Peptide‐Catalyzed Stereoselective Conjugate Addition Reaction of Aldehydes to C‐Substituted Maleimides

Abstract

Catalytic stereoselective additions with maleimides are useful one‐step reactions to yield chiral succinimides, molecules that are widespread among therapeutically active compounds but challenging to prepare when the maleimide is C‐substituted. We present the tripeptide H‐Pro‐Pro‐Asp‐NHC12H25 as a catalyst for conjugate addition reactions between aldehydes and C‐substituted maleimides to form succinimides with three contiguous stereogenic centers in high yields and stereoselectivities. The peptidic catalyst is so chemoselective that no protecting group is needed at the imide nitrogen of the maleimides. Derivatization of the succinimides was straightforward and provided access to chiral pyrrolidines, lactones, and lactams. Kinetic studies, including a Hammett plot, provided detailed insight into the reaction mechanism.

Overcoming Deactivation of Amine-Based Catalysts: Access to Fluoroalkylated γ-Nitroaldehydes

“…We have previously shown the value of amine-based catalysts with an intramolecular, well-positioned proton donor for high reactivity, stereoselectivity, and reusability. ,,− Here, we highlight another benefitthe reversal of catalyst deactivation through alkylation by an electrophile. Overall, the findings open exciting prospects for the use of highly reactive electrophiles that have proven to be highly challenging for amine-based organocatalysis.…”

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

“…We envisioned that peptide catalysts of the type H‐Pro‐Pro‐Xaa (where Xaa can be any amino acid) fulfill these requirements and allow for reactions with aldehydes bearing N‐heterocycles. Such peptides are reactive and stereoselective organocatalysts for the addition of aldehydes to nitroolefins and other electrophiles, including maleimides [9–11,22–26] . Peptide H− d Pro‐Pro‐Glu−NH 2 A even catalyzes reactions in environments consisting of multi‐component mixtures.…”

“…We focused on reactions with maleimide to yield chiral functionalized succinimides, compounds that are widespread among APIs [33,34] . Such reactions are challenging since unprotected maleimide is an electrophile but also a nucleophile that reacts with aldehydes [25,26] …”

“…Such peptides are reactive and stereoselective organocatalysts for the addition of aldehydes to nitroolefins and other electrophiles, including maleimides. [9][10][11][22][23][24][25][26] Peptide HÀ dPro-Pro-GluÀ NH 2 A even catalyzes reactions in environments consisting of multi-component mixtures. 27 Mechanistic studies, including back-reaction monitoring of quasi-enantiomers by mass spectrometry, [15] revealed that the intermediate enamine is involved in the rate-and enantioselectivity determining step.…”

“…[33,34] Such reactions are challenging since unprotected maleimide is an electrophile but also a nucleophile that reacts with aldehydes. [25,26] Previously, the peptide HÀ dPro-Pro-AsnÀ NH 2 I was established as a stereoselective catalyst for this transformation with regular aldehydes. [25] Catalyst ent-I [35] (3 mol%) converted 3-(pyridin-3-yl)propanal 1 and maleimide, but only sluggishly (27% conversion) and succinimide 11 was obtained with 4:1 d.r.…”