Concise Total Syntheses of (S)-Macrostomine and Cermizine D

The Comins research group has dedicated its efforts to the development of methodologies in order to synthesize a large number of alkaloids with a wide array of biological activities. The two main areas of research have been the directed metalation of nitrogen heterocycles, and the development of chiral N-acylpyridinium salts capable of providing addition products with high diastereoselectivity. In this work, we have employed both lines of methodology in order to complete the total syntheses of the natural products ( S)-macrostomine and cermizine D. Directed metalation methodologies were utilized in the total synthesis of (S)-macrostomine, accomplished in five steps from natural nicotine in 19% overall yield. Key steps include a Diels-Alder cycloaddition reaction, and a Kumada cross-coupling reaction to furnish the natural product. This work constitutes the shortest synthesis of this natural product published to date, and further demonstrates the value of (S)-nicotine as a chiral building block. The total synthesis of (+/-)-cermizine D was achieved using a dihydropyridone-based functionalization strategy. The synthesis is concise in six steps from 4-methoxypyridine in 14% overall yield. A key step in the synthesis is an enantioselective copper-mediated 1,4-addition to a bicyclic 2,3-dihydro-4-pyridone. This is the shortest route toward the natural product published to date, and this work restates the utility and versatility of N-acylpyridinium salt chemistry in the concise synthesis of complex molecules.