TITLE: SYNTHESIS OF TOCOTRIENOLS FROM O-CRESOL DERIVATIVES

TECHNICAL FIELD

The present invention relates to synthetic chemistry. In particular, to multistep preparation of tocotrienols from o-cresol derivatives, involving a novel regio selective functionalization of the 2-methyl chroman methanol derivatives either by halogenation/hydroxylation or by carbonylation/Dakin oxidation. The method helps in large scale preparation of tocotrienols of high purity in a facile manner, economically involving environmentally benign reagents. BACKGROUND

Anti-oxidant properties of tocotrienols/ tocopherols (major constituents of Vitamin E) are well documented. Besides anti-oxidant properties, these naturally occurring compounds exhibit various promising biological activities.

Tocotrienols have been identified to play potential pharmacological roles; exemplary being inhibition of human breast cancer cells and pancreatic cancer cells. Many literature documents inform that tocotrienols provide a promising new treatment option for pancreatic cancer. Beyond cancer, research is showing that tocotrienols have a place in reducing important risk factors for some of the most lethal chronic diseases. For example, tocotrienols have been reported to promote new artery formation after a stroke, lower homocysteine levels, improve insulin sensitivity, protect vital brain circuitry, and even prevent bone loss. In nature, tocotrienols are present in many plants. The palm fruit (Elaeisguineensis) is found to contain tocotrienols, primarily gamma-tocotrienol, alpha-tocotrienol and delta-tocotrienol in high content. Other cultivated plants that are rich in tocotrienols includes rice, wheat, barley, rye and oat. In Annatto, tocotrienols are relatively abundant and it contains no tocopherols. Besides,tocotrienols are present in various other oils, seed and fruits that are naturally occurring. Delta(6)-tocotrienol has been found to block processing of sterol regulatory element -binding proteins (SREBPs); reduction in both collagen and ADP-induced platelet aggregation; also helps in treating Carotid Atherosclerosis. Delta(5)-tocotrienol is found to have the greatest antioxidant properties among the tocotrienol isomers.

Considering the importance of tocotrienols in the management of health and due to varying levels of their occurrence in various natural sources and foods; these molecules often has to be supplemented. However, isolation of the same from natural resources would require several preparative scale reverse-phase chromatography or expensive methodologies that involve critical distillation procedures or simulated moving bed chromatography. These limitations lead to the development of various synthetic routes that give access to the tocotrienol and its derivatives.

Schudeleei al.in Helv. Chim. Acta. 1963, 46, 2517; Mayer, H. et al. in Helv. Chim. Acta. 1961, 50, 1376; Kabbe, H. J. et al.m ^' Synthesis 1978, 888; Urano, S. et aim Chem. Pharm. Bull. 1983, 31, 4341; Kajiwara, M. et al. in Heterocycles 1980, 14, 1995; Pearceei al.mJ. Med. Chem. 1992, 35, 3595; Pearce et al.mJ. Med. Chem. 1994, 37, 526 describe about the synthesis of tocotrienol analogues and derivatives.

Scott. J. et aim Helv. Chim. Acta. 1976, 59, 290; Patent documents JP 63063674; JP 01233278;US7038067; US2005124688; describe synthesis of naturally occurring form of tocotrienols.

Chenevertei al. in Tetrahedron Lett.2002,43, 7971; has demonstrated the construction of delta-tocotrienol through a stereoselective enzymatic acylation of chroman dimethanol. The synthesis is marred with setbacks like complexity associated with the synthesis of the required key starting material, umpteen number of steps resulting low yield and further it is not amenable for other members of tocotrienol family owing to the complexity associated with the synthesis of the requisite starting material Couladouros, E. et al. in J. Org. Chem.2001 , 72, 6735 describe a method of preparation of asymmetric synthesis of β-, γ- and δ-Tocotrienols. However, the reaction involves Poly methylated 1,4-dihydroxy benzene derivatives as the key starting material for the synthesis of tocotrienolswhich is not cost-effective for large scale production; use of lithium aluminium hydride for the synthesis of diol intermediate, poses safety concern if employed on larger scale, and more importantly in the reaction selective protection of one of the phenolic functionality and thereby facilitating the conversion of the phenolic derivatives to their respective chroman derivatives is low yielding and a major bottle-neck at the start of the synthesis. The large-scale synthesis of the selectively protected phenol is coupled with practical difficulties in isolating the same in pure form.

The present invention aims to circumvent the setbacks associated with the known process, and develop a cost-effective process for the large-scale synthesis of tocotrienol family members, their analogues starting on an industrial scale from readily available o-cresol derivatives and economically viable reagents.

SUMMARY OF INVENTION

The present invention provides a process for large scale synthesis of tocotrienols starting from commercially available o-cresol derivatives involving facile multistep conversion of o- cresol derivatives.

A method of preparation of compound of formula A said method comprising acts of:

WhereinRl=H, Me; and R2=H, Me

a) preparation of compound of formula 8 from compound of formula 1 ;

Formula 1 Formula 8

WhereinRl=H, Me; and R2=H, Me b) preparation compound of formula 10 from the compound of formula 8 through compound of formula 9;

Formula 8 Formula 9 Formula 10

WhereinRl=H, Me; and R2=H, Me

c) preparation of compound of formula 12 from the compound of formula 10 in presence of compound of formula 11 ;

Formula 11 Formula 12

WhereinRl=H, Me; and R2=H, Me

d) reparation of compound of formula 13 from the compound of formula 12; and

Formula 13

Formula 12

WhereinRl=H, Me; and R2=H, Me

e) deprotection hydroxyl group of the compound of formula 13 to obtain the compound of formula A.

A method of preparation of compound of formula A; said method comprising acts of a) preparing compound of formula 10 from the compound of formula 8 through compound of formula 9;

Formula 8 Formula 10

Wherein R1=H, Me; andR2=H, Me

b) preparing compound of formula 12 from the compound of formula 10 in presence of compound of formula 11 ;

Formula 11 Formula 12

Wherein R1=H, Me; andR2=H, Me

c) preparing compound of formula 13 from the compound of formula 12; and

Formula 13

Formula 12

Wherein R1=H, Me; andR2=H, Me

d) deprotecting hydroxyl group of the compound of formula 13 to obtain compound of formula A.

A compound of formula 6

Wherein R1=H, Me; R2=H, Me and X=halogen, OTs, OTf, N ₂ BF ₄ , N ₂ C1, CHO, COMe, COEt, COiPr, C0 ₂ H

A method of preparation of compound of formula 6, said method comprising acts of

a) preparation of compound of formula 3 by treating compound of formula 1 with 2- methyl-2 -propen- 1 -ol ;

Formula 1 Formula 3

Wherein R1=H, Me; and R2=H, Me

b) conversion of the compound of formula 3 by method of;

Wherein R1=H, Me; R2=H, Me and X=halogen, OTs, OTf, N ₂ BF ₄ , N ₂ C1, CHO, COMe, COEt, COiPr, C0 ₂ H

i) halogenation of the compound of formula 3 to obtain the compound of formula 6; or

ii) conversion into carbonyl compound to obtain the compound of formula 6.

Compound of formula 17 and 20

17 2δ Wherein R1=H, Me and R2=H, Me

DETAILED DESCRIPTION OF INVENTION

The present invention provides a process for the large-scale facile, cost effective synthesis of constituents of Vitamin E, namely Tocotrienol (formula A) from commercially available o- cresol derivatives.

The foregoing description of the embodiments of the invention has been presented for the purpose of illustration. It is not intended to be exhaustive or to limit the invention to the precise form disclosed as many modifications and variations are possible in light of this disclosure for a person skilled in the art in view of the figures, description and claims. It may further be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by person skilled in the art.

The present invnetion is in relation to a method of preparation of compound of formula A said method comprising acts of:

WhereinRl=H, Me; and R2=H, Me a) preparation of com ound of formula 8 from com ound of formula 1 ;

Formula 1 Formula 8

Wherein R1=H, Me; and R2=H, Me b) preparation compound of formula 10 from the compound of formula 8 through compound of formula 9;

Formula 8 Formula 9 Formula 10

Wherein R1=H, Me; and R2=H, Me

c) preparation of compound of formula 12 from the compound of formula 10 in presence of compound of formula 11 ;

Formula 11 Formula 12

Wherein R1=H, Me; and R2=H, Me

d) reparation of compound of formula 13 from the compound of formula 12; and

Formula 13

Formula 12

Wherein R1=H, Me; and R2=H, Me

e) deprotection hydroxyl group of the compound of formula 13 to obtain the compound of formula A.

In another embodiment of present invention, the compound of formula 8 is prepared by process A or process B,

Formula 8

Wherein R1=H, Me; and R2=H, Me

Process A comprises steps of

a) preparation of compound of formula 3 by treating compound of formula 1 with 2- methyl-2 -propen- 1 -ol ;

Formula 1 Formula 3

Wherein R1=H, Me; and R2=H, Me

b) separation of isomers of compound of formula 3 to R and S isomer; and

c) conversion of the S isomer of compound of formula 3 to the compound of formula 8 through compound of formula 6;

Wherein R1=H, Me; R2=H, Me and X= halogen, OTs, OTf, N ₂ BF ₄ , N ₂ C1, CHO, COMe, COEt, COiPr, C0 ₂ H

Process B comprising steps of

a) preparation of compound 16 from the compound of formula 1;

Formula 1 Formula 16

Wherein R1=H, Me; and R2=H, Me

b) preparation of compound of formula 19 from compound of formula 17 or compound of formula 18 obtained

Formula 17 Formula 18 Formula 19

Wherein R1=H, Me; and R2=H, Me

c) reducing the compound of formula 19 to compound of formula 8 and separating R and S isomers.

In still another embodiment, the separation of isomers is by enzymatic separation.

In yet another embodiment of present invention, the enzymatic separation in presence of compound selected from a group comprising succinic anhydride and Vinyl acetate; and lipase selected from a group comprising Amano IME PS30, Novozyme435, Lipolase, Lipozyme TL

1M' Arthobacter sp. (ABL) Lipaseand combination thereof.

The present invention is also in relation to a method of preparation of compound of formula A; said method comprising acts of a) preparing compound of formula 10 from the compound of formula 8 through comp

Formula 8 Formula 9 Formula 10

Wherein R1=H, Me; andR2=H, Me

b) preparing compound of formula 12 from the compound of formula 10 in presence of compound of formula 11 ;

Formula 11 Formula 12

Wherein R1=H, Me; andR2=H, Me

c) preparing compound of formula 13 from the compound of formula 12; and

Wherein R1=H, Me; andR2=H, Me

d) deprotecting hydroxyl group of the compound of formula 13 to obtain compound of formula A.

In another embodiment of present invention, the purity of compound is ranging from 90% to 99.3%.

The present invention is also in relation to a compound of formula 6

Wherein R1=H, Me; R2=H, Me and X=halogen, OTs, OTf, N ₂ BF ₄ , N ₂ C1, CHO, COMe, COEt, COiPr, C0 ₂ H The present invention is also in relation to a method of preparation of compound of formula 6, said method comprising acts of

a) preparation of compound of formula 3 by treating compound of formula 1 with 2- methyl-2 -propen- 1 -ol ;

Formula 3

Wherein R1=H, Me; and R2=H, Me

b) conversion of the compound of formula 3 by method of;

Wherein R1=H, Me; R2=H, Me and X=halogen, OTs, OTf, N ₂ BF ₄ , N ₂ C1, CHO, COMe, COEt, COiPr, C0 ₂ H

(i) halogenation of the compound of formula 3 to obtain the compound of formula 6; or

(ii) conversion into carbonyl compound to obtain the compound of formula 6.

The present invention is also in relation to a compound of formula 17

Wherein R1=H, Me and R2=H, Me

The present invention is also in relation to a compound of formula 20

m

Wherein R1=H, Me and R2=H, Me.

