Retrosynthesis and Stereochemical Aspects of Synthetic Reactions

From an achiral molecule, one enantiomer of the chiral target molecule is formed in an asymmetric reaction, also known as enantioselective reaction. Retrosynthetic analysis considers chiral target molecules as racemates and at this stage does not consider asymmetric synthesis to one enantiomer. When the second stereogenic center in the chiral molecule is introduced in a stereoselective manner, one of two possible diastereomers is formed. Such a synthetic reaction is called diastereose-lective. For the sake of simplicity, during retrosynthetic analysis the formation of diastereomers is not related to the optical purity of the target molecule. This means that starting chiral molecules are considered racemates, which in a diastereoselec-tive step affords one of the two possible racemic products. 

Before consideration of stereoselective reactions in this chapter, we had the opportunity to discuss one example of stereoselectivity in two-dimensional space. This refers to reactions where E/Z isomers are formed around a double bond, specifically in target molecules with an RCH=CHR unit (Wittig reaction, Sect. 2.2). 

Retrosynthetic analysis primarily considers the electronic properties of synthons, i.e., the stabilizing effect of neighboring groups on the charged species in the ground state. This approach is not amenable to analysis of asymmetric syntheses since their outcome is determined by the stereoelectronic properties of the transition state. Stereoselective reactions are kinetically controlled, and the rational approach to analysis of the stereoelectronic properties of the energetically preferred transition state is difficult and usually supported by specialized computer programs. 

Different stereoelectronic properties of similar groups in reacting molecules result in chemoselectivity, with higher reactivity of one group as compared to others. This difference is relatively easy to anticipate in the course of retrosynthetic analysis. The outcome of an asymmetric reaction is much more difficult to forecast in view of the difficulty in designing a transition-state stmcture on the route to the preferred enantiomer. 

In order to present the principles of various kinds of stereoselective reactions, we start with classification of the possible isomers formed in these reactions. To this aim we designed a set of isomers with the common molecular formula C11H12O (Fig. 3.1). 

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