The first asymmetric synthesis of the complete daphnane skeleton

The daphnanes, tigliane and ingenane families of diterpene esters are isolated from the Euphorbiaceae and the closely related Thymelaeceae plant families. Individual species of these families have long been noted for their diverse toxicological effects on animals and man, including the induction of inflammation to the skin, purgative action in man, and tumor promotion. They have also been used as fish poisons and as an ingredient of arrow poisons. With such diverse toxicological activities, it is not surprising that the plants of these families have been utilized as drugs in both traditional and alternative medicine as treatments for growths and tumors, migraine, parasitic infections, bacterial infections, skin conditions, purgatives and abortifacients. Resiniferatoxin (RTX) is a naturally occurring daphnane which was identified in the latex of three species of Euphorbia (E. resinifera, E. poissonii and E. unispina) on the basis of its extraordinary irritant activity. Unlike the structurally related tigliane phorbol esters, RTX functions as an ultrapotent analog of capsaicin, the major pungent constituent of red pepper and other plants of the genus Capsicum. In light of the current use of capsaicin in human therapy, the evaluation of RTX and its analogs for the desensitization of vanilloid pathways is of tremendous interest. The identification and possible cloning of the putative receptor subclasses and analysis of their individual structure activity requirements will have a major impact on the development of more selective agents with optimized spectra of actions in which undesired effects like pungency and hypothermia can be dissected by chemical modification.; This paper describes the first asymmetric synthesis of the complete daphnane skeleton, a key intermediate in our proposed synthesis of resiniferatoxin. The general strategy employed in this approach involves the rapid and stereoselective construction of the daphnane BC-ring moiety in a facially selective oxidopyrylium-alkene cycloaddition. Subsequent functionalization, and A-ring annulation allows for efficient construction of the tricarbocyclic daphnane skeleton. The first asymmetric synthesis of the daphnane skeleton was achieved in 22 steps with an overall yield of 5.6% from readily available starting materials.