Enantioselective Construction of Vicinal Angular Quaternary Stereocenters Enabled by Strained Cyclobutenones

Enantioselective construction of contiguous quaternary centers is a daunting challenge in the synthetic community. 2-Substituted 3-(methoxycarbonyl)cyclobutenone, possessing a strained CC double bond, exhibits both good stability and reactivity. Here, we report a chiral oxazaborolidinium ion (COBI)-catalyzed enantioselective Diels–Alder reaction of 2,3-disubstituted cyclobutenones with a variety of dienes to access bicyclo[4.2.0]octane derivatives, bearing two contiguous angular quaternary centers. Further transformations, including alkylation, cross-coupling reaction and oxyallyl cation reaction afforded the molecules with intriguing structural patterns. The formal total synthesis of estrone was also completed in three steps from enantio-enriched cycloadducts.

连续季碳中心的对映选择性构建是合成化学领域极具挑战性的难题。2-取代-3-(甲氧羰基)环丁烯酮含有张力型碳碳双键，兼具良好稳定性与反应活性。本文报道了一种手性氧杂硼鎓离子（chiral oxazaborolidinium ion，COBI）催化的2,3-二取代环丁烯酮与多种二烯的对映选择性狄尔斯–阿尔德反应，以制备带有两个相邻角型季碳中心的双环[4.2.0]辛烷衍生物。后续转化反应包括烷基化、交叉偶联及氧代烯丙基正离子反应，可得到具有独特结构骨架的分子。以该对映体富集的环加成产物为起始原料，仅需三步即可完成雌酮的形式全合成。