文摘
Proline derivatives with a C纬-exo pucker typically display a high amide bond trans/cis (KT/C) ratio. This pucker enhances n鈫捪€* overlap of the amide oxygen and ester carbonyl carbon, which favors a trans amide bond. If there were no difference in n鈫捪€* interaction between the ring puckers, then the correlation between ring pucker and KT/C might be broken. To explore this possibility, proline conformations were constrained using a methylene bridge. We synthesized discrete gauche and anti 5-fluoro- and 5-hydroxy-N-acetylmethanoproline methyl esters from 3-syn and 3-anti fluoro- and hydroxymethanopyrrolidines using directed 伪-metalation to introduce the 伪-ester group. NBO calculations reveal minimal n鈫捪€* orbital interactions, so contributions from other forces might be of greater importance in determining KT/C for the methanoprolines. Consistent with this hypothesis, greater trans amide preferences were found in CDCl3 for anti isomers en-MetFlp and en-MetHyp (72鈥?8% trans) than for the syn stereoisomers ex-MetFlp and ex-MetHyp (54鈥?7% trans). These, and other, KT/C results that we report here indicate how substituents on proline analogues can affect amide preferences by pathways other than ring puckering and n鈫捪€* overlap and suggest that caution should be exercised in assigning enhanced pyrrolidine C纬-exo ring puckering based solely on enhanced trans amide preference.
