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Retrosynthetic analysis

The constant goal of a retrosynthetic analysis should be to reduce the molecule to similarly
sized building blocks of lower or similar complexity. This simplification should be continued
until you reach molecules which are commercially available.

The two main operation of a retrosynthetic analysis are: 1) Functional group interconversions
(FIG) and 2) bond disconnections.

Functional group interconversion (FGI)

Many functional groups can be interconverted into each other, e.g. oxidation of an alcohol
gives an aldehyde, further oxidation a carboxylic acid. Many organic transformations can be
used to do FGIs. Carbonyl groups are particular useful in this respect. The reactivity of the
carbonyl group can be masked during synthesis as double bond (ozonolysis for FGI into
aldehyde) or dioxolane until needed.

Disconnection of covalent bonds

The key step(s) in many syntheses is (are) bond formation. In planning a synthesis the reverse
bond disconnection helps to identify suitable synthetic routes. There is no general way to
disconnect a molecule; each retrosynthetic problem requires its individual creative solution.
Retrosynthetic analysis and planning of syntheses needs experience and training. The more
reactions and their scope someone knows, there more options for synthetic routes he or she
has.

There are some general features of a molecule that can guide the analysis:

1) Pattern of oxygenated carbon atoms. If Carbonyl- and/or hydroxgroups are found in a

1,3 or 1,5 pattern, this gives a hint to use one of the classical carbonyl reactions for synthesis.
Aldol reaction and Claisen condensation give 1,3 dioxygenated structures, Michael additions
lead to 1,5 dioxygenation patterns. If the molecule to be synthesized has oxygenated carbons
in 1,2 or 1,4 position, only Umpolung or the use of cyanide anions, as a C1 equivalent yield
the desired structure. 2

2) Six-membered rings in the molecule. The Diels-Alder reaction leads to a six membered
ring by connection of diene and dienophile. A disconnection using a retro Diels-Alder
reaction can drastically reduce the complexity of a molecule.

3) Double bonds or their equivalents can serve as points of disconnection, because many
reliable methods to synthesize C=C double bond are known.
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Basic retrosynthetic key steps

Disconnection of molecules according to the functional groups present in the target molecule.

Difficult, only limited set of connecting reactions available, e.g. radical combination, aliphatic
nucleophilic substitution. Sometimes a detour is necessary, e.g. formation of a double bond
and subsequent hydrogenation.
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 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 5

Retrosynthesis training
Propose syntheses – discuss alternative routes !

Simple alcohols

OH
OH OH OH
H3C CH3
H3C H3C Ph Ph
1) 2) 3) 4)
Ph OH

OH
Ph
OAc

OH Ph OH
5) 6) Ph Ph 7)

Exercises

Br O
8) 9)

Simple Alkenes

10) 11)

Simple Carbonyl Compounds

CH3
NO2
O OH COOH

Ph
12) OMe O 13) Ph 14)
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 6

O N

15) 16) O

Exercise
OMe
OMe

MeO

HN
MeO

17) 18) O

COOH

OH
19) 20) OH α-terpinol isomers 21)

HO

20) 23)

H H
COOH
24)
Cascarillsäure aus Wolfsmilchgewächsen
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1,3- and 1,5-dioxygenated compounds can be prepared from classic carbonyl reactions.
Retrosynthesis with classic carbonyl reactions - overview
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 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 10

O O

COOEt COOEt
O
4) 5) 6)

O
CHO
HO O
O N
O
7) 8) O 9)

CN

O O EtOOC O
COOEt CH3
O

10) 11) 12) O

O O O
O

N
13) OMe 14) 15)

O O
O
COOEt

H3C

16) 17) COOEt 18)

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Functional group interconversions (FGIs)

Based on the oxidation level of carbon there are two main types FGIs: Without change of the carbon
oxidation level and with change of the oxidation level.

With chance of oxidation level, but not all are possible:

Same oxidation level:

Amino groups are of particular importance in many molecules. Therefore many methods for
their preparation from other functional groups have been developed.
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Removal of functional groups – Hydrocarbon synthesis

Two-group Disconnections:
“Illogical” disconnections, “unnatural” reactivity patterns

Use of 1,2-difunctionalysed starting materials

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Difunctionalisation of alkenes and epoxide opening

α-Functionalisation of carbonyl compounds

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Be aware of the haloform reaction!

Carboxylic acid:

Radical coupling
Radical coupling is only good when two identical molecules are being coupled or when the
reaction proceeds intramolecularly.

