Page 1197 - Advanced Organic Chemistry Part B - Reactions & Synthesis

eliminated from the molecule. As in syntheses involving resolution or enantiomerically 1173
pure starting materials, subsequent steps must give the correct configuration of newly
created stereocenters. Another approach to enantioselective synthesis is to use a chiral SECTION 13.2
catalyst in a reaction that creates one or more stereocenters. If the catalyst operates with Illustrative Syntheses
complete efficiency, an enantiomerically pure material will be obtained. Subsequent
steps must control the configuration of newly introduced stereocenters.
In practice, any of these approaches might be the most effective for a given
synthesis. If they are judged on the basis of absolute efficiency in the use of a
chiral material, the ranking is resolution < chiral reactant < chiral reagent < chiral
auxiliary < enantioselective catalyst. A resolution process inherently employs only half
of the original racemic material. A chiral starting material can, in principle, be used
with 100% efficiency, but it is consumed and cannot be reused. A chiral reagent is also
consumed, but in principle it can be regenerated, as is done for certain organoboranes
(see p. 350). A chiral auxiliary must be used in a stoichiometric amount but it can
be recovered. A chiral catalyst, in principle, can produce an unlimited amount of an
enantiomerically pure material.
The key issue for synthesis of pure stereoisomers, in either racemic or enantiomer-
ically pure form, is that the configuration at newly created stereocenters be controlled in
some way. This can be accomplished by several different methods. Existing functional
groups may exert a steric or stereoelectronic influence on the reaction center. For
instance, an existing functional group may control the approach of a reagent by coordi-
nation, which occurs, for example, in hydroxy-directed cyclopropanation (see p. 919).
An existing chiral center may control reactant conformation and, thereby, the direction
of approach of a reagent.
Generally, the closer the reaction occurs to an existing stereogenic center, the
more likely the reaction is to exhibit high stereoselectivity. For example, the creation of
adjacent stereogenic centers in aldol and organometallic addition reactions is generally
strongly influenced by adjacent substituents leading to a preference for a syn or
anti disposition of the new substituent. We also encountered some examples of 1,3-
asymmetric induction, as, for example, the role of chelates in reduction of -hydroxy
ketones (p. 412), in chelation control of Mukaiyama addition reactions (p. 94), and in
hydroboration (Section p. 342). More remote chiral centers are less likely to influence
stereoselectivity and examples of, e.g., 1,4- and 1,5-asymmetric induction, are less
common. Whatever the detailed mechanism, the synthetic plan must include the means
by which the required stereochemical control is to be achieved. If this cannot be done,
the price to be paid is a separation of stereoisomers and the resulting reduction in
overall yield.

13.2. Illustrative Syntheses

In this section, we consider several syntheses of six illustrative compounds. We
examine the retrosynthetic plans and discuss crucial bond-forming steps and the means
of stereochemical control. In this discussion, we have the benefit of hindsight in
being able to look at successfully completed syntheses. This retrospective analysis can
serve to illustrate the issues that arise in planning a synthesis and provide examples
of solutions that have been developed. The individual syntheses also provide many
examples of the synthetic transformations presented in the previous chapters and of the
use of protective groups in the synthesis of complex molecules. The syntheses shown