Synthesis of α -tocopherol (vitamin E), vitamin K 1 -chromanol, and their analogs in the presence of aluminosilicate catalysts Tseokar-10 and Pentasil

The highly effective heterogeneous catalysts, the aluminosilicates Tseokar-10 and Pentasil, were found to condense hydroquinones with tertiary isoprenoid allylic alcohols. Using these catalysts d,l - α -tocopherol, (


Introduction
α-Tocopherol is the most significant representative of the tocopherol group (vitamin E); it is a natural inhibitor of the peroxidation of lipids in vivo, and helps to retain intact the structure and functional activity of cells' membranes. 1he chemistry of tocopherol has been extensively studied over sixty years, but now this compound is of interest as a treatment-and prophylactic agent, and as a nutritional additive.At present, intensive searches are being carried out for new methods of synthesis of racemic and optically active α-tocopherol using new catalysts, reagents and synthons. 2he method based on the acid-catalyzed condensation of 2,3,5-trimethylhydroquinone (TMHQ) with phytol and isophytol to obtain racemic α-tocopherol (a mixture of all possible stereoisomers), and (2RS, 4′R, 8′R)-α-tocopherol is of great importance.Brønsted and Lewis acids e.g., НСО 2 Н, МеСО 2 Н, BF 3 ⋅OEt 2 , ZnCl 2 , are used as catalysts.Recently, data were published concerning the use of heterogeneous catalysts, whose main merits are the simple separation of a solid catalyst from the reaction mass, the absence of washing water containing the dead catalyst, and a higher purity (96-97%) of α-tocopherol. 3The aluminosilicates are most preferred heterogeneous catalysts, owing to their accessibility and capacity.The AShNTs and Tseokar-2 aluminosilicates have been used for TMHQ condensation with isophytol and dihydrolinalool. 4nthesis of all-rac.-α-tocopherol,2-ambo-α-tocopherol and vitamin K 1 -chromanol We have studied the new aluminosilicate catalyst Tseokar-10 (which contains the high module zeolite Y as the active component (10 wt.%) and is used for cracking of petroleum fractions manufactured at the Salavatnefteorgsintez plant) to condense TMHQ 1 with isophytol 2. It was found that reaction in boiling hydrocarbon solvents (n-heptane, n-nonane) gave all-rac.-αtocopherol(3) in nearly quantitative yield (≥ 98%) (Scheme 1). 5  Tseokar-10 was also effective in the synthesis of (2RS, 4′R, 8′R)-α-tocopherol 7 (equimolar mixture of 2R-and 2S-epimers, called 2-ambo-α-tocopherol). 6 This compound was obtained by the condensation of TMHQ with (2E,7R,11R)-phytol, whose syntheses are complicated and have many steps. 7The treatment of the acetone extract of chlorophyll of green plants with alkali also leads to this compound, but this pathway requires pre-purification of the chlorophyll from lipids. 8In addition, the alkaline hydrolysis of chlorophyll in acetone solution gives the products of acetone self-condensation, and salts of fatty and chlorophyll-based acids hampers the isolation of pure phytol.
In the condensation reaction with TMHQ (3RS,7R,11R)-isophytol 6 was used, which was obtained by the vinylation of (6R,10R)-6,10,14-trimethylpentadecane-2-one (R,R-phytone) 5. To synthesize the latter an effective method was developed of ozonolysis of the acetone extract of chlorophyll 4 (a mixture of chlorophyll а and b, R = Me or СНО, respectively) from the great nettle (Urtica dioica L.) without its pre-purification from accompanying lipids (Scheme 2).Ozonolysis in the presence of Ba(OH) 2 (the so-called "non-peroxide ozonolysis" 9 ) led to phytone 5 in ~90% yield (with respect to chlorophyll 4 in the acetone extract, determined using electronic spectroscopy in the range λ 640−665 nm).The pure phytone 5 was isolated most easily, and in high yield, from the ozonization product when 9 mol.equiv. of ozone, with respect to the content of chlorophyll in the extract, was used, whereas decreasing the excess of ozone hinders the isolation of the pure target product.Apparently, ozone is needed not only to cleave the double bonds in the vinyl group at C(3) and the phytyl propionate residue at C (17) in chlorophyll 4, but also to ozonize the corresponding unsaturated compounds in the acetone extract (carotenoids and xanthophylls).The condensation of isophytol 6 with TMHQ in the presence of the Tseokar-10 catalyst (nonane, boiling, 5 h) led to the target 2-ambo-α-tocopherol 7 in high yield.The same approach was used to synthesize 2,5-dimethyl-2-(4,8,12-trimethyltridecan-1-yl)-6hydroxybenzo[h]chroman, a cyclic form of vitamin K 1 , also called vitamin K 1 -chromanol, or naphthotocopherol, 9.The effect of vitamin K 1 on a number of biochemical processes (blood coagulation, conjugate oxidation, phosphorylation) is known to be caused by naphthotocopherol 10 identified in the product of the enzymic reduction of vitamin K 1 . 11pectrophotometric studies of antioxidants in the phenol series confirmed the highest activity of naphthotocopherol, whose antioxidant activity was 6.9 times as great as that of αtocopherol. 12irst, we have synthesized optically active naphthotocopherol with the chiral homogeneous side phytyl chain of (R,R)-configuration, 9, based on the condensation of 1-О-acetyl-2-methyl-1,4-naphthohydroquinone (menadiol acetate) 10 with (3RS,7R,11R)-isophytol 6 in the presence of the Tseokar-10 catalyst.The condensation product 8 was further deacetylated with lithium aluminum hydride in diethyl ether.The yield of the target naphthotocopherol 9 was equal to 68% with respect to isophytol 6.

