Semisynthesis and absolute configuration of a novel rearranged 19,20-δ-lactone (9βH)-pimarane diterpene

Abstract

Annonalide (3β,20-epoxy-3α,16-dihydroxy-15-oxo-7-pimaren-19,6β-olide, C20H26O6, 1) is the major (9βH)-pimarane diterpene isolated from tubers of Cassimirella ampla, and it exhibits cytotoxic properties upon interaction with ctDNA. We have prepared new derivatives of 1 by modification of the (9βH)-pimarane backbone and report here the semisynthesis and absolute configuration of a novel rearranged 19,20-δ-lactone (9βH)-pimarane. Our approach was the reduction of the carbonyl groups of 1 with sodium borohydride, at positions C15 (no stereoselectivity) and C3 (stereoselective reduction), followed by rearrangement of the 6,19-γ-lactone ring into the six-membered 19,20-δ-lactone ring in 4a (3β,6β,16-trihydroxy-7-pimaren-19,20β-olide monohydrate, C20H30O6·H2O). The absolute structure of the new compound, 4a, was determined unambiguously with a Flack parameter x of −0.01 (11), supporting the stereochemistry assignment of 1 redetermined here. Besides the changes in the pattern of covalent bonds caused by reduction and lactone rearrangement, the conformation of one of the three fused cyclohexane rings is profoundly different in 4a, adopting a chair conformation instead of the boat shape found in 1. Furthermore, the intramolecular hydrogen bond present in 1 is lost in new compound 4a, due to hydrogen bonding between the 3-OH group and the solvent water molecule.