Stereodivergent Desymmetrization of Phenols En Route to Modular Access to Densely Functionalized Quinazoline and Oxazine Scaffolds

The de novo assembly of stereochemically and skeletally diverse scaffolds is a powerful tool for the discovery of novel chemotypes. Hence, the development of modular, step- and atom-economic synthetic methods to access stereochemically and skeletally diverse compound collection is particularly important. Herein, we show a metal-free, stereodivergent build/couple/pair strategy that allows access to a unique collection of benzo[5,6][1,4]oxazino[4,3-a]quinazoline, quinolino[1,2-a]quinazoline and benzo[b]benzo [4,5]imidazo[1,2-d][1,4]oxazine scaffolds with complete diastereocontrol and wide distribution of molecular architectures. This metal-free process proceeds via desymmetrization of phenol derivatives. The cascade unites Mannich with aza-Michael addition reactions, providing expeditious entries to diverse classes of molecular shapes in a single operation.立体化学与骨架均具多样性的分子骨架从头组装（de novo assembly）是发现新型化学型的强有力工具。因此，开发模块化、步骤经济且原子经济的合成方法，以获取兼具立体化学多样性与骨架多样性的化合物库，具有尤为重要的意义。本文报道一种无金属、立体发散的构建-偶联-配对策略，可在完全非对映选择性控制下，得到一系列独特的苯并[5,6][1,4]恶嗪并[4,3-a]喹唑啉、喹啉并[1,2-a]喹唑啉以及苯并[b][4,5]咪唑并[1,2-d][1,4]恶嗪类分子骨架化合物，且产物的分子架构分布广泛。该无金属过程通过酚类衍生物的去对称化反应实现，其串联反应整合了曼尼希（Mannich）与氮杂迈克尔（aza-Michael）加成反应，可通过一步操作高效制备多种不同类型的分子构型。