The present invention proves process for the preparation of tocotrienols from o-cresols

A

Wherein,

R1=R2=H; δ-tocotrienol (14a)

Rl=R2=Me; a-tocotrienol(14b)

Rl= H, R2=Me; -tocotrienol(14c)

Rl=Me, R2=H; y-tocotrienol(14d)

The general scheme for the synthesis of tocotrienols starting from various o-cresol derivatives is illustrated in Scheme- 1. The present approach is amenable for the synthesis of various tocotrienols of Vitamin-E family with modification of the side chain and by choosing the appropriate o-cresol derivatives as the key starting material.

The preparation involves novel intermediate of formula 6; said compound is stable and by itself can be used as starting material for the synthesis of tocotrienols of present invention.

Formula 6 Wherein R1=H, Me; R2=H, Me and X= Wherein R1=H, Me; R2=H, Me and X= Br, CI, OTs, OTf, N ₂ BF ₄ , N ₂ C1, CHO, COMe, COEt, COiPr, C0 ₂ Me, C0 ₂ H.

The synthesis of tocotrienols is accomplished with an overall yield of 1.3% each, after 10 steps and starting from chirally pure alcohols (S)-3b-dis found to be 7.2, 17.4, 12.3% respectively for α, β, γ-tocotrienols.

SCHEME 1

The process for forming tocotrienols as detailed in scheme 1 comprises mainly the steps of a) Preparation of 2-methyl chroman methanol derivatives, 3a-d from corresponding o- cresol derivatives la-d. b) Enzymatic resolution of 2-methyl chroman methanol derivatives 3a-d using succinic anhydride4in the presence of Amano PS lipase to procure the chirally pure (S)-3a-d, through intermediate 5a-d,

(S)-3a-d 5a-d

R1=H, Me; and R2=H, Me

c) Converting the alcohol 3a-d (racemic and both their enantiomers in pure form) to their corresponding bromide 6(i)a-d is achieved by N-bromo succinimide. The bromine can be replaced by other halo/pseudo halo derivatives such as chloro, iodo, diazonium salts and the like.

6(i)a-d (S)- 6(i)a-d (fi)- 6(i)a-d

R1=H or Me; R2=H or Me, and X=halogen, OTs, OTf, N ₂ BF ₄ , N ₂ Cl,CHO, COMe, COEt, COiPr, C02H

Converting the alcohol 3a-d (racemic and both their enantiomers in pure form) to their corresponding aldehyde 7a-d involving site selective formylation. The same approach is applicable for synthesis of other carbonyl derivatives useful in the preparation process.

7a-d (S)- 7a-d (R)- 7a-d

R1=H, Me;R2=H, Me; and

X=CHO, COMe, COEt, COiPr, C0 ₂ H

d) The derivative 7a-dare converted to the corresponding diol intermediate 8a-d through metal catalysed hydroxylation. Various copper salts with appropriate ligands, selected from a group comprising diamine, oxime and acetylacetonate and the like are used. On the other hand, palladium salts are employed in combination with various phosphine ligands. Various alkali/alkaline bases selected from a group comprising KOH, NaOH, LiOH, CsOH, Ca(OH) ₂ , Ba(OH) ₂ and Mg(OH) ₂ are used as hydroxyl source. Other hydroxyl sources, such as oxime obtained from simple carbonyl compounds, are employed with other bases viz, carbonate and phosphate salts of alkali/alkaline earth metals.

(S)8a-d (R)8a-d

R1=H, Me; R2=H, Me

e) The diol intermediate 8a-d can be obtained from 7a-d eitherthrough an acid or base catalysed Dakin oxidation. Other carbonyl derivatives can also be subjected to the Dakin oxidation with similar efficiency.

f) The alcohol 8a-d, can be alternatively obtained through bromination of ester 16a-d, using N-bromo succinimide to form the bromo ester 17a-d. The method of scheme -Iholds good for all the alkyl/aryl esters as well as for amide and acid derivatives. The same strategy is applicable for synthesis of other halo/pseudo halo derivatives such as chloro, iodo, diazonium salts and the like. Also, the strategy is amenable for the synthesis of bromo acid derivative 20a-das well.

17a-d 20a-d

R1=H, Me;R2=H, Me Both compound for formula 17(a-d) and 20 (a-d) are novel intermediates and offers various advantages such as easy handling owing to its stability and high yield thus enabling to obtain target tocotrienols of present invention.

g) The bromo derivatives mentioned above can be subjected to metal mediated hydroxylation as mentioned in point-d to get the hydroxyl acid/ester derivative that can be subsequently reduced using metal hydrides to procure the diol 8a-d

Scheme-2 provides an alternate approach for the synthesis of the chiral diol intermediate (S)- 8a-d. The diol intermediate can be utilized in the synthesis of all the members of tocotrienol family using a similar strategy as detailed in scheme- 1.

Ref: J. Org. Chem. 2007 , 72, 6735

19 8a-d (S)- 8a-d

SCHEME 2

As illustrated in scheme-2, the diol 8a-d is obtained by the ester 16a-dthrough two different approach. First approach involves site -selective bromination to form bromide 17a-d and subsequent Cu(acac) ₂ mediated hydroxylation lead to the formation of the desired hydroxyl acid derivatives 19(i)a-d. In a similar manner, regioselective formylation of 16a-d lead to the formation of aldehyde 18a-d and subsequent Dakin reaction procures hydroxyl ester derivative 19(ii)a-d. The hydroxyl acid/ester derivatives 19 a-d when subjected to reduction using metal hydrides delivers the racemic diol intermediate 8a-d; which is subjected to enzymatic resolution using Amano IME PS30 lipase to get the desired chirally pure diol (S)- 8a-d with >97% ee after two cycles^

Alternatively, the key intermediate (S)-8a-d is also synthesized wherein, the desired chroman intermediate 16a-d is assembled using the hetero-Diels-Alder reaction of methyl methacrylate (15) with in situ-generated o-quinone methides by the reaction of o-cresol derivatives la-d with paraformaldehyde.

A representative synthesis of δ-tocotrienol starting from the commercially available o-cresol (la) is demonstrated following the general scheme -3. The desired product δ-tocotrienol (R)- 14ais obtained in its natural form.

Scheme-3

The desired chroman intermediate 3a is assembled using the hetero-Diels- Alder reaction of alcohol 2 with in situ-generated o-quinone methides by the reaction of o-cresol (la) with paraformaldehyde in the presence of dibutylamine and acetic acid using the protocol developed by Fukumoto et. al. (EP0645383A1). The alcohol obtained is subjected to enzymatic resolution using Amano IME PS30 lipase to get the desired chirally pure alcohol (S)-3a with >97% ee in two cycles. Various other lipase enzymes can also be utilized for the enzymatic resolution. Also, vinyl acetate can be substituted for succinic anhydride.

The alcohol (S)-3a is then converted to desired diol (S)-8a through two different approaches. First approach involves site-selective bromination to form bromide (S)-6(i)a and subsequent Cu(acac) ₂ mediated hydroxylation that incorporates the phenolic hydroxy functionality. Various other brominating agents namely Br ₂ /AcOH, l,3-Dibromo-5,5-Dimethylhydantoin (DBDMH) and tetrabutyl ammonium tribromide are employable in the preparation. Various other copper/palladium salts may be utilized, in combination with appropriate ligands. Diamine, oxime and acetylacetonate ligands can be used in the case of copper salts and phosphine ligands can be used in the case of Pd salts to effect this transformation. Similar transformation can also be affected with various other halides/pseudo halides such as, chloride, iodide, OTs, OTf, diazonium salts. Also, a site selective formylation, leading to the formation of aldehyde (S)-7a and subsequent Dakin reaction can be invoked for the synthesis of diol (S)-8a. Formylating agents used in the present study includes, 1,1-dichlorodimethyl ether, hexamethylene tetra amine in presence of various Lewis/Bronsted acids, POCI ₃ /DMF, triethylorthoformate in combination with Lewis or Bronsted acid. Among the two, bromination pathway is chosen for the sake of simplicity in handling the reagents.

Regio selective silylation of diol (S)-8a gives the silyl ether (S)-9a, which is further converted to protected δ-tocotrienol (i?)-13a. Desilylation of (R)-13a is achieved using tetrabutyl ammonium fluoride to obtain the δ-tocotrienol (R)-14a, with 99% purity by HPLC and >97% ee as a pale-yellow oil. Various other fluoride sources such as, CsF, HF or acidic/Lewis acidic conditions can also be utilized to effect this transformation.

The overall yield obtained through this strategy for the synthesis of δ-tocotrienol is -2.6% for ten steps, starting from o-cresol la. Starting from chirally pure alcohol (S)-3a, the overall yield is about 18.5% for 7 steps.

Experimental

Example 1: Procedure for the Synthesis of δ-Tocotrienol: (R)-14a

Step-1 : Synthesis of (2, 8-Dimethyl-chroman-2-yl)-methanol: (3a)

A suspension of o-cresol (la) (1 kg, 9.249 mol), 2-methyl-2-propen-l-ol (2) (2.0 kg, 27.749 mol), paraformaldehyde (611 g, 20.348 mol), di-n-butyl amine (157 mL, 0.925 mol) and acetic acid (264 mL, 4.625 mol) is taken together in an autoclave and purged with Ar for 20 min. The mixture is then heated to 160°C overnight in an autoclave (internal pressure 12 kg/cm ₃ ). After the completion of reaction (GC control), the reaction mixture is cooled to ambient temperature and transferred to a round bottomed flask. The residual contents are washed with EA (1.0 L) and collected together with the crude mixture. The crude mixture is then evaporated to remove all the volatiles and is subjected to fractional distillation (at 120°C with 0.1 mm Hg pressure) to procure the desired alcohol 3a as a colourless oil. Yield: 816 g (46%) 1H NMR (CDCI ₃ , 400 MHz): δ 6.98 (dd, J = 7.6, 0.8 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.77 (dd, J = 7.6, 7.6 Hz, 1H), 3.65 (AB, J = 11.2 Hz, 2H), 2.95 - 2.70 (m, 2H), 2.18 (s, 3H), 2.10 - 1.95 (m, 1H), 1.86 (br s, 1H), 1.80-1.65 (m, 1H), 1.28 (s, 3H).

LCMS (M+N): m/z calculated for Ci ₂ Hi ₆ 0 ₂ Na 215.4, found 215.4

Step-2 & 3: Synthesis of ((S)-2, 8-dimethyl-chroman-2-yl)-methanol: ((S)-3a)

Step-2

To a stirred solution of alcohol 3a (810 g, 4.213 mol) in MTBE (16.2 L, 20 V) is added succinic anhydride (4) (10.4 g, 0.104 mol) and Lipase PS "Amano" EV1E (162 g, 20% w/w) in portions at 25°C and stirred for 3 h at 25°C. IPC-HPLC analysis indicates the formation of acid 5a in 49.5% and unreacted C3 49%. The reaction mixture is then filtered through Celite. The filtrate is then concentrated and the crude residue is diluted with hexanes (10 V) and aqueous NaHC0 ₃ (10 V) and stirred at 25°C for 10 min. The layers are separated and the aqueous layer is then washed with hexanes (5 x 10 V). The organic layer containing the unreacted alcohol 3a; enriched with R-isomer, is collected and evaporated separately. The aqueous layer, containing the sodium salt of acid 5a, is cooled to < 10°C and solid KOH (945 g, 16.852 mol) is added in portions and stirred for 30 min at 25°C. The reaction mixture is then filtered and diluted with hexanes (10 V) and washed with brine. The organic layer is concentrated to get the desired enantioenriched alcohol (S)-3a as a syrupy liquid.

Recovery: 285 g (35%); ee - 78.5%; The same protocol is repeated to enrich the chiral purity of the (S)-3a to >97%. Overall yield: 252 g (31.1%); ee - 97.5%

[<X]D +7.734 ° (c 0.7 in CHC1 ₃ )

Step-4a: Synthesis of ((S)-6-bromo-2, 8-dimethyl-chroman-2-yl)-methanol: ((S)-6(i)a)

(S)-3a (S)-6(i)a

To a cold (0-5°C), stirred solution of alcohol (S)-3a (210 g, 1.092 mol) in dry DMF (840 niL, 4 V), N-bromosuccinimide (194.4 g, 1.092 mol) is added in portions. After complete addition, the reaction mixture is slowly warmed up to 25°C and stirred at 25°C for 2 h. After complete consumption of starting material (TLC/HPLC control), the reaction mixture is poured over ice-cold water, stirred for 10 min and is extracted with n-heptane (3 x 10 V). The combined organic layers are washed with brine, dried using anhydrous Na ₂ S0 ₄ , filtered and then concentrated under reduced pressure to give the desired bromo alcohol (S)-6(i)a as a syrupy liquid.