Synthesis of analogs of α-tocopherol and naphthotocopherol with a shortened side chain
In recent years, considerable attention has been given to the synthesis of analogs of α-tocopherol with a shortened side chain.The resulting compounds, based on linalool and dihydrolinalool, were found to exhibit high biological activity.These analogs are named С 6 -analogs of αtocopherol, from the number of carbon atoms in the side chain. 4he condensation of (3RS,4S)-3,4,8-trimethyl-1-nonene-3-ol 11, obtained from the accessible enantiomerically enriched (ее∼50%) (S)-(+)-dihydromyrcene 13,14 ) with TMHQ 14 and menadiol acetate, 10, catalyzed by Tseokar-10, resulted in new optically active analogs of α-tocopherol 12 and naphthotocopherol 14, and converted then into the acetate 13 and the alcohol 15, respectively (Scheme 3).The С 8 -chromans 12, 13 and С 8 -benzochromans 14, 15 were synthesized in equimolar mixtures of (2R,1′S)-erythro-and (2S,1′S)-threo-diastereomers.Since the starting 11 is characterized by an ее of ∼50%, it is evident that the erythro-and threodiastereomers of the chromans 12 and 15 are enriched to the same extent with the epimers with the S-configuration at the C(1′)-atom.The usual catalysts are known to be unsuitable for reactions of tertiary vinyl carbinols with unsaturated isoprenoid radicals because the reaction is complicated by side cyclization resulting in tricyclic compounds. 15At the same time, analogs of α-tocopherol with an unsaturated side chain are of interest as precursors of the corresponding chromanols with an ω-functionalized side chain, which are of interest in biological studies and as building blocks for the synthesis of other vitamin E analogs.
Oxidative cleavage of the chromanyl acetates 18 and 21 by ozonolysis in aqueous acetone in the presence of Ba(OH) 2 , gave aldehydes 24 and 25 in 52% and 80%, respectively, in one step.The hydride reduction of 24 and 25 yielded the corresponding alcohols 26 and 27 (Scheme 4).
In contrast to TMHQ, the reaction of menadiol acetate 10 with linalool 19 in the presence of the Tseokar-10 leads mainly to the cyclic compound 28 (70%, GLC).

