Page 1196 - Advanced Organic Chemistry Part B - Reactions & Synthesis

1172 becomes critically important when the target molecule has several stereogenic centers,
such as double bonds, ring junctions, and asymmetric carbons. The number of possible
n
CHAPTER 13 stereoisomers is 2 , where n is the number of stereogenic centers. Failure to control
Multistep Syntheses stereochemistry of intermediates in the synthesis of a compound with several centers
of stereochemistry leads to a mixture of stereoisomers that will, at best, result in
a reduced yield of the desired product and may generate inseparable mixtures. For
properties such as biological activity, obtaining the correct stereoisomer is crucial.
We have considered stereoselectivity for many of the reactions that are discussed
in the earlier chapters. In ring compounds, for example, stereoselectivity can frequently
be predicted on the basis of conformational analysis of the reactant and consider-
ation of the steric and stereoelectronic factors that influence reagent approach. In the
diastereoselective synthesis of a chiral compound in racemic form, it is necessary
to control the relative configuration of all stereogenic centers. Thus in planning a
synthesis, the stereochemical outcome of all reactions that form new double bonds,
ring junctions, or asymmetric carbons must be incorporated into the synthetic plan.
In a completely stereoselective synthesis, each successive stereochemical feature is
introduced in the proper relationship to existing stereocenters, but this ideal is often
difficult to achieve. When a reaction is not completely stereoselective, the product will
contain one or more diastereomers of the desired product. This requires either a purifi-
cation or some manipulation to correct the stereochemistry. Fortunately, diastereomers
are usually separable, but the overall efficiency of the synthesis is decreased with each
such separation. Thus, high stereoselectivity is an important goal of synthetic planning.
If the compound is to be obtained in enantiomerically pure form, an enantiose-
lective synthesis must be developed. As discussed in Section A.2.5, the stereochemical
control may be based on chirality in the reactants, auxiliaries, reagents, and/or catalysts.
There are several general approaches that are used to obtain enantiomerically pure
material by synthesis. One is based on incorporating a resolution into the synthetic
plan. This approach involves use of racemic or achiral starting materials and resolving
some intermediate in the synthesis. In a synthesis based on a resolution, the steps
subsequent to the resolution step must meet two criteria: (1) they must not disturb
the configuration at existing stereocenters, and (2) new centers of stereochemistry
must be introduced with the correct configuration relative to those that already exist.
A second general approach is to use an enantiomerically pure starting material. Highly
enantioselective reactions, such as the Sharpless epoxidation, can be used to prepare
enantiomerically pure starting materials. There are a number of naturally occurring
materials, or substances derived from them, that are available in enantiomerically
pure form. 17
Enantioselective synthesis can also be based on chiral reagents. Examples are
hydroboration or reduction using one of the commercial available borane reagents.
Again, a completely enantioselective synthesis must be capable of controlling the
stereochemistry of all newly introduced stereogenic centers so that they have the
proper relationship to the chiral centers that exist in the starting material. When this
is not achieved, the desired stereoisomer must be separated and purified. A fourth
method for enantioselective synthesis involves the use of a stoichiometric amount
of a chiral auxiliary. This is an enantiomerically pure material that can control the
stereochemistry of one or more reaction steps in such a way as to give product having
the desired configuration. When the chiral auxiliary has achieved its purpose, it can be

17
For a discussion of this approach to enantioselective synthesis, see S. Hanessian, Total Synthesis of
Natural Products: The Chiron Approach, Pergamon Press, New York, 1983.