A Pathway for Aldol Additions Catalyzed by l-Hydroxyproline-Peptides via a β-Hydroxyketone Hemiaminal Intermediate

Abstract

While the use of l-proline-derived peptides has been proven similarly successful with respect to enantioselectivity, the physico-chemical and conformational properties of these organocatalysts are not fully compatible with transition state and intermediate structures previously suggested for l-proline catalysis. l-Proline or l-4-hydroxyproline catalysis is assumed to involve proton transfers mediated by the carboxylic acid group, whereas a similar mechanism is unlikely for peptides, which lack a proton donor. Herein, we prepared an array of hydroxyproline-based dipeptides through amide coupling of Boc-protected cis- or trans-4-l-hydroxyproline (cis- or trans-4-Hyp) to benzylated glycine (Gly-OBn) and l-valine (l-Val-OBn) and used these dipeptides as catalysts for a model aldol reaction. Despite the lack of a proton donor in the catalytic site, we observed good stereoselectivities for the R-configured aldol product both with dipeptides formed from cis- or trans-4-Hyp at moderate conversions after 24 h. To explain this conundrum, we modeled reaction cycles for aldol additions in the presence of cis-4-Hyp, trans-4-Hyp, and cis- and trans-configured 4-Hyp-peptides as catalysts by calculation of free energies of conformers of intermediates and transition states at the density functional theory level (B3LYP/6-31G(d), DMSO PCM as solvent model). While a catalytic cycle as previously suggested with l-proline is also plausible for cis- or trans-4-Hyp, with the peptides, the energy barrier of the first reaction step would be too high to allow conversions at room temperature. Calculations on modeled transition states suggest an alternative pathway that would explain the experimental results: here, the catalytic cycle is entered by the acetone self-adduct 4-hydroxy-4-methylpentan-2-one, which forms spontaneously to a small extent in the presence of a base, leading to considerably reduced calculated free energy levels of transition states of reaction steps that are considered rate-determining.