The Highly Stereocotrolled Synthesis Of Coenzyme Q₁₀ And The Total Syntheses Of Solanesol And Analogies

Since its discovery and isolation from the mitochondria of beef heart by Crane in 1957,coenzyme Q₁₀,also known as ubiquinone-10 or vitamin Q₁₀, has been used clinically as a cardiovascular agent. It can also be applied as an antioxidizing and immunomodulating drug, and has a notable effect on cancer treatment. Although a number of methodologies for the synthesis of coenzyme Q₁₀ have been developed so far, the first industrial approach by Hideaki Fukawa at Nisshin Co. in 1974, based on direct polyprenylation of hydroquinone monoacetate by Friedel-Crafts-type coupling, is still exclusive for the partial synthesis of this vitamin. However, this process is, unfortunately, attended with some unwanted side reactions, especially partial cyclization to a chromanol type compound and (E)/(Z) isomerization during coupling. Moreover, the coupling yield is very low (20%). Therefore, an efficient and economical synthesis of coenzyme Q₁₀ is still needed.Starting from coenzyme Q₀ and solanesol, two synthetic routes for coenzyme Q₁₀ was developed in high regio- and stereo-selectivity by improved C₅+C₄₅ strategies. In the first method, the double bond in the C₅ side chain was constructed successfully by a Wittig olefination and the sulphonyl group was reductively removed efficiently using sodium naphthalide. In the second process, the C₅ side chain was prepared first and then introduced to the derivation of coenzyme Q₀ in one step in stead of linear synthesis.A convergent process is developed for the synthesis of decaprenol, which is used for preparing coenzyme Q₁₀,via (C₁₀+C₁₀)+(C₁₀+C₁₀)+C₁₀ strategy starting from commercially available geraniol. During the synthetic course, the Biellmann-Ducep coupling of two fragments each of which have multiple prenyl units is realized such as (2+2 coupling), (4+4 coupling) and (8+2 coupling), therefore this strategy is suitable for the oligoprenols bearing long carbon skeleton.Based on the solution-phase synthesis of decaprenol, solanesol was prepared by solid-phase method via the similar strategy to decaprenol, for solid-phase synthetic strategy provides facile isolation for support-bound reaction products by washing away reagents with appropriate solvents, high translation on polymer supports by using excess reagents and suppression of unwanted reactions by site isolation conditions. Geraniol, as the main starting material, was coupled to DHP resin via its alcohol, and the carbon chain was elongated by the Biellmann-Ducep coupling.In conclusion, we have developed two efficient routes for coenzyme Q₁₀ starting from coenzyme Q₀ and solanesol, a novel convergent strategy for oligoprenols bearing long carbon skeleton demonstrated by the synthesis of decaprenol and the first solid-phase synthsis of solanesol.