Cis amide conformations

The planar cis-amide conformation in the seven-membered lactam already can impose some strain on the ring and thus increase its polymerizability. 

Fig. 8. Rephcation. The amino adenosine X and the pentafluorophenyl ester Y form a hydrogen-bonded dimer XY, prior to reaction between the amine and the activated ester groups (shown in the circle). The reaction product is a <7 -amide conformer cis-Z that isomeri2es to the more stable trans- acnide Z. The rephcative process is cataly2ed by the reaction product Z (also referred to as the template). First, a termolecular complex XYZ is formed from X, Y, and Z.

A peptoid pentamer of five poro-substituted (S)-N-(l-phenylethyl)glycine monomers, which exhibits the characteristic a-helix-like CD spectrum described above, was further analyzed by 2D-NMR [42]. Although this pentamer has a dynamic structure and adopts a family of conformations in methanol solution, 50-60% of the population exists as a right-handed helical conformer, containing all cis-amide bonds (in agreement with modeling studies [3]), with about three residues per turn and a pitch of 6 A. Minor families of conformational isomers arise from cis/trans-amide bond isomerization. Since many peptoid sequences with chiral aromatic side chains share similar CD characteristics with this helical pentamer, the type of CD spectrum described above can be considered to be indicative of the formation of this class of peptoid helix in general. 

The Z-alkene isostere mimics the cis-amide bond conformation. Its molecular volume and log p values are almost identical to those of the E-isostere (Table 1). Its use in bioactive peptides is very limited, probably because of the synthetic challenge involved. One study reports the migration of the double bond to the a,(3-position in an enkephalin analogue. 4 The Z-alkene in the Alat t[Z, CH=CH]Pro dipeptide isostere, however, was reported to be stable towards isomerization.1 1X1 orf/to-Substituted aromatic or tetrazole rings have been used more frequently as ds-amide bond mimics. 

Due to the preference for a cis-amide bond[93] with the preceding residue of C2-substituted pseudoprolines, their incorporation results in a kink conformation of the peptide backbone, thus preventing peptide aggregation, self-association, or (3-structure formation. 

Cisitrans isomerization occurs around amide bonds involvingthe nitrogen of proline and other N-alkyl amino acid residues. NMR studies of both morphiceptin and PL017 found that, whereas the major isomers were the all-trans conformers, the second most common isomer (25%) had a cis amide bond between... 

U., Head, R. D., Kao, J., and Marshall, G. R. (1995) Conformational mimicry Synthesis and solution conformation of a cyclic somatostatin hexapeptide containing a tetrazole cis-amide bond surrogate. Biopolymers 36, 181-200. 

Possible conformations for Gly37-Gly38-Val39 were compared of an idealized j8-strand, conformations C (w37-38 = 0°, 38=—121°, 38 = 25°, 39 = -41°, 0)31-3% = 180°) and conformations T ( 37-38 = 180°, < 38 = 0°, i/>38 = -134°, distance constraints indicated that an unusual structure, probably involving a cis amide bond, is present in the aggregated peptide amyloid. This structure is incompatible with the accepted models of fibril structure. 

Recently, Marshall and coworkers have reported on the particular structural behavior of azaproline (azPro) derivative Ac-azPro-NHMe (Fig. 8.3) which tends to form an eight-member hydrogen bond (i — i + 1) in a typical / -turn conformation without introducing any steric bulk. It stabilizes a cis-amide bond whereas proline favors a seven-member H-bond (i + 2 — i) with a trans-amide conformation (y-turn) (Fig. 8.3) [27]. Additional N-methylation decreases the energy difference between cis- and trans-azPro conformers and hence severely perturbs the /fturn conformation [28]. In nonproline derivatives, permethylation inverted the tendency since calculation at the B3LYP/6-31G level showed that the ds-Ac-azAla-NHMe was 1.36 kcal mol-1 more stable than the trans-amide conformer, whereas trans-Ac-azAla-NHMe was favored by 1.24 kcal mol-1 [32]. 

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