Synthesis of depressin, cryptomeridiol and 4-epi-cryptomeridiol enabled by a terpenoid chiral pool-producing platform.

Abstract

Depressin (1) is a soft coral-derived diterpenoid containing the typical bicyclo[12.1.0]pentadecane casbane skeleton and a C5-keto group. Key strategies for the synthesis of depressin, as well as its casbene skeleton reported so far focused on the formation of the challenging 14-membered ring system. Cryptomeridiol (2) and 4-epi-cryptomeridiol (3) are two eudesmane-type sesquiterpene diols produced by a variety of different plants with broad biological activity. Most of the syntheses focused on the transformation of chiral pool substrates into their trans-6/6-fused ring system. We herein report the synthesis of compounds 1-3 by taking advantage of an expanded chiral pool strategy, in which the terpenoid skeletons including casbene (4) and germacrene A (5) were produced by an Escherichia coli-based heterologous host harboring the isopentenol utilization pathway and corresponding terpene cyclases. Two allylic oxidations of both C13 and C5 positions of the casbene skeleton followed by deoxygenation of C13 hydroxy group allowed the synthesis of compound 1 from 4 in nine steps. Selective acid-mediated 5,10-transannular cyclization of 5 followed by hydration reaction furnished both products 2 and 3 in two steps.