Certain members of the crambescidin natural products, [1][2][3][4][5] derived from the marine sponge Crambe crambe, have exhibited remarkable biological properties, including anticancer, anti-HIV, antifungal, and Ca 2+ ion channel blocking activities. Many compounds within this class are characterized by a polycyclic guanidine core linked to a hydroxyspermidine moiety by a linear ω-hydroxy fatty acid. Crambidine (1, Figure 1) is atypical within this family of alkaloids in that it possesses a fused pyrimidine heterocyclic core, while most of its other congeners exist in more highly reduced forms. Several elegant strategies have been reported for the synthesis of crambescidin alkaloids. 6-9 However, only a single reported synthesis of crambidine (1) has appeared, 10 involving dihydropyrimidine construction via Biginelli condensation, followed by oxidation. We report herein a synthesis of (-)-crambidine that capitalizes on two key processes, including a [4+2] annulation of thioimidates with vinyl carbodiimides and a hydroamination of alkynes with 2-aminopyrimidine nucleophiles.

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