Studies on the Syntheses of Bioactive Natural Products Having a Fused Ring System Based on Novel Skeletal Construction Methods

Abstract

Here, I describe a part of our efforts to develop synthetic strategies to construct bioactive natural products having a fused ring system. We have designed four chiral building blocks bearing contiguous quaternary stereocenters for the syntheses of bioactive C17-oxygenated steroids/triterpenoids and C9-oxygenated labdane diterpenoids. The compounds were stereoselectively synthesized from α-substituted glycolic acid (R)-3-methylcyclohex-2-enyl esters through Ireland-Claisen rearrangement to construct the stereocenters simultaneously. Synthetic utility of a β-type building block is highlighted by total syntheses of marrubiin (11 steps, 22%) and related seven labdane diterpene lactones, cyllenine C (12 steps, 29%), marrulactone (13 steps, 11%), marrulanic acid (14 steps, 10%), marrubasch F (12 steps, 14%), marrulibacetal (14 steps, 4%), marrulibacetal A (14 steps, 2%), and desertine (15 steps, 0.5%). These syntheses feature the construction of the [6.6.5]-tricyclic ring portion via a Pauson-Khand reaction, cleavage of the resultant cyclopentenone ring and an elongation of the C9 side chain by an epoxide opening reaction. The relative stereochemistry of desertine was determined to be 13R, 14S, 15S, 16R by some chemical conversions and NMR analysis. Further efforts toward total syntheses of oxygenated terpenoids using three other chiral building blocks and structure-activity relationship study of synthesized labdane diterpene lactones are currently underway in our laboratory and will be reported in due course.