Synthesis of Biologically Active Natural Products by Means of C-H Insertion Reaction

Summarized in this article are the syntheses of heterocyclic natural products by means of Rh-catalyzed C-H insertion reaction of diazoester. During the course of our total synthesis of (-)-ephedradine A (1) by application of Ns-strategy, we found that the Rh-2(S-DOSP)(4) mediated C-H insertion reaction was enabled to simplify the synthetic process and decided to use it for the natural product synthesis. In the synthesis of serotobenine (4), the C-H insertion precursor was efficiently synthesized by the Leimgruber-Batcho protocol and a regioselective Claisen rearrangement. The racemic nature of serotobenine (4) is suggested by the presence of p-quinonemethide intermediate 6. Enantioselective synthesis of SB-203207 (25a) was accomplished by desymmetric C-H insertion reaction of 33 for construction of a bicyclo [3.3.0] framework, stereoselective construction of sequential stereocenters of 37, novel conversion from an aldehyde to a carboxylic acid, and nitrile hydrolysis. Stereoselective synthesis of MFPA (54) was accomplished by intermolecular C-H insertion and the asymmetric center at the benzylic position of 58 permitted efficient incorporation of the three sequential stereochemistries on the pyrrolidine ring of 68. Synthesis of aperidine (70) was featured by the cis-selective construction of a dihydrobenzofuran ring of 82 utilizing by Hashimoto's catalyst and preparation of diazoamide of 81 by Raines' protocol.