Synthesis and solution properties of optically active poly(trans‐5‐methylproline)

An examination of the steric effects of 5-tert-butylproline on the conformation of polyproline and the cooperative nature of type II to type I helical interconversion

“…For example, in the same manner that poly(2‐methylproline) was found to be “locked” into a type II helix that did not interconvert into a type I conformation,27 only the trans amide isomer (>98%) was observed in the 13 C‐nmr spectrum of N ‐acetyl‐2‐ methylproline N ′‐methylamide 15. Inasmuch as 5‐methyl and 5‐ethyl pyrrolidine ring substituents did not perturb polyproline helicity,28–34 a 5‐position methyl group had no influence on the ratio of amide isomers in N ‐acetyl‐ cis ‐5‐methylproline N ′‐methylamide and caused only a 5% increase in the amide cis ‐isomer population in water for N ‐acetyl‐ trans ‐5‐methylproline N ′‐methylamide 16. On the other hand, bulkier 5‐position substituents appeared to impose more pronounced steric effects in polyproline than in N ‐(acetyl)alkylproline N ′‐methylamide.…”

“…In proline oligomers, 4‐position ring substituents have been shown to interact minimally with the helical structure 23–26. Alkyl 2‐ and 5‐position substituents are predisposed to interact with the proline ψ and ω dihedral angle geometries and were initially analyzed in pioneering studies of high molecular weight polyproline synthesized by polymerization of amino acid N ‐carboxyanhydrides 27–37. A comparison of studies on high molecular weight polyprolines and model prolyl peptides shows the effect of small alkyl groups on the helical nature of polyproline27–31 to parallel the influence of similar 2‐ and 5‐position substituents on the amide geometry of N ‐(acetyl)alkylproline N ′‐methylamides 15, 16.…”

“…Alkyl 2‐ and 5‐position substituents are predisposed to interact with the proline ψ and ω dihedral angle geometries and were initially analyzed in pioneering studies of high molecular weight polyproline synthesized by polymerization of amino acid N ‐carboxyanhydrides 27–37. A comparison of studies on high molecular weight polyprolines and model prolyl peptides shows the effect of small alkyl groups on the helical nature of polyproline27–31 to parallel the influence of similar 2‐ and 5‐position substituents on the amide geometry of N ‐(acetyl)alkylproline N ′‐methylamides 15, 16. For example, in the same manner that poly(2‐methylproline) was found to be “locked” into a type II helix that did not interconvert into a type I conformation,27 only the trans amide isomer (>98%) was observed in the 13 C‐nmr spectrum of N ‐acetyl‐2‐ methylproline N ′‐methylamide 15.…”

“…We have probed the hypothesis that helical interconversion is a cooperative process by examining the capacity of 5‐ tert ‐butylproline to nucleate the helical conformation of type I polyproline. We conducted our examination using enantiopure (2 S ,5 R )‐5‐ tert ‐butylproline,38 the cis diastereomer, because poly( cis ‐5‐ iso ‐propylproline) of 2000–7000 g/mole was observed by CD to adopt a conformationally fixed type I‐like helix,35, 36 and because copolymers containing proline and cis ‐5‐ iso ‐propylproline were found to be incapable of the “usual mutarotation process.”36 Instead of studying high molecular weight polymer,27–37 a systematic approach was taken to evaluate the influence of a 5‐position substituent on proline oligomer conformation. Initially, N ‐(acetyl)prolyl‐prolinamide ( 1 ) and N ‐(acetyl)prolyl‐ cis ‐5‐ tert ‐butylprolinamide ( 2 ) were synthesized and examined by nmr spectroscopy to ascertain the local influence of the 5‐ tert ‐butyl substituent on the Pro–Pro peptide bond (Figure 2).…”

Synthesis and resolution of substituted pipecolic acids

“…For some time we have been involved in the study of substituent effects on the polymerization of cyclic imino acids and of the conformational behaviour of the corresponding polypeptides [2][3][4][5][6]. This paper deals with the syntheses of 2-methyl-, 2-benzyl-and cis-6-methylpipecolic acids (2MPA, 2BPA and c6MPA, respectively) and with the resolution of 2-methyl-and cis-6-methylpipecolic acids.…”