Lecture 8: Stereoselective reactions

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8          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 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).

8.1       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.

8.1.1    Addition of X2 to alkenes

There is no regiochemical issue in the addition of a halogen (Br2, 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).
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:
8.2       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.

8.2.1    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 (Δ G‡) leading to each of them is the same, so they
form at exactly the same rate (cf. the Arrhenius equation).
8.2.2    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):
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.

8.3       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.

8.3.1    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 (2 S)-enantiomer, so each of the two diastereoisomers
produced will also be enantiomerically pure.
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.

8.3.2    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%

8.3.3    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 (LiAlH4) with a chiral alcohol gave a modified chiral reducing agent
capable 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.

Further information: S. Yamaguchi and H. S. Mosher, J. Org. Chem., 1973, 38,

1870–1877.