Total Synthesis and Bioactivity Investigation of a Chiral Diacylglycerol

Abstract Compound 1, a chiral diglyceride metabolite found in both humans and fungi, was targeted for total synthesis. A seven-step synthetic route was developed, affording compound 1 in 2.33% overall yield. The key steps involved: (1) selective protection of the terminal hydroxyl group of chiral ketal 2 with a sterically hindered benzyl group, followed by removal of the ketal moiety to generate benzyl ether 4; (2) protection of the terminal hydroxyl group of benzyl ether 4 with a bulky silyl protecting group, and subsequent esterification of the remaining free hydroxyl with erucic acid to yield ester 6; (3) removal of the silyl protecting group from ester 6, followed by esterification of the liberated hydroxyl group with pentadecanoic acid, affording ester 8; and (4) selective deprotection of the benzyl group of ester 8 to furnish compound 1. In silico screening using three databases identified 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) as a potential biological target of compound 1. However, in vitro HMGCR inhibition assays demonstrated that compound 1 did not significantly reduce cholesterol levels in human blood. These results contribute to the chemical synthesis and biological evaluation of chiral diglycerides and provide a foundation for future investigations in this area.