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 crambescidin/ptilomycalin A family of marine alkaloids. The evolution of a practical 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 neofolitispate 2 ( 7 ) are reported in full detail. The central strategic step in these convergent total syntheses is tethered Biginelli condensation of β-keto 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 commercially available 3-butyn-1-ol by way of 16 isolated and purified intermediates. Full details of our earlier total synthesis of ptilomycalin A ( 1 ) are also 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 crambescidin 800 ( 2 ) is S .