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

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