Synthesis of chromenes with isoprenoid side chains
Chromenes with isoprenoid side chains are frequently encountered in nature, being structural analogs of prenylated coumarins, chalcones, and cannabinoids, 17−19 this accounts for the increased interest in their synthesis.Two approaches have been developed most thoroughly, (1) using the pyridine-catalyzed reaction of α,β-unsaturated aldehydes with phenols, 20 and (2) a twostep route comprising the reaction of trimethylhydroquinone (TMHQ) with tertiary allylic alcohols to give prenylated 1,4-benzoquinones, and subsequent cyclization of these compounds induced by pyridine. 21Alkylation of TMHQ with allylic alcohols catalyzed by Lewis acids (usually ZnCl 2 or BF 3 ⋅OEt 2 ) is the key step in the latter method.
We synthesized prenylated 1,4-benzoquinones using a heterogeneous zeolite of the Pentasil type in the H-form. 22The reactions of TMHQ with the vinyl carbinol 16 (a 1:1 mixture of (3R,4S)-erythro-and (3S,4S)-threo-diastereomers (ee ~50%)) and linalool 19 in the presence of Pentasil were found to afford the 1,4-benzoquinones 29 and 30, respectively.Pyridine-induced cyclization of these products proceeded smoothly to give chromenes 31 and 32, respectively (Scheme 5).As in the case of the vinyl carbinols 16 and 19, the use of isophytol 2 resulted in the syntheses of the quinone 35 and chromene 36.Ozonolysis of chromenes 33 and 34 at the side-chain double bond opens the way to ωfunctionalized chromenes, which can be further converted into more complex chromene derivatives.However, under the ozonolysis conditions described previously, the chromenes gave only benzaldehydes and benzoic acids with the corresponding substituents. 17We found that in the ozonolysis of chromenyl acetates 33 and 34 with an equimolar amount of ozone it is possible to cleave selectively the double bond in the side chain and obtain the required aldehydes 37 and 38.Thus, using a zeolite catalyst of the Pentasil type, chromenes were synthesized with the isoprenoid side chain containing the double bond, and whose partial ozonolysis yielded chromenes with the aldehyde group in the side chain.

Conclusions
For the condensation of trimethylhydroquinone and 2-methyl-1,4-naphthohydroquinone with allylic isoprenoid alcohols, the new catalysts Tseokar-10 aluminosilicate and zeolite Pentasil were used.Using these catalysts, d,l-α-tocopherol, (2RS,4´R,8´R)-α-tocopherol, vitamin K 1chromanol and their analogs with the shortened side chain were synthesized in high yields.The possibility of preparing the analogs of α-tocopherol-chromanols and chromenols with the double bond in the side chain is a particular quality of the new catalysts compared to those usually used in this type of reaction.The selective ozonolysis of these compounds resulted in analogs of αtocopherol with an ω-functionalized side chain serving as synthons for α-tocopherol and its analogs.

Experimental Section
General Procedures.IR spectra were recorded on a Specord 75-IR spectrometer (in thin film); UV spectra using a Specord M-40 instrument. 1 H-and 13 C-NMR spectra were run on a Bruker AM-300 spectrometer (300.13 and 75 MHz for 1 H and 13 C, respectively) in СDСl 3 .Chemical shifts are on the δ scale, relative to internal Me 4 Si.GLC analysis used a Chrom-5 chromatograph with 2400 х 4 mm columns with the Chromaton N-AW-DMCS and SE-30 (5%) stationary phase at a temperature of50−300°C (8 K min −1 ) using helium as carrier gas.The preparative separation of acetates 21 and 23 was carried out using a Carlo Erba chromatograph (6000 х 6 mm column) with SE-30 stationary phase, at 300 °C, with helium as carrier gas.HPLC used an LKB liquid chromatograph (Sweden) equipped with UV detector (λ=249 nm) and a column with Separon-C18 as adsorbent (125 х 4 mm, 5 µm); 87:13 MeOH−H 2 O was used as eluent (0.3 mL⋅min −1 , 20°C).Optical rotation was measured using a Perkin−Elmer-141 polarimeter.Mass spectra at 70 eV, using the electron impact mode, were measured on a Finnigan MAT 8200 instrument.