Yield: 280 g (94.6%)

1H NMR (CDC1 ₃ , 400 MHz): δ 7.10-7.00 (m, 2H), 3.64 (AB, J = 11.6 Hz, 2H), 2.85 - 2.70 (m, 2H), 2.14 (s, 3H), 2.05 - 1.95 (m, 1H), 1.75-1.65 (m, 1H), 1.26 (s, 3H).

LCMS (M+): m/z calculated for Ci ₂ Hi ₅ Br0 ₂ Na 271.16, found 271.4

Step-5a: Synthesis of (S)-2-Hydroxymethyl-2,8-dimethyl-chroman-6-ol: ((S)-8a)

To a stirred suspension of bromide (S)-6(i)a (210 g, 0.774 mol) in DMSO (840 mL) and water (210 ml), Cu(acac) ₂ (2.29 g, 0.008 mol), KOH (152 g, 2.710 mol) and amide ligand (2.53 g, 0.008 mmol) is added. The reaction mixture is degassed with argon for 20 min. Then the reaction mixture is heated to 80°C and stirred for 18 h. The progress of the reaction is monitored with HPLC/TLC. HPLC/TLC indicates the complete consumption of starting material. The reaction mixture is cooled to 25°C and filtered through Celite ^® and is washed with water (5 V). The filtrate is diluted with water (10 V) and back washed with MTBE (2 x 5 V). The aqueous layer is acidified with Concentrated HC1 (6 equiv.) and extracted with isopropyl acetate (2 x 5 V). The combined organic layers are dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuum. The crude material is stirred with 10% MTBE in n- heptane for 1 h. The precipitated solid is filtered and dried to afford the desired phenolic alcohol (S)-8a as an off-white solid.

Yield: 132 g (82%)

Purity by HPLC: 99%

%ee (by HPLC) - 98.5%

[<x] _D +7.736° (c 0.7 in CHC1 ₃ )

1H NMR (CDC1 ₃ , 400 MHz): δ 6.51 (d, J = 3.0 Hz, 1H), 6.41 (d, J = 3.0 Hz, 1H), 3.63 (AB, J = 11.3 Hz, 2H), 2.81 (ddd, J = 16.8, 10.6, 6.2 Hz, 1H), 2.80 - 2.65 (m, 1H), 2.14 (s, 3H), 2.10 - 1.95 (m, 1H), 1.69 (ddd, J = 13.6, 6.2, 4.4 Hz, 1H), 1.25 (s, 3H).

LCMS (M+H): m z calculated for Ci ₂ Hi ₆ 0 ₃ 208.1, found 208.1

Step-6: Synthesis of [(S)-6-(t-butyl-dimethyl-silanyloxy)-2,8-dimethyl-chroman-2- yl]- methanol: ((S)-9a)

(S)-8a (S)-9a To a stirred solution of phenolic alcohol (S)-8a (278 g, 1.335 mol) in dry THF (1.95 L, 7 V) DBU (299 niL, 2.002 mol) is added at 15-20°C and stirred for 10 min. TBS-C1 (262 g, 1.735 mol) dissolved in dry THF (0.83 L, 3 V) is added dropwise to the reaction mixture at 15-20°C and the reaction mixture is slowly warmed up to 25°C and stirred for 30 min. After complete consumption of the (S)-8a (TLC control), the reaction mixture is quenched by adding ice-cold water (10 V). Then it is extracted with Ethyl acetate (EA) (3 x 10 V) and the combined organic layers are dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to get the crude product, which is purified by column chromatography (Eluent: EA/hexanes - 1:4) to afford the desired silyl derivative (S)-9a as pale-yellow oil.

Yield: 330 g (78.9%)

1H NMR (CDC1 ₃ , 400 MHz): δ 6.48 (d, J = 2.4 Hz, 2H); 6.40 (d, J = 2.4 Hz, 1H); 3.62 (AB, J = 11.2 Hz, 2H); 2.85-2.60 (m, 2H); 2.12 (s, 3H); 2.05-1.90 (m, 1H); 1.75-1.60 (m, 1H); 1.24 (s, 3H); 0.98 (s, 9H); 0.17 (s, 6H).

UPLC-MS purity: 99%; m/z 322.2

Step-7: Synthesis of Trifluorome thane sulfonic acid (S)-6-(t-butyl-dimethyl-silanyloxy)- 2,8- dimethyl-chroman-2-ylmethyl ester: ((S)-10a)

(S)-9a (S)-10a

To a stirred solution of alcohol (S)-9a (210 g, 0.651 mol) in dry CH ₂ C1 ₂ (2.1 L, 10 V), dry pyridine (157 mL, 1.954 mol) is added and cooled to 0°C. Triflic anhydride (164 mL, 0.976 mol) is added to the reaction mixture dropwise at 0°C and slowly warmed up to 25 °C with constant stirring for 2 h. After complete consumption of the (S)-9a(TLC control), the reaction mixture is diluted further with CH ₂ C1 ₂ (5 V) and washed with saturatedaqueous CuS0 ₄ (1% w/w w.r.t (S)-9a, 3 x 150 mL). The organic layer is then dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to procure the crude triflate (S)-10a, which is taken as such for the next step without any further purification.

Crude Weight: 290 g

Step-8: Synthesis of chroman sulfone: (S)-12a

To a cold (-78°C), stirred solution of sulfone 11 (181 g, 0.521 mol) in dry THF (1.47 L, 10 V), HMPA (302 niL, 1.738 mol) and n-BuLi (1.6 M in Hexanes, 610 mL, 0.976 mol) is added and stirred for 1 h. A solution of triflate (S)-10a (crude as such from step-7) in dry THF (48 mL, 4 V) is added dropwise to the reaction mixture at -78°C and stirred for 2.5 h. After complete consumption of the (S)-lOa(TLC control), the reaction mixture is carefully quenched by adding saturated NH ₄ C1 (120 mL) and is extracted with EA (3 x 120 mL). The combined organic layers are dried using anhydrous Na ₂ S0 ₄ ), filtered and concentrated to give the crude compound. The crude compound is then purified by column chromatography (Eluent: EA/hexanes - 1:4) to procure the desired chroman sulfone (S)-12a as a colourless oil. The product is obtained as a mixture of diastereomers and is taken as such for the next step.

Yield: 213 g (50%, 2 steps)

1H NMR (CDC1 ₃ , 400 MHz): δ 7.90-7.75 (m, 4H), 7.60-7.45 (m, 6H), 6.43 (br s, 2H), 6.35- 6.30 (m, 2H), 5.20-5.00 (m, 6H), 4.40-4.20 (m, 1H), 4.20-4.00 (m, 1H), 2.80-2.50 (m, 4H), 2.40-1.20 (m, 60H), 0.97 (s, 18H), 0.16 (s, 12H).

Step 9: Synthesis of t-Butyl-[(R)-2,8-dimethyl-2-((3E,7E)-4,8,12-trimethyl-tridec a-3,7,l,l- trienyl)-chroman-6-yloxy ] -dimethyl- silane: (R) - 13 a LiEt BH

(S)-12a (R)-13a

To a stirred, degassed solution of chroman sulfone (S)-12a (158 g, 0.243 mol) in dry THF (1.6 L, 10 V), Pd(dppp)C12 (2.9 g, 0.005 mol) is added and cooled to 0°C. A solution of LiEt ₃ BH (12% in THF, 859 mL, 0.972 mol) is added dropwise and slowly warmed up to 25°Cand stirred for 6 h. After complete consumption of (S)-12a(TLC control), the reaction mixture is quenched with saturatedaqueous sodium perboromonohydrate (1.6 L, 10 V) and is extracted with n-Heptane (3 x 5 V). The combined organic layers are dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to give the crude compound which is purified by column chromatography (Eluent: EA/hexanes - 1 :4) to procure the desired silyl protected δ- Tocotrienol (R)-13a as a pale-yellow oil.

Yield: 88 g (71.3%)

1H NMR (CDC1 ₃ , 400 MHz): δ 6.46 (d, J = 2.8 Hz, 1H), 6.37 (d, J = 2.8 Hz, 1H), 5.20-5.00 (m, 3H), 2.69 (t, J = 6.8 Hz, 2H), 2.20-1.95 (m, 13H), 1.85-1.70 (m, 2H), 1.70-1.50 (m, 14H), 1.26 (s, 3H), 0.97 (s, 9H), 0.16 (s, 6H). LCMS (M+H): m/z calculated for C ₃₃ H ₅₅ 0 ₂ Si 511.88, found 511.9

Step-10: Synthesis of δ -Tocotrienol: (R)-14a

To a stirred solution of silylated δ -Tocotrienol (R)-13a (70 g, 137 mol) in dry THF (210 mL, 10 V), TBAF- 3H ₂ 0 (21.6 g, 0.068 mol) is added and stirred at 25°C for 2 h. After complete consumption of the (i?)-13a (TLC control), the reaction mixture is diluted with water (10 V) and is extracted with n-heptane (2 x 5V mL). The combined organic layers are dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to give the crude compound. The crude compound is then purified by column chromatography (Eluent: EA/hexanes - 1 :4) to procure the desired δ -Tocotrienol (R)-14a as a colourless oil.

Yield: 46 g (85%) Purity by HPLC: 99.3%;ee - 97.85%

1H NMR (CDCI ₃ , 400 MHz): δ 6.55 - 6.45 (m, 1H), 6.39 (d, J = 3.0 Hz, 1H), 5.25 - 5.00 (m, 3H), 2.71 (dt, J = 8.2, 4.2 Hz, 2H), 2.25 - 2.00 (m, 7H), 2.05 - 1.90 (m, 5H), 1.90 - 1.75 (m, 3H), 1.69 (t, J = 1.3 Hz, 4H), 1.70 - 1.45 (m, 10H), 1.27 (s, 3H).

LCMS (M-H): m/z calculated for C ₂₇ H ₃₉ 0 ₂ 395.6, found 395.6 [<X]D -2.127° (c 1.00 in CHC1 ₃ )

Example I (a): Alternate synthesis of key diol intermediate 8a, used for δ-tocotrienol

Step-1 : Synthesis of 2,8-Dimethyl-chroman-2-carboxylic acid methyl ester (15a)

A stirred suspension of o - cresol (la) (500 g, 4.63 mol), paraformaldehyde (283 g, 9.35 mol), methyl methacrylate (15) (1.97L, 18.52 mol) and water (150 mL, 0.3 V) is heated to 180 °C at 20 kg/ cm ₂ pressure for 24 h. Completion of reaction is monitored by TLC (10% ethyl acetate in hexane). After the completion of reaction, reaction mixture is cooled to ambient temperature diluted with n-heptane and passed through pre-packed Celite plug and the filtrate obtained from above is washed with saturated aqueous NaHC0 ₃ solution. The organic layer is dried over anhydrous sodium sulphate to obtain crude product, which is further subjected to fractional distillation to get 2,8-dimethyl-chroman-2-carboxylic acid methyl ester as a pale-yellow oil. Yield: 310 g (30%)

1H NMR (CDC1 ₃ , 400 MHz): δ 7.02 - 6.94 (1 H, m), 6.86 (1 H, ddd, J = 7.6, 1.9, 0.9 Hz), 6.76 (1 H, d, J = 7.4 Hz), 3.70 (3 H, s), 2.75 - 2.66 (2 H, m), 2.40 (1 H, ddd, J = 13.4, 5.3, 4.1 Hz), 2.25 (3 H, s), 1.89 (1 H, ddd, J = 13.5, 10.2, 7.1 Hz), 1.64 (3 H, s). Step-2a: 6-Bromo-2,8-dimethyl-chroman-2-carboxylic acid methyl ester (17a)

17a

16a

To a cold (0-5°C), stirred solution of ester 16a (10 g, 0.045 mol) in dry DMF (50 mL, 5 V), N-bromosuccinimide (9.6 g, 0.054 mol) is added in portions. After complete addition, the reaction mixture is slowly warmed up to 25°C and stirred at 25°Cfor 2 h. After complete consumption of 16a(TLC control; Eluent: 4:1, Hexanes/EtOAc), the reaction mixture is then poured over ice-cold water, slowly and then stirred for 1 h. The precipitated solid is filtered and dried over reduced pressure to yield bromo ester 17a as an off-white solid.

