Cyclolignan synthesis streamlined by enantioselective hydrogenation of tetrasubstituted olefins

Abstract

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. Semisynthetic derivatization approaches to synthesize cyclolignans are limited to using natural sources with inflexible structural features. Now, a powerful, general platform for the synthesis of various types of optically active cyclolignans is achieved through the strategic application of the asymmetric hydrogenation of tetrasubstituted olefins and C(sp3)–H functionalization.