title: Synthesis of 5-fluoro- and 5-hydroxymethanoprolines via lithiation of N-BOC-methanopyrrolidines. Constrained Cγ-exo and Cγ-endo Flp and Hyp conformer mimics.
abstract: Proline derivatives with a C(γ)-exo pucker typically display a high amide bond trans/cis (K(T/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 K(T/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 K(T/C) for the methanoprolines. Consistent with this hypothesis, greater trans amide preferences were found in CDCl(3) 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, K(T/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 C(γ)-exo ring puckering based solely on enhanced trans amide preference.
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, USA. grkrow@temple.edu
authors.forename: Grant R
authors.initials: GR
authors.lastname: Krow
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shoulders
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Edupuganti
authors.forename: Deepa
authors.initials: D
authors.lastname: Gandla
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.forename: Philip E
authors.initials: PE
authors.lastname: Sonnet
authors.forename: Matthew
authors.initials: M
authors.lastname: Sender
authors.forename: Amit
authors.initials: A
authors.lastname: Choudhary
authors.forename: Charles
authors.initials: C
authors.lastname: DeBrosse
authors.forename: Charles W
authors.initials: CW
authors.lastname: Ross
authors.forename: Patrick
authors.initials: P
authors.lastname: Carroll
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Raines
mesh_terms: D008968:Molecular Conformation; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: C575977:5-fluoro-methanoproline; C575976:5-hydroxymethanoproline; D011759:Pyrrolidines; D011392:Proline