Self-Regeneration of Stereocenters (SRS)--Applications, Limitations, and Abandonment of a Synthetic Principle

摘要

In order to replace a substituent at a single stereogenic center of a chiral molecule without racemization, a temporary center of chirality is first generated diastereoselectively, the original tetragonal center is then trigonalized by removal of asubstituent, a new ligand is introduced, again diastereoselectively, and finally, the temporary center is removed. By means of these four steps (the "Self-Regeneration of Stereocenters", SRS), 2- and 3-amino-, hydroxy-, and sulfanylcarboxylic acids havebeen successfully alkylated with formation of tertiary carbon centers and without the use of a chiral auxiliary. Use of this methodology has allowed the potential of these inexpensive chiral building blocks to be expanded considerably. This article aimstodemonstrate (using, in part, examples from natural product syntheses) that chiral heterocyclic ac-etals with enamine, enol ether, enolate, dienolate, enoate, radical, and acyli-minium functionalities and also those that are potential reactants for Michael additions and pericyclic processes (for example, electron-rich and electron-poor dienophiles and dienes) are now easily accessible, more often than not, in both enantiomeric forms. Stereogenic nitrogen atoms of aziridines, boron atoms of cyclic or linear systems, and stereogenic planes of Ti-complexes can also be used as the temporary chirality element in other approaches to the realization of the SRS principle. Enan-tiomerically pure derivatives of, for example, glycine, hydroxy- and sulfanyl-aceticacid, 3-aminopropanoic acid, and 3-oxocarboxylic acids can be prepared by resolution of racemic mixtures via diastereoisomeric salts or by chromato-graphy on a chiral column. Hence, the extensive reactivity of compounds developed to test the SRS principle and, above all, the outstanding stereoselec-tivities of the reactions can be put to good use even when no suitable chiral precursor is available--even though this amounts to an abandonment of the principle! The readily available 2-tert-butyl-1,3-imidazolidin-3-one, -oxazolid-in-5-one, -dioxin-3-one, and -hydropy-rimidinone (all of which contain a single stereogenic center at the acetal C atom) can thus be used in the preparation of a vast range of 2-amino- and 3-hydroxy-carboxylic acids, and no chiral auxiliary has to be removed or regenerated during these procedures. (One example is the synthesis of 4-fluoro-MeBmt, a derivative of the C_9 ammo acid found in cy-closporin.) In the final chapter we will discuss the most useful findings gained from investigations into both the self-regeneration of Stereocenters and the use of chiral acetals in the synthesis of enan-tiomerically pure compounds (EPC synthesis): the formation and characteristics of complexes obtained from Li-enolates and other Li compounds with secondary amines; the application of a-alkoxy and a-amino-Li-alkoxides as in situ bases and sources of aldehydes in C-C bond forming reactions with unstable enolates or nitre-nates; the significance of A effects on the stereo-chemical course of nucleophilic, radical, and electrophilic reactions of W-acylated heterocycles and homo- or heterocyclic carboxylic ester enolates; and the effects of the amide protecting group on the reactivity of neighboring centers and on the stereoselectivity of the reactions at those centers. At the end of this article we have included an appendix containing tables, which are intended to summarize all the examples known in as complete a fashion as possible.