Generation of reactive intermediates and interception of these fleeting species under physiological conditions is a common strategy employed by Nature to build molecular complexity. However, selective formation of these species under mild conditions using classical synthetic techniques is an outstanding challenge. Here, we demonstrate the utility of biocatalysis in generating o-quinone methide intermediates with precise chemoselectivity under mild, aqueous conditions. Specifically, α-ketoglutarate-dependent non-heme iron enzymes, CitB and ClaD, are employed to selectively modify benzylic C-H bonds of o-cresol substrates. In this transformation, biocatalytic hydroxylation of a benzylic C-H bond affords a benzylic alcohol product which, under the aqueous reaction conditions, is in equilibrium with the corresponding o-quinone methide. o-Quinone methide interception by a nucleophile or a dienophile allows for one-pot conversion of benzylic C-H bonds into C-C, C-N, C-O, and C-S bonds in chemoenzymatic cascades on preparative scale. The chemoselectivity and mild nature of this platform is showcased here by the selective modification of peptides and chemoenzymatic synthesis of the chroman natural product (-)-xyloketal D.

中文翻译：

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化学酶促邻醌甲基化物形成

在生理条件下生成反应性中间体和拦截这些转瞬即逝的物种是大自然用来构建分子复杂性的常用策略。然而，使用经典合成技术在温和条件下选择性形成这些物种是一个突出的挑战。在这里，我们展示了生物催化在温和的水性条件下产生具有精确化学选择性的邻醌甲基化物中间体的效用。具体而言，α-酮戊二酸依赖性非血红素铁酶 CitB 和 ClaD 用于选择性修饰邻甲酚底物的苄基 CH 键。在该转化中，苄基 CH 键的生物催化羟基化产生苄醇产物，在水性反应条件下，该产物与相应的邻醌甲基化物处于平衡状态。亲核试剂或亲双烯试剂对邻醌甲基化物的拦截允许在制备规模的化学酶级联中将苄型 CH 键一锅转化为 CC、CN、CO 和 CS 键。该平台的化学选择性和温和性质在这里通过肽的选择性修饰和色满天然产物 (-)-xyloketal D 的化学酶促合成展示。