Starting material

Designing Organic Syntheses

Syntheseplanung

Target molecule

Can the Computer do the retrosynthetic analysis for me?

Computer-generated Retrosynthesis
Programme LHASA (http://lhasa.harvard.edu): E.J. Corey
Based on known reactions; interactive search for the best route.

Computer-generated Retrosynthesis
Programme LHASA (http://lhasa.harvard.edu)
Based on known reactions; interactive search for the best route.

Computer-generated Retrosynthesis
Programme LHASA (http://lhasa.harvard.edu)
Based on known reactions; interactive search for the best route.

Computer-generated Retrosynthesis
WODCA; logic-oriented programme; Gasteiger, Erlangen

Computer-generated Retrosynthesis
WODCA; logic-oriented programme; Gasteiger, Erlangen

Computer-generated Retrosynthesis
SYNGEN: http://syngen2.chem.brandeis.edu/syngen.html
Claim:
SynGen generates only the shortest and most efficient syntheses.
SynGen generates the syntheses without user intervention, freeing it from user bias
and allowing it to explore all possibilities.
All the generated syntheses have commercially-available starting materials.

Free Mac Version for

Download; no Windows
Version available

Computer-generated Retrosynthesis
SYNGEN: http://syngen2.chem.brandeis.edu/syngen.html

Computer-generated Retrosynthesis
SYNGEN: http://syngen2.chem.brandeis.edu/syngen.html

Computer-generated Retrosynthesis
SYNGEN: http://syngen2.chem.brandeis.edu/syngen.html

Functional
Group
Interconversions

Functional group interconversions (FGIs)

Change carbon oxidation level

Functional group interconversions (FGIs)

Same carbon oxidation level

Amines !

Amines !

Removal of functional groups Hydrocarbon synthesis

Disconnections

Strategic disconnection approach

10

Strategic structure approach

11

Strategic structure approach

C-C Bond Formation

12

No functional group present

One group disconnection based on normal carbonyl reactivity

13

One group disconnection based on normal carbonyl reactivity

One group disconnection based on normal carbonyl reactivity

14

Two group disconnection based on normal carbonyl reactivity

15

Retrosynthesis with classic carbonyl reactions - overview

16

17

d) Two-group Disconnections:
Unlogical disconnections, unnatural reactivity patterns

Synthetic strategies for 1,2-difunctionalysed compounds

Synthon required

18

Use of 1,2-difunctionalysed starting materials

Difunctionalisation of alkenes and epoxide opening

19

- Functionalisation of carbonyl compounds

- Functionalisation of carbonyl compounds

20

- Functionalisation of carbonyl compounds

Radical coupling

Pinacol reaction

21

Acyloin condensation

Umpolung strategies

CN-

22

Dithioacetals

23

Nitroalkanes

Imidoyl

24

Alkyne

Synthetic strategies for 1,4-difunctionalysed compounds

Commercially available starting materials

Acyl equivalent + Michael acceptor

Acyl anion synthons

25

Homoenolate + electrophilic carbonyl

resonance

26

Additional Umpolung strategies

27

Enolate + -functionalised carbonyl compound

Enolate + ,-unsaturated nitro compound (Michael type acceptors)

28

Enolate + ,-unsaturated nitro compound (Michael type acceptors)

Epoxide based transformations

29

Epoxide based transformations

Epoxide based transformations

30

Functional group addition

31

Reconnection strategies for 1,6-difunctionalysed compounds

Ozonolysis of cycloalkenes

Baeyer-Villiger rearrangement

32

Beckmann rearrangement

33

Synthesis of carbocyclic compounds

Diels-Alder disconnections

34

Synthesis of carbocyclic compounds

Cyclisation reactions

Synthesis of carbocyclic compounds

Other methods of carbocycle synthesis

35

Synthesis of heterocyclic compounds

Synthesis of oxiranes, thiirans and azirans

36

Synthesis of oxiranes, thiirans and azirans

Synthesis of oxiranes, thiirans and azirans

37

Synthesis of furans

Paal-Knoor

Synthesis of furans
Feist-Benary

Addition to alkyne

38

Thiophen

Pyrrol:
Paal-Knorr:

Knorr

39

Hantzsch

Fischer-Indole

40

Hantzsch pyridine

Quinolines (Deutsch: Chinoline!)

