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

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journal contribution
posted on 15.06.2012, 00:00 by Grant R. Krow, Matthew D. Shoulders, Ramakrishna Edupuganti, Deepa Gandla, Fang Yu, Philip E. Sonnet, Matthew Sender, Amit Choudhary, Charles DeBrosse, Charles W. Ross, Patrick Carroll, Ronald T. Raines
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.