Pinacol reaction:

Acyloin condensation:
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Umpolung strategies
A synthetic equivalent of a reagent which cannot be prepared, e.g. an acyl anion, is called a
synthon. Dithiane, cyanohydrin and sulfone are latent carbonyl groups; the carbonyl
functionality is masked in a different form and can be released at a later stage when required.
This process is called “Umpolung”, because the usually partially positively charged carbonyl
carbon is temporarily transformed into a carbanion. So the polarity is reversed. After the
reaction of the acyl anion equivalent the carbonyl functional group can be restored.

Cyanide anion + electrophilic carbonyl compound:

Cyanohydrins

Alkyne nucleophile + electrophilic carbonyl

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Dithians (thioacetal) nucleophile + electrophilic carbonyl

Synthetic strategies for 1,4-difunctionalysed compounds

Approaches to the synthesis of 1,4-difucntionalized compounds share a lot of common
features with methods for the preparation of 1,2-analogues. Again, a few commercially
available derivatives can serve as starting materials.

Acyl equivalent + Michael acceptor

This approach is analogues to the preparation of 1,5-dicarbonyl compounds via addition of
enolates to α,β-unsatuarted carbonyl compounds. However, this time, acyl-anion synthons are
used as nucleophiles. A selection of such reagents has been discussed previously.
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Acyl anion synthons:

Additional Umpolung strategies

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Reconnection strategies for 1,6-difunctionalysed compounds 21

In retrosynthetic analysis, open chain 1,6-difunctionalised compounds can be linked to

appropriate cyclic precursors. We call this reconnection strategies, which can also be used to
make compounds with two functional groups related to each other as 1,5-, 1,7- etc.

Ozonolysis of cycloalkenes
Functional groups with 1,6-relationship are too far apart for any conventional disconnection
strategies. However, ozonolysis of cyclohexene creates two functional groups which are 1,6-
related.

Baeyer-Villinger rearrangement
Another type of reconnection strategies is the hydrolysis of lactones. The required lactones
can be prepared from cyclic ketones by a ring expansion reaction, the Bayer-Villinger
rearrangement.
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Beckmann rearrangement
Analogously, a reconnection strategy for 6-amino acids is the hydrolysis of lactams. Lactams
can be prepared from cyclic ketones by the Beckmann rearrangement.
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Synthesis of carbocyclic compounds

Diels-Alder disconnections:

Other methods of carbocycle synthesis:

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Taking advantage of symmetry

The symmetry of the target molecule structure may facilitate the synthesis. Instead of a
stepwise linear synthesis a convergent approach can be used. Simultaneous formation of two
or more bonds can save steps and allows building up the target molecule from similar sized
building blocks. An example is the retrosynthetic analysis of squalene. Linear and convergent
syntheses need typically different numbers of synthetic steps.

PPh3 H Ph3P
O
O
H

squalene
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 27

“Meso trick”

The stereochemistry of the starting material of a synthesis can be used to build up complex
stereochemical patterns quick and efficient. Starting form an achiral meso compound chiral
intermediates are obtained by enantioselective reactions. The “meso trick” uses the different
reaction rates of symmetric prochiral groups. The Sharpless epoxidation of a meso bis-allyl
alcohol illustrates the different reaction pathways.

The situation is different in C2 symmetric chiral starting materials. Now reactions may
proceed diastereoselective giving C2 symmetric chiral intermediates. The diastereoselectivity
of a reaction is determined by the difference in reaction rate for the different pathways.
Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 28
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 29

Enzymes in synthesis

Advantages of using Enzymes and other Biological Methods (e.g. whole organisms)

• rate of reaction is increased

• reaction proceeds under very mild conditions
• green chemistry - very low environmental impact (increasingly important)
• can be extremely selective
• a wide variety are commercially available although some are very expensive
• chiral catalysts and can show exceptional levels of enantio- and
diastereodifferentiation on natural and unnatural substrates.
• can be exceptionally efficient catalysts - very few synthetic catalysts compare
• can achieve transformations not possible using conventional chemical reagents

