Tripeptide Organocatalysts for Stereoselective Conjugate Addition Reactions with N‐Heterocyclic Substituents

Abstract

N-heterocyclic moieties are abundant among pharmaceuticals and agrochemicals, but a challenge for metalorganic and organocatalytic transformations. We present tripeptides of the type H-Pro-Pro-Xaa as catalysts for stereoselective conjugate addition reactions between N-heterocyclic substituted aldehydes and electrophiles. Alkyl substituents at the N-terminal proline, the reactive site, were crucial for high chemo-and stereoselectivity. Different N-heterocyclic moieties, even at both reaction partners, were readily tolerated and products were obtained in yields of 61-95% and enantioselectivities of up to 98% ee.

Crystal structure analysis of N‐acetylated proline and ring size analogs

“…37 We used Pip to enhance the reactivity and stereoselectivity of a peptide catalyst. [38][39][40][41][42] Furthermore, we and others showed that both, Aze and Pip destabilize the collagen triple helix. [43][44][45] These effects arise from the structural properties of Aze and Pip, but whereas a lot is known about Pro derivatives, 1,2,16 only a few experimental studies explored the conformation of Aze and Pip derivatives.…”

“…Pip has been shown to affect the feeding/sleeping rhythm of neonatal chicks and to activate γ‐aminobutyric acid receptors 37 . We used Pip to enhance the reactivity and stereoselectivity of a peptide catalyst 38–42 . Furthermore, we and others showed that both, Aze and Pip destabilize the collagen triple helix 43–45 .…”

Recent Advancement on the Organocatalyzed Asymmetric Conjugate Addition using Maleimide as a Potential Substrate

“…Quite recently, the group extended the peptide catalysis for the asymmetric conjugate addition of N ‐heterocyclic substituted aldehydes 21 with maleimide 3 b (Scheme 16). [27] The products 22 a and 22 b derived from pyridyl and aliphatic pipecolinic‐substituted respectively were obtained with up to 89 % yield, 12 : 1 diastereoselectivity and 96 % enantioselectivity in presence of 3 mol % of the TFA salt of the catalyst 12 d .…”

“…[25] Quite recently, the group extended the peptide catalysis for the asymmetric conjugate addition of N-heterocyclic substituted aldehydes 21 with maleimide 3 b (Scheme 16). [27] The products 22 a and 22 b derived from pyridyl and aliphatic pipecolinic-substituted respectively were obtained with up to In 2020, Da group reported tetrapeptide 12 e derived from proline and primary amino acids as an efficient catalyst for the asymmetric conjugate addition of α-mono or α,α-disubstituted aldehydes 2 with unprotected or N-protected maleimides 3 (Scheme 17a). [28] The desired succinimides 23 were obtained with very high yields, diastereoselectivities and enantioselectivities in presence of 2.5 mol % catalyst loading (up to 98 % yield, 88 : 12 d.r.…”

Asymmetric aldol reaction catalyzed by amino acid tetrapeptides (l-Pro-l-Pro-l-Phe-l-Phe-OMe)

“…7 In 2016, trifluoroacetic acid was introduced into the synthesis of proline tripeptides, and the obtained catalyst had an excellent catalytic effect in conjugate addition reactions of aldehydes to maleimide. 8 In 2022, a new tripeptide catalyst was synthesized using methyl-modified proline, 9 and the material had a better catalytic effect in conjugate addition reactions between N-heterocyclic substituted aldehydes and nitroolefins. During the same period, Kudo et al developed a resin-immobilized proline helical peptide catalyst and used it for the catalysis of the kinetic resolution of a planar-chiral [2.2]paracyclophane derivative in the Michael addition of nitromethane.…”