Highly Cα-Regio-, Enantio-and Diastereoselective Mukaiyamatype Annulation of Siloxyfurans: Stereodivergent Synthesis of Multi-stereogenic Tricyclic γ-Lactones

Abstract

The first Cα-selective asymmetric reaction of 2-siloxyfurans, a class of versatile nucleophiles, has been developed with both high enantioselectivity and diastereoselectivity. Moreover, by changing the achiral co-catalyst to a newly developed combined co-catalyst, a rare diastereoselective reversal was achieved, selectively yielding the thermodynamically less stable diastereomer. DFT and experimental studies reveal that the observed Cα-selectivity results from dispersion and electrostatic interactions between 2-siloxyfurans and the electrophile/catalyst, while the diastereodivergent synthesis arises from a divergent C-O bond formation via dynamic kinetic lactonization-driven epimerization. This work not only provides a method to overcome the challenges of Cα-selective asymmetric reactions of 2-siloxyfurans, but also offers a stereodivergent synthesis of chiral tricyclic γ-lactones. Importantly, the resulting chiral tricyclic γ-lactones are not only the core structures in natural products and bioactive molecules but also serve as an appealing platform for diversity-oriented synthesis (DOS), streamlining the construction of other valuable enantioenriched compounds.