SYNTHESIS, HIGH-FIELD NMR, X-RAY STRUCTURE, AND CONFORMATIONAL-ANALYSIS OF A 10-MEMBERED DIAMIDE DISULFIDE RING

N,N'-[Dimethyl-(2,2'-dithiobisacetyl)let (1) has been synthesized in 3 0% overall yield from N,N'-dimethylethylenediamine and thioacetic acid by an improved procedure involving simultaneous deprotection and oxid ative cyclization with iodine. This cyclic diamide disulfide exists in solution as a mixture of two Z,Z and one Z,E disulfide, and amide rin g conformers and has been characterized by nuclear Overhauser effect ( NOE), H-1-H-1, H-1-C-13 shift-correlated 2D-NMR and molecular modellin g studies. Among the Z,Z ring conformers Z,Z(1) and Z,Z(2) the former predominates and interconverts with the latter isomer by rotation abou t the SS bond with an activation energy of 14.5 +/- 1.3 kcal/mol. Coal escence of N-CH3 signals occurred at ca. 127 degrees C (500 MHz), whic h corresponded to an approximate barrier to amide rotation of 19.3 kca l/mol. Aromatic solvent-induced shifts in C6D6 corroborated molecular mechanics and NOE predictions of amide stereochemistry. The structure of the Z,E stereoisomer of 1 has been determined by single-crystal X-r ay diffraction at 296 K. A large geminal N-CH2 inequivalence (>2 ppm i n CDCl3) was observed for the Z,Z conformers. Proton chemical shifts h ave been calculated for the conformers of 1 and related molecular frag ments with DFT/GIAO theory. Absolute chemical shifts are modelled with in 0.2 ppm of experiment. The unusual nonequivalence of geminal N-CH2 and S-CH2 protons can be understood as a combination of shielding mech anisms derived from short N-methyl contacts, amide group orientation, and sulfur lone-pair disposition. An implication of these results is t he possibility of using alpha-CH (and eventually (alpha-CH) shifts to probe the local conformational space in cyclic peptides and other conf ormationally constrained rings.