Diastereodivergent chiral aldehyde catalysis for asymmetric 1,6-conjugated addition and Mannich reactions

Abstract

Chiral aldehyde catalysis is a burgeoning strategy for the catalytic asymmetric α-functionalization of aminomethyl compounds. However, the reaction types are limited and to date include no examples of stereodivergent catalysis. In this work, we disclose two chiral aldehyde-catalysed diastereodivergent reactions: a 1,6-conjugate addition of amino acids to para-quinone methides and a bio-inspired Mannich reaction of pyridinylmethanamines and imines. Both the syn- and anti-products of these two reactions can be obtained in moderate to high yields, diastereo- and enantioselectivities. Four potential reaction models produced by DFT calculations are proposed to explain the observed stereoselective control. Our work shows that chiral aldehyde catalysis based on a reversible imine formation principle is applicable for the α-functionalization of both amino acids and aryl methylamines, and holds potential to promote a range of asymmetric transformations diastereoselectively.

Catalytic Asymmetric Amino Acid and Its Derivatives by Chiral Aldehyde Catalysis

“…The novel chiral 3-formyl BINOL aldehyde catalyst was displayed in the study of the Mannich reaction of 1,6-conjugated addition of amino acids (as shown in Figure 2) (Wen et al, 2020). The reaction went well in the presence of 4g chiral aldehyde and mesitylene as the solvent and tBuOK as a base, leading to good yields with 90% ee with enantioselectivity.…”

“…To demonstrate a stereoselective control, four potential reaction models were produced by DFT calculations. The key factor for the diastereoselectivity and enantioselectivity of catalysts is the steric FIGURE 2 | The 1,6-conjugated addition reaction by chiral BINOL aldehyde catalysts (Wen et al, 2020). effect of the R group.…”

The Highly Regioselective Synthesis of Novel Imidazolidin-2-Ones via the Intramolecular Cyclization/Electrophilic Substitution of Urea Derivatives and the Evaluation of Their Anticancer Activity

“…This approach is somewhat controversial due to the abovementioned utility of imidazolidine-2-ones as 1,2-diamines precursors. However, it is still used in some cases, especially with chiral diamines [ 4 , 5 , 6 , 7 ]. Novel approaches to these compounds have been developed in 2019–2020 by various research groups, indicating a growing area of interest.…”

Direct Catalytic Asymmetric α-Allylic Alkylation of Aza-aryl Methylamines by Chiral-Aldehyde-Involved Ternary Catalysis System

“…4 Recently, our group reported two diastereodivergent asymmetric transformations by chiral aldehyde catalysis. 5 Besides their use as organocatalysts, chiral aldehydes can also combine with other catalytic systems to achieve reactions that cannot be realized using single catalysis. In 2012, Aron et al reported a catalytic asymmetric α-allylation of methyl phenylalanine by a ternary catalytic system comprising picolinaldehyde, a Lewis acid, and a chiral ligand−palladium complex.…”

“…In the same year, our group developed a BINOL-derived 2-formyl chiral-aldehyde-catalyzed nucleophilic addition of glycine derivatives, including glycine esters and glycine amides to enones, which led to optically active Δ(1)-pyrrolines in high yields . Recently, our group reported two diastereodivergent asymmetric transformations by chiral aldehyde catalysis . Besides their use as organocatalysts, chiral aldehydes can also combine with other catalytic systems to achieve reactions that cannot be realized using single catalysis.…”