Asymmetric Transfer Hydrogenation of Polyoxygenated 3-Arylidenechroman-4-ones: A Powerful Tool for the Total Synthesis of Natural Homoisoflavonoids

Abstract

A mild and highly efficient one-pot asymmetric transfer hydrogenation (ATH) of challenging, electron-rich 3arylidenechroman-4-ones is reported. The protocol utilizes a Ru(II)-catalyst under neutral conditions (HCO₂Na) to reduce both the C=C and C=O bonds, affording valuable cis-3-benzylchroman-4-ols with excellent diastereo-and enantioselectivities (up to 99:1 er). The key to this success was the strategic use of intramolecular hydrogen bonding; we discovered that a C2'phenol forms an unprecedented eight-membered pseudo-ring that acts as a powerful directing group for the ketone reduction. This new mechanistic principle was rigorously supported by DFT calculations of reactivity descriptors and transition state energies. The protocol's synthetic utility was showcased in the enantioselective total syntheses of five homoisoflavonoids, enabling the first stereochemical assignment of Portulacanones A and B and the synthesis of (+)-Brazilane, which clarifies its absolute configuration in the literature.