Synthesis of 2,9,10-trioxatricyclo[4.3.1.0]decane analogues of resiniferatoxin

Abstract

Structurally simplified analogues of the daphnane diterpene resiniferatoxin (RTX)1, possessing the unusual 2,9,10-trioxatricyclo[4.3.1.0]decane system have been synthesised stereoselectively from cyclohexa-1,3-diene: functionalisation of the diene afforded the anti-epoxide, 1,4-di-O-benzyl-t-2,t-3-epoxycyclohexane-r-1,c-4-diol 4, the ring-opening of which was examined using various organo-metallic reagents; organoaluminium species were found to be the most efficient to effect this reaction. When trimethylsilyl (in place of benzyl) ethers were used to protect the diol, selective deprotection of 1,4-di-O-trimethylsilyl-2-O-(p-tolylsulfonyl)-c-3-[3-(tert-butyldiphenylsilyloxy)-prop-1-ynyl]cyclohexane-r-1,t-2,c-4-triol 16 was achieved using citric acid in methanol—the equatorially disposed trimethylsilyl ether was found to be more easily cleaved than the axially orientated one. Formation of the tricyclic orthoester was achieved by the generation of a dioxolenium ion from 1-O-phenylacetyl-2-O-(p-tolylsulfpnyl)-c-3-[3-(tert-butyldiphenylsilyloxy)-prop-1-ynyl]cyclohexane-r-1,t-2,c-4-triol 19, by heating in 2,4,6-trimethylpyridine, with in situ intramolecular trapping by the suitably orientated hydroxy group to give 1-benzyl-7-(3-tert-butyldiphenylsilyloxyprop-1-ynyl)-2,9,10-trioxatricyclo[4.3.1.0] decane 20.