Chiral Bronsted Acid-Promoted Enantioselective Desymmetrization in an Intramolecular Schmidt Reaction of Symmetric Azido 1,3-Hexanediones: Asymmetric Synthesis of Azaquaternary Pyrroloazepine Skeletons

摘要

Alkaloids containing azaquaternary pyrroloazepine skeletons including cephalotaxine and stemonamine are an important class of bioactive molecules in nature. How to directly and enantioselectively construct the azaquaternary pyrroloazepine skeleton remains a challenge. Desymmetrization reactions, which are used to synthesize chiral molecules, are proving to be a powerful method, and variations of this type of reaction have been well developed. For example, the proline catalyzed enantioselective desymmetrization of meso-1,3-diones that yield Hajos-Parrish and Wieland-Miescher ketones is widely known. When coupled with an intramolecular Schmidt reaction, which has proven to be a useful tool in the synthesis of alkaloids, it could allow facile construction of optically active lactams from readily available starting materials. The combined desymmetrization and Schmidt reaction of ketones and chiral azido alcohols in an intermolecular fashion was first developed by Aube and co-workers, wherein the products did not contain an azaquaternary center. However, an intramolecular Schmidt reaction of prochiral azido 1,3-diketones could concisely construct azaquaternary pyrroloazepine and indolizine compounds. Recent efforts to achieve enantioselective symmetry breaking of azido 1,3-diketones using this reaction failed when chiral Lewis acids were used. Herein, we report the first successful enantioselective desymmetrization in an intramolecular Schmidt reaction of prochiral azido 1,3-hexanediones; this reaction was promoted by 1,1'-bi-2-naphthal (BINOL)-derived N-triflylphosphoramides and yielded chiral azaquaternary pyrroloazepine skeletons.