Enantioselective Sulfa-Michael Research Articles

Organocatalytic Strategy for a Formal 1,6-Conjugate Hydroxylation.

Thanks to the versatile vinylogous hexafluoro iso-propyl acrylate molecular platforms, a regio- and enantioselective sulfa-Michael reaction was achieved upon organocatalytic conditions, allowing the subsequent amidation, one-pot oxidation, and Mislow-Bravermann-Evans [2,3]-sigmatropic rearrangement along with a 1,3-chirality transfer, leading eventually to a formal asymmetric 1,6-hydroxylation sequence.

Quinoxaline-specific enantioselective sulfa-michael reaction catalyzed by chiral phosphoric acid

Highly enantioselective sulfa-Michael additions (SMA) between 2-alkenyl quinoxalines and aromatic thiols are accomplished using a low loading of chiral phosphoric acid catalyst (1 mol%). It was confirmed by an investigation of a lot of azaarenes that the two C=N units of quinoxalines are indispensable for controlling the reaction enantioselectivities. A series of non-terminal 2-alkenes substituted with aryls or alkyls, even other electro-withdrawing groups such as ketones, esters, or amides, selectively reacted and afforded the desired SMA products (48 examples) in good regioselectivities with high yields (up to 99%) and good ee values (up to 97%).

Iminophosphorane Catalyst Permits Enantioselective Sulfa-Michael Addition to α,β-Unsaturated Amides

Key words sulfa-Michael addition - enamides - squareamides - iminophosphoranes

Organocatalytic Enantioselective Sulfa-Michael Additions to α,β-Unsaturated Diazoketones.

Enantioselective sulfa-Michael additions to α,β unsaturated diazocarbonyl compounds have been developed. Quinine-derived squaramide was found to be the best catalyst to promote C-S bond formation in a highly stereoselective fashion for alkyl and aryl thiols. The easy-to-follow protocol allowed the preparation of 22 examples in enantiomeric ratios up to 97:3 and reaction yields up to 94%. The mechanism and origins of enantioselectivity were determined through density functional theory (DFT) calculations.

Bifunctional Iminophosphorane-Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α,β-Unsaturated Amides

The first metal-free catalytic intermolecular enantioselective Michael addition to unactivated α,β-unsaturated amides is described. Consistently high enantiomeric excesses and yields were obtained over a wide range of alkyl thiol pronucleophiles and electrophiles under mild reaction conditions, enabled by a novel squaramide-based bifunctional iminophosphorane catalyst. Low catalyst loadings (2.0 mol %) were achieved on a decagram scale, demonstrating the scalability of the reaction. Computational analysis revealed the origin of the high enantiofacial selectivity via analysis of relevant transition structures and provided substantial support for specific noncovalent activation of the carbonyl group of the α,β-unsaturated amide by the catalyst.

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst.

Cinchona alkaloid-derived organocatalysts are widely employed in various asymmetric transformations, yielding products with high enantiopurity. In this respect, a bifunctional quinine-derived sulfonamide organocatalyst was developed to catalyze the asymmetric sulfa-Michael reaction of naphthalene-1-thiol with trans-chalcone derivatives. The target sulfa-Michael adducts were obtained with up to 96% ee under mild conditions and with a low (1 mol %) catalyst loading. Selected enantiomerically enriched sulfa-Michael addition products were subjected to oxidation to obtain the corresponding sulfones.

Bifunctional Iminophosphorane Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α-Substituted Acrylate Esters.

The highly enantioselective sulfa-Michael addition of alkyl thiols to unactivated α-substituted acrylate esters catalyzed by a bifunctional iminophosphorane organocatalyst under mild conditions is described. The strong Brønsted basicity of the iminophosphorane moiety of the catalyst provides the necessary activation of the alkyl thiol pro-nucleophile, while the two tert-leucine residues flanking a central thiourea hydrogen-bond donor facilitate high enantiofacial selectivity in the protonation of the transient enolate intermediate. The reaction is broad in scope with respect to the alkyl thiol, the ester moiety, and the α-substituent of the α,β-unsaturated ester, affords sulfa-Michael adducts in excellent yields (up to >99%) and enantioselectivities (up to 96% ee), and is amenable to decagram scale-up using catalyst loadings as low as 0.05 mol %.