Improved and scalable synthesis of potent SREBP inhibitor KK-052 via [3+2] cycloaddition

Abstract

KK-052 is a novel vitamin D-based selective SREBP suppressor lacking vitamin D genomic activity mediated through the vitamin D receptor in both in vitro and in vivo settings. In our initial synthetic effort, KK-052 was produced as one of the structural isomers obtained via the Mitsunobu reaction involving CD-ring allyl alcohol (3) and 5-phenyl-1H-tetrazole. In this work, we present a refined methodology for enhancing the selective synthesis of KK-052 through [3+2] cycloaddition involving CD-ring benzimidoyl chloride (11) and sodium azide, a technique scalable for gram-scale production. Additionally, this synthetic method permitted the production of the more potent m-methyl analogue (7).