Improved Synthesis of Triketide δ-Lactones from the Pikromycin Biosynthetic Pathway

Abstract

In connection with the generation of hybrid polyketide synthases (PKSs) derived from the pikromycin PKS system, we have been interested in δ-lactones 1 and 2. We reported a synthesis of both lactones by the routes based on the asymmetric aldol and the Reformatsky reaction as key steps. Although the desired δ-lactones 1 and 2 were prepared successfully, the synthesis did have limitations. While the δ-lactone 2 was efficiently synthesized by the reported route, the lactone 1 having an epimeric stereochemistry on C-3 could not be prepared efficiently due to the low diastereomeric selectivity in the asymmetric Reformatsky reaction step. Also, the origin of the stereoselectivity was based on the Evans chiral oxazolidinone auxiliary. It is, therefore, desirable to eliminate the use of rather expensive Evans chiral auxiliary to prepare the lactone 1 more practically. Herein, we wish to report modified synthetic routes to the δ-lactones, focusing especially on more efficient and more practical synthesis of the lactone 1.