The Wieland-Miescher
Ketone: A Journey from Organocatalysis to Natural Product Synthesis

Ben Bradshaw; Josep Bonjoch

doi:10.1055/s-0031-1290107

ACCOUNT

The Wieland-Miescher Ketone: A Journey from Organocatalysis to Natural Product Synthesis

Ben Bradshaw*, Josep Bonjoch*
Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, IBUB, Av. Joan XXIII s/n, 08028 Barcelona, Spain
Fax: +34(934)024539; e-Mail: benbradshaw@ub.edu, josep.bonjoch@ub.edu;

Abstract

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Abstract

The Hajos-Parrish-Eder-Sauer-Wiechert reaction can be considered as the origin of asymmetric organocatalysis, giving rise to the Wieland-Miescher ketone 1 (WMK), a versatile building block. Although 40 years have passed since its discovery, a highly enantioselective and scalable synthesis of the WMK has remained elusive. This account details a solution to that problem that came about in the development of methodology towards C-8a WMK analogues as part of the total synthesis of complex diterpene natural products. The work has been placed in the context of the historical background and reactivity of this important building block, highlighting the challenges faced by organocatalysis in large-scale reactions.

1 Introduction

2 The Wieland-Miescher Ketone

2.1 The Hajos-Parrish-Eder-Sauer-Wiechert Reaction: A Historical Perspective

2.2 Practicalities of the Wieland-Miescher Ketone Synthesis Using Proline

2.3 Alternative Catalysts for the Synthesis of the Wieland-Miescher Ketone

3 Background to Developing a New Wieland-Miescher Ketone Synthesis

4 Optimization of Method and Conditions

5 Key Reactions of the Wieland-Miescher Ketone

5.1 Reduction, Oxidation, Protection, and Non-C-C-Bond-Forming Reactions

5.2 C-C-Bond-Forming Reactions

5.3 Ring-Expansion and -Contraction Reactions

6 Conclusions and Future Considerations

Key words

Wieland-Miescher ketone - enantioselective direct aldol reaction - asymmetric organocatalysis - total synthesis - natural products

Full Text

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