A Short and Productive Synthesis of Racemic α-Lipoic Acid

Abstract

Lipoic A cid, Radical Induced C-C-Bond Formation, Baeyer-Villiger Oxidation, Ether Cleavage, Isothiuronium SaltsRacemic a-lipoic acid is synthesized in four steps from the base chemicals vinyl ethyl ether and cyclohexanone. The total yield is 40%. Results and DiscussionBiochemistry a-Lipoic acid is involved in central biochemical processes as a protein-bound coenzyme [1]. It oc curs, for example, as a cofactor of multienzyme complexes which control energy-producing pro cesses such as aerobic glycolysis and photosynthe sis. Scheme 1 shows the biochemical role of lipoic acid in the oxidative decarboxylation of pyruvic acid. UsePatients who suffer form diabetes mellitus or the consequences of alcohol abuse have reduced lipoic acid levels. Thus, the supply of the nerve cells with ATP is no longer guaranteed and neuro logical complications generally occur. The admin istration of lipoic acid has therefore proven suit able, in particular as a therapy in diabetic and alcoholic polyneuropathy [2 ], Together with other biological antioxidants, dihydrolipoic acid has a membrane-stabilizing action and can prevent, for example, oxidative damage in the case of reperfusion after by-pass operations [3]- SynthesisA fter the isolation and structural elucidation [4] of a-lipoic acid, num erous syntheses were pub lished in patent specifications and the scientific lit erature. They can be divided into three categories with respect to the preparation of C8 precursors * Reprint requests to Dr. J. Paust.which carry functional groups in positions 1 , 6 and 8 , Scheme 2 [5].(I) Friedel-Crafts addition of adipic acid m onoester chloride to ethylene yields the unsatu rated keto ester 2 after spontaneous elimination of hydrogen chloride.(II) Prins reaction of term inal C7-olefins affords 1,3-dioxane derivatives 3.(III) Baeyer-Villiger oxidation of 2-substituted cyclohexanones 4 leads to the caprolactones 5.In addition to the routes (I)-(I II), specific pro cesses have also been developed for the prepara tion of 1, 6 , 8 -functional interm ediates [5],The introduction of sulfur groups into the inter mediates 2, 3 and 5 is carried out either directly by heating with hydrohalic acids and thiourae [6 ] or in two steps via 6 ,8 -dihalides or -disulfonates and reaction with sulfur nucleophiles [7], Industrial syntheses of racemic a-lipoic acid are based mainly on the Friedel-Crafts route (I). Our process follows the Baeyer-Villiger strategy (III), however. It is different from the variants known from the literature [5,8 ], in particular in the first two steps, Scheme 3 [9].2-(2'-Ethoxyethyl)cyclohexanone (4, Rj = Et) is synthesized in one stage from the base chemicals vinyl ethyl ether and cyclohexanone. Di-terf-butyl peroxide is particularly suitable as a catalyst. The reaction is carried out in excess cyclohexanone as a solvent, which can be recovered and recycled during the distillative isolation of 4. 2-(2'-Acetoxyethyl)cyclohexanone (4 , R.! = AC) is analogously formed from vinyl acetate and cyclohexanone in 35% yield.The subsequent Baeyer-Vi...

α-Lipoic acid chemistry: the past 70 years

“…In 1999, Paust et al followed the Baeyer–Villiger strategy to develop an optimized synthesis. 25 As shown in Scheme 14 , initially, the key intermediate 74 was synthesized in one stage from the base chemicals, cyclohexanone 72 and vinyl ethyl ether 73, catalyzed by di- tert -butyl peroxide. The key Baeyer–Villiger oxidation was performed using performic acid generated in situ from formic acid and 30% aqueous hydrogen peroxide.…”

“…thiourea in a strong mineral acid via alkaline hydrolysis of the isothiuronium salt easily yielded DHLA, which afforded the desired ALA aer oxidation.In 1999, Paust et al followed the Baeyer-Villiger strategy to develop an optimized synthesis 25. As shown in Scheme 14, initially, the key intermediate 74 was synthesized in one stage from the base chemicals, cyclohexanone 72 and vinyl ethyl ether 73, catalyzed by di-tert-butyl peroxide.…”

Mechanism-Driven Metabolic Engineering for Bio-Based Production of Free R-Lipoic Acid in Saccharomyces cerevisiae Mitochondria

“…Lipoic acid has also shown to inhibit the proliferation of breast tumor cells, and hence demonstrates its potential application as an anti-cancer drug ( Li et al, 2015 ). Currently, lipoic acid is obtained mainly through chemical synthesis processes, which conventionally generates equal amounts of the two enantiomeric R and S forms of lipoic acid ( Balkenhohl and Paust, 1999 ; Ide et al, 2013 ). However, in biological systems, lipoic acid exists solely in the R form; S -lipoic acid is a by-product during chemical synthesis.…”

Sodium borohydride reduction of aromatic carboxylic acids via methyl esters

“…3 Examples include the borohydride reduction step in the industrial Sumitomo's synthesis of D-biotin (vitamin H) 4 and the selective hydroxy ester reduction in presence of non-substituted esters, employed in the synthesis of R-lipoic acid. 5 Sodium borohydride is versatile as a hydride reducing agent for both chemo-and diastereo-selectivity and thus has been used in the stereoselective reductions. 2,6 Hence a combination of sodium borohydride with organoborane has been developed for diastereoselective reduction of hydroxy ketone and of 'statin-type' molecules, 7 and stereoselective enamine ketone reductions.…”