Abstract
The compound 9-cis-retinyl acetate (9-cis-RAc) is a precursor to 9-cis-retinal, which has potential application in the treatment of some hereditary diseases of the retina. An attractive synthetic route to 9-cis-RAc is based on the photoisomerization reaction of the readily available all-trans-RAc. In the present study, we examine the mechanism of the photoisomerization reaction with the use of state-of-the-art electronic structure calculations for two polyenic model compounds: tEtEt-octatetraene and tEtEtEc-2,6-dimethyl-1,3,5,7,9-decapentaene. The occurrence of photoisomerization is attributed to a chain-kinking mechanism, whereby a series of S1/S0 conical intersections associated with kinking deformations at different positions along the polyenic chain mediate internal conversion to the S0 state, and subsequent isomerization around one of the double bonds. Two other possible photoisomerization mechanisms are taken into account, but they are rejected as incompatible with simulation results and/or the available spectroscopic data.
Highlights
Retinoids are a class of lipophilic compounds chemically related to vitamin A
In certain hereditary human diseases, such as Leber’s congenital amaurosis, mutations in genes encoding the proteins involved in the visual cycle disrupt the metabolism of retinoids, leading to vision impairment and loss.[3−7] Beginning in the early 2000s, a specific retinoid, 9-cis-retinal, has been investigated as a therapeutic agent for the treatment of some of these diseases.[8−18] (The designation “9-cis” and others like it refer to the location, in the polyenic chain, of a double bond with the cis configuration.) The pharmacological activity of 9-cis-retinal relies on the fact that it combines with opsin to form isorhodopsin,[13] an analogue of rhodopsin which is sensitive to light.[19,20]
The photoisomerization reaction of all-trans-retinyl acetate (RAc) was investigated by exploring the ground- and excited-state potential energy surface (PES) of two model polyenes: OT and 26DMDP
Summary
Retinoids are a class of lipophilic compounds chemically related to vitamin A. They consist of a polyenic chain with a polar functional group on one end (a hydroxyl group in retinol, an aldehyde group in retinal, etc.), and a six-membered β-ionone ring on the other end. They serve several biological functions, including acting as the chromophores of light-sensitive retinylidene proteins such as rhodopsin.[1,2]. Kahremany and co-workers[21] proposed a synthetic strategy that uses as its starting point the readily available all-trans-retinoids. A set of 20 commercially available transition metal-based catalysts were screened for the conversion of all-trans-retinoids into mono-cis isomers. The best-performing catalysts from among those considered in ref 21 achieved favorable regioselectivity, namely, a preference for the formation of the desired 9-cis isomers and moderately high conversion yields
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