Enantioselective Construction of Vicinal Sulfur‐containing Tetrasubstituted Stereocenters via Organocatalyzed Mannich‐Type Addition of Rhodanines to Isatin Imines

Abstract

The catalyzed enantioselective nucleophilic addition of rhodanines has been established by employing isatin-derived imines as suitable partners under chiral squaramide catalysis. By using this strategy, the resulting 3-substituted 3-amino-2oxindoles featuring both rhodanine and vicinal sulfur-containing tetrasubstituted stereocenters structural motifs were obtained in high yields with excellent enantioselectivities and diastereoselectivities.Skeletons with sulfur-containing tetrasubstituted carbon stereocenters are prevalent substructures found in natural products, drugs, and biologically active compounds (Scheme 1A). [1] The asymmetric construction of these framework has gained much attention and a variety of catalytic enantioselective reactions have been developed over the last decade. [2] In particular, the enantioselective nucleophilic addition of sulfurcontaining prochiral carbon centers offers a direct and efficient access to sulfur-functionalized quaternary carbon stereocenters. For example, the reaction of 5Hthiazol-4-ones has been successfully applied in the catalytic enantioselective construction of sulfur-containing tetrasubstituted carbon stereocenters (Scheme 1B). [3] Although structurally related to 5H-thiazol-4-ones, rhodanines have scarcely been employed in the asymmetric transformation in spite of the importance of being privileged scaffolds in drug discovery (Scheme 1C). [4] Until recently, the group of Ye has developed a primary amine-mediated 1,4-conjugate addition of substituted rhodanines to a,b-unsaturated ketones (Scheme 1D). [5] However, impressive results are mostly limited to acyclic a,b-unsaturated ketones and substrate dependence of catalytic system still remains an important issue. Several cases on the 1,4conjugate addition of N-phenylrhodanine to a,bunsaturated carbonyl compounds are reported by Veselý et al. and sulfur-containing spirocyclic compounds are obtained in moderate yields with stereoselectivities fluctuating over a great range (Scheme 1E). [6] The organocatalytic enantioselective aamination of 5-substituted rhodanines are established by Wang et al. to furnish chiral N,S-acetals in high yields and enantioselectivities (Scheme 1F). [7] The evaluation of the azodicarboxylate partner reveals that the ester moiety has a profound effect on the asymmetric induction. Despite their elegant works, the catalytic asymmetric nucleophilic additions of rhodanines for the construction of sulfur-containing tetrasubstituted carbon stereocenter are still rather limited. The challenges inherent in such transformations mainly include 1) finding the suitable partner to react with rhodanines; and 2) overcoming difficulties in enantiofacial control due to the lesser steric dissimilarity of non-hydrogen substituents on the prochiral carbons; and 3) solving the strong coordinating and adsorptive properties of sulfur species. [8] Therefore, finding a suitable reaction partner and developing catalytic enantioselective nucleophilic addition of rhodanines for the construction of sulfurcontaining tetr...

Organocatalytic Asymmetric Michael Addition of Rhodanines to Azadienes for Assembling of Sulfur‐containing Tetrasubstituted Carbon Stereocenters

“…The investigation of the azodicarboxylate partner indicated that the ester moiety has a profound effect on the asymmetric induction. Very recently, we have established a chiral squaramide mediated Mannich‐type additions of rhodanines to isatin imines, which enables the formation of a variety of 3‐substituted 3‐amino‐2‐oxindoles featuring both rhodanine and vicinal sulfur‐containing tetrasubstituted stereocenters structural motifs in generally high yields with excellent stereoselectivities (Scheme E) . Despite these elegant works, the organocatalytic asymmetric nucleophilic additions of rhodanines for assembling of sulfur‐containing tetrasubstituted carbon stereocenter are still far from well‐developed.…”

“…to afford the 1,4‐adducts in high yields with good to high stereoselectivities. Based on our previous work on azadienes, and as a part of our ongoing interest in the catalytic enantioselective construction of sulfur‐containing carbon stereocenters,, herein we report an organocatalytic asymmetric Michael addition of rhodanines to 2‐arylidene‐ N ‐tosylbenzofuran‐3(2 H )‐imines, affording benzofurans bearing both rhodanine and sulfur‐containing tetrasubstituted stereocenter structural motif in good to high yields with good to excellent enantio‐ and diastereoselectivities (Scheme E).…”

Recent Advances in Squaramide‐Catalyzed Asymmetric Mannich Reactions

“…In 2018, Li group [37] attempted to perform an enantioselective Mannich reaction of rhodanines 29 to isatin‐derived ketimines 23 catalyzed by bifunctional squaramide catalyst C3 (Scheme 12). Surprisingly, the desired Mannich products 30 containing chiral 3‐substituted‐3‐amino‐2‐oxindole scaffolds and rhodanines were smoothly obtained.…”

Recent Advances in Catalytic Asymmetric Reactions of Thiazolones, Rhodanines and Their Derivatives

“…In consideration of structurally related to thiazolones and based on our success in organocatalytic Mannichtype reaction of thiazolones with isatin imines, we then investigated the Mannich-type addition of rhodanines 101 to isatin imines 102 (Scheme 29). [37] In the presence of quinine-based squaramide C35 with a loading of 1 mol%, diversified optically active 3- Under the same content, Wu et al employed a tertiary amine-thiourea C36 as catalyst to complete the asymmetric Mannich-type reaction between rhodanines 104 and isatin imines 105 (Scheme 30). [38] The reaction was carried out at À 30°C and the desired products 106 were obtained in 43-99% yields with 36-97% ee and 98:2-99:1 dr.…”