STEREOCHEMICAL ASPECTS OF ORGANIC SYNTHESIS

We have studied enantiomers and diastereoisomers, their properties, methods of detection,

separation etc. In this section we will look at stereochemistry in the context of synthesis. To
start with, some important definitions:

STEREOSPECIFIC REACTIONS: A stereospecific reaction is one which, when carried

out with stereoisomeric starting materials, gives a product from one reactant that is a
stereoisomer of the product from the other. 'Stereospecific' relates to the mechanism of a
reaction, the best-known example being the SN2 reaction, which always proceeds with
inversion of stereochemistry at the reacting centre.

Examples:

STEREOSELECTIVE REACTIONS: A stereoselective process is one in which one

stereoisomer predominates over another when two or more may be formed. If the products are
enantiomers, the reaction is enantioselective; if they are diastereoisomers, the reaction
is diastereoselective. Stereoselectivity is dominated by the structural features of the
reactants.

Example:

The reaction above is stereospecific (only syn addition) but the stereoselectivity is low
(ca. 2:1). To understand such a reaction we must analyse it mechanistically. We will then

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also see that optically active products cannot be created using achiral (or racemic) starting
materials in an achiral solvent. The product in such a case must also be achiral (or racemic).

THE MECHANISTIC BASIS OF STEREOSELECTIVITY

In the limited time available, we will scratch the surface of organic synthesis and look at
some illustrative examples of selectivity. To be of synthetic use, a reaction must be reliable,
predictable and selective – features which must be analysed from a mechanistic viewpoint.

The chemistry of alkenes, alkanols and carbonyl compounds provides the core of organic
synthesis. Addition reactions of double bonds (C=C or C=O) can easily provide us with new
stereogenic centres, and we need to know how to exploit them.

Addition of X2 to alkenes

There is no regiochemical issue in the addition of a halogen (Br 2, Cl2 etc.) to an alkene
because the E and Nu are the same, but the question of stereoselection is more significant. In
the addition of HX to an alkene we saw that the addition of the electrophile (H +) leads to the
build-up of positive charge on the adjacent carbon, eventually giving rise to
a planar carbocation. Subsequent reaction with a nucleophile can in principle take place on
either face of this cation, which produces a mixture of syn- and anti-addition products. In
contrast, the bromination of simple alkenes is stereospecific; it is anti-selective due to the
intermediate formation of a cyclic bromonium ion.

The overall process is anti-addition of Br2 to the double bond because the cyclic bromonium
ion undergoes ring-opening in an SN2 process (i.e. strictly by inversion) in which the
Br– counterion serves as the nucleophile. This SN2 step takes places at the
most electropositive carbon of the cyclic ion (i.e. the location of the original positive charge).

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The attacking nucleophile can also be the solvent, and the resulting combination of versatility
and stereospecificity makes the reaction very useful in synthesis. Chloronium ions have also
been observed but they are much more reactive as electrophiles (for example, they react with
benzene). The tendency for bridging is F < Cl < Br < I.

When the cationic centre is strongly stabilised by a structural feature, e.g. an aromatic ring
(resonance-stabilised cation), the non-selective mechanism via a free carbocation competes
with the bridged ion pathway, and some syn-product is also formed. Example:

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GENERATING STEREOGENIC CENTRES WITH ACHIRAL SUBSTRATES

We have just seen a reaction in which stereogenic centres are generated from planar carbon.
Carbonyl (C=O) and alkene (C=C) bonds are prochiral and their chemistry provides many
examples which illustrate the principles of stereoselectivity in synthesis.

Nucleophilic addition to prochiral carbonyl groups

Reduction of acetophenone, which is achiral, with sodium borohydride gives 1-phenylethanol,

which contains a stereogenic centre. However the product is racemic, and we must analyse
the mechanism to understand why. Two transition states are possible for bonding between the
achiral BH4− and the achiral (planar) ketone, one leading to the (S)-alcohol and the other to the
(R)-alcohol. But the two transition states are enantiomeric, and must therefore have identical
physical properties. The activation barrier (ΔG‡) leading to each of them is the same, so they
form at exactly the same rate (cf. the Arrhenius equation).

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Hydroboration of alkenes

Hydroboration is an important synthetic process. Borane is electron-deficient and readily

reacts with -bonds (which are electron-rich). The addition is regioselective– the boron atom
adds to the least substituted end of the double bond. The addition is stereospecific, with the B
and H atoms always adding to the same face of the double bond (syn-addition).

The full mechanism of hydroboration is shown in Appendix 2. The first step is the concerted
regioselective addition of the alkene -bond (electron rich) to a B–H bond (electron poor):

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With an achiral alkene the addition can proceed with equal facility on the Re and Si faces of
the double bond, through enantiomeric transition states, leading to a chiral but racemic
product.

GENERATING STEREOGENIC CENTRES WITH CHIRAL SUBSTRATES

When a starting material already possessing a stereogenic centre undergoes a reaction which
leads to the generation of a new one, diastereoselectivity (and how to control it) becomes a
major consideration.

Nucleophilic addition to a homochiral cyclic ketone

Whereas the addition of a nucleophile to the two faces of acetophenone (sect. 8.1.1) leads to a
pair of enantiomers, the prior presence of the stereogenic centre in 2-methylcyclopentanone
means that the two faces of the carbonyl group are diastereotopic (rather than enantiotopic),
and hydride addition can lead to two separable products (diastereoisomers) in unequal
amounts. In this reaction the approach of the hydride reagent to the C=O group is easier from
the rear (Si) face, further away from the large methyl group. Our starting material is
enantiomerically pure (2S)-enantiomer, so each of the two diastereoisomers produced will also
be enantiomerically pure.

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Addition reactions like this are irreversible and so proceed under kinetic control, the product
ratio reflecting the relative rates of the two modes of addition. These are different because the
two transition states are diastereoisomeric and have unequal energies. Steric effects in the
transition states determine their energies and hence the product ratio. This is a typical
example of steric approach control, in which a substrate reacts preferentially at the least
hindered site. The more bulky the reagent, the bigger the preference for attack from the least
hindered face.

The proximity of the 2-methyl group to the prochiral reaction site (C-1) engenders a high level
of steric approach control in the above reaction, and the cyclic (inflexible) nature of the ketone
ensures that the methyl group cannot get away from the bond-forming process. More distant
stereogenic centres would be expected to exert less influence on reactions at a prochiral sites.

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Nucleophilic addition to a racemic cyclic ketone

To remind yourself of the fundamental principle that non-racemic products cannot be created
from racemic starting materials in an achiral medium, consider what would happen if the
reaction in the previous section (8.3.1) was performed on racemic 2-methylcyclopentanone.
The outcome is shown below.

The ratio of diastereoisomers formed in the reaction is 76:24 (i.e. the d.e. is 52%), and this will
be the same for both enantiomers of the starting material. So we can say:

 Racemic ketone gives 76% yield of racemic cis-2-methylcyclopentanol

 If the e.e. of the starting ketone is 60%, then each product will each have an e.e. of 60%

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Enantioselective hydride reduction of carbonyl compounds

The reduction of acetophenone with NaBH4 (section 8.2.1) confirmed that achiral hydride
reducing agents cannot react in an enantioselective manner. However, Yamaguchi and
Mosher found that the partial decomposition of lithium aluminium hydride (LiAlH 4) with a
chiral alcohol gave a modified chiral reducing agentcapable of reducing acetophenone
enantioselectively. Although the method is simple, it should be noted that the level of
enantioselection (e.e. 68%) is not ideal in a practical sense because of the difficulties
associated with purifying (i.e. resolving) the product in order to obtain a single enantiomer.