a chiral auxiliary to set up the quarternary centre. An application in the synthesis of (–)-Malyngolide is an antibiotic isolated from the blue-green marine algae Lyngbya majuscule. Tetrahedron 1996.Strategies and Tactics in Organic Synthesis Auxiliary controlled rearrangement in total synthesis The use of chiral and enantiopure auxiliaries it is possible to perform the rearrangement in enantioselective manner. 5805 Ender’s hydrazine . 52.

it could be argued that this is just a form of temporary auxiliary control! Enolate formation (enolate geometry) governs relative stereochemistry .Strategies and Tactics in Organic Synthesis Chiral reagent control in the Ireland-Claisen rearrangement It is possible to carry the reaction out under “reagent” control as in the case of chiral boroenolates. Although.

Strategies and Tactics in Organic Synthesis The use of a chiral reagent in total synthesis Dolabellatrienone is a marine diterpenoid isolated from gorgonian octocorals such as Eunicea calyculata and other marine organisms His enantioselective synthesis relies on boron enolate chemistry to establish the stereochemistry of the final molecule J. 118. 1996. Chem. Am. Soc. 1229 Via cis boroenolate .

In this case it is reasonable that the Lewis acid coordinates to the oxygen influencing the reactive conformation thus controlling enantioselectivity Coordination by Lewis acid .Strategies and Tactics in Organic Synthesis Chiral catalyst control in the Ireland-Claisen rearrangement It is also possible to perform the reactions under chiral catalyst control using for example chiral Lewis acids.

in turn.Strategies and Tactics in Organic Synthesis 2..). Transition state is under debate but it is reasonable the invoke a based on 'envelope' chair model Largest substituents adopt pseudo-equatorial position .3 Wittig rearrangement is useful for good 'chirality transfer'.3-Wittig rearrangement The 2.. Requires the formation of anion and. acidic proton (Z=electron withdrawing group) or metal-functional group exchange Driving force is stability of alkoxide (although other elements can be used.

3-Wittig rearrangement Reagent control utilising chiral boron reagent similarly to that seen in Ireland-Claisen rearrangement reactions.Strategies and Tactics in Organic Synthesis Enantioselectivity in the 2. Enammine can be used as anion and the use of chiral amine the reaction show significant enantioselection .

3]-aza-Wittig reaction in total synthesis Aza-Wittig rearrangement is less common. 51. 9741 Strained aziridine ring . Tetrahedron. 1995. The relief of ring-strain accelerates reaction.Strategies and Tactics in Organic Synthesis [2. AzaWittig rearrangement has been use in the total synthesis of indolizidine 209B from Dendrobates pumilio or the strawberry poison dart frog.

It is controlled by the ‘relative sizes’ of the π-orbitals in the LUMO & HOMO involved or on the value of their orbital coefficients. In the presence of a Lewis acid dienophile is polarised giving higher regioselectivity and a faster reaction .Strategies and Tactics in Organic Synthesis Stereoselective Diels-Alder reaction Diels-Alder (DA) reaction is incredibly valuable method for the synthesis of 6-rings and is highly regioselective.

remember that the dienophile invariably reacts from the less hindered face The ‘cube’ method is a nice way to visualise the relative stereochemistry .Strategies and Tactics in Organic Synthesis Endo vs exo selectivity Endo transition state and adduct is more sterically congested thus thermodynamically less stable but it is normally the predominant product. an effect called ‘secondary orbital overlap’. Finally. The reaction is suprafacial and the geometry of the diene and dienophile is preserved. The reason is endo transition state is stabilised by π orbital overlap of the group on C or D with the diene HOMO.

If we add a chiral auxiliary then there are two possible endo diastereoisomers.Strategies and Tactics in Organic Synthesis Chiral auxiliaries on the dienophile One diastereoisomer is formed . but one predominates. but mixture of enantiomers. thus we can prepare a single enantiomer No enantioselection Enantioselective version using a chiral auxilary .the endo product.

The rigidity of the chelate governs reactive conformationc (s-cis) and s-trans (s is referred to the double bond position in relation to carbonyl double bond).Strategies and Tactics in Organic Synthesis Origin of diastereoselectivity Coordination dienophile by the Lewis acid and its activation. For steric reason the s-trans is disfavoured. >The iso-Propyl group blocks bottom face of the double bond so the diene’s approaches from less hindered face and maximises secondary orbital overlap favouring the endo product .

Strategies and Tactics in Organic Synthesis Other auxiliaries can be utilised and most give good diastereoselectivities Camphor-derived auxiliary .

. Chem. 35.• (–)-Stenine is isolated from Stemona family of sub-shrubs (bush) is a constituent of a variety of Eastern folk medicines.Strategies and Tactics in Organic Synthesis It is possible to attach the chiral auxiliary to the diene as well Use of a chiral auxiliary in an intramolecular Diels-Alder reaction (IMDA). An example in the total synthesis of (–)-stenine. Engl. 1996. Ed. Int. Angew. 904 .

Bis(oxazoline) ligands (Box) are amongst the most versatile and well used ligands known. Simply prepared from amino alcohols (and hence amino acids).Strategies and Tactics in Organic Synthesis Chiral catalysis and the Diels-Alder reaction The fact the Diels-Alder reaction is mediated or catalysed by Lewis acids means enantioselective variants are readily carried out. utilised in enolate chemistry (aldol) reaction. Can be used in both DA and the equally useful HDA . The aluminium catalyst. is very effective also in this Diels-Alder reaction.

Strategies and Tactics in Organic Synthesis Catalytic enantioselective HDA in total synthesis (+)-Ambruticin is an antifungal agent extracted from the myxobacterium Polyangium Cellulsoum. 2001. it has shown activity against Coccidioides immitis the cause of coccidioimycosis Synthesis of (+)-ambruticin J. Soc. Am. 10772 . 123.Chem.

Strategies and Tactics in Organic Synthesis Stereoselective metal mediated reaction: The Heck reaction is a versatile method for the coupling sp2 hybridised centres .

Strategies and Tactics in Organic Synthesis Alkene isomerisation β-Hydride elimination is reversible. thus the double bond can ‘walk’ or migrate to give the most stable alkene. Only restriction is every step must be syn .

The silver salt accelerates the reaction and prevents alkene isomerisation .Strategies and Tactics in Organic Synthesis Enantioselective Heck reaction With the use of chiral ligands the Heck reaction can be enantioselective Intramolecular variant allows the construction of ring systems.

J. Soc. 10766 Review of asymmetric Heck: Chem. 2003. 2945 . 1996. Rev. 118. Am.Chem. The first total synthesis involved two Heck reactions.Strategies and Tactics in Organic Synthesis Enantioselective Heck reaction in total synthesis (+)-Xestoquinone was isolated from the Pacific sponge Xestospongia sapra and is a potent irreversible inhibitor of both the oncogenic protein tyrosine kinase pp60V-src encoded by the Rous sarcoma virus & the human epidermal growth factor kinase (EGF). the first is enantioselective to give a quaternary centre and the second gives a second 6-ring. 103.

Normally the components should be sp2 hybridised to avoid β-eliminations. .Strategies and Tactics in Organic Synthesis Suzuki-Miyuara reaction The Suzuki-Miyuara reaction is (normally) the palladium catalysed coupling of an alkenyl or aryl halide with an alkenyl or aryl boronic acid.

can be in a chiral situation. also hindered rotation. although they may be bidentate in ‘resting state’) via the phosphine . as in biphenyls. Two examples of chiral bisaryl compounds.Strategies and Tactics in Organic Synthesis Enantioselective biaryl formation Non only molecules that contain stereogenic units such stereocentres can be chiral. Both ligands are thought to be mono-dentate (in the active species at least.

epoxide etc. OCO2R.Strategies and Tactics in Organic Synthesis Enantioselective Pd catalysed allylic substitution Displacement of good leaving group (OAc. halide. The reaction does not occur by direct displacement but via a palladium η3 complex .) normally using soft nucleophile.

. diffuse charge) usually attack from opposite face to PdLn.Strategies and Tactics in Organic Synthesis Pd catalysed allylic substitution: Regio. Normally the nucleophile will add to the least hindered end of the allyl system.and stereoselectivity Palladium initially adds to the opposite face to the leaving group (although possible equilibrium). Soft nucleophiles (large.

Strategies and Tactics in Organic Synthesis Enantioselectivity Problem with inducing selectivity is that ligand is on opposite side to nucleophile. Bulky ligands can overcome this problem and to have stereogenic centre on the substrate or on the nucleophile. Stereocentre on the substrate Stereocentre on the nucloephile .

Chem. in cattle it causes symptons similar to mad cow disease (BSE) and hence plants named after the Spanish for crazy. Org. 2002. and immunoregulatory properties. On the desymmetrisation see also J. J.Strategies and Tactics in Organic Synthesis . 63. 4325. 67. 1339 desymmetrisation process . Allylic substitution in total synthesis (–)-Swainsonine can be isolated from locoweeds. antiviral. 1998. Chem. In humans it shows anticancer. Org.

The reaction involves desymmetrisation by selective reaction if one disubstituted alkene . An example of a chiral variant of the Schrock metathesis catalyst.Strategies and Tactics in Organic Synthesis Other catalytic enantioselective reactions There are now a huge number of enantioselective reactions with more being invented / developed all the time. It is highly unlikely that this research in this vast. It should be possible to develop enantioselective variants of most reactions – even those that do not initially look set-up for such chemistry. fascinating field will slow in the foreseeable future.

Strategies and Tactics in Organic Synthesis Summary of methods for stereoselective synthesis .

Justus von Liebig. Angew. Annalen der Chemie und Pharmacie 1860.. Berkessel. C. McNally. Chem. Because of their similarity in composition and description.Organocatalysis Strategies and Tactics in Organic Synthesis In organic chemistry. Organocatalysts which display secondary amine functionality can be described as performing either enamine catalysis (by forming catalytic quantities of an active enamine nucleophile) or iminium catalysis (by forming catalytic quantities of an activated iminium electrophile). Moisan. Ed . 107 (12): 5413–5883. Ed. 43. Vo. 2001. Weinheim: Wiley-VCH. the term Organocatalysis (a concatenation of the terms "organic" and "catalyst") refers to a form of catalysis. L. sulfur and other nonmetal elements found in organic compounds. "Enantioselective organocatalysis" Drug Discovery Today. 8-27. 113 . Asymmetric Organocatalysis. 2007. whereby the rate of a chemical reaction is increased by an organic catalyst referred to as an "organocatalyst" consisting of carbon. P. A. 40. N. Chem. C. B. review: "Asymmetric Organocatalytic Domino Reactions".C. M. simple organic acids have been used as catalyst for the modification of cellulose in water on multi-ton scale. D. Enders. 1570–1581. List. with acetaldehyde further identified as the first discovered pure "organocatalyst". Groeger. hydrogen. which act similarly to the then-named "ferments". This mechanism is typical for covalent organocatalysis. Int. Covalent binding of substrate normally requires high catalyst loading (for proline-catalysis typically 20-30 mol%). Chem. Gaunt. R. M. Noncovalent interactions such as hydrogenbonding facilitates low catalyst loadings (down to 0. There is no need for metal-based catalysis thus making a contribution to green chemistry. Rev. Angew. 246–247 . Int. Hüttl. In this context. (2007). Chem. Grondal. C. 3726 -3748 and Angew. I. 12(1/2). M. 2004. (2005). they are often mistaken as a misnomer for enzymes due to their comparable effects on reaction rates and forms of catalysis involved. 5138–5175.001 mol%). Justus von Liebig's synthesis of oxamide from dicyan and water represents the first organocatalytic reaction. 2007. When the organocatalyst is chiral an avenue is opened to asymmetric catalysis. H.T. 46. "Organocatalysis". Dalko. Int. Ed. A. for example the use of proline in aldol reactions.J. Organocatalysis offers several advantages. now known as enzymes. Johansson.