Disadvantages and Some Solutions

• can be extremely selective - this can be a problem if the enzyme doesn't accept your
substrate:
o if the reaction is sufficiently important it is usually possible to find a suitable
enzyme which will accept the substrate by screening.
• can be unstable in organic solvents which are required to solubilise the substrate:
o the stability of enzymes in organic solvents depends on the hydrophilicity of
the enzyme - hydrophilic enzymes tend to be less stable
o the solvent used can be important - immiscible, non polar solvents often give
the best results
o immobilising the enzyme on a support can increase stability (and also simplify
purification procedures - the enzyme can be filtered off and recovered).
• some enzymes require co-factors to operate - co-factor recycling is possible but not
always easy.
• Water is required for enzymes to maintain catalytic activity - some substrates are
water sensitive. It is often possible however to use very small amounts of water and
still maintain activity.
• some enzymes are very very expensive

I. Hydrolytic Enzymes - Lipases, Esterases, Proteases and Amidases

• catalyse the hydrolysis of ester and amide bonds

• reaction is reversible so they can also be used to catalyse the formation of ester and
amide bonds depending on the conditions
• this is the most commonly used class of enzymes
• require no co-factor so no need for co-factor recycling
• reactions are simple to carry out
• many 1000's of these enzymes are known; a large number are commercially available
and relatively inexpensive
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 30

Regioselective Protection of Alcohols

Enzymes have been used for highly regioselective protection of alcohol functionality (as
esters) in carbohydrates.

Desymmetrisation of Meso Systems

• a very useful method for accessing chiral compounds

• complete conversion possible (see kinetic resolution below) although lower yields are
often obtained when hydrolysis of the remaining acetate becomes competitive.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 31

Kinetic Resolution of Racemic Alcohols and Esters

• a very useful method for accessing enantiomerically enriched molecules

• Start with a racemate. Providing one enantiomer reacts faster than the other there is the
potential for resolution. The greater the difference in rates, the more efficient the
resolution.
• the maximum yield is 50%
• need to separate unreacted starting material from product

Problems with enzymatic kinetic resolutions of alcohols

• The reaction is reversible. This is a problem in a kinetic resolution. The major product
in the forward reaction is also going to be the faster reacting of the two enantiomeric
products in the reverse reaction. Hence there will be a loss in the enantioselectivity as
the reverse reaction proceeds.
• product inhibition caused by the release of an alcohol during the transesterification
reaction.

Solution: make the desired reaction irreversible and remove the alcohol transesterification
product.

These problems can be avoided using activated esters especially enol esters (e.g. vinyl
acetate):

• the increased reactivity of the ester facilitates the forward reaction

• the equilibrium is pushed over to the right if the ester is used in excess - vinyl acetate
is cheap and volatile so it can be used as the solvent.
• the product is an enol and therefore rapidly tautomerises to the aldehyde thereby
removing the product alcohol and rendering the reaction irreversible.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 32

Examples:

A comparison with chemical catalysis – towards a biomimetic artificial enzyme

The standard method of acylating alcohols uses 4-dimethylaminopyridine (DMAP) as a

catalyst.

• DMAP (4-dimethylaminopyridine) acts as a nucleophilic catalyst and increases the

rate of acylation by greater than 10000.
• Reaction is very general - very broad substrate selectivity.
• Rapid and high yielding.
• The active acylating reagent is the acyl pyridinium species.

Design of a chiral nucleophilic catalyst:

DMAP contains two mirror planes and therefore is achiral. If we can eliminate these mirror
planes then we can generate a chiral molecule.
Solution:
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 33

Review: G. C. Fu, Acc. Chem. Res., 2000, 33, 412-420.

II. Enzymatic Oxidation

Oxidation of Benzene

It is impossible to perform this transformation using standard chemical dihydroxylation (e.g.

OsO4). Use in the synthesis of (-) pinitol.
Retrosynthetic analysis:

Forward synthesis:
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 34

Enantioselective Baeyer-Villiger Oxidation

• This enzyme requires a cofactor (NADPH) for activity.

• Olefins are NOT epoxidised - this can be a competing process using chemical methods
(chemoselectivity).
• Oxidation is highly enantioselective and generates a synthetically useful product.

III. Reduction Reactions

Yeast reduction

• β-ketoesters are good substrates for yeast reduction

• the active enzyme is an alcohol dehydrogenase
• the reaction usually does not require the use of purified enzyme
• instead, the whole organism is used
• this can lead to problems if the substrate is accepted by two enzymes (an organism
will obviously contain thousands of enzymes) which impart opposing facial
selectivities in the reduction - if both enzymes react at similar rates there will be an
erosion in the enantioselectivity of the reaction - in this case it is better to use a
purified enzyme.