Diversity-Oriented Asymmetric Synthesis

Dedicated to Dr. Michael Harmata.

Abstract

The application of small molecules to modulate proteins by direct interactions has evolved as a powerful tool for the study of complex biological systems. Conventional genetic approaches have examined biological systems by generating random mutations which were then screened in search of a precise cellular phenotype. Analogous to the genetic approach, large random collections of small molecules can be used to elucidate the roles of specific proteins in many biological pathways. The crux of this ‘chemical genetic’ approach is the design and synthesis of libraries of compounds which span large tracts of biologically relevant chemical space. Diversity-oriented asymmetric synthesis (DOAS) is an exceptional methodology for preparing structurally and stereochemically diverse small molecule libraries which show a greater variety not only in their physiochemical properties but also in their biological activities. Herein, we describe some of the most effective strategies that have been used in asymmetric diversity-oriented synthesis library design and preparation.

1 Introduction

2 Philosophy of DOAS

3 Stoichiometric Reactions

3.1 DOAS with Chiral Auxiliaries

3.2 DOAS with Chiral Templates

3.3 DOAS with Chiral ‘Linchpins’

3.4 DOAS from Natural Products via a Ring-Distortion Strategy

3.5 DOAS via Chiral Reactions

4 DOAS towards Peptidomimetics

5 Catalytic Reactions

6 Conclusion

Key words

diversity-oriented asymmetric synthesis - linchpin - ring-distortion strategy - organocatalysis - spiroketals

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