Substituted 2-azabicyclo[2.1.1]hexanes as constrained proline analogues: implications for collagen stability.
Among the proteinogenic amino acids, only proline is a secondary amine and only proline has a saturated ring. Electronegative substituents on C-4 (that is, C(gamma)) have a substantial effect on the trans/cis ratio of the prolyl peptide bond and the pucker of the pyrrolidine ring. 2-Azabicyclo[2.1.1]hexane is, in essence, a proline analogue with two C(gamma) atoms, one in each of the two prevalent ring puckers of proline. Here, 2-azabicyclo[2.1.1]hexane analogues of 2S-proline, (2S,4S)-4-hydroxyproline, and (2S,4S)-4-fluoroproline residues were synthesized, and their trans/cis ratios were shown to be invariant in a particular solvent. Thus, the substitution of a proline residue on C-4 affects the trans/cis ratio by altering the pucker of its pyrrolidine ring. This finding has implications for the conformation of collagen, which has an abundance of 2S-proline and (2S,4R)-4-hydroxyproline residues, and can be stabilized by (2S,4R)-4-fluoroproline and (2S,4S)-4-fluoroproline residues.
Jenkins
Cara L
CL
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Lin
Guoliang
G
Duo
Jingqi
J
Rapolu
Deepa
D
Guzei
Ilia A
IA
Raines
Ronald T
RT
Krow
Grant R
GR
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D003094:Collagen / Q000737:chemistry*; D006586:Hexanes / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation
D019086:Bridged Bicyclo Compounds, Heterocyclic; D006586:Hexanes; D003094:Collagen; D011392:Proline