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Stereocontrol and ring formation

Stereocontrol in acyclic systems
Reactions of acyclic molecules can generate diastereomers and the term controlling
stereochemistry usually refers to an attempt to generate one diastereomer in preference to
another as the mayor product of a reaction. The types of situations where attempts to control
stereochemistry are important include:
1. Regioselectivity (Markovnikov/anti-Markovnikov)
2. Retention versus inversion of configuration
3. Cis-Trans selectivity
4. Syn-Anti selectivity
5. Hereroatom chelation effects
Regioselectivity
A typical reaction that illustrates Markovnikov addition is the reaction of HBr with 2-methyl-2butene to give 2-bromo-2methylbutane. This reaction proceeds by formation of the more stable
carbocation, which reacts with the nucleophilic bromide ion. If the anti-Markovnikov bromide is
desired, a different mechanistic pathway must be followed. A typical anti-Markovnikov addition
reaction is addition of borane to the alkene, giving primary alcohol (2) after oxidation of the
intermediate alkylborane. This alcohol can be converted to the anti-Markovnikov bromide 3, by
treatment with PBr3.

with concomitant loss of sulfur dioxide (SO2) gives (S)-2-chloropentane (6). then the HCl byproduct is trapped as the pyridinium hydrochloride salt and nucleophilic chloride ion is in the medium. If pyridine (or another basic tertiary amine) is added. and it is also another example of changing stereochemistry by modifying the mechanism of the reaction. The presence or absence of a nucleophilic chloride ion allows one to control the stereochemistry of the reaction. The Lindlar catalyst allows selective reduction of alkynes to the cis-alkene. Both retention of configuration (neat SOCl2) and inversion (SOCl2 + pyridine) are possible. Once . as in the conversion of 25 to 26. Cis-trans selectivity. Thionyl chloride reacts with (S)-2-pentanol to produce a chlorosulfinate ester (5).Retention versus inversion of configuration. The synfacial delivery of chlorine generates the chloride with retention of configuration of the original hydroxyl moiety. Displacement of the chlorosulfinate ester by chloride in an SN2 reaction gives chloride 8 with net inversion of configuration. as in the conversion of 23 to 24 in Kaiser´ s synthesis of niphatoxin B. This contrasts sharply with treatment of an alkyne with alkali metals to give the trans alkene. Control of cis-trans geometry is well illustred by catalytic hydrogenation of alkali metal reduction of alkynes. The HCl byproduct escapes from the reaction medium and an intramolecular delivery of chloride in what is called a SN1 mechanism. A classical example of controlling the configuration of a stereocenter is conversion of a chiral secondary alcohol to the corresponding secondary chloride with thionyl chloride.

Heteroatom chelation. Syn-anti selectivity There are many reactions that generate a mixture of syn and anti diastereomers. It is a diastereospecific reaction. An example is the conversion of alkenes to 1. a fundamental understanding of the difference in these two reaction mechanisms allowed control of the cis-trans geometry of the final product. One major way to control diastereoselectivity is to take advantage of the chelating effect of neighboring hereroatom groups (neighboring group effects) with certain reagents. with either Nmethylmorpholine oxide (NMO) or tert-butylhydroperoxide with osmium tetroxide (OsO4). and if the reaction is diastereoselective. The . Coordination with the oxygen and delivery of the electrophilic oxygen from that side gave epoxy alcohol 39 as the major diastereomer. which means that coordination directs the stereochemical course of the reaction. Sharpless developed a protocol for high asymmetric induction by adding quinidine (33). The Sharpless asymmetric epoxidation esploits this chelation effect because its selectivity arises from coordination of the allylic alcohol to a titanium complex in the presence of a chiral agent. As seen in the hydroxylation of trans-stilbene. wich can be illustrated by reaction of chiral allylic alcohol 37 with a peroxyacid.2diols. Reactions of alkenes with aqueous permanganate or osmium tetroxide lead exclusively to a cis diol via the syn hydroxylation mechanism.again. the syn-diol 34 is the major product. one predominates.

