INTERNAL LEWIS-ACID COORDINATION AS A POWERFUL TOOL TO PROMOTE HIGHLYSTEREOSELECTIVE ALKYLATION OF ALPHA-ALKYL-BETA-HYDROXY KETONES WITH GRIGNARD-REAGENTS

An efficient and highly diastereoselective protocol is described for t he alkylation of beta-hydroxy ketones that contain an a-stereocenter. This method is based on the preliminary transformation of the beta-hyd roxy group into a titanium alcoholate by means of the facile transmeta lation of the corresponding beta-silyloxy derivative with TiCl4 (Metho d A) or by reaction of the lithium alcoholate with TiCl4 (Method B). O n account of the strong internal coordinating action of the Lewis acid , this intermediate assumes a rigid half-chair conformation with the a lpha-alkyl substituent in a pseudoaxial position, This geometrical arr angement facilitates the attack of the entering carbanion on the carbo nylic function apposite to the alpha-substituent. The method uses simp le Grignard reagents as the alkylating agents and allows the addition of a wide variety of carbon frameworks to the carbonyl function. inclu ding primary and secondary alkyl chains, arylic, alkynylic, vinylic, a nd benzylic moieties, with high efficiency and stereoselectivity.