QUADRONE STRUCTURAL AND SYNTHETIC STUDIES - TOTAL SYNTHESIS OF NATURAL (-)-QUADRONE, THE (+)-ENANTIOMER, AND THE RACEMATE - CONFORMATIONAL-ANALYSIS, CIRCULAR-DICHROISM, AND DETERMINATION OF ABSOLUTE STEREOCHEMISTRY

A concise (17 steps, 1.8% overall yield) and highly stereoselective synthesis of the architecturally novel, cytotoxic sesquiterpene (-)-quadrone (1) has been achieved, together with parallel constructions of the unnatural (+)-enantiomer and the racemate. The cornerstone of the strategy involved generation of the tricarbocyclic quadrone skeleton via an efficient, acid-promoted rearrangement of [4.3.2]propellane derivative 11. Further elaboration of rearrangement product 14 furnished enone acid 3, an advanced intermediate which had previously been converted to terrecyclic acid A (2) and thence to 1. Detailed conformational analysis of quadrone, encompassing molecular mechanics calculations, 2D NMR studies, and X-ray crystallography, converged upon two energetically significant conformers (D and E; predicted ratio 97.5:2.5 at 25-degrees-C). An empirical method for estimation of the sign and magnitude of DELTA-epsilon indicated that strain effects and octant-dissignate contributions of the pseudoaxial alpha-hydrogens dominate the circular dichroism spectrum of (-)-1.