Synthesis and reactions of Biginelli-compounds. Part 14.¹ A rhodium-induced cyclization–cycloaddition sequence for the construction of conformationally rigid calcium channel modulators of the dihydropyrimidine type

Abstract

Conformationally rigid polyheterocycles 14a,b which mimic the putative receptor-bound conformation of dihydropyridine type calcium channel modulators are prepared in a six-step reaction sequence starting from urea, ethyl acetoacetate and 2-alkenylbenzaldehydes. The key step in the synthesis involves the regio- and diastereoselective intramolecular 1,3-dipolar cycloaddition reaction of a dihydropyrimidine-fused isomünchnone dipole. Deprotection of the CBZ-protected intermediates 13a,b leads to the desired target molecules 14a,b. Prolonged exposure of these cyclic enamines in solution to the atmosphere results in oxidation to the corresponding α-hydroxy imines 16a,b. Catalytic hydrogenation of the related N-benzyl-protected polycycle 19 furnishes the fully saturated hexahydropyrimidine derivative 20. The relative stereochemistry in 20 was established by an X-ray crystallographic analysis.

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