2.3.6- Trimethylhydroquinone isophytol

Although all four tocopherols have been synthesized as their all-rac forms, the commercially significant form of tocopherol is i7//-n7i a-tocopheryl acetate. The commercial processes ia use are based on the work reported by several groups ia 1938 (15—17). These processes utilize a Friedel-Crafts-type condensation of 2,3,5-trimethylhydroquinone with either phytol (16), a phytyl haUde (7,16,17), or phytadiene (7). The principal synthesis (Fig. 3) ia current commercial use iavolves condensation of 2,3,5-trimethylhydroquiQone (13) with synthetic isophytol (14) ia an iaert solvent, such as benzene or hexane, with an acid catalyst, such as ziac chloride, boron trifluoride, or orthoboric acid/oxaUc acid (7,8,18) to give the all-rac-acetate ester (15b) by reaction with acetic anhydride. Purification of tocopheryl acetate is readily accompHshed by high vacuum molecular distillation and rectification (<1 mm Hg) to achieve the required USP standard. 

An enantioselective hydrogenation of this type is also of interest in the production of a-tocopherol (vitamin E). Totally synthetic a-tocopherol can be made in racemic form from 2,3,5-trimethylhydroquinone and racemic isophytol. The product made in this way is a mixture of all eight possible stereoisomers. 

This first example of a Bi(OTf)3-catalyzed Friedel-Crafts alkylation originated in the following procedures, including benzylations of 2,4-pentanediones or hydroarylation and hydroalkylation reactions. A related procedure was simultaneously developed by Bonrath et al. [39]. The authors utilized Bi(OTf)3 in the synthesis of (all-rac)-a-tocopherol (Vitamin E) [39], Besides rare earth metal triflates, such as Ga(OTf)3, Hf(OTf)3, Sc(OTf)3 and Gd(OTf)3, Bi(OTf)3 was shown to be the most efficient catalyst for the Friedel-Crafts-type reaction between trimethylhydroquinone acetate 10b and isophytols 11a, b. With only 0.02 mol% Bi(OTf)3 (substrate to catalyst ratio 5,000 1) the desired a-tocopherols 12a and 12b were isolated in excellent yields (Scheme 10). 

The direct formation of racemic a-tocopherol from trimethylhydroquinone and isophytol occurs at low temperature in the presence of boron trifluoride or aluminum chloride (71JOC2910). It is important that the solvent should not be able to complex with the Lewis acid rather, it is the phenol-catalyst complex which is alkylated. 

The synthesis of Vitamin E, that is, a-tocopherol (5,7,8-trimethyltocol) in the past has been accomplished primarily by reacting trimethylhydroquinone (TMHQ) with isophytol (3,7,ll,15-tetramethylhexadec-l-en-3-ol) or phytol (3,7,ll,15-tetramethylhexadec-2-en-l-ol) in a condensation reaction. The reaction is well known and has been practiced for many years (Stalla-Bourdillon, Ind. Chim. Belg., 35, 13 (1970) "The Vitamins" Vol. 5, pages 168-223, Academic Press, New York, 1967). 

A complex multistep synthesis of the 8-CD3 analogue of 5-tocopherol has been described <03EJ02840>. The super Lewis acid, Me3Si[C6FsCTf2], is an effective catalyst for the regioselective condensation between trimethylhydroquinone and isophytol that yields ( )-a-tocopherol <03AG(E)5731>. 

Based on these biological data, two commercial forms of a-tocopherol (or their more stable acetate derivatives) are currently being produced by independent approaches [7, 8], Totally synthetic vitamin E, which is an equimolar mixture of all eight stereoisomers of a-tocopherol, is produced at a rate of over 25000 tons per year for the application in feed, food, and the pharma industry. The large-scale industrial synthesis of (all-rac)-a-tocopherol uses 2,3,5-trimethylhydroquinone (11) as the aromatic building block and the C2o compound isophytol (12). The acid-catalyzed condensation reaction in the last step delivers (all-rac)-3 (Fig. 2) [21-25],... 

More recent work has tended to concentrate on the usage of synthetic phytol or isophytol in the form of derivatives. In this second group of reactions intermediates such as the aldehyde phytal have been exploited. The importance of the 2R stereochemistry in tocopherol itowards imparting higher biological than manifested in the RS mixture has directed attention to more selective methodologies than achievable in the reaction of trimethylhydroquinone and the phytols. 

