Natural products have long been valuable sources of inspiration for drug discovery. Unfortunately, the inherent limitations of direct semisynthetic derivatizations have become clear, and the need to overcome these limitations is now particularly urgent because the most valuable natural products tend to be isolated in minute amounts; de novo synthesis with ideal modularity and diversity is therefore a critical goal in drug discovery research. Herein we report a powerful, general platform for cyclolignan synthesis that involves challenging rhodium-catalysed enantioselective hydrogenation of tetrasubstituted 1,2-dihydronaphthalene esters (>40 examples; up to 99% yield, >99% e.e.). This unique platform allows ready access to various types of cyclolignans, as exemplified by the expedient and mostly protecting-group-free synthesis of over thirty cyclolignans, including many that have not previously been synthesized, such as 6-methoxy podophyllotoxin, cleistantoxin, picrobursenin, austrobailignan-4, (+)-lirionol, (+)-gaultherin C, ovafolinin D, fimbricalyxoid A, and aglacins D, F–H (with three revised structures). We expect this work to inspire modular, de novo syntheses of other important classes of natural products and thus to rejuvenate the role of natural products in drug discovery and development.

天然产物长期以来一直是药物发现的宝贵灵感来源。不幸的是，直接半合成衍生化的固有局限性已经变得很明显，并且克服这些局限性的需要现在特别紧迫，因为最有价值的天然产物往往是微量分离的；因此，具有理想模块化和多样性的从头合成是药物发现研究的关键目标。在此，我们报告了一个强大的通用环木脂素合成平台，涉及具有挑战性的铑催化四取代1,2-二氢萘酯的对映选择性氢化（％3E40示例；高达99％产率，％3E99％ee）。这个独特的平台可以方便地获得各种类型的环木脂素，例如可以方便且大多数无保护基合成三十多种环木脂素，包括许多以前未合成的环木脂素，例如6-甲氧基鬼臼毒素、闭花毒素、picrobursenin、 austrobailignan-4、(+)-lirionol、(+)-gultherin C、ovafolinin D、fimbricalyxoid A 和 aglacins D、F–H（具有三个修订的结构）。我们希望这项工作能够激发其他重要类别天然产物的模块化、从头合成，从而重振天然产物在药物发现和开发中的作用。