Enolate Activation of α-Haloaldehydes: Highly Enantioselective Aza-[4 + 2] Cyclization for the Rapid Assembly of Multifunctionalized Isothioureas

The catalytic asymmetric activation of sterically hindered functionalized aldehydes remains a significant challenge, especially when using traditional covalent activation strategies. In this study, we present an alternative noncovalent enolate activation strategy to address this issue. Specifically, we utilized various α-halogenated aldehydes─α-fluoro, α-chloro, and α-bromo aldehydes─as latent enolates to achieve a highly enantioselective aza-[4 + 2] cyclization. This Bro̷nsted base organocatalytic protocol facilitates the asymmetric synthesis of a broad spectrum of highly functionalized, halogenated isothioureas, delivering high yields and enantioselectivities under mild conditions. Furthermore, we successfully performed several synthetic transformations to enhance the structural diversity of the chiral isothiourea products. Additionally, density functional theory (DFT) calculations rationalize the observed diastereo- and enantioselectivity.