D.. derivatives of BINOL such as NOBIN. Chem. C. and organocatalysts based on thioureas S. Rev. 2178–2189 A certain class of imidazolidinone compounds (also called MacMillan organocatalysts) are suitable catalysts for many asymmetric reactions such as asymmetric DA reactions. MacMillan. K. Bertelsen.. Am. including TADDOLS. 4243-4244 . A. Borths. 38. 2009. C. Jørgensen.. The original such compound was derived from the biomolecule phenylalanine in two chemical steps (amidation with methylamine followed by condensation reaction with acetone) which leave the chirality intact Ahrendt. phenylalanine. Hydrogen bonding catalysts. J. certain oligopeptides. The cinchona alkaloids. W. A. 122. Synthetic catalysts derived from biomolecules. K. Soc. Secondary amines in general. Chem.Strategies and Tactics in Organic Synthesis CHIRAL ORGANOCATALYSIS Organocatalysts for asymmetric synthesis can be grouped in several classes: Biomolecules: notably proline. J. Soc. Soc 2000.

Strategies and Tactics in Organic Synthesis Regular achiral organocatalysts are based on nitrogen such as piperidine used in the Knoevenagel condensation.R. D. Thiazolium salts are employed in the Stetter reaction. 39. A pioneering reaction developed in the 1970s is called the Hajos-Parrish reaction: Z. DMAP used in esterfications and DABCO used in the Baylis-Hillman reaction. Org. 1974. Parrish J. 1615-1621 Baylis–Hillman reaction . These catalysts and reactions have a long history but current interest in organocatalysis is focused on asymmetric catalysis with chiral catalysts and this particular branch is called asymmetric organocatalysis or enantioselective organocatalysis . Hajos. G. Chem..

129. C. 39. 2006. 4955-4957 J. Lelais and D. Soc. This iminium activation is similar to activation of carbonyl groups by a Lewis acid and both catalysts lower the substrates LUMO. Chem. MacMillan Aldrichimica Acta .Strategies and Tactics in Organic Synthesis This catalyst works by forming a iminium ion with carbonyl groups of α. Am. W. 2007. 79 Angew.42. Chem. G. Int. 2003.β-unsaturated aldehydes (enals) and enones in a rapid chemical equilibrium. 3. Ed. 15438-15439 .

Strategies and Tactics in Organic Synthesis Organocatalytic hydrogenation A recent development is the use of small organic molecules to achieve hydrogenation • Inspire by nature • Based on the formation of a highly reactive iminium ion (this is the basis of many organocatalytic reactions) .

2002.Strategies and Tactics in Organic Synthesis Organocatalytic epoxidations As with most chemical reactions. 4599 . Org. 67. Most are based on the in situ conversion of ketones to the active. epoxidation has seen a move towards ‘greener’ chemistry and the use of catalytic systems that do not involve transition metals A number of systems exist. J. Chem. a blood pressure reducing agent. that actually performs the epoxidation Dioxirane. epoxidation reagent Tanabe Seiyaku Co. utilise organocatalysis in the synthesis of diltiazem-L®. dioxirane species. notably the catalysts of Shi & Armstrong.

Chem.Strategies and Tactics in Organic Synthesis Organocatalytic epoxidations in the industrial synthesis of Diltiazen-L® by Tanabe Seiyaku Co. M. . J. Seki. Hatsuda and M. 4599 Cat. T. Furutani. 2002. 67. a blood pressure reducing agent. Org. Imashiro. R.

Clean. green and effective . tartaric acid. Catalyst derived from simple nature product. intramolecular hydrogen bond organises Catalyst.Strategies and Tactics in Organic Synthesis Lewis acid organocatalysis Intermolecular hydrogen bond acts as a Lewis acid and activates carbonyl.

Enone is activated by formation of the charged iminium species The catalyst also blocks one face of the enone allowing selective attack .Strategies and Tactics in Organic Synthesis Organocatalysis in Michael addition New small molecule organic catalysts are now achieving remarkable results.

Strategies and Tactics in Organic Synthesis Organocatalysis in Michael addition: electronrich aromatic ring can be emploied in Michael addition .

Strategies and Tactics in Organic Synthesis Organocatalysis in Michael addition An interesting reaction is the Stetter reaction .this is the conjugate addition of an acyl group onto an activated alkene and proceeds via Umpolung chemistry (the reversal of polarity of the carbonyl group) .

Strategies and Tactics in Organic Synthesis Organocatalysis in Michael addition The thio(urea) moiety acts as a Lewis acid via two hydrogen bonds The amine both activates the nucleophile and positions it to allow good selectivity .

Austin.Strategies and Tactics in Organic Synthesis Organocatalysis in Michael addition Beautiful example of enantioselective conjugate addition in total synthesis. Christopher J. From the synthesis of a marine alkaloid from the Bryozoa. Wen-Jing Xiao. Sinz. C. 5482 . 101. and David W. Flustra foliacea by Joel F. PNAS 2004. Sung-Gon Kim. MacMillan.

Strategies and Tactics in Organic Synthesis Catalysis in total synthesis (R)-Muscone is the primary contributor to the odour of musk. Soc. synthetic version is used in perfumes. 1593 (R)-Muscone . 115. Am. a glandular secretion of the musk deer.1993.. Chem. J. •A racemic.

This charged species lowers the energy of the LUMO thus catalysing the reaction In addition one face of dienophile is blocked thus allowing the high selectivity Application tio the total synthesis of the marine metabolite solanapyrone D. a phytotoxic polyketide isolated from thefungus Altenaria solani .Strategies and Tactics in Organic Synthesis Organocatalysis and the Diels-Alder reaction Organic secondary amines can catalyse certain Diels-Alder reactions. The reaction proceeds via the formation of an iminium species.

. The amine catalyst acts as a Lewis acid via two hydrogen bonds Tf= CF3SO2 Another hetero-Diels-Alder reaction.Strategies and Tactics in Organic Synthesis An example of a hetero-Diels-Alder reaction The aldehyde is the dienophile and the counterpart is a very electron rich diene.. It looks very similar to the previous reaction but.It is believed that only one hydrogen bond coordinates the aldehyde and the other is used to form a rigid chiral environment for the reaction .

Interaction with atoms and with molecules Photophysical processes Photochemistry: Photochemical processes Organic photostimulated reactions: Dissociation into radicals Dissociation into ions or “internal” electron transfer Intramolecular rearrangement Photoisomerization Hydrogen atom abstraction Photodimerization or photoaddition Photosensitized reactions Photoionisation reactions Miscellaneous reactions Photoreactivity of aromatic compounds Photochemistry of diazo.and azido compounds Photocleavable protecting groups Photopolimerization Chemoluminescence 4. . Technical and experimental aspects. interaction of light with the matter and photostimulated processes.Organic Photochemistry Introduction: Photophysics.

2) Electrons in the excited state are in high energy molecular orbitals. thus specific reactions for specific functionalities are possible . so they are more prone to react in comparison to that in bounding orbitals 3) Different type of excited states are possible with different chemical behavior 4) Electrons of different finctionalities can be excited by simple selecting the light energy.Organic Photochemistry Thermally stimulated reactions A + B ∆ heat A B ‡ transition state products Photochemically stimulated reactions products A + hν ( A )* exited state B products Differences between thermally and photochemically stimulated reactions: 1) Excited state has usually higher energy than transition state.

Organic Photochemistry .

Organic Photochemistry .

Organic Photochemistry The energy of light does not match with the difference in energy between occupied and unoccupied atomic orbitals or occupied bonding and unoccupied antibonding molecular orbitals.e. i. . The light is reflected or refracted by the matter and these phenomena are governed by the laws of classic optical physics. there is no absorption of light by the matter. sen i = c1/c2 sen r c1/c2=n21 refraction index .

Organic Photochemistry Irf/I0=(n21-1/ n21+1) 2 .

1s different from 0 or ∞ 0 means no interaction of light with electrons. In this case the energy is called resonant with the frequencies at which electrons oscillate in bonds and around nuclei.e. Typically these frequencies fall in the range of 10 15-1016 s-1 i. which occurs at 121. 200-700nm (visible and ultraviolet region). 3d 2s and 2p Prerequisites for absorption and emission 1) The electronic transition between orbitals must generate (absorption) or destroy (emission) a node 2) The transition moment must a determined value i. ∞ means ionization process and not transition between orbitals. .e. This process is pictured for a hydrogen atom for a transition of an electron from a 1s orbital to a 2p orbital. 3p.Organic Photochemistry: photophysics processes Interaction of light with atoms The energy of light matches with the energy gap between bonding and antibonding molecular orbital or atomic orbitals.6 nm 3s. The interaction in such a case forces the electron to oscillate resonantly with the electromagnetic radiation and its motion describes an orbital at higher energy.

2nm light H bond axis π -like molecular orbital one node σ molecular hydrogen orbital bond axis no node hν: 110.Organic Photochemistry Interaction with molecules direction of light propagation parallel to molecular axis E σ molecular hydrogen orbital no node hν: 121.9nm σ∗ molecular orbital one node direction of light propagation perpendicular to molecular axis E light H photophysics .

fluorescence S1 kF kIC S0 T1 kP electron jump ψ electron jump and spin flip hν.Organic Photochemistry Possible transition ground state hν electron jump Possible processes singlet reaction intersystem crossing excited state spin allowed absorption singlet (spins paired) hν singlet (spins paired) ψ* S1 k RS kST triplet reaction kRT ψ* T1 ψ electron jump and spin flip spin forbidden absorption ψ S0 ψ* singlet-singlet absorption fluorescence internal conversion intersystem crossing singlet (spins paired) triplet (spins parallel) hν. The arrows indicate electrons and the spin orientation. wavy arrows indicate photons singlet-triplet absorption phosphorescence S0 State energy diagram photophysics . phosphorescence Energy level description of absorption and emission.

Under this description. in molecules atoms in a bond vibrate from their equilibrium position. thus the ground electronic state is splitted into vibrational modes Bonds are usually described as spring connection atoms. the bond energy is related to spring force k by Hooke law E= 1/2kr2 photophysics .Organic Photochemistry Vibrational level Differently from single atoms.

Organic Photochemistry Vibrational level Eυ = hν (ν +1/2) Lennard-Jones curve for real molecule photophysics .

which is very fast. negligible movement of atoms from their equilibrium position is observed .Organic Photochemistry Absorption bands Ground and excited state Lennard-Jones curve photophysics Intensity of absorption band follows the Franck-Condon principle which states: The electronic transition starts from the lowest ν0 vibration state and the intensity is related to the sign and value of the function describing the vibrational state in the ground state and the arriving vibrational mode in the excited state. The transitions are describe by vertical lines and this because during the transition.

Organic Photochemistry Radiative relaxing processes From the excited state: Fluorescence and phosphorescence Radiative processes occur from The lowest vibrational state of the excite state: Kasha rule Vibrational modes photophysics .

Organic Photochemistry Absorption and emission band structure and energy In atoms absorption and emission bands have the same energy since only atomic orbital are involved. the emission is at lower energy with respect to absorption E absorption E emission a Atoms hν λ E λ distint vibrational states in molecules b hν absorption absorption emission λ emission E absorption emission unresolted vibrational states in molecules c hν absorption emission λ a: sharp line absorption and emission spectrum typical of atoms at low pressure vapor phase b:broad-band absorption and emission spectrum typical of certain rigid molecule at low pressure vapor phase with resolted vibrational bands c:broad-band absorption and emission spectrum typical of molecule in solution with unresolted vibrational bands photophysics . In molecules due to the presence of vibrational modes and to Kasha rule.

