Department of Chemical Engineering, Stanford University, Stanford, California 94305, United States.
Department of Chemical Engineering and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, United States.
J Am Chem Soc. 2021 Apr 7;143(13):5011-5021. doi: 10.1021/jacs.0c13164. Epub 2021 Mar 29.
Phenylpropanoids are a class of abundant building blocks found in plants and derived from phenylalanine and tyrosine. Phenylpropanoid polymerization leads to the second most abundant biopolymer lignin while stereo- and site-selective coupling generates an array of lignan natural products with potent biological activity, including the topoisomerase inhibitor and chemotherapeutic etoposide. A key step in etoposide biosynthesis involves a plant dirigent protein that promotes selective dimerization of coniferyl alcohol, a common phenylpropanoid, to form (+)-pinoresinol, a critical C symmetric pathway intermediate. Despite the power of this coupling reaction for the elegant and rapid assembly of the etoposide scaffold, dirigent proteins have not been utilized to generate other complex lignan natural products. Here, we demonstrate that dirigent proteins from in combination with a laccase guide the coupling of natural and synthetic coniferyl alcohol analogues for the enantioselective synthesis of pinoresinol analogues. This route for complexity generation is remarkably direct and efficient: three new bonds and four stereocenters are produced from two different achiral monomers in a single step. We anticipate our results will enable biocatalytic routes to difficult-to-access non-natural lignan analogues and etoposide derivatives. Furthermore, these dirigent protein and laccase-promoted reactions of coniferyl alcohol analogues represent new regio- and enantioselective oxidative heterocouplings for which no other chemical methods have been reported.
苯丙素类是一类在植物中广泛存在的丰富结构单元，来源于苯丙氨酸和酪氨酸。苯丙素聚合生成第二丰富的生物聚合物木质素，而立体和位置选择性偶联则生成一系列具有强大生物活性的木质素天然产物，包括拓扑异构酶抑制剂和化疗药物依托泊苷。依托泊苷生物合成的关键步骤涉及一种植物定向蛋白，它促进常见苯丙素松柏醇的选择性二聚化，形成 (+)-松脂醇，这是一个关键的 C 对称途径中间体。尽管这种偶联反应对于依托泊苷支架的优雅和快速组装具有强大的作用，但定向蛋白尚未用于生成其他复杂的木质素天然产物。在这里，我们证明与漆酶结合的来自 的定向蛋白可引导天然和合成松柏醇类似物的偶联，从而对映选择性合成松脂醇类似物。这种生成复杂性的方法非常直接和高效：两个不同的手性单体在一步中产生三个新键和四个立体中心。我们预计我们的结果将能够为难以获得的非天然木质素类似物和依托泊苷衍生物提供生物催化途径。此外，这些松柏醇类似物的定向蛋白和漆酶促进反应代表了新的区域和对映选择性氧化杂偶联，目前尚无其他化学方法报道。
