The “Azido Gauche Effect”Implications for the Conformation of Azidoprolines

Abstract

The "azido gauche effect" was examined both experimentally and theoretically and was found to determine the conformation of, for example, (4R)- and (4S)-azidoproline (Azp) derivatives. For (4R)Azp derivatives, the azido gauche effect induces a preferred C(4)-exo conformation of the pyrrolidine ring, which leads to stabilization of the s-trans amide conformer of, e.g., Ac-(4R)Azp-OCH(3) (5R) via an n-->pi interaction between the nonbonding electrons of the oxygen of the acetyl group and the carbonyl group of the ester. For (4S)Azp derivatives, the azido gauche effect results in a C(4)-endo conformation of the pyrrolidine ring that does not allow for this stabilizing n-->pi interaction of the s-trans conformer. Consequently, a significantly higher s-trans:s-cis amide conformer ratio is observed for (4R)Azp compared to (4S)Azp derivatives (e.g., 6.1:1 versus 2.6:1 in D(2)O for Ac-(4R)Azp-OCH(3) (5R) compared to Ac-(4S)Azp-OCH(3) (5S)). These conformational preferences are reflected in the higher tendency of (4S)Azp-containing peptides to form cyclic peptides with all-cis amide bonds compared to (4R)Azp derivatives. Ab initio calculations demonstrate that the strength of the azido gauche effect is comparable to that of the well-known "fluorine gauche effect". For azidoethane derivatives N(3)-CH(2)CH(2)-X (X = N(3), NHCOH, NHAc, or N(CH(3))Ac), the ab initio calculations revealed energy differences of 5-13 kJ mol(-)(1) between the anti and gauche conformations in favor of the gauche conformer. Calculations were also performed for the (4R)Azp and (4S)Azp derivatives 5R and 5S, supporting the experimentally observed data.

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

“…31,35,45,[66][67][68] To determine the effect of 4-chloro substitution on proline ring pucker and peptide-bond isomerization, we prepared Ac-clp-OMe (9) and Ac-Clp-OMe (10), as shown in Scheme 1. Acidic methanol was used to cleave the N-Boc group and introduce the methyl ester.…”

“…This n→π* interaction is known to stabilize the trans conformation of the amide bond. 35,[43][44][45][46] Structural parameters for crystalline Ac-Clp-OMe and Ac-Hyp-OMe 66 are listed in Table II.…”

“…40 Consequently, substitution of flp or (2S,4R)-4-methylproline (mep) for Pro in the Xaa position of CRPs stabilizes triple helices (Table 1). 39,41,42,31 Although the C γ -endo pucker preorganizes the φ and ψ angles to those required for triple-helix assembly, it does not preorganize the ω angle because proline derivatives with a C γ -endo pucker have an enhanced preference for the cis peptide bond due to another stereoelectronic effect-an n→π* interaction-described elsewhere, 35,[43][44][45][46] whereas all peptide bonds in collagen are trans. Despite its preference for the C γ -endo pucker, (2S,4S)-4-hydroxyproline (hyp) in the Xaa position does not allow for the formation of stable triple helices (Table I), 23 perhaps due to deleterious hydration absent from flp and mep or to idiosyncratic conformational preferences.…”

(4R)- and (4S)-Azidoprolines – Conformation Directing Amino Acids and Sites for Functionalization

“…[4] Conformational analysis by 1 H NMR spectroscopy revealed considerable differences in their s-cis:strans conformer ratios and the conformation of the pyrrolidine rings. Regardless of the solvent, the s-trans conformer was the major conformer in both diastereoisomers, however, in the spectra of the (4R)-configured stereoisomer a significantly higher portion of the s-trans conformer was observed.…”

“…Proline derivatives bearing a substituent at the γ-carbon (C(4)) are an important tool in this respect since their s-cis:s-trans conformer ratios often differ from that of unsubstituted proline. [3,4] We became interested in (4R)-and (4S)-azidoproline (Azp) as versatile amino acids that allow for further functionalization. Our research started by utilizing the diketopiperazine 1R derived from (4R)Azp as a template for two-armed peptide receptors (Fig.…”