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(9 Z )‐ and (11 Z )‐8‐Methylretinals for Artificial Visual Pigment Studies: Stereoselective Synthesis, Structure, and Binding Models
Author(s) -
Alvarez Rosana,
Domínguez Marta,
Pazos Yolanda,
Sussman Fredy,
de Lera Angel R.
Publication year - 2003
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200304847
Subject(s) - chemistry , steric effects , stereoselectivity , stereochemistry , chromophore , rhodopsin , suzuki reaction , isopropyl , visual phototransduction , alkyl , retinal , photochemistry , medicinal chemistry , organic chemistry , biochemistry , aryl , catalysis
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 (C6C7), and a highly stereocontrolled Horner–Wadsworth–Emmons or Wittig condensation (C11C12). The cyclohexenylboronic acid was prepared by trapping the precursor cyclohexenyllithium species with B(O i Pr) 3 or B(OMe) 3 . The cyclohexenyllithium species is itself obtained by n BuLi‐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.