Strategies to Bypass the Taxol Problem. Enantioselective Cascade Catalysis, a New Approach for the Efficient Construction of Molecular Complexity

Abstract

Millions of years of evolution have allowed Nature to ­develop ingenious synthetic strategies and reaction pathways for the construction of architectural complexity. In contrast, the field of chemical synthesis is young with its beginnings dating back to the early 1800’s. Remarkably, however, the field of chemical synthesis appears capable of building almost any known natural isolate in small quantities, yet we appear to be many years away from operational strategies or technologies that will allow access to complexity on a scale suitable for society’s consumption. This essay attempts to define some of the issues that currently hamper our ability to efficiently produce complex molecules via large-scale total synthesis. In particular, issues such as ‘regime of scale’ and ‘stop-and-go synthesis’ are discussed in terms of a specific example (the taxol problem) and more broadly as they apply to the large-scale production of complex targets. As part of this essay we discuss the use of enantioselective cascade catalysis as a modern conceptual strategy to bypass many of the underlying features that generally prevent total synthesis being utilized on a manufacturing scale. Last we provide a brief review of the state of the art with respect to complex ­molecule production via enantioselective cascade catalysis.

1 Introduction

1.1 Taxol

1.2 Benefits and Therapy

1.3 Commercialization Problems and Ultimate Production Route

1.4 Chemical Synthesis of Taxol

1.5 Regime of Scale

1.6 The Problem of ‘Stop-and-Go’ Synthesis

1.7 Nature’s Approach to the Synthesis of Complexity

2 Cascade Catalysis as a Key Strategy for Laboratory ­Complex Target Synthesis

2.1 Iterative Cascade Catalysis

2.2 Cascade Catalysis Based on Multiple Reaction Types

2.3 Cycle-Specific Cascade Catalysis

3 Summary

Key words

cascade catalysis - organocatalysis - stop-and-go synthesis - natural product synthesis - enantioselective catalysis

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25

This number is based on collective discussions with Paul Reider and Mike Martinelli, Amgen Pharmaceuticals and Malcolm MacCoss, Merck Pharmaceuticals.

31

Given that this review is focused on the use of multiple catalytic cycles to generate complexity, we have restricted this discussion to cascade catalytic sequences that incorporate more than one asymmetric induction event.