Strategy for the Synthesis of Epoxide‐ and Carbonate‐Containing Dienediyne Models of the Neocarzinostatin Chromophore – Application to the 6‐Ring/11‐Ring Case[1]

Abstract

AbstractA novel synthetic strategy leading to bicyclic dienediyne models of the chromophore 1 of the anti‐tumor antibiotic neocarzinostatin is described. Its key step is a ring‐closing McMurry reaction of the dienediyne keto aldehydes 17 or 23. It leads to dienediynediols (compounds 19 and 24, respectively) or to trienediynes (compounds 18 and 25, respectively). Low temperatures favor the formation of dienediynediols while high temperatures favor the formation of trienediynes, so that the McMurry reactions of keto aldehyde 23 show an almost perfect temperature‐dependent chemoselectivity (Scheme 6). The trienediyne 25 contains a ketal group which was removed by acid‐catalyzed methanolysis (Scheme 8). The resulting diol 31 was mono‐tert‐butylsilylated to provide the allyl alcohol 36 (Scheme 10). It was epoxidized regio‐ and stereoselectively with Sharpless' asymmetric epoxidation reagent. The resulting epoxide 37 was converted into the dienediyne epoxycarbonate syn‐33 in the final step of a sequence totaling seven steps and 5% yield starting from the bistriflate 3b; 3b itself is accessible from 2‐formylcyclohexa none in two steps and 47% overall yield. The dienediyne epoxycarbonate syn‐33 is the first synthetic congener of the neocarzinostatin chromophore furnished both with the – correctly configured – epoxide and carbonate rings.