The Nicholas Reaction: A Powerful Tool for the Stereoselective Synthesis of Bioactive Compounds

ABSTRACT Polyether units are a frequent heterocyclic fragment present in numerous natural products of great biological importance and constitute significant synthons for the synthesis of pharmacologically relevant compounds. Likewise, compounds having ­stereochemically defined alkyl-branched hydrocarbon chains are widespread in nature and the development of new synthetic ­methodologies to achieve their preparation in high yields and levels of stereocontrol is currently a challenging endeavour in organic synthesis. In this account, we describe our own approach to the stereoselective synthesis of bioactive compounds using the Nicholas reaction, the discovery of unexpected reaction pathways as well as some unreported results. The scope of the title reaction, within our research interests, and its synthetic applications are outlined. ­Reference to important related work from others in the field is also included. 1 Introduction 2 Synthesis of Symmetrical and Unsymmetrical Linear ­Propargylic Ethers 3 Synthesis of Cyclic Propargylic Ethers 3.1 Primary and Secondary Alcohols as Nucleophiles 3.2 Epoxides as Nucleophiles 4 Asymmetric Intermolecular Nicholas Reaction 5 Synthesis of Homopropargylic Ketones 6 Intramolecular Propargylic Reduction 7 Summary