Intramolecular Enolate Alkylation: From Steroids through Cladiellins to Isolaurallene

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 <i>trans</i>-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 <i>Laurencia</i> 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′-<i>cis</i>-Disubstituted Medium-Ring Oxa­cyclic Marine Natural Products 5 Synthesis of α,α′-<i>trans</i>-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