Total synthesis, structural revision and biological evaluation of γ-elemene-type sesquiterpenes

Abstract

Total synthesis and absolute configuration confirmation of γ-elemene-type sesquiterpenes, which possess vast potential for biological activities, was investigated based on a convergent synthetic strategy. A key intermediate with all functional groups of this family of natural products was accessed by an intermolecular aldol reaction and then an acetylation of a known ketone (12) derived from commercially available verbenone. The versatile intermediate can be easily transformed into structurally different γ-elemene-type sesquiterpenes based on control of base-promoted cyclization manipulation in different solvents. The utility of this robust approach is illustrated by the first syntheses of elema-1,3,7(11),8-tetraen-8,12-lactam (4′) and 8β-methoxy-isogermafurenolide (6a), as well as the syntheses of elem-1,3,7,8-tetraen-8,12-olide (3) and hydroxyisogermafurenolide (5) in only 6 or 7 steps. In addition, the structure of the reported 5βH-elem-1,3,7,8-tetraen-8,12-olide (1) was revised as elem-1,3,7,8-tetraen-8,12-olide (3) by comparison of their identified datum, and the absolute configuration of elema-1,3,7(11),8-tetraen-8,12-lactam was confirmed as 4′. Furthermore, the inhibitory effect of all synthesized natural compounds and their natural analogues on cancer cell proliferation was evaluated. Among them compounds 3, 4 and 4′ were found to possess potent inhibitory activity against Kasumi-1 and Pfeiffer. Meanwhile, preliminary structure–activity relationships for these compounds are discussed.