title: Synthesis of conformationally constrained 5-fluoro- and 5-hydroxymethanopyrrolidines. Ring-puckered mimics of gauche- and anti-3-fluoro- and 3-hydroxypyrrolidines.
abstract: N-acetylmethanopyrrolidine methyl ester and its four 5-syn/anti-fluoro and hydroxy derivatives have been synthesized from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photoproduct. These conformationally constrained mimics of idealized C(β)-gauche and C(β)-anti conformers of pyrrolidines were prepared in order to determine the inherent bridge bias and subsequent heteroatom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-fluoro or 5-hydroxy substituents have minimal influence upon the K(T/C) values of N-acetylamide conformers in both CDCl(3) (43-54% trans) and D(2)O (53-58% trans). O-Benzoylation enhances the trans amide preferences in CDCl(3) (65% for a syn-OBz, 61% for an anti-OBz) but has minimal effect in D(2)O. The synthetic methods developed for N-BOC-methanopyrrolidines should prove useful in the synthesis of more complex derivatives containing α-ester substituents. The K(T/C) results obtained in this study establish baseline amide preferences that will enable determination of contributions of α-ester substituents to trans-amide preferences in methanoprolines.
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States. grkrow@temple.edu
authors.forename: Grant R
authors.initials: GR
authors.lastname: Krow
authors.forename: Ram
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: Matthew
authors.initials: M
authors.lastname: Sender
authors.forename: Philip E
authors.initials: PE
authors.lastname: Sonnet
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zdilla
authors.forename: Charles
authors.initials: C
authors.lastname: DeBrosse
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Cannon
authors.forename: Charles W
authors.initials: CW
authors.lastname: Ross
authors.forename: Amit
authors.initials: A
authors.lastname: Choudhary
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shoulders
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Raines
mesh_terms: D000577:Amides / Q000737:chemistry; D008968:Molecular Conformation; D011392:Proline / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000577:Amides; D011759:Pyrrolidines; D011392:Proline