New possibilities in a synthesis of ( 2 R , 4 ' R , 8 ' R )-α-tocopherol ( natural vitamin E )

New methods for the synthesis of homochiral C14 and C15-terpenoids desired as building blocks for phytilic side chain of natural α-tocopherol have been developed. A natural phytone resulted from the proposed effective method of chlorophyll ozonolysis was used in a synthesis of optically active terpenoids. Chiral chroman compound for vitamin E, namely, (S)-(-)-6benzyloxy-3,4-dihydro-2,5,7,8-tetramethylchroman-2-methanol was obtained by enantioselective transesterification of the corresponding racemic alcohol catalysed by Amano PS lipase from Burkholderia cepacia in ionic liquid [bmim]PF6.


Introduction
(2R,4'R,8'R)-α-Tocopherol is the most studied principal component of vitamin E which defines its anti-oxidant properties. 1,2In addition, (2R,4'R,8'R)-α-tocopherol participates in transmission of signals between cells, decreases activity of C proteinkinase, inhibits proliferation of the smooth muscle cells and governs the expression of α-tropomiosine gene. 3The last decade studies showed that the specific liver transport protein (α-TTP) recognizes only the natural α-tocopherol out of all tocopherol isoforms and provides its transportation to plasma. 4t present a simple and economic overall synthesis of natural α-tocopherol does not exist.A semisynthetic isomerically pure (2R,4'R,8'R) -α-tocopherol is obtained from vegetable oils, mainly from soya deodorizes distillates in a limited volume (~2000 tons per year) according to the complex technology. 5,6ethodology based on the combination of chiral trimethyllated 2-substituted chromanes with optically pure C 14 -and C 15 -terpenoids is widely used in the laboratory practice (Scheme 1). 6For the building blocks of chromane and isoprenoid structure the various synthetic schemes were developed with the use of microbiological methods, 7 chemoenzymatic transformations, 8 chiral auxiliaries 9 or asymmetric metal complex catalysis. 10As a rule, these methods were shown to be multistep, based on the use of atmosphere sensitive reagents and catalysts, and low perspective for practical application.
Phytone 1 is usually obtained by the ozonolysis of (2E,7R,11R)-phytol isolated from green plants by alkaline treatment of acetone extract of chlorophyll.This method requires a prepurification of the chlorophyll from lipids.In addition, an alkaline saponification of chlorophyll in acetone gives sodium salts of high fat acids, and products of acetone self-condensation, that impedes the isolation of phytoll in pure form. 11The method for the preparation of phytone 1 proposed by us is simple and includes ozonolytic oxidation of acetone extract of chlorophyll from great nettle without pre-purification of extract from related impurities.The reaction in the presence of Ba(OH) 2 (acceptor of peroxide oxygen) led to phytone 1 in ~90% yield (in calculation on a chlorophyll content in the acetone extract).The main problem in the transformation of phytone 1 to 5 or 7 compounds concludes in the shortening of the starting C 18 -isoprenoid chain by three or four C atoms respectively.The pathway based on the enolization of ketone 1 to ∆ 2,3 -enol esters and its ozonolitic oxidation to C 16 -acid 4 seems to be the most rational.The desired ∆ 2,3 -enol acetates 2 (mixture of Eand Zisomers) were successfully obtained by the reflux (7h) of ketone 1 with acetic anhydride in the presence of TsOH•H 2 O under conditions of thermodynamic control. 13The other ∆ 1,2 -izomer was not formed.Conversion of ketone 1 was 49%.The use of microwave irradiation allowed us to considerably decrease the reaction time with complete retention of regeoselectivity reaction.Conversion of starting ketone 1 to the mixture of ∆ 2,3 -enol acetates 2 consisted of 57% after irradiation for 10 min (power 750W).Enol acetates 2 can be easily separated from the unreacted phytone 1 by column chromatography on silica gel, and the recovered phytone 1 can be repeatedly involved into the enolysation reaction.
Aldehyde 3 was obtained by the ozonolysis of mixture of enol acetates 2 in acetone in the presence of Ba(OH) 2 and was oxidized by the Jones reagent to acid 4. When enol acetates 2 are treated with excess ozone, they are converted to acid 4 in a single step.The Hunsdiecker reaction was used for the transformation of C 16 -acid 4 to the target C 15 -bromide 5.The interaction between the silver salt of C 16 -acid 4 and Br 2 in CCl 4 afforded the target bromide 5 in 46% yield.The oxidative decarboxylation of acid 4 led to (3R,7R)-3,7,11-trimethyl-1-dodocene 6. Ozonolysis of the latter gave alcohol 7. 14
Chroman-2-methanol (±)-9 was obtained by the three-step transformation of commercially available (±)-chroman-2-carboxylic acid (±)-8 according to the described methods. 8From commercially available and inexpensive enzymes, such as lipases from Burkholderia cepacia (Amano PS), Candida cylindracea (CCL) and Hog pancreas (PPL) tested, the lipase Amano PS has been chosen.It was found, that Amano PS lipase showed a high catalytic activity and enantioselectivity.Kinetic resolution of alcohol (±)-9 through selective acylation with succinic anhydride in [bmim]PF 6 proceeded (at 0º or 20ºC) with low stereoselectivity to afford the products with an optical rotation within the measurement error.When, vinyl acetate was employed as the acyl donor (substrate : enzyme weight ratio of 1.5:1, 20ºC, 24 h, 39% conversion), (S)-acetate (S)-10 (  We have studied the reaction of partial acetyllation of chromanmethanols (±)-9 in the presence of Amano PS lipase in diisopropylether or in a mixture of organic solvent and [bmim]PF 6 and established a sufficient influence of ionic liquid upon the stereoselectivity of the biocatalyst.Thus, this reaction in [bmim]PF 6 afforded alcohol (S)-9 with [α] D 20 -2.2º (c 0.7 CHCl 3 ) and in (Pr i ) 2 O -(S)-9 with [α] D 20 -1.4º (c 0.9 CHCl 3 ).In the mixture of solvents at volume ratio [bmim]PF 6 and (Pr i ) 2 O equal to 3:1, 1:1 or 1:3 the value of optical rotation of (S)-9 consisted of -2.0º, -1.9º and -1.5º respectively (lit 8 [α] D 20 -2.36º (CHCl 3 )).In addition we found that Amano PS lipase containing in the ionic liquid [bmim]PF 6 retaines its initial activity and enantioselectivity reaction even after the third catalytic cycle, that evidences for the stability of biocatalyst under the reaction conditions.