Organic Photochemistry Time scale of photophysical processes photophysics .

Organic Photochemistry More important Photophysical processes photophysics .

Organic Photochemistry Exctited states and photophysical transitions between these states in a "typical" organic molecule 2nd excited singlet state 1st excited singlet state S2ν S2 state IC2 S1ν 1st excited triplet state e 2 n d ex cited s inglet gle t Jablonski Diagram IC1 S1 ISC1 T1ν S0ν' absorp tion to exc ited sin stat to 1 s t S0ν T1 flu es or tion ISC2 ce en e sc or ph os ph ce quantized r rotational level abs orp n ce quantized ν vibrational level S0 ground state S0 Jablonski Diagram: solid lines are radiative transition. ISC: intersystem crossing photophysics . horizontal IC: internal conversion. wave lines are radiationless processes: vertical are vibratioan and rotational relaxation processes.

Organic Photochemistry: photochemical processes Photophysical radiative process (fluorescence and phosphorescence) rates span from 10-15 to 1 sec. so only ultrafast reactions can be observed from singlet states. Fast chemical reaction can be competitive with radiative process from triplet states .

Organic Photochemistry: photochemical processes The first law of photochemistry formulated by Grotthus (1817) and Draper (1843) in the early nineteenth century: Only the light which is absorbed by a molecule can be effective in producing photochemical change in the molecule. As an example in radical halogenation of alkane the primary process is the halogen-halogen bond fission and the subsequent radical halogenation of alkane occurs without light so in the dark. In this case the quantum yield is>1 photochemistry . that is ∑φi= 1. One halogen molecule bond fission produce many halogenated alkane molecules. A + hν → B Φ = Molecules of B formed x unit of volume x unit time/quanta absorbed by A x unit of volume x unit time Under the validity of photochemistry law proposed by Stark-Bodenstain it is possible to correlate the absorption of light to the characteristics of any absorbing material. where φi is the quantum yield of the ith primary process. so that the sum of all primary process quantum yields φ must be unity. This law was then reformulated by Stark (1908-1912) and Einstein (1912-1913):The absorption of light by a molecule is a one-quantum process. This is well expressed by the BeerLambert law T= I/I0 = 10-εcl A= -log I/I0 = εcl Secondary chemical processes are all those started by the intermediates produced in the primary process.

Organic Photochemistry: photochemical processes ENERGETIC CONSIDERATIONS kcal/mol S1 110 T1 bond energy O-H ultraviolet 300nm 90 C-H 80 75 C-C C-Cl 60 C-Br 400nm ketones 80 70 UV Lamps violet Sun Light visible C-I 700nm O-O 40 electronic excitation vibrational excitation C-H streching C=O streching photochemistry 10 5 red infrared 3000 nm 6000 nm .

or + "External" electron transfer D ABC+ or -+ AB+ or .or + photochemistry "Internal" electron transfer .+ C.Organic Photochemistry PRIMARY PHOTOCHEMICAL PROCESSES AB + C ACB ABC' (S1) or ABC' (T1) R-H Dissociation into radicals Intramolecular rearrangement ABC' (S0) Photoisomerization (ABCH) + R (ABC)2 ABC + products ABC+ + e- Hydrogen abstraction Photodimerization (photoaddition) ABC (S1) or ABC (T1) ABC D Photosensitized reactions Photoionization D.

HCl N-OH ON H NO H . + Cl. + X.Organic Photochemistry Dissociation into radicals ABC (S1 or T1) → AB. while the nitrosil and chloro radicals photogenerated from excited NOCl are industrially used for transforming cyclohexane into cyclohenanoneoxima.. + O. chloro-chloro or bromo-bromo bond can be homolitically broken by irradiation with mercury or tungsten lamps and the generated halogen radicals are exploited in the halogenation of alkanes. [NOCl]* → NO. a precursor of e-caprolactam NO-Cl hν H NO + Cl H . X =Cl or Br [NO2]* → NO. .C [X-X]* → X.

ca 100% d. solid state reaction O Me R S CN O O Ph hν -C=O Ph Ph 1) hν 2) α-cleav.>95% . while in aromatic ketones. . diphenylindanone Enanthioselective Norrish I. . This process is less common in solution chemistry where hydrogen atom abstraction is usually the predominant process. R.Organic Photochemistry Dissociation into radicals Photochemical behavior of carbonyl compounds Ketones and aldehydes show two principal electronic transitions n→π* (excitation of an electron from oxygen nonbonding orbitals to antibonding π* orbital) in the 280-330 nm range and π→π* transition (excitation of an electron from π bonding orbital to antibonding π* orbital) usually below 250 nm.e. known as Norrish Type I cleavage reaction 2) Norrish Type II photoelimination reaction The Norrish Type I reaction dominates gas phase photochemistry of many aldehydes and ketones and is an homolitic carbon-carbonyl bond scission affording acyl radical and alkyl radical. R-CO-R’ + hν→ R CO-R’ or R’.CO-R → R-R’ + C=O R. The acyl radical collapses into carbon monoxide and alkyl radical.e. . this latter reacts with another alkyl radical (generated in the first step) to give hydrocarbons. Aromatic ketones are often used as excellent triplet sensitizers. Singlet excited state photochemistry is generally observed in aliphatic aldehydes or ketones. 3) -CO Me Me Ph MeO2C C CN Ph MeO2C R R CN Ph MeO2C Ph Ph Ph enantiopure e. Ph R-CHO + hν→ → + C=O + →R-H . There are two main photochemical pathways from an excited carbonyl function: 1) α-cleavage reaction.CO-H H. such as benzophenone or acetophenone. triplet states are involved. The n→π* transitions (~300 nm) are the more convenient to stimulate a photochemical reaction.

Organic Photochemistry Dissociation into radicals Norrish Type II photoelimination reaction : formation of aldehydes and alkenes R2CH-CR2CR2-CHO + hν → R2C=CR2 + CR2=CH-OH→ CR2H-CHO R2CH-CR2CR2-CO-R + hν → R2C=CR2 + CR2=CR-OH→ CR2H-CO-R Examples in cyclic ketones O hν O H O H O Si(Me)3 hν MeOH O H Si(Me)3 .

Photochemistry of Anhydrides R2CH-CO-O-CO-R' hν hν R2CHCO2 + . anhydrides give carboxylic acids. CO and CO2. hydrocarbons. CO-R' CO2 + R2CH-R' + CO R2C=C=O + R2CHCO2H . In the case of carboxylic acids the main products are hydrocarbons. ketenes and CO2 while esters afford alcohols. CO and CO2. It must be made clear that these processes occur employing high energy radiation so that normally they are absent or negligible in almost all photochemical reactions. R'-R' CO2 + R-R'. . + R' . Photochemistry of Esters R CO-O-R' hν hν R + CO-O-R' R CO-O .Organic Photochemistry Dissociation into radicals The a-cleavage reaction occurs also in other carbonyl compounds such as carboxylic acids. R'-R' . Photochemistry of Carboxylic acids hν hν R CO-O-H R + CO-O-H R CO-O . anhydrides and esters by irradiation around 220nm. + H . CO2 + R-R'. . CO2 + R-H CO2 + R-H . R-R. R-R. .

If φ is known the intensity of incident light Io can be evaluated . the photogenerated oxene inserts itself into the C-H benzylic bond. the 2nitro-benzaldehyde (NBA) is transformed into 2-nitrosobenzoyc acid by irradiation at 350-400nm with 0. To avoid the use of nitromethane or nitroethane as photoreaction solvent. differently aromatic nitro derivatives are transformed into nitroso compounds loosing an atom of oxygen (oxene) when irradiated at 350-400 nm. By plotting [NBA] against time a straight line is usually obtained with k0 slope and therefore it is possible to evaluate the intensity of incident light . If the concentration of NBA (called actinometric compound) and the optical pathway of the exposed sample cell are sufficiently high to make the reaction rate approximately of zero order.Organic Photochemistry Dissociation into radicals More attention must be devoted to molecules containing particular functional groups: E.g.5 quantum yield. thus plotting [Act] vs a line is usually obtained with ko slope. Alkylnitro compounds decompose into alkyl radical and nitrosyl radical (. the intensity of incident light is inversely proportional to the quantum yield (I0 = k0/φ).NO2) or nitrous acid and alkenes. diazo compounds decompose when irradiated at 320nm into carbenes loosing nitrogen (shown later). This latter photochemical process has been exploited in developing a new photolabile protecting group for carbonyl compounds and alcohols (shown later) and to measure (actinometry) the intensity of incident light on the photochemical system. When benzylic hydrogens are present in substituents in the ortho position to the nitro group.(in the range of 350-400nm) O H NBA hν - d[Act] dt = I0 φ f I0= light intensity φ=quantum yield f=fraction of absorbed light [Act]= concentration of NBA NO2 f= (I0-I)/I0 or =1-I/I0 where I=absorbed light from Lambert-Beer Law log(I0/I)=εl[Act] x 1/φ x 1/(1-10-εl[Act]) O O-H NO f = 1-10-εl[Act]. thus Io= - d[Act] dt under the zero order condition Io=ko/φ. For example.

Organic Photochemistry Dissociation into ions or “internal” electron transfer ABC (S1 or T1) → AB+ . R'=R"=N(Me)2 Crystal violet leucocianide. variation of absorbing properties is observed in these processes. This phenomenon is called Photochromism 1) heterolitic bond scission with production of cations and anions: Other photochromic systems: spiropyran–merocyanine dyes hν1 R R CN R' hν R' O CN polar solvents N colorless hν 2 O N colored R" R" Malachite green leucocianide.CTwo possible pathways can be active: 1) heterolitic bond scission with production of cations and anions: Any possible reaction is related to the electrophilic or nucleophilic nature of photogenerated ions 2) Internal electron transfer without bond scission. R=H. Generally. R= R'=R"=N(Me)2 Used in photochromatic lenses or optical memories . A typical example of the first type is observed in photolysis of leucocynides (triphenylacetonitriles such as Malachite Green or Crystal violet) in polar solvent where this scission produces triphenylmethyl carbocations and cyanide.

from the excited S1 state of an olefin two possible pathways can be followed namely a true internal electron transfer giving a zwitterionic excited state (indicated by Z) or the expulsion of an electron affording a radical cation (termed as D±). In detail. Both these excited states. This process is observed in olefins. .Organic Photochemistry Dissociation into ions or “internal” electron transfer 2) Internal electron transfer without bond scission. The zwitterionic excited state can subsequently collapse into a radical cation by expulsion of an electron. can react with nucleophiles or electrophiles eventually present in the reaction medium zwitterionic excited state Z hν S1 Rydberg States + eD± radical cation excited state D± state needs the presence of electron accepting molecules. called Rydberg states.

Organic Photochemistry 2) Internal electron transfer without bond scission. R R hν R R Z R strained trans cycloalkenes R ROH R'O R + R'O - R carbonium ion addition product R H H Ar products from alkyl and hydride migration -H R" + R CH CH hν Ar CH CH R hν R'OH R'O R'OH R Ar CH CH 2 R R H skeleton rearrangement More stable zwitteronic excited state .

