5,5‐Dimethylthiazolidine‐4‐carboxylic acid (DTC) as a proline analog with restricted conformation

Publisher Website
Google Scholar
Abstract
Spectroscopic evidence is presented for the lack of intramolecular hydrogen bonding in a simple peptide derivative of 5,5-dimethylthiazolidine-4-carboxylic acid (Dtc). The infrared spectrum of Boc-Pro-Ile-OMe 1 in nonpolar solvents displays two N-H stretching bands at 3419 and 3330 cm-1 in CCl4 and one at 3417 and 3328cin-1 in CHCl3. The low frequency band at 3328–3330cm-1 may be assigned to conformations with an intramolecular hydrogen bond between the Ile N-H and Boc C=O. The band at 3417-3419 cm-1 is the normal Ile N-H stretch. In the polar solvent CH3 CN only one NH stretching band at 3365 cm-1 is observed. The IR spectrum of Boc-Dtc-Ile-OMe 2, on the other hand, displays one N-H stretching band at 3423cm-1 in CCI, and one at 3418cm-1 in CHCI3. The IR spectrum of 2 does not display the N-H stretching band that would arise from intramolecular hydrogen bonding between the Boc C=O and Ile N-H. The lack of intramolecular hydrogen bonding for Boc-Dtc-Ile-OMe 2 was evident also in the NMR spectra in nonpolar solvents. The 1H-NMR spectrum of the Pro dipeptide 1 in 50% CDCl3/C6D6 at 20° displayed two Ile-NH signals at 6.58 and 7.74 ppm. The latter signal corresponds to the intramolecularly hydrogen bonded Ile-NH in the trans-Boc isomer of 1 (60% of the total population), while the former signal corresponds to the nonhydrogen bonded Ile-NH in the cis-Boc isomer. The 1H-NMR spectrum of the Dtc dipeptide 2 displayed two slowly exchanging cis- and trans-Boc amide isomers as well, but both amide proton resonances were observed upfield at 6.67 and 6.74 ppm, which correspond only to a nonhydrogen bonded Ile N-H. The X-ray crystal structure of Boc-Dtc displays only a cis-Boc-Dtc urethane amide group and two conformations for the Dtc ring, one in which the beta carbon atom is anti to the carboxyl group and the other in which the gamma sulfur atom is anti to the carboxyl group. Conformational analysis of Ac-Dtc-NHMe suggests that in the hydrogen bonded C7 conformation steric interaction between the syn-beta methyl group and carbonyl group of Dtc adds nonbonded and angle strain energies to counteract the stabilizing coulombic interaction between the Boc C=O and terminal amide N-H. Whereas the C7 conformation is a prominent conformation for peptide derivatives of proline, other conformations are favored in peptide derivatives of Dtc (ψ -ñ 110-150° or ñ 320-360°). These results suggest that, in peptides where substitution of Pro appears to maintain or enhance biological activity, the substitution of Dtc for Pro may test the functional importance of the C7 conformation in that position of the peptide sequence.