Organocatalytic Transannular Approach to Stereodefined Bicyclo[3.1.0]hexanes

A diastereodivergent
approach to highly substituted bicyclo[3.1.0]­hexanes
has been developed through a transannular alkylation reaction that
builds up the bicyclic core employing asymmetric organocatalysis as
the tool for the installation of all stereocenters. On one hand, a
Michael/Michael cascade process between enals and 4-alkenyl sulfamidate
imines under the iminium/enamine activation manifold provides an oxathiazole-2,2-dioxide-fused
cyclohexane adduct that, after isolation, is subsequently engaged
in a transannular alkylation/hydrolysis through enamine activation
by the use of a primary amine. On the other hand, the corresponding
C-2 epimers are directly obtained from the same starting materials
in a single operation through a cascade Michael/Michael/transannular
alkylation/hydrolysis sequence through sequential iminium/enamine/enamine
combination of aminocatalytic activation manifolds.

本研究开发了一种非对映发散性（diastereodivergent）合成策略，用于制备高度取代的双环[3.1.0]己烷（bicyclo[3.1.0]hexanes）。该策略依托跨环烷基化反应构建双环核心，并以不对称有机催化作为引入全部手性中心的手段。
一方面，在亚胺鎓/烯胺活化模式下，烯醛与4-烯基磺酰胺亚胺之间发生迈克尔/迈克尔级联反应，得到恶噻唑-2,2-二氧化物稠合环己烷加合物；分离该加合物后，可通过伯胺介导的烯胺活化路径，进一步发生跨环烷基化/水解反应。
另一方面，以相同原料为起始物，通过依次采用亚胺鎓/烯胺/烯胺氨基催化活化模式的迈克尔/迈克尔/跨环烷基化/水解级联序列，可一步直接获得对应的C-2位差向异构体。