Heteroarotinoids: Analytical criteria for the rapid identification of E and Z isomers of these novel retinoids via NMR, UV, and X-ray analyses of selected examples

Article abstract of DOI:10.1021/jo00300a009

A series of derivatives of E and Z isomers of 4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)- propenyl]benzoic acid and 4-[2-(2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-1- propenyl]benzoic acid and sulfur-containing counterparts have been examined in terms of ¹H, ¹³H, and ultraviole (UV) analyses for the purpose of establishing which parameters are diagnostic for identifying E and Z isomers in this family of heteroarotinoids. Several members of the latter have previously exhibited potentially useful anticancer properties. In addition, X-ray diffraction analyses for methyl (E)-[2-(2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-1-propenyl]benzoate [(E)-3b], methyl (E)-4-[2-(2,3-dihydro-3,3-dimethylbenzo[b]thien-5-yl)-1- propenyl]benzoate [(E)-3d], and methyl (Z)-4-[2-(2,3-dihydro-3,3-dimethylbenzo[b]thien-5-yl)-1- propenyl]benzoate [(Z)-3d] were performed to confirm the arrangment around the central double bond in the solid state in these rare examples containing a fused, five-six-membered ring system. The proton NMR analyses of solutions of the E versus the Z isomers, particularly the enhanced shielding of the vinylic proton and protons at ''ortho'' positions on the aryl groups attached to the double bond, provide markers to identify the Z isomers in these heteroarotinoids. In the ¹³C spectra, the methyl carbon attached to the double bond was usually about 10 ppm downfield in the Z isomer compared to the counterpart in the E isomer. These data, taken on the whole, suggest that in solution the two aryl rings in the Z isomers [and possibly the E isomers] are turned out of plane of the double bond, and, due to the closer proximity of the rings, induced shielding of nearby protons occurs to a greater extent in the Z isomers compared to the E isomers. This evaluation is supported by UV spectral data which show maxima in two ranges, namely at 210-270 and 280-350 nm. The ''conjugation band'' at the longer wavelength is always more intense, relative to the band at the shorter wavelength, in the E isomers. This is taken to imply improved overlap of p orbitals in the double bond with those in the aryl rings in the E isomers. In contrast, the band at shorter wavelength is more intense than the band at long wavelength in the Z isomers. These two features are clearly distinguishing for the two isomeric forms in solution and are reminiscent to some degree of the situation found in stilbenes. Characterization of (E)-3b, (E)-3d, and (Z)-3d via X-ray diffraction analysis of single crystals is confirmatory in that the rings in both isomeric alkenes lack coplanarity with the central double bond in the solid state. The deviation from overall planarity is greatest for the Z isomers with the internal torsional angle being 10.7° in (Z)-3d rather than the ''ideal'' value of 0°. Moreover, the aryl rings are not far from being nearly perpendicular to each other in (Z)-3d. Molecular mechanics calculations, using the MMP2 program, indicate the deviation from planarity is less than that found from X-ray analysis on solid (Z)-3d. These data provide a foundation for rapid identification of certain groups of heteroarotinoids. A comparison of crystal data of (E)-3b and (E)-3d with that of trans-retinoic acid (1) was also made. The least-squares ''fit'' is quite satisfactory in spite of differences in conformational angles, and an RMS value of 0.90 A is calculated. It appears that placing the ester group of (E)-3b or (E)-3d in a ''meta'' position would improve the fit considerably. Consequently, the work has ramifications for aiding in the design of potential medicinal agents in this family of heterocycles.