King size: Utilization of large-size supramolecular rings in the pre-transition state (pre-TS) of enamine-based Michael reactions for high asymmetric induction is described. Enantiomerically pure, druglike hexahydroxanthenes with three contiguous stereocenters were synthesized through supramolecular catalysis by D-proline and quinine-NH-thiourea followed by reductive etherification from simple precursors under mild conditions (see scheme).

Functionalized chiral tetrahydroquinolines were synthesized through supramolecular organocatalysis using quinidine-NH-thiourea 3c/L-phenylalanine 4i followed by reductive amination from the simple substrates.

The recent past has witnessed tremendous growth in the field of asymmetric synthesis through “asymmetric supramolecular organocatalysis (ASO)”. ASO emerges from many interactions between substrates and catalysts: namely substrate–catalyst, catalyst–catalyst and substrate–substrate interactions. As a result, ASO has come to be the fourth pillar of asymmetric catalysis. This review summarizes recent advances in the high‐yielding asymmetric synthesis of chiral compounds from functionally rich substrates with the aid of combinations of two or more organocatalysts working synergistically through relatively stable pre‐transition states. ASO not only assists in product formation from highly functionalized substrates with high rate/selectivity, but also sheds some light on understanding of the fundamental aspects of the pre‐transition state structures.

Herein, for the first time, a combination of L-amino acid, (R)-5,5-dimethyl thiazolidinium-4-carboxylate (L-DMTC) with simple Brønsted acid TFA is reported as the suitable synergistic catalyst for the List-Lerner-Barbas aldol (LLB-A) reaction of less reactive 2-azidobenzaldehydes with various ketones at ambient temperature to furnish the optically active functionalized (2-azidophenyl)alcohols with very good yields, dr's, and ee's. This method gives first time access to the novel azido-containing multifunctional compounds, which are applicable in material to medicinal chemistry. Chiral functionalized (2-azidophenyl)alcohols were transformed into different molecular scaffolds in good yields with high selectivity through Lewis acid mediated NaBH4 reduction, aza-Wittig and Staudinger reaction (azide reduction), followed by oxidative cyclizations, allenone synthesis, and click reaction, respectively. Chiral LLB-A products might become suitable starting materials for the total synthesis of natural products, ingredients, and inhibitors in medicinal chemistry. The mechanistic synergy of L-DMTC with TFA to increase the rate and selectivity of LLB-A reaction in DMSO-D6 is explained with the controlled and online NMR experiments.

Herein, we present the Brønsted-acid-controlled, primary-amine-catalyzed stereoselective asymmetric synthesis of druglike six-membered spirooxindoles from simple aliphatic