Abstract
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.
Highlights
The development of efficient and practical strategies for the stereoselective construction of C−C bonds still stands as a crucial ongoing objective and preserves a preferred position in the organic chemistry research.1 Especially interesting are those synthetic tools able to generate structural diversity in a single operation
Focusing on hetero-inverse-electron-demand Diels−Alder (IEDDA) metal-free systems, numerous studies have been reported over the past decades, involving a highest occupied molecular orbital (HOMO)-raising activation of electron-deficient dienophiles by aminocatalysis, being one of the preferred approaches for such a challenging goal.3a−e,4a This strategy involves in situ generation of an enamine that reacts with electron-poor dienes such as α,β-unsaturated systems to generate a variety of oxygen- and nitrogen-based heterocycles.3a−e,4a,5 This approach has been later extended to dienamine as dienophile species when formed from the corresponding α,β-unsaturated aldehyde.3a−e,4a In this context, the majority of these interesting studies showed how the dienamine reacted through the terminal β,γ-alkene
Reduction operation step is usually required to obtain the corresponding lactams/piperidines since the diastereoselectivity of the mentioned hemiaminal stereocenter is usually low.5a−c,7 The thermodynamic control of the different quasibarrierless steps involved in the preparation of a hemiaminal has for long limited its asymmetric synthesis,13 their enantioselective synthesis could be of crucial interest for the preparation of chiral oxazolidines.13b
Summary
The development of efficient and practical strategies for the stereoselective construction of C−C bonds still stands as a crucial ongoing objective and preserves a preferred position in the organic chemistry research. Especially interesting are those synthetic tools able to generate structural diversity in a single operation. The development of efficient and practical strategies for the stereoselective construction of C−C bonds still stands as a crucial ongoing objective and preserves a preferred position in the organic chemistry research.1 Interesting are those synthetic tools able to generate structural diversity in a single operation. Reduction operation step is usually required to obtain the corresponding lactams/piperidines since the diastereoselectivity of the mentioned hemiaminal stereocenter is usually low.5a−c,7 The thermodynamic control of the different quasibarrierless steps involved in the preparation of a hemiaminal has for long limited its asymmetric synthesis, their enantioselective synthesis could be of crucial interest for the preparation of chiral oxazolidines.13b Taking all of these and our previous experience into consideration, we envisioned that the reaction of silyl dienol ethers in the presence of a H-bond donor-based bifunctional organocatalyst would lead to a new asymmetric aza-IEDDA reaction with the alternative ipso,α-selectivity of the dienolate (1,3-selectivity). Cycloadducts bearing an aromatic ring, using phenylacetaldehyde-derived silyl enol ether as the phenyl installation remains as a scope limitation for previously reported non-vinylogous enamine-based organocatalytic methods.5a−c,7
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