Synthesis of 5-Fluoro- and 5-Hydroxymethanoprolines via Lithiation of N-BOC-methanopyrrolidines. Constrained Cγ-Exo and Cγ-Endo Flp and Hyp Conformer Mimics

Proline derivatives with a Cγ-exo pucker typically display a high amide bond trans/cis (KT/C) ratio. This pucker enhances n→π* overlap of the amide oxygen and ester carbonyl carbon, which favors a trans amide bond. If there were no difference in n→π* 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 α-metalation to introduce the α-ester group. NBO calculations reveal minimal n→π* 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 (72–78% trans) than for the syn stereoisomers ex-MetFlp and ex-MetHyp (54–67% 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→π* overlap and suggest that caution should be exercised in assigning enhanced pyrrolidine Cγ-exo ring puckering based solely on enhanced trans amide preference.