Intramolecular Enolate Alkylation: From Steroids through Cladiellins to Isolaurallene

On the eve of my retirement, it is my great pleasure to dedicate this account to Professors Steven Weinreb and Gilbert Stork for their insightful tutelage and inspiration throughout my career.

Abstract

This account of the author’s contributions over his career attempts to sketch out a research arc that stretches all the way from very simple beginnings, taking inspiration from the steroidal trans-hydrindane problem, to the development of a general strategy for the stereoselective construction of cycloalkanecarboxylates via a folding and allylic strain controlled intramolecular ester enolate alkylation, with applications thereof to the total syntheses of natural products of modest complexity. Examination of the corresponding S_N2′ version of this methodology led to a serendipitous discovery that ultimately produced the olefin geometry dependent intramolecular amide enolate alkylation. Applications and extensions of this methodology have enabled completely substrate-controlled asymmetric total syntheses of diverse medium-ring oxacyclic marine natural products, and a fortuitous discovery along the way involving an organoselenium-based method led to an intriguing biomimetic synthesis of Laurencia metabolites. Observations are made regarding aspects of a research career in retrospect.

1 Introduction

2 Intramolecular S_N2 Enolate Alkylation

3 Intramolecular S_N2′ Enolate Alkylation

4 Synthesis of α,α′-cis-Disubstituted Medium-Ring Oxa­cyclic Marine Natural Products

5 Synthesis of α,α′-trans-Disubstituted Medium-Ring Oxa­cyclic Marine Natural Products

6 General Synthetic Plan for Dioxabicyclic Bromoallene ­Marine Natural Products Having either a 2,10-Dioxabi­cyclo[7.3.0]dodecene or 2,9-Dioxabicyclo[6.3.0]undecene Skeleton

7 Conclusion

Key words

intramolecular enolate alkylation - natural products - substrate-controlled synthesis - medium-ring ethers - ring-closing metathesis

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