A New and Efficient Approach to Macrocyclic Keto Lactones

Article abstract of DOI:10.1021/jo00289a040

A new and efficient method for macrolactonization has been developed.The intramolecular nucleophilic displacement of chloride from the highly electrophilic α-chloro ketone moiety in 15 by a remote carboxylate nucleophile resulted in the clean formation of the 11-membered keto lactone 1.Relatively high substrate concentrations (up to 18 mM) could be employed without formation of dimeric or oligomeric byproducts.The slow mixing of substrate and base was not required.This macrolactonization reaction was studied in various solvents at a number of substrate concentrations and reaction temperatures in order to evaluate its scope and limitations.A low-temperature Ti(III) ion/peroxide induced radical addition reaction has been developed.The lowering of the reaction temperature from 0 deg C to -78 deg C consistently afforded a dramatic increase in product yield from such reactions.This lowering of the reaction temperature proved essential when the highly functionalized acetoxymethyl vinyl ketone was employed as the radical acceptor.