Unlocking Access to Cyclopropanones as Divergent Reactive Intermediates in Synthesis

摘要 应变环状化合物是生物活性药物合成中的关键中间体。 和天然产物通过扩环、开环等应变释放反应 流程。而环丁酮等小环酮在 这些转化，类似地使用环丙酮衍生物作为底物，已经严重 落后，因为这些化合物长期以来被认为是不可持续的合成中间体 由于它们的极端应变和运动不稳定性。本工作建议使用1-磺酰基环丙醇 作为一类稳定的环丙酮类化合物，在有机合成中，解锁了无数 以前无法通过应变释放反应进行合成断开。这些措施包括(1) 亲核试剂引发的重排反应，(2)过渡金属催化的C-C活化 和解构策略，以及(3)环丙酮衍生物作为1，1-环丙基的应用 转接销。我们已经开发了一种有效的对映选择性路线来合成这些化合物，并已经 在每一种类型的反应中获得了重要的初步数据，导致了各种手性 难以通过其他方法访问的合成子。磺酰基团的电子性质和空间性质 在这些替代物中，它在这里作为不稳定的碱性保护基团并赋予结晶度 这些化合物被发现对它们与环丙酮的平衡速度有至关重要的影响， 突出了它们的可调反应性和它们作为合成材料广泛应用的潜力 中间体。在资助期内，利用获得的机械知识，这项技术 导致对映体富集化的1-磺酰基环丙醇将延伸到形成1-磺酸基环丙醇。 磺酰环丙胺和肼作为手性环丙胺和联胺的模数前体 并将允许以新的方式获得含手性胺的支架以及 拉伸手性卡宾的等价物。我们坚信，稳定性、易合成性和模块化 这些试剂的特性将作为通用解决方案，以收获尚未开发的多功能性 环丙酮及其类似物在合成中作为高活性构件的研究。因此，这项工作将 大大扩展了应变环领域中化学家可用的断开范围 活化和官能化，使这些严重紧张的衍生物从化学上的好奇心进化到 多种合成中间体，极大地有助于简化生物相关产品的生产 有机分子。

ABSTRACT Strained cyclic compounds are often used as key intermediates in the synthesis of bio-active drugs and natural products through strain-releasing reactions such as ring-expansion and ring-opening processes. While small ring ketones such as cyclobutanones have found widespread applicability in these transformations, the analogous use of cyclopropanone derivatives as substrates has seriously lagged behind, as these compounds have long been considered unsustainable synthetic intermediates due to their extreme strain and kinetic instability. This work proposes the use of 1-sulfonylcyclopropanols as a general class of stable cyclopropanone surrogates in organic synthesis, unlocking access to myriad previously inaccessible synthetic disconnections via strain-releasing reactions. These include (1) rearrangements initiated by the addition of nucleophiles, (2) transition metal-catalyzed C–C activation and deconstruction strategies, and (3) application of cyclopropanone derivatives as 1,1-cyclopropyl linchpins. We have already developed an efficient enantioselective route to these compounds and have obtained significant preliminary data in each of these types of reactions, leading to a variety of chiral synthons difficult to access by other methods. Both the electronic and steric nature of the sulfonyl moiety in these surrogates, which is acting here as a base-labile protecting group and conferring crystallinity to these compounds, is found to have a crucial impact on their rate of equilibration to cyclopropanone, highlighting their tunable reactivity and the potential for their widespread applicability as synthetic intermediates. During the funding period and using the mechanistic knowledge acquired, this technology leading to enantioenriched 1-sulfonylcyclopropanols will be extended to the formation of 1- sulfonylcyclopropylamine and hydrazines as modular precursors of chiral cyclopropanimines and hydrazones, respectively, and will allow novel access to chiral amine-containing scaffolds as well as strained chiral carbene equivalents. We firmly believe that the stability, ease of synthesis and modular character of these reagents will serve as a general solution to harvest the untapped versatility of cyclopropanones and its analogues as highly reactive building blocks in synthesis. Thus, this work will significantly expand the scope of disconnections available to chemists in the realm of strained ring activation and functionalization, evolving these severely strained derivatives from chemical curiosities to versatile synthetic intermediates, greatly contributing to streamline the production of biologically relevant organic molecules.