Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck College, London WC1E 7HX, U.K.
Department of Chemistry, Christopher Ingold Building, University College London, London WC1H 0AJ, U.K.
Org Lett. 2021 Aug 20;23(16):6342-6347. doi: 10.1021/acs.orglett.1c02110. Epub 2021 Aug 6.
Tetrahydroprotoberberine and protoberberine alkaloids are a group of biologically active natural products with complex molecular scaffolds. Isolation from plants is challenging and stereoselective synthetic routes, particularly of methylated compounds are limited, reducing the potential use of these compounds. In this work, we describe chemoenzymatic cascades toward various 13-methyl-tetrahydroprotoberberbine scaffolds using a stereoselective Pictet-Spenglerase, regioselective catechol -methyltransferases and selective chemical Pictet-Spengler reactions. All reactions could be performed sequentially, without the workup or purification of any synthetic intermediates. Moreover, the naturally occurring alkaloids have the (+)-configuration and importantly here, a strategy to the (-)-isomers was developed. A methyl group at C-8 was also introduced with some stereocontrol, influenced by the stereochemistry at C-13. Furthermore, a single step reaction was found to convert tetrahydroprotoberberine alkaloids into the analogous protoberberine scaffold, avoiding the use of harsh oxidizing conditions or a selective oxidase. This work provides facile, selective routes toward novel analogues of bioactive alkaloids.
四氢原小檗碱和原小檗碱类生物碱是一组具有复杂分子支架的生物活性天然产物。从植物中分离具有挑战性,且立体选择性合成途径(特别是甲基化化合物)有限,这降低了这些化合物的潜在用途。在这项工作中,我们使用立体选择性的Pictet-Spenglerase、区域选择性儿茶酚-O-甲基转移酶和选择性的化学 Pictet-Spengler 反应,描述了针对各种 13-甲基-四氢原小檗碱支架的化学酶级联反应。所有反应都可以顺序进行,无需对任何合成中间体进行后处理或纯化。此外,天然存在的生物碱具有(+)构型,重要的是,在这里开发了一种(-)异构体的策略。C-8 位上的一个甲基也被引入,具有一定的立体控制,受 C-13 立体化学的影响。此外,发现一步反应可以将四氢原小檗碱生物碱转化为类似的原小檗碱支架,避免使用苛刻的氧化条件或选择性氧化酶。这项工作为生物活性生物碱的新型类似物提供了简便、选择性的合成途径。