Abstract
Artificial visual pigment formation from ring‐demethylated retinals was studied in an effort to understand the effect that methyl groups on the chromophore cyclohexenyl ring have on the visual cycle. The stereoselective synthesis of the 11‐cis‐ring‐demethylated analogues involves thallium‐accelerated Suzuki cross‐coupling reactions and highly stereocontrolled Wittig reactions to form key bonds. Only 11‐cis‐1,1,5‐trisdemethylretinal (2) failed to form an artificial pigment, whilst variable pigment‐formation yields were determined for the remaining analogues, increasing with the number (and location) of the chromophore hydrophobic ring methyl groups. Our results with the monodemethylated analogues 11‐cis‐5‐demethylretinal (4) and 11‐cis‐1‐demethylretinal (5) show that the C1–2‐CH~3~ groups are more important for pigment formation than the C5‐CH~3~ substituent. This is reflected in the absorption maxima of the artificial pigments, with values closer to that of native rhodopsin for 4. Docking studies based on a rhodopsin crystal structure, however, predict a lower pigment stability for 4 than for 5. Gas‐phase DFT (B3LYP/6‐31G*) computations of the free‐ligand geometries, conformational searches about the C6C7 bond, and docking studies revealed that, although the conformation of bound 5 is close to that of the native chromophore, the ligand needs to overcome the energy cost of shifting the unbound favored 6‐s‐trans conformation to the bound 6‐s‐cis form. In addition, the presence of an extra methyl group at C18 (11‐cis‐18‐methylretinal, 7) is tolerated well and adds further stability to the complex, most probably due to increased hydrophobic interactions.