Catalytic synthesis of 9-cis-retinoids: mechanistic insights.
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| Title: | Catalytic synthesis of 9-cis-retinoids: mechanistic insights. |
|---|---|
| Authors: | Kahremany, Shirin1,2, Kubas, Adam3, Tochtrop, Gregory P.4, Palczewski, Krzysztof1,2 |
| Source: | Dalton Transactions: An International Journal of Inorganic Chemistry. 7/28/2019, Vol. 48 Issue 28, p10581-10595. 15p. |
| Subjects: | Drug synthesis, Heat treatment, Chemistry, Isomerization, Therapeutics, Isomers |
| Abstract: | The regioselective Z-isomerization of thermodynamically stable all-trans retinoids remains challenging, and ultimately limits the availability of much needed therapeutics for the treatment of human diseases. We present here a novel, straightforward approach for the catalytic Z-isomerization of retinoids using conventional heat treatment or microwave irradiation. A screen of 20 transition metal-based catalysts identified an optimal approach for the regioselective production of Z-retinoids. The most effective catalytic system was comprised of a palladium complex with labile ligands. Several mechanistic studies, including isotopic H/D exchange and state-of-the-art quantum chemical calculations using coupled cluster methods indicate that the isomerization is initiated by catalyst dimerization followed by the formation of a cyclic, six-membered chloropalladate catalyst–substrate adduct, which eventually opens to produce the desired Z-isomer. The synthetic development described here, combined with thorough mechanistic analysis of the underlying chemistry, highlights the use of readily available transition metal-based catalysts in straightforward formats for gram-scale drug synthesis. [ABSTRACT FROM AUTHOR] |
| Copyright of Dalton Transactions: An International Journal of Inorganic Chemistry is the property of Royal Society of Chemistry and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
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