Yield: 12.9 g (95%)

1H NMR (CDCI ₃ , 400 MHz): δ 7.10 (1 H, dq, J = 2.4, 0.8 Hz), 7.01 - 6.96 (1 H, m), 3.70 (3 H, s), 2.71 - 2.61 (2 H, m), 2.39 (1 H, ddd, J = 13.5, 5.3, 4.0 Hz), 1.86 (1 H, ddd, J = 13.6, 10.3, 7.3 Hz), 1.63 (3 H, s).

Step-3a: 6-Hydroxy-2,8-dimethyl-chroman-2-carboxylic acid (19(i)a)

17a 19(i)a

The 6-bromo-2,8-dimethyl-chroman-2-carboxylic acid methyl ester (17a) (2 g, 6.68 mmol), Cu(acac) ₂ (0.175 g, 0.66 mmol), KOH (1.125 g, 20.05 mmol) and amide ligand (0.22 g, 0.66 mmol) are placed into a Sealed tube (50 niL) with a magnetic stir bar and DMSO (16 mL) and degassed water (4 ml) are added under a positive argon pressure. The contents in the reaction vessel is degassed with argon for 20 min. The reaction mixture is vigorously stirred at 60°C for 24 h. After completion of reaction, the resulting reaction mixture is cooled and acidified with 1.5 N HC1, then diluted with ethyl acetate. The organic phase is separated and dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The crude product obtained is slurred with hexane and filtered to get 6-Hydroxy-2,8-dimethyl-chroman-2-carboxylic acid (19(i)a) as pale brown solid.

Yield: 1.2 g (81%) 1H NMR (CDC1 ₃ , 400 MHz): δ 6.52 (d, J = 2.8 Hz, 1H), 6.39 (d, J = 2.8 Hz, 1H), 2.80-2.70 (m, 2 H), 2.45-2.30 (m, 1H), 2.06 (s, 3H), 2.00-1.85 (m, 2H), 1.62 (s, 3H).

LCMS (M+H): m/z calculated for Ci ₂ Hi ₃ 0 ₄ 221.24, found 221.3

Step-2b: Synthesis of 6-formyl-2,8-dimethyl-chroman-2-carboxylic acid methyl ester (18a)

16a 18a

Procedure- 1 : Using Hexamine and TFA

To a stirred mixture of 2,8-dimethyl-chroman-2-carboxylic acid methyl ester (16a) (10 g, 0.045 mol) and hexamine (12.6 g, 0.09 mol) under nitrogen atmosphere TFA (50 mL) is added drop wise at 0-5°C and warmed to 50°C for 16 h. Completion of reaction is monitored by TLC (30% ethyl acetate in hexane). After the completion of reaction, reaction mixture is evaporated under reduced pressure, residue obtained is basified to pH- 8 with ice cold saturated aqueous NaHC0 ₃ solution and extracted with ethyl acetate. Organic layer obtained is dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude product as a pale brown wax. The Crude product obtained is further purified by column chromatography using silica gel (230-400) in Ethyl acetate/ hexane solvent to afford 6- formyl-2,8-dimethyl-chroman-2-carboxylic acid methyl ester (18a) as pale-yellow solid.

Yield: 6.8 g (61%) Procedure-2: Using 1,1-dichlorodimethyl ether and TiC

A stirred solution of 2,8-dimethyl-chroman-2-carboxylic acid methyl ester (16a) (10 g, 0.045 mol) in DCM (100 mL, 10 V) is degassed for 10 min with N ₂ . To the above solution 1,1- dichlorodimethyl ether (8.2 mL, 0.091 mol) and TiCl ₄ (12.6 mL, 0.114 mol) are added dropwise successively at ambient temperature and stirred for lh. Completion of reaction is monitored by TLC (30% ethyl acetate in hexane). After the completion of reaction, reaction mixture is added to ice cold saturated aqueous NH ₄ C1 solution and extracted with ethyl acetate. The ethyl acetate layer from above washed with aqueous saturated NaHC03 solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude product as pale-yellow wax which is further purified triturating with n-heptane to afford 6- formyl-2,8-dimethyl-chroman-2-carboxylic acid methyl ester (18a) as pale yellow solid.

Yield: 9.8 g (87%)

1H NMR (CDC1 ₃ , 400 MHz): δ 9.81 (1 H, s), 7.54 (1 H, s), 7.43 (1 H, d, J = 2.0 Hz), 3.72 (3 H, s), 2.97 - 2.59 (2 H, m), 2.46 (1 H, ddd, J = 13.7, 5.7, 3.4 Hz), 2.30 (3 H, s), 1.69 (3 H, s).

Step-3b: Synthesis of 6-hydroxy-2, 8-dimethyl-chroman-2-carboxylic acid methyl ester

18a 19(ii)a To a suspension of boric acid (29.4 g, 0.48 mol) in THF (160 mL, 8 V) at 25°C, aqueous H ₂ 0 ₂ (50%, 13.6 mL, 0.2 mol) is dropwise added and stirred for 10 min. To the above suspension cone. H ₂ S0 ₄ (8 mL, 0.4 V) is added dropwise within 10 min and the resulting suspension is stirred for 20 min. The above reaction mixture is cooled in an ice bath and6- formyl-2,8-dimethyl-chroman-2-carboxylic acid methyl ester (18a) (20 g, 0.08 mmol) in THF (40 mL, 2 V) is added dropwise and stirred at ambient temperature for 1 h. Completion of reaction is monitored by TLC (30% ethyl acetate in hexane). After the completion of reaction, reaction mixture is added to ice cold saturated aqueous NaHC0 ₃ solution (200 mL) and extracted with ethyl acetate. Organic layer is separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude product as a pale brown wax. The Crude product is further purified triturating with hexane to afford ethyl 6-hydroxy-2,8- dimethyl-chroman-2-carboxylic acid methyl ester (19(H) a) as an off-white solid.

Yield: 12.3 g (64%)

1H NMR (DMSO-d ₆ , 400 MHz): δ 8.65 (1H, s), 6.37 (1H, d, J = 2.9 Hz), 6.23 (1H, d, J = 2.8 Hz), 3.61 (3H, s), 2.57- 2.48 (2H, m), 2.24 (1H, ddd, J = 13.3, 5.7, 3.1 Hz), 2.05 (3H, s), 1.79 (1H, ddd, J = 13.6, 11.5, 5.9 Hz), 1.51 (3H, s)

Step-4: Synthesis of 2-Hydroxymethyl-2,8-dimethyl-chroman-6-ol (8a)

19a

8a

Procedure- 1 : From intermediate- 19(i)a

To a stirred solution of 6-hydroxy-2,8-dimethyl-chroman-2-carboxylic acid (19a) (1.2 g, 5.399 mmol) in THF (20 V) at 0°C, Red-Al (5 mL, 16.20 mmol) is added dropwise and the resulting reaction mixture is stirred at 25-30°C for 2 h. After completion of the reaction, the reaction mixture is cautiously added to 1.5 N HC1, then diluted with n-heptane. The organic phase is separated, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The crude product obtained is slurried with n-heptane and filtered to get 2-Hydroxymethyl-2,8- dimethyl-chroman-6-ol (8a) as off-white solid (0.92 g, 82%). Procedure-2: From intermediate- 19(ii)a

To a stirred solution of Methyl-6-hydroxy-2,8-dimethyl-chroman-2-carboxylate (19(ii)a) (6 g, 0.027 mol) in THF (10 V) at 0°C, Red-Al (22 mL, 0.067 mol) is added dropwise and the resulting reaction mixture is stirred at 0-5°C for 2 h. After completion of the reaction, the reaction mixture is cautiously added to 1.5 N HC1, then diluted with n-heptane. The layers are separated and the organic layer is washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to afford 2-hydroxymethyl-2,8-dimethyl-chroman-6-ol (8a) as an off- white solid (4.58 g, 82%).

1H NMR (CDC1 ₃ , 400 MHz): δ 6.51 (d, J = 3.0 Hz, 1H), 6.41 (d, J = 3.0 Hz, 1H), 3.63 (AB, J = 11.3 Hz, 2H), 2.81 (ddd, J = 16.8, 10.6, 6.2 Hz, 1H), 2.80 - 2.65 (m, 1H), 2.14 (s, 3H), 2.10 - 1.95 (m, 1H), 1.69 (ddd, J = 13.6, 6.2, 4.4 Hz, 1H), 1.25 (s, 3H).

LCMS (M+H): m z calcd. for Ci ₂ Hi ₆ 0 ₃ 208.1, found 208.1

Example 2: Procedure for the synthesis of a-Tocotrienol: (R)-14b

Step-1 : Synthesis of (2,5,7, 8-Tetramethyl-chroman-2-yl)-methanol (3b)

A suspension of 2,3,5-trimethylphenol (lb) (100 g, 0.7342 mol), paraformaldehyde (48.5 g, 1.615 mol), 2-methyl-2-propen-l-ol (2) (158.8 g, 2.230 mol), (n-Bu) ₂ NH (123.7 mL, 0.734 mol) and AcOH (21.0 mL, 0.3671 mol) is taken together in an autoclave and purged with Ar for 20 min. The mixture is heated to 160°C overnight in an autoclave (internal pressure 12 kg/cm ₃ ). After the completion of reaction (TLC control), the reaction mixture is cooled to ambient temperature and transferred to a round bottomed flask. The residual contents are washed with EA (2 x 5 L) and collected together with the crude mixture. The crude mixture is evaporated to remove all the volatiles and is subjected to fractional distillation (at 160-180°C with 2 mbar pressure) to procure the desired alcohol 3b as an off-white solid.

Yield: 74.0 g (46%)

1H NMR (400 MHz, CDC1 ₃ ):56.61 (s, 1H), 3.65 (AB, J = 11.2 Hz, 2H), 2.70 - 2.60 (m, 2H), 2.23 (s, 3H), 2.19 (s, 3H), 2.10 (s, 3H), 2.10 - 1.95 (m, 1H), 1.75 (ddd, J = 13.6, 6.0, 4.8 Hz, 1H), 1.25 (s, 3H);

LCMS (M+H): m/z calculated for Ci ₄ H ₂ i0 ₂ 221.3, found 221.2

Step-2 & 3: Synthesis of (S)-(2,5,7,8-Tetramethyl-chroman-2-yl)-methanol ((S)-3b)

Step-2

To a stirred solution of alcohol (3b) (74.0 g, 0.4539 mol) in MTBE (2.0 L, 20 V), succinic anhydride (4) (36.31 g, 0.3631 mol) and Lipase PS "Amano" IME (20.0 g, 20% w/w) is added in portions at 25°C and stirred for 3 h at 25°C. IPC-HPLC analysis indicated the formation of acid 5b in 49.5% and unreacted 3b 49%. The reaction mixture is filtered through Celite. The filtrate is concentrated and the crude residue is diluted with hexanes (10 V) and saturated aqueous NaHC0 ₃ (10 V) and stirred at 25°C for 10 min. The layers are separated and the aqueous layer is washed with hexanes (5 x 10 V).The organic layer containing the unreacted alcohol 3b; enriched with R-isomer, is collected and evaporated separately. The aqueous layer, containing the sodium salt of acid 5b, is cooled to < 10°C and solid KOH (101.8 g, 1.8156 mol) is added in portions and stirred for 30 min at 25°C. The reaction mixture is filtered and diluted with hexanes (10 V) and washed with brine. The organic layer is concentrated to get the desired enantioenriched alcohol (S)-3b as an off-white solid. Recovery: 34.0 g (40%); ee - 78.5%; The same protocol is repeated to enrich the chiral purity of the (S)-3b to >97%.

