Properties of the Amide Bond Involving Proline 4,5‐methanologues: an Experimental and Theoretical Study

Abstract

Herein we disclose a combined experimental and theoretical study on the conformational properties of amide bonds involving diastereomeric 4,5‐methano‐L‐proline congeners as N‐acetyl ethyl esters and dimeric amide ethyl esters as substrates for cyclization to diketopiperazines. The results are discussed in light of density functional theory calculations aimed at delineating the importance of the n→π* stabilization of the trans‐amide conformations. The transitions states for the cyclization of diastereomeric 4,5‐methano‐L‐proline ethyl esters to diketopiperazines were calculated and correlated to the experimental studies.

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

“…The tertiary amide bond in N -acylprolyl can exist in two conformational states, s- trans and s- cis ( Scheme 2 ), with the former being thermodynamically preferred in most cases [ 66 – 67 ]. The intrinsic contextual preference in the amide isomerism around the proline residue is usually characterized using small molecular models such as esters of N -acetylproline, similar to those in this study [ 35 , 68 – 69 ]. Within this model, the trans -amide prevalence is not large, and both rotameric states are readily observed in NMR spectra.…”

“… a Determined in 1 H (and 19 F) one-dimensional NMR spectra, analyte 50 ± 10 mM, 298 K; b measured by 1 H and 19 F{ 1 H} EXSY NMR at 50 ± 10 mM analyte concentration; c as reported in [ 69 ]. …”

My 50-Plus Years of Academic Research Collaborations with Industry. A Retrospective

“…As an academic, it has been rewarding that cis- and trans- 4,5-methano prolines have rendered valuable service to the development of marketed drugs and to new prototypes that are currently being exploited in ongoing clinical trials many years after publication of our results. Other applications of 4,5-methano L-proline in the context of synthetic methodology, catalysis, − and PP2 type helical oligomers have been reported from our group.…”

Catalytic properties of 4,5-bridged proline methano- and ethanologues in the Hajos–Parrish intramolecular aldol reaction

“…The extensive flattening of the pyrrolidine ring in the proline methanologues 29 4 and 5 highlighted by an increased sp 2 -character of the C 5 -N and C 5 -H bonds, 30 is no longer present in the ethano derivatives, probably due to the added flexibility provided by the ethano-bridge. 24,30 We were surprised to see a strong 1 ppm downfield shift on the C 5 proton resonance, as well as more than a 10 ppm shift for the 13 C resonance, in comparison to methano-proline (Fig. 3).…”