Ph hν Ph Ph ROH Ph OR RO Ph - Ph Ph Ph H Ph H RO- Ph Ph H 50% Ph H 30% OR Ph hν. ROH Ph-CO-Me Ph OR via zwitterionic excited state Z Ph Ph hν. ROH Ph-CO-Me no addition product is formed H .Organic Photochemistry 2) Internal electron transfer without bond scission.

where q is an integer. q=1) by a disrotatory process while conjugated hexatrienes (6 electrons involved 4q+2. the excited state evolves by bond formation or breaking followed by internal rearrangement of the molecular skeleton. Rule 2: photochemical electrocyclic reactions proceed via disrotatory pathways when the number of interacting electrons in the cyclic array is 4q. i. This process is generally observed in conjugated polyunsaturated systems and regulated by Woodward-Hoffman rules. Conjugated dienes give cyclobutanes (4 electrons involved = 4q. Electrocyclic reactions and sigmatropic rearrangements represent typical examples of this process. In conjugated polyenes a photochemically stimulated electrocyclic reaction starts from their excited states.e. The process occurs stereospecifically and determines the observed stereochemistry in the final cycloadducts. When the electrocyclic reaction represents the primary photochemical process.Organic Photochemistry Intramolecular rearrangement: ABC (S1 or T1) → ACB. the following selection rules generally hold: Rule1: The stereochemical pathway of photochemical electrocyclic ring opening is the same as for ring closure. q=1) give cyclohexadienes by a conrotatory process excited diene π*orbital hν trans-trans disrotatory ring closure photochemically allowed excited triene π*orbital hν trans cyclobutene trans-cis-trans conrotatory ring closure photochemically allowed trans cyclohexadiene . In this process. Rule 3: photochemical electrocyclic reactions proceed via conrotatory pathways when the number of interacting electrons in the cyclic array is 4q+2 (q is an integer).

Organic Photochemistry Intramolecular rearrangement: Electrocyclic reactions Disrotatory ring closure: synthesis of Dewar benzene O O O O O O Pb(OAc)4 Dewar Benzene hν HO HO ∆ Provitamine D3 Conrotatory ring opening: synthesis of provitamine D3 HO Vitamine D3 .

5] hydrogen sigmatropic shift hν [1. the migration via supra-antara with inversion is allowed from the excited state (supra-supra .7] hydrogen sigmatropic shift H H H C 6 electrons supra-antara 8 electrons supra-supra hν H . thermally allowed).3 shift H H CN H1 H R hν H H H1 H R CN hν [1.Organic Photochemistry Intramolecular rearrangement: sigmatropic rearrangements These rearrangements or sigmatropic shifts involve a migration of a group or p-bond across an adjacent p-system. 4n + 2 electrons.3] supra-supra hydrogen or alkyl migration with retention retention 4 electrons supra 1. thermally allowed). [1. the migration via supra-supra with retention is photochemically allowed from excited state (supra-antara. The type of activation (thermal or photochemical) and the stereochemistry can often be predicted by the Woodward-Hoffmann rules which are based on the total number of electrons (those in the p-system + those of single bonds) involved in the rearrangement process: 4n electrons.

C(Ph)2 Ar R [1. Zimmermann in the late sixties) where the migration of different groups from hydrogen is observed. This rearrangement is observed in 4.2]-sigmatropic rearrangement [1.4-disubstituted cyclohexenones or related derivatives and generally occurs with high stereospecificity.Organic Photochemistry Intramolecular rearrangement: sigmatropic rearrangements Other examples: [1.2]-sigmatropic rearrangement in alicyclic compounds Ph Ph Ph hν Ph H hν. CH2Cl2 Ph Ph CO2Me CO2Me COOMe COOMe Ph Ph Ph CO2Me Ph CO2Me Ph N PhCO-Me Ph Ph N O-COPh O-COPh Ph Ph mechamism of migration Ph . O 1 2 3 O hν antara with inversion 5 4 3 mechamism of migration X hν X migration mechamism O 2 Ar Ar X 5 4 R R R R R R=alkyl R Ar Ar X= O.2] sigmatropic rearrangement (also known as di-π-methane rearrangement or Aza-di-π-methane rearrangements discovered by H.

A classical photoisomeration reaction occurs in the photochemical cis-trans interconversion of alkenes. The composition of this photostationary state is correlated to the absorption properties of the two isomers.Organic Photochemistry Photoisomerization: ABC (S1 or T1) → ABC’ (S1 or T1) → ABC’ Excited molecules undergo internal rearrangements without any bond scission and produce a new spatial disposition of molecular constituting units.e. by the equation [trans]s [cis]s = εcis Φ cis εtrans Φtrans trans cis Generally εtrans > εcis and. This state is referred to as p (perpendicular) geometry and its energy is settled at a minimum between that for singlet and triplet excited states b a cis b a hν b a p geometry b a hν b a trans a b H Ph Ph hν H H Ph p geometry Ph H hν H Ph Ph H cis stilbene trans stilbene . a photochemical steady state is established between the cis and trans isomers and this is usually more enriched in the cis isomer than that in the ground state. cis→trans and trans→cis quantum yields and the εcis and εtrans extinction coefficients. This generally requires short wavelength irradiation extending to about 200 –210 nm. The double bond isomerization is believed to involve an excited state where the two sp2 carbons are twisted 90° with respect to their position in the ground state. i. On irradiation. the concentration [cis]s > [trans]s. The formation of the lowest excited singlet state of simple alkenes arises from the allowed π-π* transition. assuming the quantum yield of cis→trans ≈ trans→cis.

green and red components of white light enabling color vision H3C CH3 CH3 hν H3C CH3 CH3 H N CH3 11-cis retinal CH3 H N 11-trans retinal opsine opsine hν RODOPSINE visual signal 11-cis retinal + opsine isomerasi 11-trans retinal + opsine .Organic Photochemistry Photoisomerization: The cis → trans isomerization plays an important role in vision processes where light promotes the transformation of cis retinal into trans retinal bonded to a lysine residue of opsine by an imine function. The adduct retinal-opsine is called rodopsine and three different rodopsines are present in the rods of the retina which absorb the blue.

the cis isomer can be reconverted to the trans isomer or undergoes fragmentation with production of radicals which further evolve.e up to 53% R OOC * COOR * chiral sensitizer Photoisomerization in azo derivatives Azo group is another unsaturated system that undergoes photochemically induced trans-cis isomerization. R R N N ∆ R trans azo derivative hν N N R R cis azo derivative -N2 hν N N ∆ Ph2CO N N via triplet excited state ∆ R N2 + R2 N N N R R N + via singlet excited state .Organic Photochemistry Photoisomerization: enantioselective process hν chiral sensitizer R*OOC H H + H COOR* H e. for example trans diarylazo compounds absorb in the visible region (coloured compounds) while the cis in the UV (white compounds). Dramatic changes in absorption properties occurs during this isomerization. into hydrocarbons. losing nitrogen. By thermal treatments.

Their subsequent thermal or photochemical rearrangements afford rearranged isomers of the starting heterocycle R h r∆ νo X 3 [1.3] shift overall process hν sh ift Aromatic heterocycles undergo electrocyclic photorearrangements that may be unified under two common primary processes that convert the excited singlet states into: bicyclic isomers via 4q electrocyclic reaction or a cyclopropene derivative via a [1. while isoxazoles to oxazoles under irradiation H R S R R hν N S R N O R or H N or S R S N O H O O R .3] shift.3] X R electrocyclic process [4e] R [1. t hif s ] X cyclopropenylcarbonyl derivative R hν For example 2-substituted thiophenes isomerize to 3-substituted ones.Organic Photochemistry Photoisomerization: hν or ∆ electrocyclic process [4e] R X Dewar like structure hν X R [1 .

trans/cis isomerization HH cis stilbene trans stilbene electrocyclic reaction oxidation O2/J2 phenantrene H H dihydro-phenantrene -H2 Application to the synthesis of hexaelicene hν O2/J2 hexaelicene .Organic Photochemistry Photoisomerization: Photoisomerizations followed by oxidation: Synthesis of Helicenes.

the diradical intermediate can be singlet or triplet in nature and this reflects on the timing of cyclobutane ring formation: very fast from singlet. slow from triplet singlet or triplet carbonyl excited state hydrogen migration from γ position O H R H OH R H H hν H O R H H O singlet or triplet carbonyl excited state hydrogen migration from γ position H H hν R O HO R H radical coupling R 1. Depending on the multiplicity of the excited state (singlet or triplet) and on the efficiency of intersystem crossing (from singlet to triplet). This reaction is quite common with carbonyl compounds where both singlet and triplet excited states show diradical character and are able to abstract hydrogen atoms either intramolecularly or intermolecularly from molecules possessing weak R-H bonds (called hydrogen donors).4-diradical intermediate cyclobutanols H H R OH R OH R OH R OH cyclobutanols cyclohexanols . Intramolecular hydrogen abstraction with the formation of cyclocarbinols (Yang reaction) The intramolecular hydrogen abstraction is very common when hydrogens are present at the g position to form a diradical intermediate which evolves into cyclobutanols via intramolecular coupling of radical centres. the generated radical species are responsible for the observed chemical reactions. After the hydrogen abstraction step.Organic Photochemistry Hydrogen atom abstraction ABC (S1 o T1) + R-H→ ABC-H + R. From molecular singlet or triplet excited states hydrogen atom abstraction reaction can be observed.

Organic Photochemistry Intramolecular hydrogen atom abstraction An interesting example of this reaction is reported in stereoid chemistry where a angular methyl is involved in the hydrogen abstraction process which becomes included in a cyclobutane ring.γ-unsaturared esters. The structure of carbonyl compounds strongly influence the course of reaction. The carbonyl group of ester function can be involved in hydrogen abstraction. In the following example the migration of the double bond is observed after hydrogen abstraction affording β. In special cases the fragmentation of the molecule represents the main process as in the formation of α-cyclopropyloxyacephenone or decaline derivatives R OEt OEt OEt OEt R O CH3 hν diradical intermediate pregnan-11-one HO CH2 O H hν OH OH O R HO H2C O Ph H O hν Ph diradical intemediate O Ph OH O unstable enol OH Ph diradical intermediate unstable enol O + Ph O H hν Ph OH O + diradical intemediate Ph .

For example the irradiation of cyclodecalone at 254nm affords the isomeric decanols.Organic Photochemistry Intramolecular hydrogen atom abstraction: other examples O hν OH OH H H H 42% + H 10% In cyclic ketones. respectively in 42 and 10% yields O O H S O N O O O S hν OH O O S N OH O N COOMe O The hydrogen abstraction can occur also at 4 and more carbon atoms far from the carbonyl oxygen atom. In this latter case fused polycyclic derivatives and macrocycles (up to 14membered rings) can be obtained. ftalimido and β-lactam derivatives COOMe COOMe diradical penicillin derivative (β-lactam) O N O H S CH2 hν O N O diradical S CH2 R 80% HO O N CH2S 9-membered ring R R O CO(CH2)5 H O hν O CO(CH2)5 OH diradical O CO(CH2)5 OH 14-membered ring . Significant examples of these type are reported in the field of steroid. the hydrogens in the γ position are physically inaccessible to the carbonyl oxygen thus the abstraction occurs across the ring from a carbon which results in close proximity to the excited carbonyl function.