Overall yield: 27.0 g (36%); ee - 97.5%

Step-4a: Synthesis of ((S)-6-Bromo-2,5,7,8-tetramethyl-chroman-2-yl)-methanol: ((S)-6(i)b)

(S)- ^3b (S)-6(i)b

To a cold (0-5°C), stirred solution of alcohol (S)-3b (26.5 g, 0.1202 mol) in dry DMF (265 mL, 10 V), N-bromosuccinimide (22.47 g, 0.1262 mol) is added in portions. After complete addition, the reaction mixture is slowly warmed up to 25°C and stirred for 2 h. After completion of the reaction (TLC control), the reaction mixture is poured over ice-cold water, stirred for 10 min and extracted with n-heptane (3 x 10 V). The combined organic layers are washed with brine, dried with anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the desired bromo alcohol (S)-6(i)b as a syrupy liquid.

Yield: 33.6 g (94%)

1H NMR (400 MHz, CDC1 ₃ ): δ 3.65 (AB, J = 11.6 Hz, 2H), 2.80 - 2.65 (m, 2H), 2.40 (s, 3H), 2.36 (s, 3H). 2.18 (s, 3H), 2.10 - 1.95 (m, 1H), 1.93 (br s, 1H), 1.75 (ddd, J = 4.8, 6.4, 13.6 Hz, 1H), 1.24 (s, 3H);

LCMS (M+H): m/z calculated for Ci ₄ H ₂₀ BrO ₂ 300.2, found 300.9 Step-5: Synthesis of (S)-2-Hydroxymethyl-2,5,7,8-tetramethyl-chroman-6-ol ((S)-8b)

Step-5a: Copper mediated hydroxylation

Cu(acac) ₂ (1 mol%)

To a suspension of bromide (S)-6(i)b (33.0 g, 0.1110 mol), Cu(acac) ₂ (0.5812 g, 0.0022 mol), KOH (21.8 g, 0.3885 mol) and amide ligand (0.7289 g, 0.0022 mol), DMSO (297mL) and water (33 mL) is added. The reaction mixture is degassed with argon for 20 min and mixture is then stirred vigorously at 80°C for 24 h. After completion of reaction, the resulting reaction mixture is cooled to 25°C, filtered through Celite , diluted with water (0.5 L) and backwashed with MTBE (2 x 1 L). The aqueous layer is acidified with Cone. HC1 and extracted with EtOAc (3 x 1 L). The organic layer is washed with water (2 x 500 mL) and brine (2 x 500 mL), dried using anhydrous Na ₂ S0 ₄ , filtered and then concentrated in vacuo. The crude product obtained is dissolved with 30% EA in hexanes (2 L, 10 V) and stirred for 2 h. The clear solution obtained is decanted and concentrated to 2 V level. The solid obtained is filtered and dried to afford the desired phenolic alcohol (S)-8b as an off-white solid.

Yield: 20.7 g (79%)

Purity by HPLC: 99%; %ee - 99.18%

1H NMR (400 MHz, CDC1 ₃ ): δ 4.27 (br s, 1H), 3.63 (AB, J = 11.2 Hz, 2H), 2.80 - 2.60 (m, 2H), 2.18 (s, 3H), 2.12 (s, 3H), 2.10 - 1.95 (m, 1H), 1.74 (ddd, J = 4.8, 6.4, 13.6 Hz, 1H), 1.23 (s, 3H);

LCMS (M+H): m/z calculated for Ci ₄ H ₂ i0 ₃ 237.3, found 237.1 Step-6: Synthesis of {(S)-6-[(tert-Butyl-dimethyl-silanyloxy)-methyl]-2,5,7,8-tet ramethyl- chroman-2-yl} -methanol: ((S)-9b)

(S)-8b (S)-9b

Sodium hydride (60% wet) (7.1 g, 0.1777 mol) in dry THF (100 mL, 5 V) is cooled to -5 to 0°C, then phenolic alcohol (S)-8b (20.0 g, 0.0846 mol) in dry THF (60 mL, 3 V) is added slowly by maintaining temperature below 5°C. Reaction mass is stirred for 30 to 45 minutes at 0-5°C. A solution of TBS-C1 (16.6 g, 0.1100 mol) dissolved in dry THF (60 mL, 3 V) is added dropwise to the reaction mixture at 0-5°C and the reaction mixture is slowly warmed up to 25°C and stirred for 3 h. After completion of the reaction, the reaction mixture is quenched by adding ice-cold water (10 V). It is extracted with n-heptane (2 x 5 V) and the combined organic layers are washed with brine (5 V), dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to get the crude product, which is purified by column chromatography (Eluent: EA/hexanes - 0.3:9.7) to afford the desired silyl derivative (S)-9b as pale-yellow oil. Yield: 13.2 g (44%)

1H NMR (400 MHz, CDC1 ₃ ): δ 3.63 (AB, J = 11.2 Hz, 2H), 2.70 - 2.60 (m, 2H), 2.12 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 2.10 - 1.95 (m, 1H), 1.88 (br, s, 1H), 1.80 - 1.70 (m, 1H), 1.23 (s, 3H), 1.07 (s, 9H), 0.15 (s, 6H);

LCMS (M+H): m z calculated for C ₂ oH ₃₅ 0 ₃ Si 351.6, found 352.0 Step-7: Synthesis of Trifluoromethane sulfonic acid (S)-6-[(tert-butyl-dimethyl-silanyloxy)- methyl] -2,5,7, 8-tetramethyl-chroman-2-ylmethyl ester: ((S)-10b)

(S)-9b (S)-10b

To a stirred solution of alcohol (S)-9b (12.5 g, 0.0356 mol) in dry CH ₂ C1 ₂ (250 mL, 20 V), dry pyridine (8.65 mL, 0.1069 mol) is added and solution is cooled to 0°C. Triflic anhydride (11.96 mL, 0.0713 mol) is added to the reaction mixture dropwise at 0°C and slowly warmed up to 25°C with constant stirring for 2 h. After completion of the reaction (TLC control), the reaction mixture is diluted further with CH ₂ C1 ₂ (62.5 mL, 5 V) and washed with saturated aqueous NaHC0 ₃ (10% solution, 2 x 125 mL). The organic layer is then dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to procure the crude triflate (S)-10b. Crude extract is stripped-off two times with Toluene and dried completely and taken as such for the next step without any further purification.

Crude Weight: 15 g

Step-8: Synthesis of chroman sulfone: (S)-12b

To a cold (-70°C) stirred solution of sulfone 11 (9.88 g, 0.0285 mol) in dry THF (125 mL, 10 V), HMPA (16.5 mL, 0.0952 mol) and n-BuLi (2.5M in Hexanes, 21.36 mL, 0.0534 mol) is added and stirred for 1 h. A solution of triflate (S)-10b (crude as such from step-7) in dry THF (62.5 mL, 5 V) is added to the reaction mixture at -70°C and stirred for 12 h. After completion of the reaction,(TLC control), the reaction mixture is carefully quenched by adding saturated N¾C1 (125 mL) and is then extracted with n-heptane (2x 125 mL). The combined organic layers are dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to give the crude compound. The crude compound is purified by column chromatography (Eluent: EA/hexanes - 0.3:9.7) to procure the desired chroman sulfone (S)-12b as a Pale-yellow oil. The product is obtained as a mixture of diastereomers and is taken as such for the next step.

Yield: 11.5 g (48%, 2 steps)

1H NMR (400 MHz, CDC1 ₃ ): δ 7.90 - 7.40 (m, 5H), 5.15 - 5.00 (m, 3H), 4.20 - 4.05 (m, 1H), 2.60 - 2.45 (m, 3H), 2.10 - 1.95 (m, 18H), 1.80 - 1.70 (m, 3H), 1.70 (s, 3H), 1.57 (s, 8H), 1.33 (s, 2H), 1.27 (br s, 1H), 1.24 (s, 1H), 1.17 (d, J = 10 Hz, 3H), 1.06 (d, J = 5.2 Hz, 9H), 0.12 (s, 6H);

LCMS (M+H ₂ 0): m/z calculated for C ₄ iH ₆₄ 0 ₅ SSi 680.1, found 696.7

Step 9: Synthesis of tert-Butyl-dimethyl-[(R)-2,5,7,8-tetramethyl-2-((3E,7E)-4,8, 12- trimethyl-trideca-3,7,1 l-trienyl)-chroman-6-yloxy]-silane: ((R)-13b)

(S)-12b (R)-13b

To a stirred degassed solution of chroman sulfone (S)-12b (11.0 g, 0.0162 mol) in dry THF (110 mL, 10 V), Pd(dppp)Cl ₂ (0.19 g, 0.0003 mol) is added. A solution of LiEt ₃ BH (12% in THF, 56.69 mL, 0.065 mol) is added dropwise at 25°C and stirred for 15 h. After completion of the reaction, the reaction mixture is quenched with saturated aqueous sodium perboromonohydrate (1% solution, 1 L, 15 V) and extracted with n-heptane (2 x 110 mL). The combined organic layers are washed with brine (5 V), dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to give the crude compound which is then purified by column chromatography (Eluent: EA/hexanes - 0.1 :9.9) to procure the desired silyl protected a- Tocotrienol (R)-13b as a pale-yellow oil.

Yield: 6.11 g (70%) 1H NMR (400 MHz, CDC1 ₃ ): 5 5.15 - 5.05 (m, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.20 - 1.95 (m, 19H), 1.75 - 1.50 (m, 14H), 1.90 - 1.75 (m, 2H), 1.26 (s, 3H), 1.06 (s, 9H), 0.13 (s, 6H);

LCMS (M+H): m/z calculated for C ₃ 5H ₅₉ 0 ₂ Si 539.94, found 541.4

Step-10: Synthesis of a-Tocotrienol: (R)-14b

To a stirred solution of silylateda-Tocotrienol (R)-13b (6.0 g, 0.011 mol) in dry THF (30 mL, 5 V), TBAF (1M in THF, 16.7 mL, 0.0167 mol) is added and stirred at 25°Cfor 1 h. After completion consumption of the starting material, the reaction mixture is quenched by adding saturated NH ₄ CI (30 mL) and extracted with n-heptane (3 x 60 mL). The combined organic layer is washed with purified water (2 x 60 mL) and dried using anhydrous Na ₂ S04, filtered and concentrated to give the crude compound. The crude compound is then purified by column chromatography (Eluent: EA/hexanes - 1 :4) to procure the desired a-Tocotrienol (R)- 14b as a pale-yellow syrupy oil.

Yield: 3.1 g (66%); Purity by HPLC: 98.3%; ee - 99.02%

1H NMR (400 MHz, CDC1 ₃ ): δ 5.20 - 5.05 (m, 3H), 4.19 (br s, 1H), 2.62 (t, J = 6.8 Hz, 2H), 2.20 (s, 3H), 2.10 (d, J = 2.0, 7H), 2.10 - 2.03 (m, 4H), 2.00 - 1.95 (m, 4H), 1.90 - 1.70 (m, 2H), 1.68 (d, J = 0.8 Hz, 3H), 1.65 - 1.50 (m, 12H), 1.25 (s, 3H);

LCMS (M+H): m/z calculated for C ₂₉ H ₄₅ 0 ₂ 425.6, found 425.1 [a] _D -4.6° (c 2.47 in CHC1 ₃ )

Example 2 (a): Alternate synthesis of key diol intermediate 8b, used for a-tocotrienol Step-1 : Synthesis of 2,5,7,8-Tetramethyl-chroman-2-carboxylic acid methyl ester (16b)

A suspension of 2,3,5-trimethyl-phenol (lb) (50 g, 0.367 mol), paraformaldehyde (22.2 g, 0.741 mol), methyl methacrylate (15) (195 mL, 1.838 mol) and water (15 mL, 0.3 V) are taken together in an autoclave and purged with Ar for 20 min. The mixture is then heated to 180°C for 18 h in an autoclave (internal pressure 12-15 kg/cm ₃ ). After the completion of reaction (TLC control), the reaction mixture is cooled to ambient temperature and concentrated. The crude reaction mixture obtained is purified by column chromatography (Eluent - 30%, EtOAc/Hexanes) to procure the desired product, chroman ester 16b as a white solid.