Addition to a substituted π bond leads to geometrical isomers. The terms syn and anti have no meaning in cyclic systems. Stereocontrol in cyclic systems Many of the problems encountered in acyclic systems also arise in cyclic systems. Bredt´ s rule. and only three discussions fundamental to cyclic molecules will be presented: control of diastereoselectivity. These effects provide the tools to control selectivity. invoking the Hammond postulate. The same . which is due to the late transition state of the reaction. Regioselectivity The problems associated with regioselective addition to cyclic molecules are essentially the same as those noted in acyclic molecules. effectively locking the conformation in that transition state. regioselectivity is important in the formation of double bonds in elimination reactions. As we have just seen in the formation of 53 or 54. inversion of configuration of a sterogenic center. and in most cyclic systems control of the absolute configuration of a stereogenic center is associated with cis-trans isomers and/or with diastereomer formation.most effective additive was a tartaric acid ester (tartrate). The methods for controlling Markovnikov and anti-Markovnivkov regiochemistry and retention or inversion of the configuration are essentially the same as in acyclic systems. and its presence led to high enantioselectivity in the epoxidation. Regiocontrol in the elimination was achieved by binding the base to the molecule (an internal base for anti-elimination). An important and differentiating feature of cyclic systems is the relatively rigid conformations assumed by these molecules. and the electronic requirements that position the leaving group anti to the hydrogen being removed. and the chelating effects of heteroatoms. It is difficult to separate regiochemical (mode of addition) effects and retention versus inversion effects from cis-trans isomerism in cyclic molecules. Treatment of a halide such as 55 with potassium tert-butoxide in tert-butanol led to anti elimination and formation of the more substituted alkene (56).

is the inability of the ring to rotate about the carbon-carbon bonds. Retention versus inversion (diastereocontrol) Las mentioned previously. 2.effect is observed in cyclic halides such as cis-2-bromo-1-methylcyclopentane (57). 3. For homologs with different S values. . For a given bicyclic ring skeleton. of course. For both syn and anti-elimination. Kobrich established three guidelines that govern the application of Bredt´ s rule. the ring strain varies inversely with the size of the bridge containing the bridgehead double bond. which gives methylcyclopentene (58) upon treatment with base. For a given S. the betahydrogen and the leaving group are fixed by the regiochemistry of the halide. The major difference. Reaction of sodium azide (NaN3) and cis-4-tertbutyl-1-bromocyclohexane gives trans-4-tert-butylazidocyclohexane with complete inversion of configuration via an SN2 pathway. Subsequent treatment with methanolic potassium carbonate liberated alcohol 76 with the inverted hydroxyl. the ring strain varies inversely with the size of the larger of the two rings with respect to which the bridgehead bond is endocyclic. dictating removal of the beta-hydrogen that is syn to the leaving group. The presence of an acid or acid salt (such as potassium benzoate) in the reaction medium leads to nucleophilic displacement with clean inversion to generate an ester. A synthetic example of a reaction that proceeds with inversion in the Mitsunobu reaction that featured chiral alcohol 75. Nonetheless. reactions of cyclic molecules that involve formation of sterogenic centers are similar to those of acyclic systems in that they can proceed with clean retention or inversion of configuration. the ring strain varies inversely with S. 1. in Mori´ s synthetic work toward poitediol. or a mixture of the two. the more highly substituted (more stable) alkene is also produced. Syn-elimination involves intramolecular attack of base.

