Improved and Environmentally Friendly Large-Scale Preparation of Cyclohexadienyl-, Cycloheptadienyl Sulfone and Enantiopure Epoxy Cycloheptyl Sulfones

Abstract

Kilogram-scale amounts of cycloheptadienyl phenylsulfone and cyclohexadienyl phenylsulfone were prepared by one operation in 5 stages with over 50% yield and requiring no purification. A practical and efficient method for the Jacobsen asymmetric epoxidation of 1,3-cycloheptadienyl sulfone is described. The reported method is suitable for large-scale synthesis, does not use halogenated solvents nor does it require chromatography As a part of our program to develop short and scalable syntheses of polypropionate containing natural products, it became essential to develop efficient preparations of dienes 1 and 2 and the enantiopure epoxides 3 and 4 derived from them (Scheme 1). 1 In 2002, Meyers developed an improved method for the preparation of 1 and 2; although this method was highly satisfactory for generation of hundred gram quantities of diene 1, and 2, it still was unsuitable for the multi-kilogram scale. 2 In 1997, Hentemann found that Jacobsen asymmetric epoxidation (JAE) of cyclohexadienyl and cycloheptadienyl sulfones 1 and 2 gave the enantiopure epoxides 3 and 4 in good yield and outstanding ee. Additionally, one could obtain either epoxide enantiomer by application of the appropriate commercially available enantiomeric catalyst. 3,4 A major drawback of the JAE was scalability of the reaction. The development of an optimized process for the preparation of diene 1, 2 and epoxide 3 is now at hand.Optimization of each individual step for the kilogram synthesis of 1 and 2 has now been accomplished. The new optimized syntheses are now one-operation procedures that involve 5 distinct stages but require no purification.