Yield: 27 g (29%)

1H NMR (CDC1 ₃ , 400 MHz): δ 6.59 (s, 1H), 3.70 (s, 3H), 2.70 - 2.60 (m, 1H), 2.55 - 2.40 (m, 2H), 2.22 (s, 3H), 2.16 (s, 3H), 2.13 (s, 3H), 1.88 (ddd, J = 8.4, 13.2, 21.6 Hz, 1H), 1.63 (s, 3H); LCMS (M+H): m z calculated for Ci ₅ H ₂ i0 ₃ 249.32, found 249.3

Step-2: Synthesis of 6-Bromo-2,3,7,8-tetramethyl-chroman-2-carboxylic acid methyl ester

(17b)

To a cold (0-5°C) stirred solution of ester 16b (2 g, 8.054 mmol) in dry DMF (20 mL, 10 V), N-bromosuccinimide (1.5 g, 8.456 mmol) is added in portions. After complete addition, the reaction mixture is slowly warmed up to 25°Cand stirredfor 3 h. After completion of the reaction, (TLC control; Eluent: 4:1, Hexanes/EtOAc), the reaction mixture is poured over ice- cold water, slowly and stirred for 1 h. The precipitated solid is filtered and dried at reduced pressure to yield bromo ester 17b as an off-white solid.

Yield: 2.4 g (91%) 1H NMR (CDCI ₃ , 400 MHz): δ 3.62 (s 3H), 2.75 - 2.65 (m, 1H), 2.50 - 2.35 (m, 1H), 2.40 - 2.30 (m, 4H), 2.23 (s, 3H), 2.15 (s, 3H), 1.83 (ddd, J = 6.4, 11.6, 17.6 Hz, 1H), 1.56 (s, 3H);

LCMS (M+H): m/z calculated for Ci ₅ H ₂ oBr0 ₃ 328.22. found 329.3

Step-3: Synthesis of 6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (19(i)b)

17b 19(i)b

To a suspension of bromide 17b (1 g, 3.056 mmol), Cu(acac) ₂ (8 mg, 0.030 mmol), KOH (1.02 g, 18.34 mmol) and amide ligand (10 mg, 0.030 mol), DMSO (10 mL) and water (2 mL) is added. The reaction mixture is degassed with argon for 20 min and stirred vigorously at 100°C for 18 h. After completion of reaction, the resulting reaction mixture is cooled to 25°C, filtered through Celite ^® , diluted with water (4.5 L) and backwashed with MTBE (2 x 1 L). The aqueous layer is acidified with Cone. HC1 and extracted with EtOAc (3 x 1 L). The organic layer is washed with water (2 x 500 mL) brine (2 x 500 mL), dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The crude compound 19(i)b obtainedis taken as such for the next step without any further purification.

Yield: 340 mg (45%) 1H NMR (CDC1 ₃ , 400 MHz): δ 4.34 (br, s 1H), 3.61 (s, 1H), 2.75 - 2.55 (m, 2H), 2.45 - 2.30 (m, 1H), 2.18 (s, 6H), 2.10 (s, 3H), 1.94 (ddd, J = 2.8, 5.2 12 Hz, 1H), 1.62 (s, 3H); LCMS (M+H): m/z calculated for C ₁₄ H ₁₉ 0 ₄ 251.3 found 251.3

Step-4: Synthesis of 2-Hydroxymethyl-2,5,7,8-tetramethyl-chroman-6-ol (8b)

19(i)b 8b

To a cold (0-5°C) solution of hydroxyl acid 19(i)b (300 mg, 1.20 mmol) in dry THF (3 mL) Red-AL (50% w/w in toluene, 7.2 mL, 3.60 mol) is added at 0-5°C. After complete addition of Red-Al, the reaction mixture is slowly warmed up to 25°C and stirred for 1 h (TLC control). The reaction mixture is cooled to 0-5°C and carefully quenched with 6 N HCl (3 V) and extracted with MTBE (3 x 5 V). The combined organic layers are dried using anhydrousNa ₂ S0 ₄ , concentrated and the crude compound is purified by column chromatography to get the desired product 8bas an off-white solid.

Yield: 232 mg (82%)

1H NMR (CDC1 ₃ , 400 MHz): δ 6.50 (s, 1H), 3.63 (AB, J = 11.2 Hz, 2H), 2.80 - 2.60 (m, 2H), 2.12 (s, 3H), 2.11 (s, 3H), 2.10 - 1.95 (m, 1H), 1.74 (ddd, J = 4.4, 6.4, 13.6 Hz, 1H), 1.23 (s, 3H); LCMS (M+H): m/z calculated for C 13H19O3 223.3, found 223.4

Example 3: Procedure for the Synthesis of β-Tocotrienol; (R)-14c

Step-1 : Synthesis of (2,5,8-Trimethyl-chroman-2-yl)-methanol: (3c) A suspension of 2,5-dimethyl phenol (lc) (100 g, 0.818 mol), paraformaldehyde (54 g, 1.79 mol), 2-methyl-2-propen-l-ol (2) (207 mL, 2.45 mol), (n-Bu) ₂ NH (14 mL, 0.081 mol) and AcOH (24 mL, 0.409 mol) is taken together in an autoclave and purged with Ar for 20 min. The mixture is then heated to 160°C overnight in autoclave (internal pressure 12 kg/cm ₃ ). After the completion of reaction (TLC control), the reaction mixture is cooled to ambient temperature and transferred to a round bottomed flask. The residual contents are washed with EA (2 x 1 L) and collected together with the crude mixture. The crude mixture is then evaporated to remove all the volatiles and is subjected to silica gel column chromatography (Eluent: 100% hexanes) to procure the desired alcohol 3c as a colourless oil. Yield: 81 g (48%)

1H NMR (CDC1 ₃ , 400 MHz): δ 6.90 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 3.65 (AB, J = 11.2 Hz, 2H), 2.75 - 2.60 (m, 2H), 2.21 (s, 3H), 2.16 (s, 3H), 2.10 - 1.90 (m, 2H), 1.77 (ddd, J = 4.8, 6.0, 13.6 Hz, 1H), 1.26 (s, 3H);

LCMS (M+H): m/z calculated for d ₃ Hi ₉ 0 ₂ 207.4, found 207.1 Step-2 & 3 : Synthesis of ((S)-2,5,8-Trimethyl-chroman-2-yl)-methanol: ((S)-3c)

Step-2

To a stirred solution of alcohol 3c (20 g, 0.097 mol) in MTBE (400 mL, 20 V), succinic anhydride (4) (7.76 g, 0.077 mol) and Lipase PS "Amano" EV1E (4 g, 20% w/w) is added in portions and stirred for 4 hat25°C. The reaction mixture is then filtered through Celite ^® . The filtrate is then concentrated and the crude residue is diluted with hexanes (10 V) and saturated aqueous NaHC0 ₃ (10 V) and stirred at 25°C for 10 min. The layers are separated and the aqueous layer is washed with hexanes (5 x 10 V). The organic layer containing the unreacted alcohol 3c; enriched with R-isomer, is collected and evaporated separately. The aqueous layer, containing the sodium salt of acid 5c, is cooled to < 10°C and solid KOH (21.76 g, 0.388 mol) is added in portions and stirred for 30 min at 25°C. The reaction mixture is then filtered and diluted with hexanes (10 V) and washed with brine. The organic layer is concentrated to get the desired enantioenriched alcohol (S)-3c as a syrupy liquid.

Recovery: 4.8 g (48%); ee - 91.19%; The same protocol is repeated to enrich the chiral purity of the (S)-3c to >97%.

Overall yield: 3.3 g (16%); ee - 97.6% Step-4a: Synthesis of ((S)-6-Bromo-2,5,8-trimethyl-chroman-2-yl)-methanol: ((S)-6(i)c)

(S)-3c (S)-6(i)c

To a cold (0-5°C) stirred solution of alcohol (S)-3c (81 g, 0.393 mol) in dry DMF (405 mL, 5 V), N-bromosuccinimide (70 g, 0.393 mol) is added in portions. After complete addition, the reaction mixture is slowly warmed up to 25°C and stirred for 2 h. After completion of the reaction, (TLC control), the reaction mixture is poured over ice-cold water, slowly and stirred for 1 h. The precipitated solid is filtered and dried over reduced pressure to yield bromo alcohol(S)-6(i)c asan off-white solid.

Yield: 94.5 g (84%)

1H NMR (CDC1 ₃ , 400 MHz): δ 7.20 (s, 1H), 3.64 (AB, J = 11.6 Hz, 2H), 2.80 - 2.60 (m, 1H), 2.30 (s, 3H), 2.12 (s, 3H), 2.10 - 1.95 (m, 1H), 1.88 (br s, 1H), 1.76 (ddd, J = 4.4, 6.0, 13.6 Hz, 1H-.), 1.24 (s, 3H); LCMS (M+H): m/z calculated for Ci ₃ Hi ₈ Br0 ₂ 286.2, found 286.0

Step-5a: Synthesis of (S)-2-Hydroxymethyl-2,5,8-trimethyl-chroman-6-ol: ((S)-8c)

Cu(acac) ₂ (1 mol%)

To a suspension of bromide (S)-6(i)c (93.5 g, 0.327 mol), Cu(acac) ₂ (1.7 g, 0.006 mol), KOH (73.39 g, 1.30 mol) and amide ligand (2.15 g, 0.006 mol), DMSO (748 mL) and water (187 mL) is added. The reaction mixture is degassed with argon for 20 min and stirred vigorously at 80°C for 12 h. After completion of reaction, the resulting reaction mixture is cooled to about 25°C, filtered through Celite ^® , diluted with water (4.5 L) and backwashed with MTBE (2 x 1 L). The aqueous layer is then acidified with Cone. HC1 and extracted with EtOAc (3 x 1 L). The organic layer is washed with water (2 x 500 mL), brine (2 x 500 mL), dried usinganhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The crude product obtained is dissolved with 30% EA in hexanes (2 L, 10 V) and stirred for 2 h. The clear solution obtained is decanted and concentrated to 2 V level. The solid obtained is filtered and dried to afford the desired phenolic alcohol (S)-8c as an off-white solid. Yield: 45 g (59%)

1H NMR (CDC1 ₃ , 400 MHz): δ 6.50 (s, 1H), 3.63 (AB, J = 11.2 Hz, 2H), 2.80 - 2.60 (m, 2H), 2.12 (s, 3H), 2.11 (s, 3H), 2.10 - 1.95 (m, 1H), 1.74 (ddd, J = 4.4, 6.4, 13.6 Hz, 1H), 1.23 (s, 3H);

LCMS (M+H): m/z calculated for d ₃ Hi ₉ 0 ₃ 223.3, found 223.4 Step-6: Synthesis of [(S)-6-(tert-Butyl-dimethyl-silanyloxy)-2,5,8-trimethyl-chro man-2-yl]- methanol: ((S)-9c)

(S)-8c (S)-9c

To a stirred solution of phenolic alcohol (S)-8c (10.0 g, 0.045 mol) in dry THF (70 mL, 7 V), DBU (10.1 mL, 0.067 mol) is added at 15-20°C and stirred for 10 min. TBS-Cl (8.9 g, 0.058 mol) dissolved in dry THF (30 mL, 3V) is added dropwise to the reaction mixture at 15-20°C and the reaction mixture is slowly warmed up to 25°C and stirred for 30 min. After completion of the reaction, the reaction mixture is quenched by adding ice-cold water (10 V). It is then extracted with EA (2 x 5 V) and the combined organic layers are washed with brine (5 V), dried with anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to get the crude product, which is purified by column chromatography (Eluent: EA/hexanes - 1:4) to afford the desired silyl derivative (S)-9c as pale-yellow oil.

