Jenkins Cara L, Lin Guoliang, Duo Jingqi, Rapolu Deepa, Guzei Ilia A, Raines Ronald T, Krow Grant R
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
J Org Chem. 2004 Dec 10;69(25):8565-73. doi: 10.1021/jo049242y.
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.
在构成蛋白质的氨基酸中，只有脯氨酸是仲胺，并且只有脯氨酸具有饱和环。C-4（即C(γ)）上的吸电子取代基对脯氨酰肽键的反式/顺式比率以及吡咯烷环的构象有重大影响。本质上，2-氮杂双环[2.1.1]己烷是一种脯氨酸类似物，有两个C(γ)原子，分别处于脯氨酸两种常见环构象中的一种。在此，合成了2S-脯氨酸、(2S,4S)-4-羟基脯氨酸和(2S,4S)-4-氟脯氨酸残基的2-氮杂双环[2.1.1]己烷类似物，并且它们的反式/顺式比率在特定溶剂中显示为不变。因此，C-4上脯氨酸残基的取代通过改变其吡咯烷环的构象来影响反式/顺式比率。这一发现对胶原蛋白的构象有影响，胶原蛋白含有大量的2S-脯氨酸和(2S,4R)-4-羟基脯氨酸残基，并且可以被(2S,4R)-4-氟脯氨酸和(2S,4S)-4-氟脯氨酸残基稳定。
