First Synthesis of Shimobashiric Acid C With Acetonide as the Catechol Protecting Group

Abstract

Shimobashiric acid C (SBA-C) shows excellent hyaluronidase inhibition but its natural isolation yield is only 0.0092 %. We report its first synthesis via a convergent seven-step route from caffeic and rosmarinic acids in 35% overall yield. Direct protection of D-Danshensu (D-DSS) with 2,2-dimethoxypropane gave an isochroman; the desired acetonide-protected D-DSS building block was instead prepared from methyl rosmarinate via bis-acetonide formation followed by methanolysis. Acetonide-protected caffeic acid was synthesized and crystallized in a P-1 lattice, where linear hydrogen-bonded caffeic acid pairs pack with adjacent alkenyl bonds aligned at 3.919 Å for head-to-tail solid-state [2+2] photodimerization. Irradiation at 365 nm gave the acetonide-protected α-truxillic acid building block. The two blocks were condensed via Steglich esterification to give acetonide-protected SBA-C methyl ester. Selective deprotection of the acetonide groups was achieved with 55% trifluoroacetic acid in the presence of trace water in nearly quantitative yields. This mild deprotection caused no noticeable side reactions and may be applied to synthesis of other D-DSS-containing phenolic acids, such as salvianolic acids.