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,α-position
of the dienophile, in contrast to the reactivity observed for dienolates
in situ generated from β,γ-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.

本研究开发了一种高效的对映选择性反电子需求氮杂Diels–Alder（aza-Diels–Alder）反应，反应底物为氮杂磺酰基-1-氮杂-1,3-丁二烯与硅基（二）烯醇醚。该方法可高选择性地合成带有三个连续手性中心的苯并呋喃稠合2-哌啶醇衍生物，甚至半胺醛中心的构型也实现了完全控制。密度泛函理论（DFT）计算结果表明，基于氢键供体的双功能有机催化剂通过亲双烯体的ipso位与α位选择性触发反应，这与β,γ-不饱和衍生物原位生成的烯醇负离子的反应活性截然不同。此外，该计算阐明了该反应的反应机理，以及氢键供体核心可选择性水解烯醇醚E型异构体的能力。为验证硅基烯醇醚作为亲核试剂在不对称合成具有应用价值的苯并呋喃稠合衍生物中的适用性，本研究还将该催化体系用于哌啶加成产物中芳香环的高效引入。