Enantioselective total syntheses of 13,14,15-isocrambescidin 800 and 13,14,15-isocrambescidin 657

The first total syntheses of 13,14,15-isocrambescidin 800 (1) and 13,14, 15-isocrambescidin 657 (2) were accomplished in convergent fashion. The central strategic step was tethered Biginelli condensation of guanidine aminal 14 and beta-ketoester 15 to give 1-iminohexahydropyrrolo[1,2-c]pyrimidine carboxylic ester 16. This step united all the heavy atoms of the pentacyclic guanidine nucleus and set the critical trans C10-C13 stereorelationship. Acidic treatment of derivative 18 triggered tricyclization to generate pentacyclic guanidine 19b in high yield. After cleavage of the allyl ester, the derived acid underwent coordinated epimerization at C14 and C15 in the presence of triethylamine to form the pentacyclic isocrambescidin nucleus. The synthesis of 1 was achieved in 11% overall yield from amine 12 by a sequence involving five isolated intermediates. As detailed in the preceding account, 12 can be accessed from commercially available 3-butyn-1-ol in 30% overall yield by way of nine isolated and purified intermediates. Mosher derivatives were prepared from (S)-(-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid and natural 1, synthetic 1, and synthetic C43 epimer 31. Analysis by F-19 NMR showed that the Mosher derivatives of natural and synthetic 1 were identical, thus establishing for the first time that the stereochemistry of 13,14,15-isocrambescidin 800 (1) at C43 is S. The mechanism of the tricyclization and epimerization steps is discussed, as are the relative energies of the 13,14,15-isocrambescidin, 13,15-epicrambescidin, and 13-epicrambescidin guanidine moieties.