The potential of Song’s chiral oligoethylene glycols (oligoEGs) as catalysts was explored in the enantioselective protonation of trimethylsilyl enol ethers in combination with alkali metal fluoride (KF and CsF) and in the presence of a proton source. Highly enantioselective protonations of various silyl enol ethers of α-substituted tetralones were achieved, producing chiral α-substituted tetralones in full conversion and with up to 99% ee. The established protocol was successfully extended to the synthesis of biologically relevant chiral α-substituted chromanone and thiochromanone derivatives.

AbstractDescribed herein is the enantioselective construction of oxygen-containing [5-6-5] tricyclic heterocycles by an organocatalyzed asymmetric [4+2] cycloaddition of vinylidene ortho-quinone methides and benzofurans. According to this methodology, a series of oxygen-containing [5-6-5] tricyclic heterocycles with various functional groups were synthesized in excellent enantio- and diastereoselectivities (>99 % ee, >20:1 d.r.). Furthermore, the deuterium-labeling experiments and high-resolution mass spectroscopy demonstrated that a vinylidene ortho-quinone methide intermediate was involved and possibly resulted from a prototropic rearrangement of 2-ethynylphenol. Remarkably, a catalyst loading as low as 0.1 mol %, and a gram-scale synthesis were achieved for this transformation.

AbstractIn this study, the concept of cooperative cation-binding catalysis was applied for direct generation of two contiguous trisubstituted and tetrasubstituted stereogenic centers. Using the readily accessible chiral oligoethylene glycol (oligoEG) as a cation-binding catalyst, asymmetric Mannich reactions of α-thiocyanato cyclic ketones as Mannich donors were performed with α-amidosulfones as the bench-stable imine precursors in the presence of potassium fluoride as the base, affording 2-thiocyanato-2-(1-aminoalkyl)-substituted 1-tetralones and 1-indanones possessing fully substituted C–SCN centers. The salient features of this process include (i) a transition metal-free and operationally simple procedure, (ii) direct use of α-amidosulfones as bench-stable precursors of sensitive imines, (iii) direct enolization of racemic cyclic α-thiocyanato ketones and (iv) excellent stereoselectivity with up to 99% ee and >20:1 diastereoselectivity (anti:syn). This protocol is easily scalable and provides a new approach for the syntheses of some biologically relevant products possessing fully substituted C–SCN centers.

Heterocyclic skeletons play major roles in pharmaceuticals and biological processes. Cycloaddition reactions are most suitable synthetic tools to efficiently construct chemically diverse sets of heterocycles with great structural complexity owing to the simultaneous or sequential formation of two or more bonds, often with a high degree of selectivity. Herein, we report an unprecedented formal cycloaddition of N-Boc-N-hydroxy amido sulfones as the nitrone precursors with terminal-hydroxy α,β-unsaturated carbonyls in the presence of Song’s chiral oligoethylene glycol as a cation-binding catalyst and KF as a base to afford a wide range of highly enantio- and diastereo-enriched six-membered dioxazinane and seven-membered dioxazepane heterocycles. In this process, nitrones as well as terminal-hydroxy α,β-unsaturated carbonyls serve as “amphiphilic” building units, and the reaction proceeds through a tandem pathway sequence of oxa-Mannich reaction/oxa-Michael reaction/tautomerization/protonation. The cation-binding catalysis in a densely confined chiral space in situ formed by the incorporation of potassium salt is the key to this successful catalysis. This strategy opens a new pathway for the asymmetric synthesis of diverse heterocyclic skeletons of great complexity.