Rhodium(II)-Catalyzed Strain-Enabled Stereoselective Synthesis of Skipped Dienes

Skipped dienes are not only present in fatty acid primary
metabolites
and natural products but also serve as reactive intermediates in diverse
chemical synthesis. Despite this, the regioselective and stereoselective
synthesis of skipped dienes remains a challenging goal. Strain release
in organic molecules is a powerful tool for creating chemical complexity
under mild conditions. The reactivity of strained bicyclo[1.1.0]butane
(BCB) systems is mainly dominated by transformations relying on their
innate electrophilic reactivity. Herein, we report a rare example
of the carbene-type reactivity of the BCB system based on rhodium–carbene
chemistry, which enables the highly stereoselective synthesis of skipped
dienes through strain release. The reaction is compatible with a diverse
range of functional groups on both diazo compounds and BCBs and could
be applied successfully to complex structures, providing highly valuable
and functionalizable skipped dienes. The functional groups introduced
during the reaction served as synthetic handles for downstream manipulations.
The high stereoselectivity observed has been rationalized based on
DFT calculations, which suggests that the reaction is likely proceeding
via a concerted mechanism, and noncovalent interactions between the
metallocarbene and BCB mainly control the observed exclusive selectivity.

隔离双烯（skipped dienes）不仅存在于脂肪酸初级代谢物与天然产物中，同时也是多种化学合成过程中的活性中间体。尽管如此，实现隔离双烯的区域选择性与立体选择性合成仍是一项极具挑战性的目标。有机分子中的张力释放是在温和条件下构建复杂化学结构的有力策略。张力双环[1.1.0]丁烷（bicyclo[1.1.0]butane，BCB）体系的反应性主要由依赖其固有亲电活性的转化所主导。本文报道了一例基于铑-卡宾化学的BCB体系卡宾型反应性的罕见案例，该反应通过张力释放实现了隔离双烯的高立体选择性合成。该反应对重氮化合物与BCBs上的多种官能团均具有良好的兼容性，且可成功应用于复杂结构的合成，得到极具应用价值且可进一步功能化的隔离双烯产物。反应过程中引入的官能团可作为合成手柄，用于后续的衍生化操作。实验观察到的高立体选择性可通过密度泛函理论（Density Functional Theory，DFT）计算得到合理解释：该反应大概率通过协同机理进行，金属卡宾与BCB之间的非共价相互作用是主导该反应专一选择性的核心因素。