Catalytic enantioselective acyl transfer: the case for 4-PPY with a C-3 carboxamide peptide auxiliary based on synthesis and modelling studies.
A series of 4-pyrrolidinopyridine (4-PPY) C-3 carboxamides containing peptide-based side chains have been synthesised and evaluated in the kinetic resolution of a small library of chiral benzylic secondary alcohols. A key design element was the incorporation of a tryptophan residue in the peptide side chain for promoting π-stacking between peptide side chain and the pyridinium ring of the N-acyl intermediate, in which modelling was used as a structure-based guiding tool. Together, a catalyst containing a LeuTrp-N-Boc side chain (catalyst 8) was identified that achieved s-values up to and in slight excess of 10. A transition-state model based on the modelling is proposed to explain the origin of enantioselectivity. This study establishes the usefulness of modelling as a structure-based guiding tool for enantioselectivity optimization as well as the potential for developing scalable peptide-based DMAP-type catalysts for large-scale resolution work.
Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa. Roger.Hunter@uct.ac.za.
Rudy E
RE
Cozett
Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa. Roger.Hunter@uct.ac.za and Scientific Computing Research Unit, University of Cape Town, Rondebosch, 7701, South Africa.
Gerhard A
http://orcid.org/0000-0003-3993-1198
GA
Venter
Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa. Roger.Hunter@uct.ac.za.
Maheswara Rao
MR
Gokada
Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa. Roger.Hunter@uct.ac.za.
Roger
R
Hunter
D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
D010455:Peptides; D011725:Pyridines; C021249:4-pyrrolidinopyridine