(9Z)- and (11Z)-8-methylretinals for artificial visual pigment studies: stereoselective synthesis, structure, and binding models.
Artificial visual pigment formation was studied by using 8-methyl-substituted retinals in an effort to understand the effect that alkyl substitution of the chromophore side chain has on the visual cycle. The stereoselective synthesis of the 9-cis and 11-cis isomers of 8-methylretinal, as well as the 5-demethylated analogues is also described. The key bond formations consist of a thallium-accelerated Suzuki cross-coupling reaction between cyclohexenylboronic acids and dienyliodides (C6-C7), and a highly stereocontrolled Horner-Wadsworth-Emmons or Wittig condensation (C11-C12). The cyclohexenylboronic acid was prepared by trapping the precursor cyclohexenyllithium species with B(OiPr)(3) or B(OMe)(3). The cyclohexenyllithium species is itself obtained by nBuLi-induced elimination of a trisylhydrazone (Shapiro reaction), or depending upon the steric hindrance of the ring, by iodine-metal exchange. In binding experiments with the apoprotein opsin, only 9-cis-5-demethyl-8-methylretinal yielded an artificial pigment; 9-cis-8-methylretinal simply provided residual binding, while evidence of artificial pigment formation was not found for the 11-cis analogues. Molecular-mechanics-based docking simulations with the crystal structure of rhodopsin have allowed us to rationalize the lack of binding displayed by the 11-cis analogues. Our results indicate that these isomers are highly strained, especially when bound, due to steric clashes with the receptor, and that these interactions are undoubtedly alleviated when 9-cis-5-demethyl-8-methylretinal binds opsin.
Alvarez
Rosana
R
Departamento de Química Orgánica, Facultad de Ciencias, Universidade de Vigo, 36200 Vigo, Spain.
Domínguez
Marta
M
Pazos
Yolanda
Y
Sussman
Fredy
F
de Lera
Angel R
AR
D001665:Binding Sites; D008956:Models, Chemical; D012172:Retinaldehyde / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D012243:Rhodopsin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
C503081:5-demethyl-8-methylretinal; D012243:Rhodopsin; D012172:Retinaldehyde