Concise Asymmetric Total Synthesis of (−)-Cribrostatin 4 via Development of a Rh-Catalyzed Asymmetric Hydrogenation of 2,5-Diketopiperazine-Derived Enamides

A 13-step asymmetric total synthesis of (-)-cribrostatin 4 is disclosed. The synthetic route begins with the development of an asymmetric double hydrogenation of 2,5-diketopiperazine-derived enamides enabled by a novel spiropyrrolidine-derived diphosphine (SPDP) ligand. Employment of mono- and oxidative Pictet-Spengler cyclizations allows for expedient construction of the tetrahydroisoquinoline and benzo[3.3.1]-bridged rings along with an enamide alkene. At a late stage, an unprecedented stereochemical editing approach for direct β-epimerization of a primary alcohol was developed by virtue of borrowing hydrogen catalysis. Collectively, these methodological advances contribute to a concise synthesis of this structurally unique bis-tetrahydroisoquinoline (bis-THIQ) alkaloid.