The Si face of carbonyl is less HO Si face favoured by steric interaction with N benzoisoxazole moiety of the chiral N Re face Re face template O O steric intraction N H N H H H O N N O N O O N O N COOMe O hν OH H N COOMe O OH N COOMe O If the Norrish type II and Yang reaction are not allowed for structural reasons. a photoreduction of the carbonyl function can be observed.Organic Photochemistry Stereoselective intramolecular hydrogen atom abstraction HN HO Ph HO Ph O hν H S Ph OH R H HO Ph R S + N exo adduct HN O N N HN toluene N HN Hydrogen abstraction can also be H HO Ph performed a stereoselective manner. The strong hydrogen bonding endo adduct between the substrate and a chiral origin of stereoselection template forces the ring closure at the endo with respect to exo with respect to diradical species to occur from the Re Ph Ph face of carbonyl function and cyclic urea exo adduct endo adduct OH ring. as in the case of phtalimmido derivative of valine. . For H HO Ph O O S example the enantioselective hydrogen yields up to 80% S S S + abstraction at the δ in cyclic urea affords e.e up to 60% N HN N HN exo/endo up to 4:1 via a Norrish-Yang cyclization bicyclic derivatives in good enantio and diastereo O O selection.

the intramolecular hydrogen abstraction can involve the methyl group producing a diene intermediate (via photogenerated diradical) which can be involved in Diels-Alder [4+2]-cycloaddition reaction acetilenic dienophiles to produce dihydronaphtalene derivatives CH2 O Ph H CH2 OH Ph diradical CH2 OH Ph unstable enol diene trapped by Diels-Alder reaction EtOOC COOEt COOEt COOEt HO Ph . particular cases In some particular (substituted compounds) for example ortho-methyl benzophenones.Organic Photochemistry Intramolecular hydrogen atom abstraction.

In this case the presence of good hydrogen donor molecules is needed or molecules with X-H bond energy lower than the energy of carbonyl excited states (exothermic reaction). aromatic C-H bonds and O-H of aliphatic alcohols is too high to be used as hydrogen donors triplet state O π* OH H X +X RCH2O endothermic reaction RCH2 OH O n π* ∆H>0 ∆H<0 70-75 kcal/mol exothermic reaction R3Sn Qualitative comparison of the energetics for hydrogen abstraction from different hydrogen donors by triplet state of alkyl or aryl ketones . A n→π* electronic transition is of about 70-75 kcal/mole thus suitable hydrogen donors are tertiary C-H in the isopropanol.Organic Photochemistry Intermolecular hydrogen atom abstraction Hydrogen abstraction occurs also intermolecularly. O-H bond of phenols and Sn-H bond in tin hydrides. The energy of aliphatic C-H.

The reaction is completely inhibited in the presence of catalytic amounts of triplet quencher such as naphthalene Ph N Ph O Ph N O IPA OH N hν IPA Ph O Ph N Me Ph NH + Me Ph OH HN Ph NH Aromatic aldimines undergo a similar photoreductive dimerization reaction. The benzopinacol is produced by coupling of two α-hydroxy radicals produced in the hydrogen abstraction step.Organic Photochemistry Intermolecular hydrogen atom abstraction O Ph hν Me O Ph Ph H Me OH OH Ph Ph Ph isopropanol Ph HO Ph Ph OH Ph dimerization Ph C N R H hν Ph2C=O H-Donor Ph Ph C N R + H Ph H H Ph C N R H Ph C N R H 95% OH Ph Ph H H O + Ph C N R T1: tripket excited state with diradical behavior A didactic example of this reaction is the photoreductive dimerization of benzophenone to benzopinacol where the reaction is performed in isopropanol as solvent and as hydrogen donor. As an example phenylazobenzene and nitrobenzene respectively undergo reduction to hydrazines and primary amines .2diamino derivative obtained generally in high yields. In this case the final product is a 1. Isopropanol is used both as hydrogen source and solvent. N hν Me H OH Ph N H + Me Isopropanol (IPA) is used as hydrogen source in many other photoreduction reactions.

In some cases O-acylated products are observed and a possible explanation involve electron transfer processes from acyl radical to quinone with to formation od quinone radical anion and acylcation. solvent. In 1.1-diphenylethylene. two limiting mechanisms have been proposed: in-cage scenario proposed by Schenck and Maruyama free-radical mechanism suggested by Moore. quinone or aldehyde applied). This latter was confirmed by trapping experiments with styrene and 1.2naphthoquinone both in-cage and out-of-cage mechanism operated more or less simultaneously. O OH O Ph-C=O .Organic Photochemistry Hydrogen atom abstraction intermolecular process: photo-Friedel-Craft of quinones 6 O 7 3Q For the formation of the acylated photoproducts. depending on the specific reaction conditions (temperature.

04 Me Me Me + Me Me Me Me Ph Ph + Ph Me Me Ph Me Me hν Me Me Me Me 95% The nature of olefins plays an important role in discriminating the possible photo-adducts.Organic Photochemistry Photodimerization or photoaddition: ABC (S1 o T1) → (ABC)2 HOMO excited π∗ orbital Processes where excited molecules react giving dimeric adducts. From the Woodward-Hoffmann based orbital symmetry rules. the quantum yield for trans/cis isomezation is often higher than that for [2+2] cycloaddition so the distribution of stereoisomers is random Me Me 2 Me φ=0. The [2+2] cycloaddition reaction represents one of the most important examples of photodimerization. it can occur between two C=C bonds and give cyclobutanes or between C=C and a C=O bond to give oxetanes (PaternòBüchi reaction) .5 2 Me Me φ=0. these reactions are only photochemically allowed and it is assumed that the HOMO excited π* orbital symmetry of a double bond matches with that of the LUMO ground state π* orbital of the others cyclobutane LUMO ground state π∗ orbital From the HOMO excited π* orbital. thus the intermolecular [2+2] cycloaddition reactions occur with a low stereochemical control.04 Me Me Me Me Me + Me Me Me φ=0. trans/cis double bond isomerization is also possible. For example from the photoreaction between trans-stilbene and tetramethylethylene affords only the mixed photoadduct in high yields and without trans/cis isomerization . In addition.

This stereochemical outcome is the result of two synergic effects: 1) the paracyclophane-template keeps the two double bonds of the cimmanic units at a correct distance to react and 2) avoids the trans/cis isomerization. At the end of photocycloaddition the dimer of cinnamic acid is collected as a single diastereoisomer and the paracyclophane-diamine is collected in high yield and is recyclable COCl NH2 + 2 H N OC H N OC hν.2HCl HCl 98% HOOC single diastereoisomer . A good example is represented by [2+2] photocycloaddition of trans-cinnamic-amide and paracyclophane-diamine which affords only one of all the possible stereoisomers.Organic Photochemistry Photodimerization or photoaddition Topochemical control of [2+2] cycloaddition reactions in solution The selectivity of [2+2] photocycloaddition reactions can increase if the environment in which the reaction occurs has a specific geometry. 78% N OC H H N OC NH2 A HOOC + A.

This situation is not easy to find and only limited cases are described in the literature.4.3.pentafluorofluoro-stilbene where perfluoroarene-arene π-π interactions in the crystal are strong enough to force the distance of the double bonds below 4 Å.Organic Photochemistry Photodimerization or photoaddition Topochemical control of [2+2] cycloaddition reactions in the solid state [2+2] cycloaddition reactions can occur in the solid state if the crystal packing is able to bring the distance between the two reacting double bonds below 4 Å.6. The transformation occurs in high yield (>90%) and with high stereoselection (controlled by crystalline packing forces) H H F F F perfluoroarene-arene H π−π interaction H F F F F H F <4 Å F H F H H solid state hν F H F H F F F F F F F F . A representative example is the solid state photodimerization of 2.5.

the number of possible stereoisomers can be reduced by structural constrains. 254 nm O n O tetronic derivative Et2O H O n=1 yield 74% n=2 yield 71% O O n . 92% O OBz O O 87% In some cases. 350nm O R O O R R= H. 90% R= CH2OBz. this changes completely by adding only a CH2 in the chain containing the double bond O benzene O hν. 350nm O benzene O OBz O O R hν. the [2+2] cycloaddition reaction can occur intramolecularly affording bicyclic or polycyclcic derivatives. In fact. No stereocontrol is usually observed. For example in furanone derivatives. Si(Me)2 hν benzene 65% Si(Me)2 O OBz hν.Organic Photochemistry Photodimerization or photoaddition O O + O CN Intramolecular [2+2] cycloaddition reactions O hν benzene O O O O O sensitizer: O O O CN When both reacting double bonds are in the same molecule. the length of the side chain containing the double bond controls the regioselectivity of the [2+2] photocycloaddition.

e.e.e. -60° C toluene n = 2.Organic Photochemistry Photodimerization or photoaddition [2+2] photocycloaddition can be performed in an enanthioselective manner and an example is reported in scheme 47. The presence of an excess of chiral template a is needed to bind completely to the substrate to prevent the photochemical [2+2] photocyclization occurring on uncoordinated substrate. . 87%. 77%.6 equiv.>90% O H N H O a 2.>90% H N N O N H H H O n H N O N O H N O H O H hν. e. The length of the side chain containing the double bond controls the regioselectivity of the [2+2] photocycloaddition O O O N O + n hν. The chemical yields are high with enantiomeric excess over 90%. -60° C toluene n = 1. where the chiral template a is used to bind reversibly by hydrogen bonding to the substrate.

Photolyases an enzimatic system containing redox cofactor flavin (reduced photochemically at radical anion state).Organic Photochemistry Photodimerization or photoaddition The formation of cyclobutane is a reversible reaction. It is known that damage of DNA occurring where dimerization of two thymine residues stimulated by UV light produces a thymine cyclobutane dimer. is able to promote stepwise cyclobutane ring opening repairing in this way the damaged DNA O HN O CH2OH O O O P OO N thymine O NH HN HOH2C UV-damage Photolyase O O P OO O O O cyclobutane O NH CH2OH O O O P OO N O N CH2OH O O O P OO N O . This is extremely important in biological systems.

under this condition. [2+2] or/and [4+2] cycloaddition reactions are observed hν triplet sensitizer [2+2] adducts cis/trans mixture + [4+2] adducts hν triplet sensitizer [2+2] adducts cis/trans mixture + [4+2] adducts 2 hν diantracene .Organic Photochemistry Photodimerization or photoaddition The photochemical outcome can be different in the presence of triplet sensitizers. Indeed.

e.Organic Photochemistry Photodimerization or photoaddition Paternó Büchi reaction In this reaction the excited state of the carbonyl function is involved. 2) abstraction of an electron from the alkene with the formation of a radical anion and radical cation which collapse into oxetane via the formation of a diradical species O* carbonyl excited state O* + exciplex O O O diradical species . Two different mechanisms can be followed: 1) the formation of an exciplex (i. a complex between the excited carbonyl function and the alkene) which collapses directly into oxetane or via the formation of a diradical species.

In fact.dialkoxyalkene Me Ph O + Ph Me Me hν Φ= 0. in the case of reaction of benzophenone with isobutene the isomer with vicinal quaternary carbon atoms is formed in a 9:1 ratio compared to that where the carbon atoms are separated by a CH2.2. This ratio can be explained considering the major stability of tertiary radicals in the diradical intermediate.Organic Photochemistry Photodimerization or photoaddition Paternó Büchi reaction The Paternò-Büchi reaction shows a certain level of regioselectivity. Enolethers can be used as alkenes. Cistrans isomerization goes with the [2+2] photocyclization and a mixture of oxetanes are formed as in the case of the reaction of acetone with a cis-1.5 Ph O Me + Ph Ph 10% O Me Me Ph 90% Me O Ph diradical intermediate O diradical more stable than Me Me Ph Me Ph Ph OR O + OR Me Me OR RO OR trans isomer Me O Me + RO hν mixture of cis and trans oxetane .

only the regioisomer with geminal oxygen is formed) MeOOC H O The Paternò-Büchi reaction can also occur intramolecularly affording polycyclic derivatives Ph O O (CH2)9 hν O Ph (CH2)9 83% O O .Organic Photochemistry Photodimerization or photoaddition Paternó Büchi reaction: other examples O O O MeOOC H + O hν benzene MeOOC H + O O Furanes can be used as enolethers. In this latter case bicyclic derivatives are obtained with high regioselectivity (i.e.

e. e. -10° C toluene 56%.>90% N H O OH H N O H O O + H O O .Organic Photochemistry Photodimerization or photoaddition Paternó Büchi reaction: enantio and diastereoselective reactions Chiral phenylglioxilic esters or reversible binding of alkene derivative to chiral template allow to perform diastereo and enanthioselective Paternò-Büchi reactions O O + OR* O O H H N O O hν O O O + O O O O *RO R*= OR* major diastreoisomer O N O H H N N H O O O O H O hν.