Quinoline

Isoquinoline

Skraupsch synthesis

41

Birschler-Napieralski

Pictet-Spengler

Oxazole

Isoxazole

42

Thiazole

Pyrazole

1,4-Dioxane

43

Assessment of Syntheses and Strategies

The assessment of a synthesis depends on the aim of the synthesis.

shortest synthesis (time required)

cheapest synthesis (material needed)
a new synthesis (to get a patent)
environmental benign synthesis (minimize waste)
synthesis without toxic risk (no toxic reagents and intermediates)
reliable synthesis (no risk of failure)

Assessment of a chemical reaction

High chemical yield
Good chemo-, regio- and stereochemistry
Catalytic reagents, not stoichiometric
Minimal energy input; efficient energy intake and perfect control of reaction
(microwave, irradiation, microreactor)
Use of renewable resources (natural products)
No use of mutagenic and teratogenic compounds; consideration of oecoand human toxcicity of all chemicals involved

Assessment of a chemical reaction

The ideal synthesis is,
safe
simple
100 % yield
one step
resource efficient
environmentally acceptable
uses available, if possible renewable, starting materials

Assessment of a chemical compound

The assessment of a chemical compound depends on its use, but there
are also general considerations particular important large scale commodities

No oeco- or human toxicity

Distribution and persistence in the environment should be limited
Complete degradation and mineralization possible
Lifetime of the compound adjusted to its use
Highly effective in its properties; minimal amount needed to perform
the desired task
Not mutagenic, teratogenic or carcinogenic

Assessment of a chemical compound

The ideal chemical compound (material, drug, dye, polymer etc.) is

safe and non-toxic
cheap
shows high performance during its life cycle
then completely degrades to minerals
can be recycled to safe energy and material resources
does not accumulate in the environment

Assessment of a chemical compound

Materials and compounds that later turned out not to be good:
Cl
Cl

- DDT
Cl
Cl

Cl

- Asbestos

- PCB

Cln

Cln

Assessment of a synthesis
Number of steps as indicator
The ideal synthesis creates a complex molecule .. in a sequence of only
construction reactions involving no intermediary refunctionalizations, leading
directly to the target, not only its skeleton but also its correctly placed
functionality. Hendrickson, J. Am. Chem. Soc. 1975, 97, 5784
Generation of complexity
- Complexity generating reactions, e.g. cycloaddition yielding tricycles
- Late increase of complexity in the synthesis is advantageous
Linear vs convergent strategies
- Higher overall yield achievable by convergent strategies
Risk of failure
-Unknown or hypothetical key step increases risk of failure
- Good syntheses has at least on safe alternative
- Change in sequence of steps increases flexibility
Get the most done in the fewest steps and the highest yield!

Protecting groups for alcohols

Silyl ether

Silyl ether

Silyl ether

Silyl ether

Carbonate

Carbonate

Ester

Ether

Photolabile protecting groups

Orthogonal protecting groups

Key steps of the synthesis

Weinreb Amide

10

Corey-Bakshi-Shibata Reduction
Itsuno-Corey Reduction

Practical enantioselective reduction of ketones using oxazaborolidine catalyst generated in situ

from chiral lactam alcohol and borane
Y. Kawanami, S. Murao, T. Ohga, N. Kobayashi, Tetrahedron, 2003, 59, 8411-8414.

An Efficient and Catalytically Enantioselective Route to (S)-(-)-Phenyloxirane

E. J. Corey, S. Shibata, R. K. Bakshi, J. Org, Chem., 1988, 53, 2861-2863.

11

Alder Ene Reaction

12

Asymmetric allylic alkylation

BF3 OEt2,
-78oC, 94%

13

Homologous Aldol addition

14

Dess Martin Periodinane

Corey Fuchs

15

Cyclopropane synthesis

Radical chlorination of cyclopropane

16

Corey-Fuchs reaction

17

Metathese

Takai Olefination

Stille Coupling reaction

18

19

Schmidt glycosydation

20