A range of tocopherols have been synthesised from methylbenzo-1,4-quinone, 2,6-dimethyl-1,4-benzoquinone and trimethylbenzo-1,4-quinone by cyclocondensation with phytol or isophytol (ref. 124) under reductive conditions. Thus the respective benzoquinone in formic acid containing copper-zinc powder at 85°C was treated with isophytol and refluxed during 2 hours to afford racemic products with yields generally in excess of 70%. There is little relative novelty in this approach since the oxidative formation of the quinone from trimethylhydroquinone or other quinone used in this general method imposes a reductive step in the methodology. 

A variety of methods is now available for the synthesis (artificial production) of the tocopherols. In the most commonly used procedure, 2,3,5-trimethylhydroquinone is reacted with isophytol over one of many possible catalysts. A small amount of the vitamin is still obtained from natural sources, usually as the by-product in the treatment of one of its natural sources. 

Vitamin E is the most important lipid-soluble antioxidant in biological systems. (all-rac)-a-Tocopherol (synthetic vitamin E, 1) is the economically most important product industrially prepared on a multi-10 OOOt/year scale and mainly used in animal nutrition [50]. In the large-scale syntheses of 1, 2,3>5-trimethylhydroquinone (6) is used as the aromatic key building block, which is condensed with isophytol (2) to yield 1 by all producers worldwide (Scheme 7.1). Trimethylhydroquinone (TMHQ, 6), in turn, is obtained from trimethylquinone (TMQ, 5) by reduction procedures, in particular catalytic hydrogenation. Besides other possibilities to access TMHQ (6), this route is generally preferred, and efficient oxidation processes for the production of quinone 5 from alkylated phenols are, therefore, of high interest [51]. 

Friedel-Crafts alkylations of arenes with mesylates, benzyl or allyl alcohols, aldehyde/diol combinations (reductive alkylation), 1,3-dienes, or alkenes in an ionic liquid are also effectively catalyzed by Sc(OTf)3. Sc(OTf)3 works as an efficient catalyst for the condensation reaction of trimethylhydroquinone with isophytol to afford a-tocopherol. 2-Aminoalkylation of phenols with a-iminoacetates (or glyoxylate/amine) is catalyzed by Sc(OTf)3 to produce amino acid derivatives. The Sc(OTf)3-catalyzed alkylations of indoles with a-hydroxy esters, aziri-dines, acetals, and aldehydes have been utilized as key steps of total syntheses as exemplified in eq 15. ... 

The technical syntheses are based on the condensation of phytol or isophytol with trimethylhydroquinone, which can be prepared from 3,5-dimethylphenol by the Mannich reaction followed by a series of obvious steps. We prepared radioactive C -labelcd trimethylhydroquinone (specific activity 11.8 ic/mg), os shown in Fig. 2. 

This catalyst is highly effective for the regioselective condensation of trimethylhydroquinone with isophytol to afford ( )-Q -tocopherol (eq 19). ... 

A process is described for preparing a-tocopherol or tocopheryl acetate by cyclocondensation of trimethylhydroquinone wilii phytol or isophytol in the presence of an acid catalyst in liq. or SCCO2, optionally followed by acetylation. 

Figure 6.18 Schematical Synthesis of (AII-rac)-a-Tocopherol (Vitamin E) via Two-Step Friedel-Crafts Alkylation-Cyclization of 2,3,6-Trimethylhydroquinone (TMHQ) with Isophytol (IP).

The industrial synthesis of this valuable compound is based on the condensation of 2,3,6-trimethylhydroquinone (TMHQ) with isophytol (IP), which proceeds through consecutive Friedel-Crafts alkylation-cyclization (Figure 6.18) steps [91] in the presence of ZnClj/HCl as catalyst [92],... 

Sn(OTf) -MCM-41 and Sn(OTf) ,-UVM-7 solids have been tested as catalysts for the acylation of aromatic sulfonamides, in the synthesis of (DL)-[a]-tocopherol through the condensation of 2,3,6-trimethylhydroquinone with isophytol (Equation (8.56)) and for the transesterihcation of sunflower oil [109-112]. The acylation of aromatic sulfonamides was possible on these materials with a very high atom economy using acetic acid as the acylat-ing agent. These catalysts were also found active for the synthesis of 4,4 -methylenediani-line (a key intermediate for the production of polyurethanes) from aniline and 4-aminoben-zyl alcohol [74]. 

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