Electron poor olefins seem more reactive with the S2 excited state affording thietanes. The photoreaction can be initiated both from S2 (π→π*) or T1 (n→π*). The cycloaddition is stereospecific but not regiospecific from S2 and regiospecific but not stereospecific from T1.4-dithianes R R S S R R hν R S R hν C=C S thietane R R Photodimerization or photoaddition 1.Organic Photochemistry Paternó Büchi reaction of thioketones Thioketones undergo photoreaction analogous to ketones e. Because of the reactivity of S2 the reaction involving thioketones are wavelength dependent.4-dithiane .4-dithietane derivatives. In absence of reacting substrates the thioketone dimerizes to 1.4-dithietane Ph S Ph hν Ph S Ph S2 C=C * Ph S Ph T1 C=C * C=C Ph Ph Ph Ph S Ph S Ph S 1. photoreduction and cycloaddition. while in the presence of alkenes [2+2] cycloaddition reaction occurs. while T1 affords thietanes and 1. A special feature of thioketones is that the reaction can also involve the S2 excited state.g.

the oxygen is not particularly reactive as oxidazing agent or its reaction with molecules occurs with very slow reaction rates. here.Organic Photochemistry Photosensitized reactions: ABC (S1 o T1) + D→ ABC + products from excited state of the molecule D This reaction is promoted by energy transfer from an excited molecule (sensitizer) to another which undergoes chemical transformation. while in its S2 or 1Σ state is described as a diradical species with paired electrons on two different π* molecular orbitals (termed πx* and πy* i. Oxygen exists in nature in a triplet ground state. attention is focused on photosensitized reactions involving the oxygen as reagent. The two different singlet oxygen states show different chemical behaviour S2 πx* πy* S1 * 1 Σ O O diradical character paramagnetic state y x z 1 πx * πy * πx ∆ O O πy * * O O πx To πx* πy * electronic state 3 Σ O O diradical character paramagnetic state O O πy* spectroscopic designation Lewis structure . Examples of sensitized reactions have been analysed in the photodimerization or photoaddition and photoisomerization sections. Two singlet states are possible for oxygen: S1 or 1∆ state as commonly designated spectroscopically. antibonding π* orbital along x and y axis). Reactions are faster if oxygen is excited to its singlet state.e. In this state. the oxygen molecule is described O=O.

S.Organic Photochemistry Photosensitized reactions: singlet oxygen reactions Singlet oxygen can be generated from triplet oxygen in many solvents by a broad variety of sensitizers and the more common are porphorhyns (usually tetraphenylporphyrine). Bengal rose and 1-cianonaphthalene. N-R . O. 1.2-dioxetane derivatives decompose under irradiation or by heating into carbonyl derivatives by C-C scission.2-dioxetanes or [4+2] oxygen: 1O Diels-Alder like reaction. furane.10-diphenyl-antracene affording endoperoxides respectively typically from 1∆ singlet excited state (O=O behavior). Ph O2 O O Ph Cl Cl Cl J Na+ -O J O J Cl COO Na J O + N H N H N N CN Oxygen sensitizers 1-cianonaphtalene Rosa Bengala sodium salt tetraphenylporphyrine . thiophene.2 dioxetane [4+2] cycloaddition Ph X 1 Ph 1 O2 X O O X = CR2. pyrrole O O or 9. with conjugated 1 dienes such as for example ∆ excited state cyclopentadiene. one of the carbonyl derivatives is in its excited state [2+2] cycloaddition O O hν or ∆ O O* + excited carbonyl derivative 1. Typical organic reactions of singlet oxygen (both in its 1Σ and 1∆ excited state) are: 1) [2+2] cycloaddition reactions with alkenes giving 1.

the reactivity of an alkene in this reaction increases with alkyl substitution. In some cases phenols can be used. Suitable candidates for this aim are tertiary aliphatic amines and in particular 1. In general.2.e bearing more alkyl substituents since statistically more allylic hydrogens are present) OH OH OH O2.2]-octane (DABCO).4-diazabicyclo[2. DABCO N . TPP. hν 1-cianonaphtalene S S O 80% N If singlet oxygen is deleterious for an organic reaction.Organic Photochemistry Photosensitized reactions: singlet oxygen reactions 2) allylic hydroperoxidation to give hydroperoxides. The mechanism can be described as an ene-type reaction. The presence of 1-ciano-naphtalene as oxygen sensitizer is required S S O2. If several allyl positions are present the hydrogen abstraction occurs from the side of the double bond that is more substituted (i. typically from O2 in its 1Σ excited state (diradicaloid nature). Terminal alkenes usually do not react. hν HOO + HOO oxygen singlet 1Σ diradicaloid character O OH O H Oxygen singlet is also involved in oxygen atom transfer photoreactions as for example in the oxidation of sulfide to sulfoxides or phosphines to phosphinoxides. oxygen must be excluded from the reaction mixture or its production inhibited using singlet oxygen quenchers.

+ A + → AO2 reaction of radical cation of substrate with superoxide radical anion In other cases the triplet state of the sensitizer abstracts hydrogen from the substrate and the resulting radical of the substrate reacts with triplet oxygen affording a radical peroxide which can initiate a radical chain reaction. The oxidation potential of the substrate must be lower than that of the sensitizer. +A + photoelectron transfer process A + + 3O2 → A-O-O+ reaction of radical cation of substrate with oxygen A-O-O+. + hν → 1Sens* sensitizer excitation 1Sens → 3Sens* intersystem crossing process: evolution of singlet to triplet 3Sens* + A-H → H-Sens. A-H → A-O-O-H +A.. + hν → 1Sens* sensitizer excitation 1Sens* + A → Sens. reaction of peroxiradical with substrate with propagation of the radical chain. + 3O2 → A-O-O. A-O-O. This latter is more prone to react with triplet oxygen (diradical nature). → Sens +AO2 (oxidized substrate) 1Sens In some reactions the radical anion of the sensitizer reacts with the triplet oxygen producing superoxide radical anion. + Sens. reaction of radical cation of substrate with oxygen to give peroxiradical. reacts with the radical cation of the substrate. Starting radical chain process (primary photochemical process) A.Organic Photochemistry Photosensitized reactions: triplet oxygen reactions Oxygen can also react in its natural triplet state.. in turn. +A. 1Sens . Sens. + 3O2 → Sens + O2.superoxide radical anion production O2. which. In this case the sensitizer must transfer its excitation to the substrate by a photoelectron transfer process (PET) into a radical cation.

Organic Photochemistry Photosensitized reactions: triplet oxygen reactions An example of the latter process is the transformation of benzaldehyde into perbenzoic acid by photolysis in presence of oxygen and benzophenone as triplet sensitizer radical chain initiation Ph2C=O hν Ph2C O triplet state + H Ph C=O Ph2C OH + Ph C=O radical chain propagation Ph C=O + O2 Ph O-O C=O Ph H C=O Ph O-OH C=O + Ph C=O radical chain termination O-O Ph C=O + Ph2C + OH Ph O-OH C=O + Ph2C=O perbenzoic acid .

This process can produce both radical cation and a radical anion couple or cation or anion species and are called external electron transfer: ABC (S1 o T1) + D→ ABC.(+.+ λmax 620nm λmax 670nm . This process is more common in metal or metal oxides and it is the basis of the photoelectric effect.Organic Photochemistry Photoionisation reactions: ABC (S1 o T1)→ ABC+ + e- Process where an electron is removed from the molecule.2-dimethoxybenzene the abstraction of an electron is possible by irradiation with formation of an aromatic radical cation. +) The external electron transfer between benzophenone and a triarylamine is a typical example. In this reaction the triplet state of the carbonyl compound removes an electron from the lone pair of nitrogen Ph2C=O +Ar3N → Ph2C .-O . This latter undergoes nucleophilic aromatic substitution in the presence of nucleophiles such as cyanide anion OMe OMe -e - OMe OMe hν. CNt-ButOH. +) radical species ABC (S1 o T1) + D→ ABC(+.(-. -) + D. OMe CN Processes where an electron jumps from an excited molecule to another in its ground state are more common. H2O hν . In molecules this process is less common and requires light of high energy in the range of X or γ-ray. In very electron rich aromatic substrates such as 1. Ionization processes can occur in the stratosphere and it is responsible for the generation of radical chlorofluorohydrocarbons (freons) which are highly effective in removing ozone (triplet oxygen) from the atmosphere. -) + D(-.+ Ar3N.

the ketyl radical anion further evolves by extracting a hν proton transfer hydrogen from an alkyl electron transfer process substituent of the amine radical process H cation affording an α-hydroxy N(CH2CH3)3 O O H C CH-NEt benzyl radical. (CH3CH2)3N OH CH3 2 pinacol radical dimerization OH CH3 When tertiary aliphatic amine are used.Organic Photochemistry Photoionisation reactions: O CH3 hν. and an amino radical CH3 CH3 and the whole process is the photoreduction of a carbonyl carbonyl excited compound like that observed in Ketyl radical anion triplet state presence of hydrogen donor the photoinduced electron transfer from sacrificial triethylamine can be exploited in other photoreductive process such as cyclopropane and epoxide reduction O hν N(Et)3/EtOH 8:2 O O OMe hν. N(Et)3 CH3CN O O OMe O 79% O OH . which evolves into 3 2 pinacols.

THis latter is different from that obtained from the photolysis in absence of nitrile and involving the D± Rydberg state ionic pair of an excited alkene H Ph O R Ph H O R . The photogenerated radical of 9.e+ e- reduction process CN CN + e- CN CN electron acceptor SiMe3 O COOEt COOEt +e - An example of this type is the photooxidation of enol silyl ether of cyclopentanone bearing a dimethylbutenyl substituent in a position. The removal of an electron generates a radical cation able to react with nucleophiles such as alcohols affording the corresponding addition product. and reductive.9dicianoanthracene as electron acceptor) since alkenes are more easy to oxidize than to reduce O SiMe3 O . Two pathways are possible: oxidative leading to a radical cation.Organic Photochemistry Photoionisation reactions: Photoinduced electron transfer reactions can be used to initiate radical reactions of alkenes. leading to a radical anion. More common are oxidative processes (induced by the presence of 1.10-diciano-anthracene is intercepted intramolecularly by the double bond affording a bicyclic derivative CN CN electron acceptor Ph + R-CN * olefin excited state electron transfer Ph + [R-CN] D ROH Aromatic nitriles are generally employed to intercept the zwitterionic S1 excited state of an olefin.ehν COOEt CN CN oxidation process .RCN Ph O R H + [R-CN] .

g. while if the irradiation is performed at 203 nm. 254nm low pressure Hg lamps MeO 95% CN . The reactivity of aromatic compounds arises from changes in the electron distribution in the excited state.Organic Photochemistry Miscellaneous Photoreactivity of aromatic compounds Aromatic compounds are usually unreactive under photochemical conditions and normally used as reaction solvent (e.4-dimethoxybenzene gives [2+2] cycloaddition in reaction with acrylonitrile affording the corresponding cyclobutane derivatives in high yield OMe + MeO CN OMe hν. However for prolonged irradiation in the UV spectrum (200÷254nm where the aromatic compounds show strong absorption bands) certain reactivity can be observed. the formation of Dewar benzene is observed hν 203 nm hν 254 nm + Dewar benzene benzvalene fulvalene Some functionalized benzene derivatives show a more prone photoreactivity. For example. if benzene is irradiated with light of 254 nm small amounts of benzvalene and fulvene are formed. toluene or benzene). For example the 1.

