酮羰基不对称α-联烯化及其桥环骨架天然产物集群式全合成应用研究

Chemical synthesis has commonly generated individual or small groups of natural products, however, efficient methodologies allowing the synthesis of a large collection of natural products remain scarce. Despite substantial progress has been achieved in the field of asymmetric α-allylation and -arylation of ketone, catalytic asymmetric α-allenylation of ketone has not been reported thus far. By integrating the unique activation modes of organocatalysis with the well-established chemistry of metal catalysis, a new strategy of synergistic primary amine/thiourea/Lewis acid catalysis for the unprecedented catalytic asymmetric α-allenylation of ketone will be developed. This methodology will provide rapid access to the bridged core skeleton of Strychnos and Akuammiline alkaloids (2-azabicyclo[3.3.1]nonane) and simultaneous assembly of functional groups that could be easily elaborated (e.g., allenyl group). Based on the preliminary progress of this methodology (up to 95% yield, 98% ee), a concise collective total synthesis of multiple members of Strychnos and Akuammiline alkaloids is expected to be realized.

目前实现单个或少数几个相同类型天然产物的全合成已不再遥不可及，但快速高效地实现多个天然产物的集群式全合成仍然极具挑战性，依赖于方法学在原理和效率上的进一步突破。酮羰基不对称α-烯丙基化和-芳基化反应已经得到长足的发展，不对称催化的羰基α位直接联烯化反应却未见文献报道。申请人课题组拟通过整合有机催化和金属催化优点，探索新颖的胺基硫脲手性小分子催化剂和金属协同催化模式，发展不对称催化的酮羰基α位联烯化反应方法学，构建马钱子属和阿枯米灵类生物碱的通用桥环核心骨架—2-氮杂二环[3,3,1]壬烷，并同步实现联烯等易多样化衍生官能团的组装，进而实现马钱子属和阿枯米灵类生物碱的集群式高效全合成。目前，我们已取得较好的方法学进展（up to 95% yield, 98% ee），并实现了该桥环核心骨架的构建。

不对称酮的alpha-官能团化是一类应用广泛的合成反应。但相较于发展成熟的alpha-烯丙基化、烷基化、芳基化、烯基化反应，酮羰基的alpha-联烯化反应却鲜有报道。通过项目的执行，我们使用金属和有机催化协同催化的策略，成功发展了一种不对称催化的酮羰基alpha-联烯化方法学，高效构建了马钱子碱的桥环核心骨架，并同步引入环外联烯基团，以此为基础，高效完成了9个马钱子碱的集群式全合成；建立了吡咯和AgN(OTf)2的协同作用的羰基alpha-联烯化反应体系，高效构建了萨杷晋碱的1-氮杂双环[2.2.2]辛烷骨架，完成了5个萨杷晋碱以及生源关联的3个钩吻碱的集群式全合成。这些成果不仅解决了羰基alpha-联烯化方法学长期存在的难题，还为桥环生物碱的全合成提供了一种新策略。