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

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-OCH3 (5R) via an n→π* 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→π* 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 D2O for Ac-(4R)Azp-OCH3 (5R) compared to Ac-(4S)Azp-OCH3 (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 N3−CH2CH2−X (X = N3, NHCOH, NHAc, or N(CH3)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.