Tripeptides of the Type H‐D‐Pro‐Pro‐Xaa‐NH₂ as Catalysts for Asymmetric 1,4‐Addition Reactions: Structural Requirements for High Catalytic Efficiency

Abstract

Analysis of the structural and functional requirements within the asymmetric peptidic catalyst H-D-Pro-Pro-Asp-NH(2) led to the development of the closely related peptide H-D-Pro-Pro-Glu-NH(2) as an even more efficient catalyst for asymmetric conjugate addition reactions of aldehydes to nitroolefins. In the presence of as little as 1 mol % of H-D-Pro-Pro-Glu-NH(2), a broad range of aldehydes and nitroolefins react readily with each other. The resulting gamma-nitroaldehydes were obtained in excellent yields and stereoselectivities at room temperature. Within the structure of the peptidic catalysts, the D-Pro-Pro motif is the major contributor to the high stereoselectivities. The C-terminal amide and the spacer to the carboxylic acid in the side-chain of the C-terminal amino acid are responsible for the fine-tuning of the stereoselectivity. The peptidic catalysts not only allow for highly effective asymmetric catalysis under mild conditions, but also function in the absence of additives.

Adapting to Substrate Challenges: Peptides as Catalysts for Conjugate Addition Reactions of Aldehydes to α,β‐Disubstituted Nitroolefins

“…In contrast to many other chiral secondaryamine-based catalysts, peptide 1 a strongly favors the conjugate addition reaction over competing homo-aldol reactions of the aldehyde. [6] This high chemoselectivity of the peptidic catalyst 1 a is remarkable, in particular because the closely related peptide H-Pro-Pro-Asp-NH 2 is a very good catalyst for aldol reactions. [13] It demonstrates that slight variations in the structure of peptides of the type Pro-Pro-Xaa allow for a fine tuning of their chemoselectivity.…”

“…[11] Our group has recently introduced peptides of the general type Pro-Pro-Xaa, where the turn inducing Pro-Pro-motive is combined with a C-terminal acidic amino acid (Xaa), as effective catalysts for enamine catalysis. [5][6][7]13] For example, the peptide H-d-Pro-Pro-Glu-NH 2 (1 a) is an excellent catalyst for conjugate addition reactions of aldehydes to b-monosubstituted nitroolefins. [5][6][7] In the presence of as little as 1 mol % of 1 a a broad variety of aldehydes react readily with both aliphatic and aromatic nitroolefins to provide the corresponding g-nitroaldehydes in very good yields and steAbstract: Conjugate addition reactions of aldehydes to a,b-disubstituted nitroolefins are important because they provide synthetically useful g-nitroaldehydes bearing three consecutive stereogenic centers.…”

“…[5][6][7]13] For example, the peptide H-d-Pro-Pro-Glu-NH 2 (1 a) is an excellent catalyst for conjugate addition reactions of aldehydes to b-monosubstituted nitroolefins. [5][6][7] In the presence of as little as 1 mol % of 1 a a broad variety of aldehydes react readily with both aliphatic and aromatic nitroolefins to provide the corresponding g-nitroaldehydes in very good yields and steAbstract: Conjugate addition reactions of aldehydes to a,b-disubstituted nitroolefins are important because they provide synthetically useful g-nitroaldehydes bearing three consecutive stereogenic centers. Such reactions are challenging due to the drastically lower reactivity of a,b-diA C H T U N G T R E N N U N G substituted nitroolefins compared to, for example, b-monosubstituted nitroolefins.…”

Exploiting the benefits of continuous-flow processing for the development of novel sustainable catalytic procedures

“…128 These functional groups play similar roles as in conventional proline-mediated transformations. 128,129 The peptide H-Pro-Pro-Asp-NH 2 (Asp=aspartic acid) was found to be an efficient catalyst for direct aldol reactions, 130 polymer-bound oligo-L-Leu compounds in a continuously operated chemzyme membrane reactor for the asymmetric epoxidation of chalcone, where a nanofiltration membrane retained the polymer-enlarged catalyst, while the resulting epoxide and unconverted chalcone could freely pass through. 137 Kee and Gavriilidis recently designed a dedicated microflow system for homogeneous poly-L-Leu-catalyzed chalcone epoxidation, in which gram-scale production was attainable.…”

“…The supported peptidic catalyst was obtained in a TFA salt form after the SPPS, and the effect of a basic additive was next examined to promote the liberation of the N-terminal secondary amine and maybe facilitate catalysis. 129 On the basis of literature data, Nmethylmorpholine (NMM) was chosen as base, 131 and the effects of different amounts of NMM were then investigated under the previously optimized CF reaction conditions. It emerged that the diastereoselectivity decreased dramatically upon addition of the base, whereas the yield and enantioselectivity remained intact (Table 9).…”