title: Robust trans-amide helical structure of oligomers of bicyclic mimics of β-proline: impact of positional switching of bridgehead substituent on amide cis-trans equilibrium.
abstract: Because homooligomers of 7-azabicyclo[2.2.1]heptane-2-endo-carboxylic acid, a bridged β-proline analogue with a substituent installed at the remote C4-bridgehead position, completely biased the amide cis-trans equilibrium to the cis-amide structure, we expected that introduction of a substituent at the C1-bridgehead position adjacent to the carboxylic acid moiety, rather than the remote C4-bridgehead position, would tip the cis-trans amide equilibrium toward trans-amide structure without the aid of hydrogen bonding. Thus, in this work we established an efficient synthetic route to an optically active bicyclic analogue of 1,1-disubstituted β-proline, bearing a substituent at the C1-bridgehead position. Crystallographic, spectroscopic, and computational studies showed that indeed oligomers of this analogue take a consistent helical structure involving all-trans-amide linkages, independently of the number of residues, from the dimer up to the octamer. Oligomers composed of (R)-β-amino acid units form an extended left-handed helix with about 2.7 residues per turn and an approximately 4.0 Å rise per residue, characterized by complete lack of main-chain hydrogen bonding. This unique helical structure shows some similarity in shape to the trans-amide-based polyproline II (PPII) helix. The present helix was stable in various kinds of solvents such as alcohols. The present work provided a fundamental structural basis for future applications.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Wang
authors.forename: Yuko
authors.initials: Y
authors.lastname: Otani
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kawahata
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohwada
mesh_terms: D000577:Amides / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry*; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry; D011487:Protein Conformation; D013237:Stereoisomerism
chemical_list: C000594713:7-azabicyclo(2.2.1)heptane-2-endo-carboxylic acid; D000577:Amides; D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002264:Carboxylic Acids; D010455:Peptides; C011083:polyproline; D011392:Proline; C072401:beta-proline