One-Step Asymmetric Construction of 1,4-Stereocenters via Tandem Mannich-Isomerization Reactions Mediated by a Dual-Functional Betaine Catalyst

Abstract

The construction of chiral motifs containing nonadjacent stereocenters stands out as a major challenge as they are usually constructed in separate steps utilizing different chiral catalysts. Therefore, the development of new strategies to streamline the construction of such complex motifs has become a major focus of asymmetric synthesis. We report here an unprecedented asymmetric tandem Mannich-isomerization reaction that allows the direct construction of 1,4-stereocenters in a highly stereoselective manner. This asymmetric transformation demonstrated the potential of a tandem nucleophilic addition-isomerization reaction as a broadly useful strategy for the efficient construction of 1,4-stereocenters. Notably, this tandem reaction was mediated by a single chiral betaine as a dual-functional catalyst, promoting first an enantioselective intermolecular C–C bond forming reaction and next a stereoselective intramolecular 1,3-proton transfer reaction.

Chiral Betaine-Mediated Efficient Organocatalytic Asymmetric Isomerization of β,γ-Unsaturated Butenolides

“…We recently discovered that chiral ammonium betaines derived from precursors such as QD-2 (Scheme 1c) by treatment with a base can serve as highly efficient proton-transfer catalysts in the asymmetric isomerization of N-(p-nitrobenzyl)trifluoromethylimines 12 and in tandem Mannich/isomerization reactions of butenolides and ketimines. 13 These betaines showed a significantly higher efficiency than the previously reported bifunctional organocatalysts in proton-transfer catalysis. 14 We envisaged that chiral betaines might be developed as new and efficient catalysts for the asymmetric isomerization of ,-unsaturated butenolides.…”

“…We next examined the impact of the N-arylmethyl substituents on the reactivity and enantioselectivity. 12,13,15 To our delight, in the presence of QD-5, bearing an N-benzyl group, the reaction proceeded to 45% conversion in ten minutes, furnishing 2A in 82% ee (entry 5). On adding two tert-butyl groups at the meta-positions of the N-benzyl substituent, the reaction with QD-6 proceeded to 69% conversion in ten minutes, furnishing 2A in 81% ee (entry 6).…”

Accessing unnatural α-amino acids with tetrasubstituted stereogenic centersviacatalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides

“…49 The intermediate adduct, which is created through reaction at the In 2022, Luo, Deng, and co-workers constructed 1,4stereocenters using direct Mannich-type reaction and subsequent isomerization catalyzed by chiral bifunctional betaine 78 (Scheme 29). 50 Betaine 78 efficiently catalyzed enantioselective C(sp 3 )-C(sp 3 ) bond-formation chemistry involving cyclic aiminoesters 39b, butanolides, and diastereoselective 1,3proton transfer in this tandem sequence.…”

Synergistic Pd/Cu-Catalyzed 1,5-Double Chiral Inductions

“…A large number of synthetic approaches have been developed to achieve the asymmetric construction of single stereocenters and the simultaneous construction of two adjacent stereocenters (Figure ). However, very limited reports have been disclosed on the one-step synthesis of structural motifs bearing nonadjacent stereocenters. − It is expected that the challenge will increase dramatically as the distance between two stereogenic centers increases due to the lack of reliable chiral induction models for both chiral entities. To date, no example of the asymmetric catalytic construction of 1,5-nonadjacent or more remote stereocenters has been reported.…”