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。带有张力碳碳双键的2-取代-3-(甲氧羰基)环丁烯酮，同时具备优异的稳定性与反应活性。本研究报道了一种手性氧杂硼鎓离子（chiral oxazaborolidinium ion，缩写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（Diels–Alder）反应，可得到含有两个相邻角型季碳中心的双环[4.2.0]辛烷衍生物。后续通过烷基化、交叉偶联反应以及氧烯丙基正离子反应等转化，能够获得具有独特结构特征的目标分子。以该反应得到的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。