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Bifunctional Tripeptide with a Phosphonic Acid as a Brønsted Acid for Michael Addition: Mechanistic Insights
Author(s) -
CortesClerget Margery,
Jover Jesús,
Dussart Jade,
Kolodziej Emilie,
Monteil Maelle,
MigianuGriffoni Evelyne,
Gager Olivier,
Deschamp Julia,
Lecouvey Marc
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201700604
Subject(s) - bifunctional , chemistry , tripeptide , enamine , organocatalysis , nitroalkene , catalysis , michael reaction , aldehyde , bifunctional catalyst , enantioselective synthesis , organic chemistry , stereochemistry , amino acid , biochemistry
Abstract Enamine catalysis is a widespread activation mode in the field of organocatalysis and is often encountered in bifunctional organocatalysts. We previously described H‐Pro‐Pro‐pAla‐OMe as a bifunctional catalyst for Michael addition between aldehydes and aromatic nitroalkenes. Considering that opposite selectivities were observed when compared to H‐Pro‐Pro‐Glu‐NH 2 , an analogue described by Wennemers, the activation mode of H‐Pro‐Pro‐pAla‐OMe was investigated through kinetic, linear effect studies, NMR analyses, and structural modifications. It appeared that only one bifunctional catalyst was involved in the catalytic cycle, by activating aldehyde through an ( E )‐enamine and nitroalkene through an acidic interaction. A restrained tripeptide structure was optimal in terms of distance and rigidity for better selectivities and fast reaction rates. Transition‐state modeling unveiled the particular selectivity of this phosphonopeptide.