Conclusions
The short and efficient synthesis of C 14 -and C 15 -terpenoids as synthones for the natural αtocopherol has been developed using a microwave-activated regioselective enolization of homochiral phytone.The method for the synthesis of (S)-(-)-6-benzyloxy-3,4-dihydro-2,5,7,8tetramethyl-2H-1-benzopyran-2-methanol (S)-9 has been proposed by kinetically selective acylation with vinyl acetate of the corresponding racemic alcohol in the presence of Amano PS lipase in [bmim]PF 6 .The ionic liquid is an efficient recyclable solvent in this reaction allowing to give a target (S)-(-)-enantiomer of high enantiomeric purity.

Experimental Section
General. 1 H-and 13 C-NMR spectra were recorded on a Bruker Avance-400 spectrometer (400.13 and 100.62 MHz for 1 H and 13 C respectively) in CDCl 3 .Chemical shifts are on the δ scale, relative to internal Me 4 Si.HPLC analysis used a Helwett Packard 1050 chromatograph with 250×4.6 mm columns C-18 "zorbax", the rate of elution was 1 ml/min, CH 3 COCN:H 2 O -80:20 + 1% Et 3 N with UV-detector under wavelength 254 nm.IR spectra were recorded on a Specord IR-75 spectrometer by CARL ZEISS JENA in tablet of KBr.Specific angles of rotation was determined using a Perkin-Elmer-141 polarimeter.