Yield: 12.1 g (80%)

1H NMR (CDC1 ₃ , 400 MHz): δ 6.49 (s, 1H), 3.62 (AB, J = 11.2 Hz, 2H), 2.70 - 2.55 (m, 2H), 2.11 (s, 3H), 2.10 - 1.95 (m, 4H), 1.87 (br s, 1H), 1.73 (ddd, J = 4.8, 6.4, 13.6 Hz, 1H), 1.22 (s, 3H), 1.02 (s, 9H), 0.19 (s, 3H), 0.18 (s, 3H); LCMS (M+H): m/z calculated for 337.6, found 337.6

Step-7: Synthesis of Trifluoromethane sulfonic acid (S)-6-(tert-butyl-dimethyl-silanyloxy)- 2,5,8-trimethyl-chroman-2-ylmethyl ester: ((S)-10c)

(S)-9c (S)-10c

To a stirred solution of alcohol (S)-9c (8.5 g, 0.025 mol) in dry CH ₂ C1 ₂ (170 mL, 20 V) dry pyridine (5.99 mL, 0.075 mol) is added and cooled to 0°C. Triflic anhydride (14.2 mL, 0.0504 mol) is added to the reaction mixture dropwise at 0°C and is slowly warmed up to 25°Cand stirred for 2 h. After completion of the reaction, (TLC control), the reaction mixture is diluted further with CH ₂ CI ₂ (75 mL, 5 V) and washed with saturated aqueous CuS0 ₄ (1% w/w w.r.t (S)-9c, 3 x 150 mL). The organic layer is then dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to procure the crude triflate (S)-10c, which is taken as such for the next step without any further purification.

Step-8: Synthesis of Sulfone: (S)-12c

To a cold (-78°C) stirred solution of sulfone 11 (7.0 g, 0.020 mol) in dry THF (127.5 mL, 15 V), HMPA (12.05 mL, 0.067 mol) and n-BuLi (2.5 M in Hexanes, 20.2 mL, 0.050 mol) is added and stirred for 1 h. A solution of triflate (S)-10c (crude as such from step-7) in dry THF (48 mL, 4 V) is added to the reaction mixture at -78°C and stirred for 2.5 h. After completion of the reaction (TLC control), the reaction mixture is carefully quenched by adding saturated N¾C1 (120 mL) and is extracted with EA (3 x 120 mL). The combined organic layers are dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to give the crude compound. The crude compound is then purified by column chromatography (Eluent: EA/hexanes - 1 :4) to procure the desired chroman sulfone (S)-12c as a colourless oil.

The product obtained as a mixture of diastereomers is taken for the next step.

Yield: 12.1 g (72%) 1H NMR (CDCI ₃ , 400 MHz): δ 7.86 - 7.43 (m, 5H), 6.43 (s, 1H), 5.18 - 5.00 (m, 3H), 2.52 (m, 2H), 2.07 - 1.94 (m, 15H), 1.79 (m, 1H), 1.78 (m, 2H), 1.69 (s, 3H), 1.60 (d, J = 1.3 Hz, 6H), 1.30 - 1.27 (m, 3H), 1.23 (s, 1H), 1.15 (t, J = 7.2 Hz, 3H), 1.01 (s, 9H), 0.89 - 0.84 (m, 2H), 0.17 (s, 6H). LCMS (M+2K): m/z calculated for C ₄ oH ₆ oK ₂ 0 ₄ SSi 744.07, found 744.7

Step 9: Synthesis of tert-Butyl-dimethyl (R)-2,5,8-trimethyl-2-((3E,7E)-4,8, 12-trimethyl- trideca-3,7,1 l-trienyl)-chroman-6-yloxy]-silane: ((R)-13c)

(S)-12c (R)-13c

To a stirred degassed solution of chroman sulfone (S)-12c (3.5 g, 0.005 mol) in dry THF (35 mL, 10 V), Pd(dppp)Cl ₂ (680 mg, 0.0001 mmol) is added. A solution of LiEt ₃ BH (12% in THF, 18.4 mL, 0.021 mol) is added dropwise at 25°Cand stirred for 15 h. After completion of the reaction, the reaction mixture is quenched with saturated aqueous sodium perboromonohydrate (1% solution, 50 mL, 15 V) and is extracted with n-heptane (2 x 50 mL). The combined organic layers are washed with brine (5 V), dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to give the crude compound which is purified by column chromatography (Eluent: EA/hexanes - 1 : 19) to procure the desired silyl protected β- Tocotrienol (R)-13c as a pale-yellow oil.

Yield: 2.2 g (80%) 1H NMR (CDC1 ₃ , 400 MHz): δ 6.47 (s, 1H), 5.20 - 5.05 (m, 3H), 2.60 (t, J = 6.8 Hz, 2H), 2.20 - 1.95 (m, 15H), 1.90 - 1.70 (m, 2H), 1.69 (s, 3H), 1.65 - 1.45 (m, 12H), 1.25 (s, 3H), 1.02 (s, 9H), 0.18 (s, 6H);

Step-10: Synthesis of β-Tocotrienol: (R)-14c

To a stirred solution of silyl atedp-Tocotrienol (R)-13c (1 g, 1.905 mmol) in dry THF (10 mL, 10 V), TBAF- 3H ₂ 0 (601 mg, 1.905 mol) is added and stirred at 25°C for 1 h. After completion of the reaction, the reaction mixture is quenched by adding saturated NH ₄ C1 (30 mL) and is extracted with EtOAc (3 x 20 mL). The combined organic layers are concentrated to give the crude compound. The crude compound is then stirred with saturated NH ₄ C1 (1 g in 10 mL water) and solid NaCl (1 g) for 1 h and is extracted with EtOAc (2 x 20 mL). The combined organic layers are dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to give the crude compound to which toluene (3 x 10 mL) is added and evaporated at 45 °C. The crude compound is then purified by column chromatography (Eluent: EA/hexanes - 1:4) to procure the desired β-Tocotrienol (R)-14c as a colourless oil.

Yield: 600 mg (76%) 1H NMR (CDCI ₃ , 400 MHz): δ 6.49 (s, 1H), 5.20 - 5.05 (m, 3H), 4.19 (br s, 1H), 2.62 (t, J = 6.8 Hz, 2H), 2.20 - 1.90 (m, 16H), 1.90 - 1.75 (m, 2H), 1.70 (s, 3H), 1.70 - 1.50 (m, 11H), 1.26 (s, 3H).

LCMS (M+Na): m/z calculated for C ₂₉ H4 ₂ Na0 ₃ 433.63, found 434.0 Alternate synthesis of key diol intermediate 8c, used for β-tocotrienol: Step-1 : Synthesis of 2,5,8-Trimethyl-chroman-2-carboxylic acid methyl ester (16c)

A suspension of 2,5-dimethyl-phenol (lc) (10 g, 0.082 mol), paraformaldehyde (4.9 g, 0.164 mol), methyl methacrylate (15) (44 mL, 0.409 mol) and water (3 mL, 0.3 V) are taken together in an autoclave and purged with Ar for 20 min. The mixture is then heated to 180°C for 18 h in an autoclave (internal pressure 12-15 kg/cm ₃ ). After the completion of reaction (TLC control), the reaction mixture is cooled to ambient temperature and concentrated to dryness. The crude reaction mixture obtained is purified by column chromatography (Eluent - 9:1, Hexanes/Ethyl acetate) to procure the desired product, chroman ester 16c as a white solid.

Yield: 5.2 g (28%)

1H NMR (CDCI ₃ , 400 MHz): δ 6.91 (d, J = 7.6 Hz, lH), 6.66 (d, J = 7.6 Hz, 1H), 3.70 (s, 3H), 2.75 - 2.60 (m, 1H), 2.60 - 2.40 (m, 2H), 2.24 (s, 3H), 2.17 (s, 3H), 1.91 (ddd, J = 8.0, 12.8, 18.8 Hz, 1H), 1.64 (s, 3H)

LCMS (M+H): m/z calculated for C ₁₄ H ₁₉ O ₃ 235.3, found 235.2

Step-2: Synthesis of 6-Bromo-2,5,8-trimethyl-chroman-2-carboxylic acid methyl ester (17c)

16c 17c

To a cold (0-5°C), stirred solution of 16c ester (1 g, 4.268 mmol) in dry DMF (4 mL, 4 V), N-bromosuccinimide (0.798 g, 4.481 mmol)isaddedin portions. After complete addition, the reaction mixture is slowly warmed up to 25°Cand stirred for 2 h. After completion of the reaction, (TLC control; Eluent: 4: 1, Hexanes/EtOAc), the reaction mixture is poured over ice- cold water, slowly and then stirred for 1 h. The precipitated solid is filtered and dried over reduced pressure to yield bromo ester 17c as an off-white solid.

Yield: 1.2 g (92%)

1H NMR (CDCI ₃ , 400 MHz): δ: 7.20 (s, 1H), 3.69 (s, 3H), 2.70 (ddd, J = 3.2, 6.8, 17.2 Hz, 1H), 2.60 - 2.40 (m, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.87 (ddd, J = 5.6, 10.8, 16.8 Hz, 1H), 1.62 (s, 3H) LCMS (M+H): m/z calculated for Ci ₄ Hi ₈ Br0 ₃ 314.1, found 314.9

Step-3: Synthesis of 6-Hydroxy-2,5,8-trimethyl-chroman-2-carboxylic acid (19(i)c)

To a suspension of bromide 17c (1 g, 3.1934 mmol), Cu(acac) ₂ (78 mg, 0.319 mmol), KOH (1.07 g, 19.16 mmol) and amide ligand (98 mg, 0.319 mol), DMSO (8 mL) and water (2 mL) is added. The reaction mixture is degassed with argon for 20 min and stirred vigorously at 100°C for 18 h. After completion of reaction, the resulting reaction mixture is cooled to 25°C, filtered through Celite, diluted with water (5 V) and backwashed with MTBE (2 x 5 V). The aqueous layer is then acidified with Cone. HC1 to pH ~3 and extracted with EtOAc (3 x 5 V). The organic layer is washed with water (2 x 5 V), brine (2 x 5V), dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The crude compound 19(i)c obtainedis taken as such for the next step without any further purification.

Yield: 549 mg (73%)

LCMS (M-H): m/z calculated for Ci ₃ Hi ₅ 0 ₄ 235.2, found 235.0

Step-4: Synthesis of 2-Hydroxymethyl-2,5,8-trimethyl-chroman-6-ol (8c)

19(i)c 8c

To a cold (0-5°C) solution of hydroxyl acid 19(i)c(500 mg, 2.12 mmol) in dry THF (3 mL), Red-AL (50% w/w in toluene, 12.7 mL, 6.35 mol) is added at 0-5°C in portions. After complete addition of Red-Al, the reaction mixture is slowly warmed up to 25°Cand stirred for 1 h (TLC control). The reaction mixture is cooled to 0-5°C, carefully quenched with 6 N HC1 (3 V) and extracted with MTBE (3 x 5 V). The combined organic layers are dried using anhydrous Na ₂ S0 ₄ , concentrated and the crude compound is purified by column chromatography to get the desired product as an off-white solid.

