Asymmetric aldol reactions using catalytic d(+)-proline: a new, economic and practical approach to a commonly employed C1–C6 keto-acid synthon of the epothilones

A new approach to ketoacid , a common C1–C6 fragment used in the total synthesis of epothilones was initiated by direct aldol reaction of acetone with a pivaldehyde-like substance , catalyzed with d-proline, leading to a 2,6-diketoalcohol with better than 99% ee. Further intramolecular closure of the diketone followed by oxidation of the silyl protected hydroxycyclohexenone led to the desired product . None of the steps have been optimized, yet the overall yield for the four-step process is 31%. The use of commercially available d-proline to construct the chiral center of under very mild reaction conditions provided an economical and practical method for its construction.