Building Complexity and Achieving Selectivity through Catalysis – Case Studies from the Pharmaceutical Pipeline

Dedicated to Prof. Barry M. Trost in recognition of his contributions to the advancement of transition-metal catalysis and his efforts in training the next generations of organic chemists.

Abstract

The last decade of small-molecule process development has witnessed a trend of increasing molecular complexity for clinical candidates. The continued advance of novel catalytic methods and subsequent translation to efficient and scalable processes has enabled process chemists to overcome the challenges associated with increasing complexity. This Account highlights several examples from the process chemistry laboratories at Amgen.

1 Introduction

2 The Evolution of Molecular Complexity

3 Catalysis as a Lever to Build Complexity

4 Ru(II)-Catalyzed Dynamic Kinetic Resolution Enabling the Manufacture of AMG 232

5 Application of Enzymatic Desymmetrization toward Scale-Up of the MCL-1 Inhibitor AMG 176

6 Synthesis of Fucostatin 1: Catalytic Asymmetric Transfer Hydrogenation

7 Manganese-Catalyzed Asymmetric Epoxidation To Prepare a Carfilzomib Intermediate

8 Asymmetric Reduction Strategies: Novel Apelin Receptor Agonists and AMG 986

9 Conclusions

Key words

catalysis - process development - drug development - green chemistry - synthetic methods

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