4dimethoxy 1-nitro benzene the positive charge in the meta position is stabilized by the electron donating methoxy group.Organic Photochemistry Photoreactivity of aromatic compounds Photoinduced aromatic substitution reactions OH thermal: para-orientation OMe The reactivity of aromatic compounds changes dramatically under photochemical conditions. in 3. while the methoxy group in meta position is substituted under photochemical condition. thermal nucleophilic substitution of the para-methoxy group with OH-. This is one of differentiating aspects of photochemical reactivity from thermal reactivity ∆. The nucleophilic aromatic substitution follows a different pathway from that occurring under thermal conditions. Thus under photochemical conditions the charge distribution on the aromatic ring is the reverse of that of the ground state (where the meta position is less electron rich). The reverse is also observed in the chemical behaviour to nucleophilic substitution W electron withdrawing group W W . This foresees the localization of the negative charge on the carbon bearing the electron withdrawing group and the positive one localised in meta position as described by cyclopropane containing structures generated by a redistribution of π-electrons. In addition. 1-nitro benzene undergoes. OH- OH Photochemical: meta-orientation resonant structures describing the aromatic π∗ excited state The explanation of this different behavior can be found in the zwitterionic nature of the excited state of aromatic compounds when an electron withdrawing group is present. For example. as expected. OHOMe OMe NO2 OMe NO2 electron withdrawing group NO2 hν.4-dimethoxy. 3.

This undergoes Chalogen bond scission with formation of an aryl radical which reacts with the starting nucleophile affording a new aromatic radical anion. dialkylphosphite anions and thiolates. β-diketone enolates. This type of aromatic substitution is called monomolecular radical nucleophilc aromatic substitution or SRN1.Organic Photochemistry Photoreactivity of aromatic compounds Photoinduced nucleophilic aromatic substitution reactions Under photochemical conditions it is possible to carry out nucleophilic substitution even on electron rich halogen aromatic compounds. Good nucleophiles in this type of reactions are: ketone enolates. I hν X -XNu- hν. The latter subsequently transfers an electron to the starting aromatic substrate propagating the aromatic nucleophilc substitution. Bromo and iodo arenes are the suitable substrates and the reaction tolerates alkoxy and acyl substituents. X + NuX = Br. In some cases the reaction occurs by homolitic scission of the C-halogen bond generating an aryl radical which reacts with the nucleophile electron releasing group OMe hν. In a first step.formation of an aromatic radical anion. the nucloephilic substitution is promoted by the photostimulated transfer of an electron from the nucleophile to the aromatic with the + Nu. CNhν OMe Cl OMe CN- CN Cl In other cases the nucleophilic substitution follows a different mechanism especially when negative charged nucleophiles are employed. Nu- Ph-X Nu Nu .

OHO2N H OMe hν.Organic Photochemistry Photoreactivity of aromatic compounds Photoinduced nucleophilic aromatic substitution reactions In naphtalenic substrates only the nucleophilic substitution at the α-position is observed independently of the nature of substituents present on the aromatic nucleus NO2 hν. CNO2N OH 100% α-substitution CN OMe .

NH hν α-cleavage O X R hν photo-Fries R R XH O tautomerization R + O H + O XH recombination R X H O X If the ortho position is blocked by substituents only the [1.3] or [1. An interesting application of an intramolecular photo-Fries has been devised to generate paracyclophanes Me O N Me (CH2)11 hν Me O N Me (CH2)11 [1.5] acyl shift.6] shift Me O NH Me (CH2)11 paracyclophane derivative .Organic Photochemistry Miscellaneous The photolysis of esters of phenols and amides of anilines produces the cleavage of C-O or C-N bond followed by a [1. called photo-Fries reaction.6] acyl rearrangement can be observed. affording ortho or para acylated derivatives O X R X= O.

addition of a nucleophile or (less commonly) an electrophile. stereospecific insertion into σ-bonds. stereospecific insertion into π-bonds. addition of radicals or radical-like substrates.and azido compounds The most characteristic photoreaction of diazo and azido compounds is photoelimination of a molecule of N2 followed by reaction of the resulting carbene and nitrene. Singlet carbene or nitrene show a zwitterionic nature and diradicaloid in their triplet states. Typical reaction of triplet states are: atom abstraction reaction with production of radicals.N2 triplet R N R N R N R N zwitterionic character N N hν . nonstereospecific addition to insertion into π-bonds.N2 R R R C triplet R R diradicaloid character R R R R C singlet R C zwitterionic character diradicaloid character singlet .Organic Photochemistry Miscellaneous Photochemistry of diazo. The reactivity reflects the singlet or triplet nature of these species. The presence of sensitizers (benzophenone) is needed in the photochemical production of triplet excited states of diazo or azido compounds diazo compound R N R R N R azide R N N N hν R N N N .e spin conservation in a elemental chemical step: from a singlet excited state singlet carbene or nitrenes are generated while triplet carbene or nitrene from triplet exited states.2 sigmatropic shift with formation of a double bond. Using the Wigner spin rule. i. Typical reactions of singlet states are: 1.

the reaction of diphenylcarbene (photogenerated from diphenyldiazomethane) in the presence of isopropanol affords different products in relation to its electronic state: diphenyl-isopropylether from singlet state (reaction as zwitterionic character) and diphenyl-methane and acetone from triplet state (diradicaloid state) Ph C Ph Ph C Ph + HO Me Me Ph C Ph H O Me Me Ph CH Ph Me O Me Ph N N Ph singlet zwitterionic nature Ph C Ph triplet diradicaloid nature Me H Me Ph OH Ph CH + Me OH Me Ph CH2 + Ph Me O Me Difference in chemical behaviour is also observed in reactions of carbenes with double bonds. For example singlet photogenerated carbene from diazomethane adds in a stereospecific manner to cis 2-butene affording a single cyclopropane derivative. Ph2CO + via triplet carbene . while triplet carbene (photoproduced from diazomethane in the presence of benzophenone as triplet sensitiser) affords a mixture of two possible stereoisomers hν via singlet carbene CH2N2 hν.and azido compounds As an example.Organic Photochemistry Photochemistry of diazo.

while triplet ketocarbene cannot undergo Wolff rearrangement without violation of Wigner spin rule thus normally evolves to methylketone by hydrogen abstraction hν singlet O Ph CH O Ph CH [1.Organic Photochemistry Photochemistry of diazo.2] Wolff rearr. undergoes Wolff [1.and azido compounds Diazoketones are photodecomposed to singlet ketocarbene which. but give insertion reactions in C-H or in double bonds CO-N3 Ph N3 CO-N acylnitrene hν Ph N .2] rearrangement to ketenes captured by nucleophiles such as alcohols to give esters. in turn. Ph2CO (Me)2CH-OH PhCOCH3 via hydrogen abstraction triplet diradicaloid behavior OMe H3C hν insertion OMe H3C HN CH2 CO OMe Acylazides are photodecomposed to acylnitrenes which do not undergo Curtius rearrangement to isocianate as occurs under thermal conditions. PhCH=C=O ketene (Me)2CH-OH PhCO-O-CH(Me)2 PhCO CHN2 hν.

The conditions necessary for their cleavage have to be very specific for a given group in order to leave intact all the others (the so-called “orthogonality”). otherwise incompatible with acids or bases. Photolabile protecting groups bring an interesting feature: they do not require any reagent for their cleavage. o-nitrobenzylic derivatives The most popular photolabile protecting groups are based on o-nitrobenzyl derivatives which undergo a photochemically-induced photoisomerisation into o-nitrosobenzaldehyde. subsequently the so formed diradical species evolves into a cyclic acetal derivative whose hydrolysis yields o-nitrosobenzaldehyde liberating the moiety X bounded (bonded) to the benzylic carbon atom in high or quantitative yields O N OH O NO2 X hν OH N O X N O + acetalic function hydrolysis X hydrogen X abstraction N O O N OH X X-H CHO N O OH X . just light. This category of protecting groups opens the possibility of dealing with extremely sensitive molecules.Organic Photochemistry Photocleavable protecting groups Protecting groups are often a necessity in organic synthesis along with all the drawbacks associated with their use as for example the fact that their introduction and cleavage require two synthetic steps and introduce complications to the synthetic plan by their incompatibility with some organic reagents. The complication increases rapidly with the number of different protecting groups on the same molecule. The mechanism is: the excited triplet state of the nitro function abstracts a hydrogen from the ortho benzylic carbon atom.

The N-(o-nitrobenzyl) protecting group of the imidazole side-chain of histidine is removed quantitative yields giving back histidine without any racemisation: The tertButhoxycarbamoyl (BOC) nitrogen protection is stable under photolysis conditions NO2 hν N O OH 100% N H N N COOH NH-Boc + NO CHO N N COOH N COOH NH-Boc NH-Boc imidazole protected histidine NO2 O O P 2 OH PCl5 NO2 O O 2 P Cl + HO O OAc Thy phosphate protected motiety The ortho-Nitrobenzyl alcohol derivatives were used for the protection of the phosphate group in nucleotide synthesis. Both protection and deprotection occur very efficiently O HO P O O OAc hν Thy >305 nm 70% NO2 O O 2 P O O OAc Thy HO .Organic Photochemistry Photocleavable protecting groups Different functionalities can be protected by this group such as for example nitrogen of heterocycles or hydroxy functionalities.

Organic Photochemistry Photocleavable protecting groups Orthogonal photolabile groups i. group which can be removed using light of different wavelength. .e.

CO2 H2N R COOH + MeO O MeO NO2 H Nitroveratroyloxycarbonyl protecting group (NVOC) O COOH R hν. For example. is not affected The simpler ortho-nitro-benzyloxycarbonyl group (NBOC) is normally used with less light sensitive substrates MeO MeO NO2 hν. even the tryptophan. HO Photolysis gives quantitative yields of glucose. with both types of photolabile groups OH O O OH O2N R R hν quant. Under these conditions. OMe . one of the most light-sensitive compounds. 350nm O O H N COOH R NO2 H N O . 260nm Nitrobenzyloxycarbonyl protecting group (NBOC) Both NVOC and NBOC groups can be OH used for the protection of the hydroxy groups in carbohydrate chemistry. the hemiacetalic form of glucose HO can be protected as a mixed acetal.Organic Photochemistry Photocleavable protecting groups The 6-nitroveratroyloxycarbonyl group (NVOC) is undisputedly the most popular and used photolabile protecting group for the amino function in amino-acids. HO HO OH O OH R= H. The two methoxy groups were introduced to increase the absorbance at wavelengths longer than 320 nm.

Organic Photochemistry Photocleavable protecting groups The 1-(2-nitrophenyl)ethylenglicole can be effectively used in the protection of the carbonyl function of ketones. 350 nm PhH OH N O O R1 O R2 NO O OH + R1 O R2 . NO2 OH OH + R1 O R2 TsOH/PhH .H2O 70-97% 31-90% NO2 O O R1 R2 hν.

