Flow Photo-Oxidative Dearomative Cyclization Enables Unified Asymmetric Synthesis of Trichodermamides A–F

A unified approach to the divergent asymmetric synthesis of fungal secondary metabolites trichodermamides A-F, including the first asymmetric synthesis of trichodermamides C, D, E, and F, is described herein. The key to accessing the trichodermamides was the rapid construction of the optically active cis-1,2-oxazadecalin core utilizing a new gas-liquid two-phase continuous flow photo-oxidation process. This method comprises a tandem oxidative dearomatization/stereoselective cyclization of a tyrosine-derived hydroxylamine. Another key feature of the synthetic route was the dimethyldioxirane and iBu2AlH-mediated one-pot oxidation and reduction process to assemble the highly functionalized oxazadecalin skeleton. Together, these approaches provided a multigram preparation of optically active trichodermamide D that enabled late-stage divergent transformation into a series of trichodermamides via the bis-allylic alcohol. Finally, our synthetic efforts elucidated a revised structure of trichodermamide E.