A practical entry to the crambescidin family of guanidine alkaloids. Enantioselective total syntheses of ptilomycalin A, crambescidin 657 and its methyl ester (neofolitispates 2), and crambescidin 800

Among the most structurally remarkable guanidine natural products are the c rambescidin/ptilomycalin A family of marine alkaloids. The evolution of a p ractical strategy for preparing pharmacologically significant crambescidin/ ptilomycalin A alkaloids that lack oxidation at C13 is described. The first total syntheses of crambescidin 800 (2), crambescidin 657 (6), and neofoli tispate 2 (7) are reported in full detail. The central strategic step in th ese convergent total syntheses is tethered Biginelli condensation of beta-k eto ester 24 with ureido aminal 61 to combine all carbons of the guanidine nucleus and set the pivotal C10-C13 stereorelationship. The total synthesis of crambescidin 800 (2) was accomplished in 3% overall yield from commerci ally available 3-butyn-1-ol by way of 16 isolated and purified intermediate s. Full details of our earlier total synthesis of ptilomycalin A (1) are al so presented. The total syntheses described in this disclosure confirm the stereochemical assignments of 1, 2, 6, and 7 and rigorously establish that the absolute configuration of the hydroxyspermidine side chain of crambesci din 800 (2) is S.