The deprotection follows an external electron transfer process O R1 N R2 + O-Ac MeO hν.Organic Photochemistry Photocleavable protecting groups Benzophenone as photooxidant The N-(2-acetoxyethyl) group (introduced by alkylation of an amine with 2-acetoxyethyl bromide) can be used as amine protecting photolabile group.4 -dimethoxybenzophenone (the electron acceptor). and irradiation at 350 nm. The deprotection requires a stoichiometric amount of 4. 350 nm external electron transfer process O OMe MeCN/H2O R1 N R2 O-Ac MeO OMe OH R1 NH R2 + MeO OMe .

A heterolytic mechanism of C-O bond scission has been proposed with formation of benzylic carbocation and carbammic acid anion.254 nm R + - O O H N R1 COO- O + OH H3N R1 COO- . The presence of electron-releasing groups on the aromatic ring or of water in the reaction medium increases the quantum yield of the deprotection reaction R H N O R1 H2O .Organic Photochemistry Photocleavable protecting groups Benzyl alcohol derivatives The N-benzyloxycarbonyl (Cbz) amino protecting group is usually removed by hydrogenolysis but it is found that its cleavage can be performed in significant chemical yields (~ 70%) by a photosolvolysis process upon irradiation at 254 nm.CO2 R hν COO. In the presence of water both these intermediates evolve into benzylic alcohol and amine with evolution of CO2.

Thiohydroxamate derivatives are also used as traceless linkers in solid state synthesis S S N OH + R O OH Coupling reagent S S N O O R hν hydrogen donor X-H S SH N Me + CO2 + R-H Me thiohydroxamic acid Me O S S N O O NMe hν. TMS3SiH or t-BuSH.Organic Photochemistry Photocleavable protecting groups Thiohydroxamate derivatives Thiohydroxamate derivatives of carboxylic acids can be regarded as protecting groups of a C-H bond. The deprotection reaction requires the use of an external hydrogen donor agent such as Bu3SnH. 350 nm hydrogen donor Me NMe + O SH S N Me Me .

Under irradiation benzophenone is excited to a triplet state with diradical nature and.Organic Photochemistry Photopolimerization The generation of radicals by homolitic bond scission or molecular excited states with radical character can be exploited to initiate polymerization. permeation.2-dimethoxy-2-phenyl-acetophenone DMPA . A recent application of this possibility is the surface modification of polypropylene microporous membranes by means of a polymeric layer with the aim of improving its hydrophilicity. as already seen in the previous sections. can stimulate many photochemical processes as well as be exploited as radical photoinitiator of polymerization processes. This has been realized by photopolymerization of suitable methylacrylate induced by catalytic amounts of benzophenone as photoinitiator photoinitiators Me O X hν photoinitiator Me n O X O Ph O Ph MeO Ph OMe Ph benzophenone methaacrylate derivative polymethylmethacrylate 2. hemocompatibilty and anti-fouling properties.

N2 3 O O O 3-amino-phtalate triplet excited state endoperoxide O luminol NH2 Light + O O O O NH2 O O O O 1 intersystem crossing NH2 O 3-amino-phtalate singlet excited state . The most significant examples of chemoluminescence are: oxidation of luminol by oxygen under alkaline conditions.Organic Photochemistry Chemoluminescence Chemoluminescence is a phenomenon that occurs when a sizeable amount of exothermicity (∆G) of a chemical reaction is converted into electronic excitation energy of a reaction product which then relaxes emitting light (hν). The light is emitted after intersystem crossing from the triplet state to the singlet NH3 O N NH 2 OH- NH2 O N N O O2 NH2 O O O O N N . The treatment of luminal by NaOH transforms it into the corresponding dianion which reacts with oxygen producing an endoperoxide whose decomposition produces N2 and the triplet state of 3-aminopthalate.

The enzyme system (termed luciferase) associated with lumophore is called luciferin.CO2 N HO S N S O * N HO S N S O + Light excited lumophore . Commonly a molecule of oxygen is also required and aquantum yield of 1 for chemoluminescence process has been measured. The decarboxylation of a peroxolactone is believed to be a key step in producing the excited intermediate whose relaxation occurs radiatively N HO S lumophore N S H CO-OH luciferase ATP HO N S O2 N S H CO-AMP + P2O7-2 H O N S O AMP O O N HO S N S O O HO N S endoperoxide .Organic Photochemistry Chemoluminescence Bioluminescence observed in fireflies (Photinus pyralis) represents a particular and well know aspect of chemoluminescence. Bioluminescence requires a lumophore and an enzime system that acts as mediator of chemoluminescence step.

emits in the visible region (yellow green) excited carbondioxyde molecule O PhO O OPh + H2O2 O O O * Rubrene C O + O C O O O peroxydione energy transfer to Rubrene Ph Ph * Ph Light + Ph Ph Ph Ph Rubrene Ph excited Rubrene . one of which is in the excited state is believed to be at the basis of the chemoluminescence process. in turn. A peroxydione intermediate (peranhydride of oxalic acid) decomposes into two CO2 molecules.25) involves the reaction of H2O2 with diphenylester of oxalic acid. The excitation of CO2 is transferred to a suitable energy acceptor as for example Rubrene which.Organic Photochemistry Chemoluminescence One of the most efficient “synthetic” chemoluminescent systems (quantum yield Φ~0.

If available. UV spectra from the reaction mixture may help to identify ground state interactions between the reagents or CT complexes. but plays a particular and important role in photochemical reactions since the reactive species are photogenerated at very low concentration and can be captured or quenched by the presence of impurities. therefore the choice of the right solvent is critical. For practical reasons most photochemical reactions are performed in solution. The solvent must be transparent or at least it must show a very low extinction coefficient in comparison with the “photoactive” compound. a UV spectrum of the product should also be recorded. 3) In principle. which can be useful as a guide to individuate the best reaction conditions. In Table 2 the optical characteristics of some utilized solvents for photochemical reactions are reported.Organic Photochemistry Technical and experimental aspects In order to perform photochemical reactions correctly. The extinction coefficient gives an idea of the power of light source to be used: low extinction coefficient need high intense radiation to produce enough excited molecules. From UV spectra recorded with different compound concentrations. 2) Before starting a photochemical reaction a UV/vis spectrum of the “photoactive” compound should be recorded. The “photoactive” compound is the electronically excited molecule which undergoes or initiates a primary photochemical process from its excited singlet or triplet state. if the extinction coefficient of the “photoactive” compound is only 10 times higher than that of the solvent at the irradiation wavelength. safely. trace metal ions). of course. The solvent must be free of impurities (ethylendiamine tetracetic acid EDTA can be useful to remove. by complexation. expressed by the cut off wavelength (lcutoff) together with the parameter normally used for valuating the solvent polarity (dielectric constant e and the Dimroth-Reichardt value). technical and experimental protocols and indications should be followed. The solvent must. 1) Purity of starting materials. and with success. At longer wavelength than lcutoff the solvent can be considered completely transparent . a significant solvent filter effect can be observed with the consequence that the reaction is much slower than it could be. allows to evaluate the extinction coefficients in the whole range of interest. UV spectra of all reagents should be recorded to be sure that there is no or little interference in absorption with the “photoactive” compound. in solid state or in solution. In fact. dissolve the reactants. photochemical reactions can be performed in the gas phase. This is a prerequisite valid in general for any procedure in organic synthesis. The polarity of the solvent plays an important role in stabilizing or destabilizing the ground and excited states of a molecule and consequently this reflects on their reactivity and on the energy needed for performing a photochemical reaction.

17 46.81 7.91 20.27 2.7 39.1 51.02 6.5 38.88 24.30 35.58 6.21 8.3 33.9 40.5 42.4-dioxane Methylene chloride Chloroform Tetrhydrofurane Ethyl acetate Acetic acid Dimethylsulfoxide Benzene Toluene Pyridine Acetone Cut-off wavelength nm 185 190 195 204 205 215 215 230 230 245 245 255 250 277 280 285 305 330 εT 78.38 12.Organic Photochemistry Technical and experimental aspects Solvent Water acetonitrile n-hexane Ethanol Methanol Cyclohexane Diethylether 1.56 ET(30) 63.7 45.20 2.4 30.2 .0 40.1 45.02 4.0 51.9 55.5 36.66 2.1 37.6 31.45 2.5 32.93 4.94 1.9 34.1 34.

00 0.75 0.Table 3: Sensitizer and Quencher in non-polar solvents Solvent Benzene Toluene Methyl benzoate Acetone Acetophenone Xanthone Benzaldehyde Triphenylamine Benzophenone Fluorine Triphenylene Biphenyl Phenanthrene Styrene Naphtalene 2-acetylnaphtalene biacetyl benzil Anthracene Eosine Rose bengala Methylene blue ET (kJ/mol)a 353 346 326 332d 310 310 301 291d 287 282 280 274 260 258 253 249 236d 223 178 177 164 138 Es (kJ/mol)b 459 445 428 372 330 324 323 362 316 397 349 418 346 415 385 325d 267d 247 318 209 213 180 ΦISC c 0.00 0.22 0.71 0.73 0.40 0.61 0.92 0.00 0.86 0.90/1.52 .85d 1.00d 1.84 0.00 1.88 1.33 0.25 0.53 0.

useful wavelenghts from 360÷600 nm. 546 and 577÷579 nm. medium and high pressure mercury lamps are commercialized from 125 up to 500W.). 436. 577÷579 nm. Never switch off the cooling system immediately after switching off the lamp. the more used are: 1) Apparatus for external irradiation (the simplest case is an irradiated flask) or Raynet a or Immersion-well reactor b in which the lamp is surrounded by the reactions electric supply motor water outlet acqua water inlet acqua reflecting walls UV lamps photoreactors cooling fan cooling walls Hg medium pressure bulb a b In all cases the lamp usually needs cooling to avoid its overheating and heating of the reaction solution. Never move or touch lamps during operation.Organic Photochemistry Technical and experimental aspects Different light sources can be used for photochemical reactions: 1a) the sun. useful wavelenghts 300÷1400 nm. useful wavelenghts: 185. useful wavelengths: 365 (the most intense).and high pressure sodium lamps. 2) medium pressure Hg lamps (Hg vapor pressure 5 atm). 3) high pressure Hg lamps (Hg vapor pressure approx. 1) low-pressure mercury lamp (Hg approx. . Among the different typologies of photoreactors commercialized or homemade. 4) low. (broad emission). useful wavelenghts 589 nm. 10-5 atm). Most lamps operate at high temperature (400÷700°C) and at high vapor pressure. Low pressure mercury lamps are commercialized from 1 W to tens of Watts. 100 atm. 254 (the most intense).

sample thickness 2mm quartz pyrex 80 60 trasmittance % 40 20 200 250 300 λ nm 350 400 . For irradiation at 254 nm quartz glass (expensive apparatus) is needed. For irradiation at 300 nm pyrex glass is needed. Quartz and Pyrex transmittance. The glass acts as a solid filter.Organic Photochemistry Technical and experimental aspects The material of the reactor depends on the necessary irradiation energy. Additional solid or liquid optical filters may be used to restrict the irradiation wavelength. and for irradiation > 350 nm normal lab glass (window glass) is sufficient.

Sign up to vote on this title
UsefulNot useful

Master Your Semester with Scribd & The New York Times

Special offer for students: Only $4.99/month.

Master Your Semester with a Special Offer from Scribd & The New York Times

Cancel anytime.