Synthesis of a Small-Molecule Library with Skeletal Diversity from Hemslecin A via the Reaction-Discovery Strategy

An efficient reaction
tool box was developed for the synthesis
of skeletally diverse and stereochemically complex templates for a
small-molecule library based on the common synthon Q,
which was prepared from hemslecin A in four steps. The reaction tool
box comprises three acid-promoted rearrangements: semipinacol, Wagner–Meerwein,
and cyclopropylmethyl cation rearrangements. More importantly, a Mn-mediated
C–H oxidation was developed to achieve a high level of complexity,
which provides a new entry for C–H functionalization of inert
angular methyl groups in the chemistry of triterpenes. Our reaction-discovery
strategy based on hemslecin A provides a basis for the inherent chemistry
of triterpenes and could be applied for the further transformation
of triterpenes.

本研究开发了一套高效反应工具箱，用于基于通用合成子（synthon）Q构建骨架多样、立体化学结构复杂的小分子库模板，该合成子Q可通过四步反应从hemslecin A制备得到。该反应工具箱包含三类酸促进重排反应：半频哪醇重排（semipinacol）、瓦格纳-迈尔外因重排（Wagner–Meerwein）以及环丙基甲基正离子重排（cyclopropylmethyl cation rearrangements）。更为关键的是，本研究开发了一种锰（Mn）介导的C-H氧化反应以实现高度结构复杂度的构建，该方法为三萜类化学中惰性角甲基的C-H官能化提供了全新途径。本研究基于hemslecin A的反应发现策略，为三萜类固有化学研究提供了基础，并可应用于三萜类化合物的后续转化。