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

• Published in: Journal of the American Chemical Society 2000-05, Vol.122 (20), p.4893-4903
• Main Authors: Coffey, D. Scott, McDonald, Andrew I, Overman, Larry E, Rabinowitz, Michael H, Renhowe, Paul A
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja000234i

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.