Highly enantioselective addition of primary alkyl Grignard reagents to carbocyclic and heterocyclic arylketones in the presence of magnesium TADDOLate preparative and mechanistic aspects

Abstract

In the presence of equimolar amounts of the Mg alkoxide from α,α,α′,α′-tetraphenyl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol (a TADDOL) primary Grignard reagents (Et, Pr, Bu, Oct, 3-butenyl) add to carbo- and heteroaromatic methyl ketones in THF at −100°C to give tertiary alcohols of enantiomeric excesses reaching values above 98%. The scope and limitation of the method are investigated. The reaction, which occurs in a vigorously stirred heterogeneous mixture, gives best results in the absence of steric hindrance of the reacting centers; Grignard reagents made from alkyl bromides are superior to those obtained from chlorides; there is a perfect linear relationship between the ee of the TADDOL and of the product 2-phenyl-2-decanol; those tertiary alcohols of which the absolute configuration is known, are formed by nucleophilic attack from the Re face of the keto carbonyl groups. Three tentative mechanistic models for the stereochemical course of the reaction are discussed.