of course. which is due. In cyclic systems. which gave primarily 121 via delivery from the less sterically hindered face. . There are many examples. delivering the electrophilic oxygen from that face to give 119. A cyclic system can be used to position functional groups.and stereochemistry. which contrasts with epoxidation of allylic acetate 120. often with control of regio. and delivery of the nucleophilic oxygen is from the less sterically hindered face so the epoxide unit is on the opposite side of the ring.Diastereoselectivity If one stereoisomer can be produced when more than one is possible (a diastereoselective reaction). Synthetic chemists have exploited this fact for many years. The ring is then opened to give an acyclic system and the regiochemistry and stereochemistry of the substituents has been fixed. and stability of the final product are critically important for predicting and controlling stereochemistry. to the conformational bias inherent in cyclic systems. Peroxyacid epoxidation of 117 proceeded via coordination of the peroxyacid to the alcohol (118). The acetate group inhibits coordination with the peroxyacid. conformational preferences in the transition state. this is desirable and obviously related to the concepts discussed in previous sections in the context of acyclic systems. Neighboring group effects and chelation effects The influence of heteroatom substituents in directing reactions to one face or another has been noted in this as well as several preceding chapters. the conformation of the ring. Acyclic stereocontrol via cyclic precursors It is apparent from preceding sections that stereocontrol in cyclic systems is much easier than in acyclic systems.

In the latter case.5-cyclooctadiene to give diol 146 in 85% yield. a cyclic molecule acts as a template and the other rings are built onto the template (this is called annulation). 148. Conversion to the dibromide and two copper assisted displacements followed by epoxidation led to the racemic sex pheromone of the female face fly. Ring-forming reactions Baldwin´ s rules. Examining the overall sequence shows that the requisite functional groups at the α-and ω-positions were inserted by the sequential alkylation reactions. it is clear that cyclic compounds play an important role in organic synthesis. . and must often be prepared by cyclization reactions from acyclic precursors. however. first to 146 giving 147 and then to 147 to give the alkene precursor to 148. This section will discuss the salient features of ring forming reactions commonly encountered in synthesis.The utility of the process is demonstrated by the ozonolysis of 1. From the preceding discussion. The desired compound is not always commercially available. An excess of the organocruprate reagent was required for reasonable yields of the coupling products due to decomposition and disproportionation of the copper reagents. which is particularly true for large ring (macrocyclic) compounds and poly-cyclic molecules.

For exo processes. This approach is based on the stereochemical requirements of both reagent and substrate as well as the angles of approach that are allowable when two reactive centers come together. The bond angles are 120°. but upon reaction the sp2 atom is converted to a sp3 atom. for example) is about 109. it is first necessary to establish what angles of attack are possible. and exo-dig reaction will generate ring 164. and cationic ringclosing processes and found a predictable pattern of reactivity. imines. In this latter case. ring formation is difficult (disfavored). Attack at an sp hybridized atom (163) is dig. Attack at an sp2 atom (157) is termed trig (forming the ring 158 or 160). and on the stereochemistry of the product. the best trajectory for attack of a sp2 atom (a carbonyl. the two reactive centers are connected by a tether of atoms (usually carbon atoms but not always) and this imposes constraints on angles from which they can approach one another. If the proper geometry cannot be attained. alternative but competitive processes usually dominate. Displacement at a sp3 carbon generally requires backside attack (165) and the incoming group (X) must approach the Y-bearing carbon at an angle close to 180°. hemolytic. Reactions at double bonds (trig) are controlled by the planar nature of alkenes. When two reactive ends of a molecule come together. called the angle of attack. If the length and nature of the chain (tether) linking terminal atoms X and Y allows this geometry to be attained. Ring closures categorized by Baldwin´ s rules. as in 161. If the atom being attacked is sp3 hybridized. they can approach each other only from certain trajectories. . Baldwin classified ring closing reactions in two categories: exo (the electron flow of the reaction is external to the ring being formed [158 from 157] and endo [the electron flow is within the ring being formed (160 from 159)]. Baldwin further classified reactions according to the hybridization of the atoms accepting the atom in the ring closing process. Before discussing Baldwin´ s rules. To form a ring. and carbonyls. Since sp3 atoms are tetrahedral (with bond angles of 109). the reaction is termed tet and an exo-tet reaction will generate a ring such as 162. this is usually easy but for endo processes it can be difficult. Baldwin studied many nucleophilic.An introduction to cyclization reactions is best begun with a discussion of Baldwin rules for ring closure or simply Baldwin´ s rules. Elliot and Graham-Richards described a method for predicting the preferred approach angles based only on the substrate. ring formation is possible (favored) and we make the predication that the reaction will succeed.

