Enantioselective Inverse-Electron Demand Aza-Diels-Alder Reaction: ipso,α-Selectivity of Silyl Dienol Ethers

A highly efficient enantioselective inverse-electron-demand aza-Diels-Alder reaction between aza-sulfonyl-1-aza-1,3-butadienes and silyl (di)enol ethers has been developed. The presented methodology allows the synthesis of benzofuran-fused 2-piperidinol derivatives with three contiguous stereocenters in a highly selective manner, as even the hemiaminal center is completely stereocontrolled. Density functional theory (DFT) calculations support that the hydrogen-bond donor-based bifunctional organocatalyst selectively triggers the reaction through the ipso,alpha-position of the dienophile, in contrast to the reactivity observed for dienolates in situ generated from beta,gamma-unsaturated derivatives. Moreover, the calculations have clarified the mechanism of the reaction and the ability of the hydrogen-bond donor core to hydrolyze selectively the E isomer of the dienol ether. Furthermore, to demonstrate the applicability of silyl enol ethers as nucleophiles in the asymmetric synthesis of interesting benzofuran-fused derivatives, the catalytic system has also been implemented for the highly efficient installation of an aromatic ring in the piperidine adducts.

Automated summary

A highly efficient enantioselective inverse-electron-demand aza-Diels-Alder reaction has been developed, allowing the synthesis of benzofuran-fused 2-piperidinol derivatives with three contiguous stereocenters in a highly selective manner. Density functional theory calculations support the reaction mechanism and reveal the mode of action of the hydrogen-bond donor.