Endo-selective epoxide-opening cascades in water

Abstract

Chapter I. Introduction to the Ladder Polyethers. We introduce the bioactivity of the ladder polyether natural products and provide an overview of the puzzle that is their biogenesis. Cascades of endo-selective epoxide opening inspired by the biosynthetic proposal and promoted by simple neutral water can provide efficient access to these compounds. Chapter II. Water-Promoted Epoxide Opening Accommodates Methyl Substitution. ... Methyl (Me) substitution poses a challenge to the achievement of endo-selective epoxide-opening cascades, as these groups can direct the regioselectivity of epoxide opening. Water as reaction solvent and promoter overcomes such directing effects and enables the incorporation of proximally Me-substituted epoxides into endo-selective cascades. However, Me-substituted epoxides do reduce the overall efficiency of cascades. Chapter III. Kinetics of an Epoxide-Opening Cascade Promoted by Neutral Water. Evidence for a Stepwise Mechanism. ... Detailed investigation of the kinetics of an endo-selective epoxide-opening cascade in water reveals a stepwise mechanism, not a concerted one. While the first step proceeds with poor rate and selectivity, the second cyclization, which is templated by a fused THP diad, proceeds with excellent endo selectivity. Chapter IV. Preliminary Investigation of a Dioxane Template for Endo-Selective Epoxide-Opening Cyclization. ... Use of a 1,3-dioxane as template ring, a methylene acetal engenders endoselective epoxide opening under both acidic and basic conditions. Cyclization in neutral water proceeds with superb endo selectivity. Chapter V. Progress Toward the Synthesis of Gambierol via Endo-Selective Epoxide-Opening Cascades Promoted by Water. ... We report progress toward the biomimetic total synthesis of the ladder polyether gambierol. The FGH ring system has been synthesized in a 20 step longest linear sequence, via an endo-selective epoxide-opening cascade promoted by water. Chapter VI. Conclusion: Potential Implications of the Foregoing Work on the Biosynthesis of the Ladder Polyethers. We summarize lessons learned from in vitro emulation of the hypothesized biosynthesis of the ladder polyethers and speculate on the possibility of ring junction methylation subsequent to the epoxide-opening cascade step.