Enantioselective synthesis of the bromopyrrole alkaloids manzacidin A and C by stereospecific C-h bond oxidation.
The manzacidins represent a small family of structurally unique secondary metabolites found only sparingly in nature. Efforts to probe the pharmacological profile of these intriguing bromopyrrole alkaloids have been precluded by a deficiency of available material. Access to substantive quantities of both manzacidins A and C is now made possible through a rapid, enantioselective, and highly efficient synthesis that is described herein. The path to these targets showcases for the first time the distinct power of our catalytic C-H bond amination methodology for simplifying problems in alkaloid total synthesis. Application of this chemistry enables the facile and enantiospecific installation of tetrasubstituted carbinolamine stereocenters, functionality common to all of the manzacidins. The requisite materials for implementing our plan are assembled using modern tools for catalytic asymmetric synthesis that include both carbonyl-ene and directed hydrogenation reactions. In addition, a new protocol for tetrahydropyrimidine synthesis is established. The synthesis of each manzacidin comprises a 10-step sequence that proceeds in an overall yield of approximately 30%.
Wehn
Paul M
PM
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA.
Du Bois
J
J
D000470:Alkaloids / Q000138:chemical synthesis*; D000818:Animals; D010084:Oxidation-Reduction; D011161:Porifera / Q000737:chemistry; D011743:Pyrimidines; D011758:Pyrroles / Q000138:chemical synthesis; D013237:Stereoisomerism; D013379:Substrate Specificity
D000470:Alkaloids; D011743:Pyrimidines; D011758:Pyrroles; C470325:manzacidin A; C470326:manzacidin C