Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chemical Biology Research Center, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China.
Acc Chem Res. 2022 Oct 4;55(19):2780-2795. doi: 10.1021/acs.accounts.2c00486. Epub 2022 Sep 19.
Atropisomers, arising from conformational restriction, are inherently chiral due to the intersecting dissymmetric planes. Since there are numerous applications of enantiopure atropisomers in catalyst design, drug discovery, and material science, the asymmetric preparation of these highly prized molecules has become a flourishing field in synthetic chemistry. A number of catalysts, synthetic procedures, and novel concepts have been developed for the manufacture of the atropisomeric molecules. However, due to the intrinsic properties of different types of atropisomers featuring biaryl, hetero-biaryl, or non-biaryl architectures, only very few methods pass the rigorous inspection and are considered generally applicable. The development of a broadly applicable synthetic strategy for various atropisomers is a challenge. In this Account, we summarize our recent studies on the enantioselective synthesis of atropisomers using the vinylidene -quinone methides (VQMs) as pluripotent intermediates.The most appealing features of VQMs are the disturbed aromaticity and axial chirality of the allene fragment. At the outset, the applications of VQMs in organic synthesis have been neglected due to their principal liabilities: ephemeral nature, extraordinary reactivity, and multireaction sites. The domestication of this transient intermediate was demonstrated by in situ catalytic asymmetric generation of VQMs, and the reactivity and selectivity were fully explored by judiciously modifying precursors and tuning catalytic systems. A variety of axially chiral heterocycles were achieved through five-, six-, seven- and nine-membered ring formation of VQM intermediates with different kinds of branched nucleophilic functional groups. The axially chiral C-N axis could be constructed from VQM intermediates via N-annulation or desymmetrization of preformed C-N scaffolds. We take advantage of the high electrophilicity of VQMs toward a series of sulfur and carbon based nucleophiles leading to atropisomeric vinyl arenes. Furthermore, chiral helical compounds were realized by cycloaddition or consecutive annulation of VQM intermediates. These achievements demonstrated that the VQMs could work as a nuclear parent for the collective synthesis of distinct and complex optically active atropisomers. Recently, we have realized the isolation and structural characterization of the elusive VQMs, which were questioned as putative intermediates for decades. The successful isolation of VQMs provided direct evidence for their existence and an unprecedented opportunity to directly investigate their reactivity. The good thermal stability and reserved reactivity of the isolated VQMs demonstrated their great potential as synthetic reagents and expanded the border of VQM chemistry.
旋光异构体是由于构象限制而产生的，由于相交的不对称平面，它们本身就是手性的。由于对映纯旋光异构体在催化剂设计、药物发现和材料科学中有许多应用，因此这些高价值分子的不对称制备已成为合成化学中的一个蓬勃发展的领域。已经开发了许多催化剂、合成程序和新概念来制造旋光异构体分子。然而，由于具有联芳基、杂联芳基或非联芳基结构的不同类型的旋光异构体的固有特性，只有极少数方法通过严格的检查，并被认为具有普遍适用性。开发一种广泛适用于各种旋光异构体的合成策略是一个挑战。在本报告中，我们总结了我们最近使用乙烯基-醌甲硅烷（VQMs）作为多功能中间体对旋光异构体的对映选择性合成的研究。VQMs 最吸引人的特点是丙二烯片段的芳香性和轴向手性受到干扰。起初，由于 VQMs 的主要缺点，即短暂的存在、非凡的反应性和多反应位点，它们在有机合成中的应用被忽视了。通过原位催化不对称生成 VQMs 证明了这种瞬态中间体的驯化，通过巧妙地修饰前体和调整催化体系充分探索了反应性和选择性。通过 VQM 中间体与不同类型支化亲核官能团的五元、六元、七元和九元环形成，实现了各种轴向手性杂环。通过 VQM 中间体的 N-环化或预形成的 C-N 支架的去对称化，可以构建轴向手性 C-N 轴。我们利用 VQMs 对一系列硫和碳基亲核试剂的高亲电性，得到旋光异构的芳基乙烯基芳烃。此外，通过 VQM 中间体的环加成或连续环化反应实现了手性螺旋化合物。这些成就表明，VQMs 可以作为不同复杂的光学活性旋光异构体的集体合成的核母体。最近，我们已经实现了难以捉摸的 VQMs 的分离和结构表征，这些 VQMs 几十年来一直被质疑为假定的中间体。VQMs 的成功分离为它们的存在提供了直接证据，并为直接研究它们的反应性提供了前所未有的机会。分离出的 VQMs 的良好热稳定性和保留的反应性表明它们作为合成试剂具有巨大的潜力，并扩展了 VQM 化学的边界。