X and Y are reactive functional groups that generate a new group. In this model. or both). An exception is the formation of large rings. In the 1920s and 1930s Ruzicka and Ziegler studied macrocyclic reactions. is a functional group exchange process. Macrolactonization. however. Illuminati and Mandolini described the ring-closing reactions of bifunctional chain molecules. Y. Ruggli discovered that high substrate concentrations favor polymerization while low concentrations favor cyclization. Z (which may contain X. where cyclization gives the monocyclic product. Macrocyclic ring formation requires an intramolecular cyclization reaction of a bifunctional molecule such as 213. Repeated intermolecular reactions give the oligomers or polymers (216). The principles discussed here for preparing large ring lactones are applicable to most other macrocyclizations. Baldwin´ s rules explain most of the cyclization reactions for small and medium-sized rings encountered in previous chapters and those that are seen in succeeding chapters.Macrocycles Macrocyclic ring closures. 214. The rate of cyclization is a function of the structure of the . An important reaction that competes with cyclization is the intermolecular reaction where initial coupling generates the dimeric 215. and large lactone rings are also an important feature of many natural products. Formation of carbocyclic rings will be discussed in later chapters in connection with the appropriate carbon-carbon bond-forming reactions.

Cyclization has also been observed using a mixture of trifluoroacetic acid and trifluoroacetic anhydride. was used to convert 220 to 222 in 31% yield. Trifluoroacetic anhydride. naturally occurring lactones. A variety of cyclization techniques have been developed.open-chain precursor and that of the product-like transition state. The initially formed mixed anhydride (221) activated the carbonyl to attack by the hydroxyl moiety. The activation energy for ring closure is largely determined by the strain energy of the final ring. For medium rings. but all are based on the idea that the carbonyl end of a ω-substituted acid is activated to facilitate attack by or at the other functionalized end. for example. The first is the parameter Cα/Mo. Kr/Kp should be < 0. An alternative synthetic route required a macrocyclization reaction but it involved Friedel-Crafts acylation. Synthetic approaches to macrocyclic lactones. The EM is supposed to be the first-order rate constant for ring closure times the second order rate constant for reaction between chain ends (if they were not connected) but EM for five and sixmembered rings exceeds the real concentration. Two parameters similar to EM are useful for predicting conditions under which a ring can be synthesized. the yield is not less than 55%. free of significant polymerized byproducts. . where Kr is the rate of ring formation of cyclic monomer and Kp is the rate of formation of cyclic dimer. If the initial concentration is less than unity (α < 1). There are many examples of biologically important.1 M. The relative preference of a reaction is given by the effective molarity (EM)= Kintra/Kinter. leading to 222 in the Taub synthesis of zcaralenone.

One last piece of information is required for synthesis in order to manipulate functional groups. Without this understanding. With knowledge of these principles a useful plan can be assembled for the synthesis of even complex molecules. If there is a theme to this chapter. methods are available to temporarily block it. In addition. it is that organic chemists can exercise a significant amount of control over synthetic reactions. syntheses beyond a very few simple steps will be doomed to failure. or inserted earlier or later in a synthesis. In those cases where a heteroatom functional group interferes with a transformation and cannot be removed. . which is possible by understanding the mechanism of the transformations and the various interactions of heteroatoms and reagents. A thorough understanding of the conformational aspects of reactivity is essential. many of the principles used in the important chapters dealing with making carboncarbon bonds have been discussed.Conclusion. modified.