Yield: 353 g (75%) 1H NMR (CDC1 ₃ , 400 MHz): δ 6.50 (s, 1H), 3.63 (AB, J = 11.2 Hz, 2H), 2.80 - 2.60 (m, 2H), 2.12 (s, 3H), 2.11 (s, 3H), 2.10 - 1.95 (m, 1H), 1.74 (ddd, J = 4.4, 6.4, 13.6 Hz, 1H), 1.23 (s, 3H);

LCMS (M+H): m/z calculated for Ci ₃ Hi ₉ 0 ₃ 223.3, found 223.4 Example 4: Procedure for the Synthesis of γ-Tocotrienol: (R)-14d Step-1 : Synthesis of (2,7,8-Trimethyl-chroman-2-yl)-methanol: (3d)

A suspension of 2,3-dimethyl phenol (Id) (50 g, .409 mol), paraformaldehyde (26.5 g, .899 mol), 2-methyl-2-propen-l-ol (2) (88.5 g, 1.22 mol), (n-Bu)2NH (5.16 mL, 0.040 mol) and AcOH (12.01 mL, 0.204 mol) is taken together in an autoclave and purged with Ar for 20 min. The mixture is then heated to 160°C overnight in an autoclave (internal pressure 12 kg/cm ₃ ). After the completion of reaction (TLC control), the reaction mixture is cooled to ambient temperature and transferred to round bottomed flask. The residual contents are washed with EA (2 x 1 L) and collected together with the crude mixture. The crude mixture is then evaporated to remove all the volatiles and is subjected to silica gel column chromatography (Eluent: 100% hexanes) to procure the desired alcohol 3d as a colourless oil. Yield: 35 g (41%) 1H NMR (CDCI ₃ , 400 MHz): δ 6.84 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 3.65 (AB, J = 11.2 Hz, 2H), 2.85 - 2.70 (m, 2H), 2.25 (s, 3H), 2.11 (s, 3H), 2.01 (ddd, J = 6.0, 10.4, 16.4 Hz, 1H), 1.71 (ddd, J = 4.4, 6.0, 13.2 Hz, 1H), 1.28 (s, 3H).

LCMS (M+HC1): m/z calculated for Ci ₃ Hi ₉ 0 ₂ Cl 242.3, found 242.7

Step-2 & 3 : Synthesis of ((S)-2,7,8-Trimethyl-chroman-2-yl)-methanol: ((S)-3d))

To a stirred solution of alcohol 3d (21 g, 0.101 mol) in MTBE (420 niL, 20 V), succinic anhydride (4) (8.1 g, 0.081 mol) and Lipase PS "Amano" IME (4.2 g, 20% w/w) is added in portions at 25°C and stirred for 3 h. The reaction mixture is then filtered through Celite ^® . The filtrate is concentrated and the crude residue is diluted with hexanes (10 V) and saturated aqueous NaHC0 ₃ (10 V) and stirred at 25°Cfor 10 min. The layers are separated and the aqueous layer is washed with hexanes (5 x 10 V). The organic layer containing the unreacted alcohol 3d; enriched with R-isomer, is collected and evaporated separately. The aqueous layer, containing the sodium salt of acid 5d, is cooled to < 10°C and solid KOH (22.8 g, 0.407 mol) is added in portions and stirred for 30 min at 25°C. The reaction mixture is then filtered and diluted with hexanes (10 V) and washed with brine. The organic layer is concentrated to get the desired enantioenriched alcohol (S)-3d as a syrupy liquid.

Recovery: 3.3 g (31%); ee - 61.69%; The same protocol is repeated to enrich the chiral purity of the (S)-3d to >97%. Overall Yield: 2.5 g (24%);ee - 97.5%

Step-4a: Synthesis of ((S)-6-Bromo-2,7,8-trimethyl-chroman-2-yl)-methanol: ((S)-6(i)d)

(S)-3d (S)-6(i)d

To a cold (0-5°C) stirred solution of alcohol (S)-3d (11 g, 0.534 mol) in dry DMF (110 mL, 10 V), N-bromosuccinimide (10.4 g, 0.587 mol) is added in portions. After complete addition, the reaction mixture is slowly warmed up to 25°C and stirred for 2 h. After completion of the reaction, (TLC control), the reaction mixture is poured over ice-cold water, stirred for 10 min and extracted with n-heptane (3 x 10 V). The combined organic layers are washed with brine, dried using anhydrous Na ₂ S0 ₄ , filtered and then concentrated under reduced pressure to give the desired bromo alcohol (S)-6(i)d asan off-white solid.

Yield: 11.2 g (73%) 1H NMR (CDCI ₃ , 400 MHz): δ 7.15 (s, 1H), 3.64 (AB, J = 11.2 Hz, 2H), 2.85 - 2.70 (m, 2H), 2.33 (s, 3H), 2.17 (s, 3H), 2.05 - 1.95 (m, 1H), 1.70 (ddd, J = 4.4, 6.4, 13.6 Hz, 1H), 1.58 (br s, 1H), 1.25 (s, 3H).

LCMS (M+H): m/z calculated for Ci ₃ Hi ₈ Br0 ₂ 286.1, found 285.7

Step-5a: Synthesis of (S)-2-Hydroxymethyl-2,7,8-trimethyl-chroman-6-ol: ((S)-8d)

Cu(acac) ₂ (1 mol%)

To a suspension of bromide (S)-6(i)d (4 g, 0.163 mol), Cu(acac) ₂ (420 mg, 0.016 mol), KOH (5.4 g, 0.960 mol) and amide ligand (520 mg, 0.016 mol), DMSO (32 mL) and water (8 mL) is added. The reaction mixture is degassed with argon for 20 min and stirred vigorously at 80°C for 12 h. After completion of reaction, the resulting reaction mixture is cooled to about25°C, filtered through Celite ^® , diluted with water (100 mL) and backwashed with MTBE (2 x 100 mL). The aqueous layer is then acidified with Cone. HCl and extracted with EtOAc (3 x 50 mL). The organic layer is washed with water (2 x 100 mL), brine (2 x 100 mL), dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The crude product obtained is dissolved with 30% EA in hexanes (10 V) and stirred for 2 h. The clear solution obtained is decanted and concentrated to 2 V level. The solid obtained is filtered and dried to afford the desired phenolic alcohol (S)-8d as an off-white solid.

Yield: 2.7 g (75%)

1H NMR (CDC1 ₃ , 400 MHz): δ 6.40 (s, 1H), 3.63 (AB, J = 11.2 Hz, 2H), 2.85 - 2.60 (m, 2H), 2.15 (s, 3H), 2.00 (ddd, J = 6.0, 10.8, 16.8 Hz, 1H), 1.68 (ddd, J = 4.4, 6.4, 13.6 Hz, 1H), 1.24 (s, 3H).

LCMS (M+H): m/z calculated for C 13H19O3 223.2, found 223.1 [<x] _D +8.5° (C 1.0 in CHCl ₃ )

Step-6: Synthesis of [(S)-6-(tert-Butyl-dimethyl-silanyloxy)-2,7,8-trimethyl-chro man-2-yl]- methanol: ((S)-9d)

(S)-8d (S)-9d

To a stirred solution of phenolic alcohol (S)-8d (250 mg, 1.16 mol) in dry THF (2.5 mL, 10 V), DBU (0.25 mL, 1.68 mol) is added at 15-20°C and stirred for 10 min. TBS-C1 (192 mg, 1.467 mol) dissolved in dry THF (550 mL, 2 V) is added dropwise to the reaction mixture at 15-20°Cand the temperature is slowly warmed up to 25°C and stirred for 30 min. After completion of the reaction, the reaction mixture is quenched by adding ice-cold water (10 V). It is then extracted with EA (2 x 5 V) and the combined organic layers are washed with brine (5 V), dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to get the crude product, which is purified by column chromatography (Eluent: EA/hexanes - 1:4) to afford the desired silyl derivative (S)-9d as pale-yellow oil.

Yield: 200 mg (52%) 1H NMR (CDCI ₃ , 400 MHz): δ 6.38 (s, 1H), 3.62 (AB, J = 11.2 Hz, 2H), 2.85 - 2.70 (m, 1H), 2.75 - 2.60 (m, 1H), 2.11 (s, 6H), 2.05 - 1.95 (m, 1H), 1.75 - 1.65 (m, 1H), 1.25 (s, 3H), 1.02 (s, 9H), 0.19 (s, 6H).

Step-7: Synthesis of Trifluoromethane sulfonic acid (S)-6-(tert-butyl-dimethyl silanyloxy)- 2,7,8-trimethyl-chroman-2-ylmethyl ester: ((S)-10d)

(S)-9d (S)-10d

To a stirred solution of alcohol (S)-9d (5.7 g, 0.016 mol) in dry CH ₂ C1 ₂ (114 mL, 20 V), dry pyridine (4.0mL, 0.050 mol) is added and cooled to 0°C. Triflic anhydride (9.5 mL, 0.034 mol) is added to the reaction mixture dropwise at 0°C and slowly warmed up to 25°Cand stirred for 2 h. After completion of the reaction, (TLC control), the reaction mixture is diluted further with CH ₂ C1 ₂ (30 mL, 5 V) and washed with saturated aqueous CuS0 ₄ (1% w/w w.r.t(S)-9d, 3 x 30 mL). The organic layer is then dried using anhydrous Na ₂ S0 _4i filtered and concentrated to procure the crude triflate (S)-10d, which is taken as such for the next step without any further purification.

Step-8: Synthesis of Sulfone: 12d

11 (S)-10d (S)-12d To a cold (-78°C) stirred solution of sulfone 11 (4.69 g, 0.013 mol) in dry THF (85.5 mL, 15 V), HMPA (8.1 mL, 0.045 mol) and n-BuLi (2.5 M in Hexanes, 13.5 mL, 0.034 mol) is added and stirred for 1 h. A solution of triflate (S)-10d (crude as such from step-7) in dry THF (23 mL, 4 V) is added to the reaction mixture at -78°C and stirred for 2.5 h. After completion of the reaction, (TLC control), the reaction mixture is carefully quenched by adding saturated NH ₄ C1 (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers are dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to give the crude compound. The crude compound is then purified by column chromatography (Eluent: EA/hexanes - 1:4) to procure the desired chroman sulfone (S)-12d as a colourless oil. The product is obtained as a mixture of diastereomers and is taken as such for the next step.

Yield: 8.0 g (71%)

LCMS (M+H ₂ 0): m/z calculated for C ₄₀ H6 ₂ O ₅ SSi 683.0, found 683.2

Step 9: Synthesis of tert-Butyl-[(R)-2-((3E,7E)-8,12-dimethyl-trideca-3,7,l l-trienyl)-2,7,8- trimethyl-chroman-6-yloxy]-dimethyl-silane ((R)-13d)

(S)-12d (B)-13d

To a stirred, degassed solution of chroman sulfone (S)-12d (1.4 g, 0.002 mol) in dry THF (14 mL, 10 V), Pd(dppp)Cl ₂ (24 mg, 4.2x10-5 mol) is added. A solution of LiEt ₃ BH (12% in THF, 7.35 mL, 0.008 mol) is added dropwise at 25°Cand stirred for 15 h. After completion of the reaction, the reaction mixture is quenched with saturated aqueous sodium perboromonohydrate (1% solution, 21 mL, 15 V) and extracted with n-heptane (2 x 20 mL). The combined organic layers are washed with brine (5 V), dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated to give the crude compound which is purified by column chromatography (Eluent: EA/hexanes - 1 :19) to procure the desired silyl protected γ- Tocotrienol (R)-13d as a pale-yellow oil.

Yield: 800 mg (72%)

1H NMR (CDCI ₃ , 400 MHz): δ 6.35 (s, 1H), 5.15 - 5.05 (m, 3H), 2.69 - 2.67 (m, 2H), 2.15 - 2.05 (m, 12H), 2.00 - 1.95 (m, 4H), 1.80 - 1.70 (m, 2H), 1.69 (s, 3H), 1.60 (s, 9H), 1.55 - 1.50 (m, 2H), 1.27 (s, 3H), 1.01 (s, 9H), 0.19 (s, 6H);

LCMS (M+H): m z calculated for C ₃ 4H ₅₇ 0 ₂ Si 525.9, found 525.9

Step-10: Synthesis of γ-Tocotrienol: (R)-14d

To a stirred solution of silylatedy-Tocotrienol (R)-13d (780 mg, 1.486 mmol) in dry THF (7.8 mL, 10 V), TBAF- 3H ₂ 0 (469 mg, 1.486 mmol) is added and stirred at 25°C for 1 h. After completion of the reaction, the reaction mixture is quenched by adding saturated NH ₄ C1 (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers are concentrated to give the crude compound. The crude compound is then stirred with saturated NH ₄ CI (1 g in 10 mL water) and solid NaCl (1 g) for 1 h and is extracted with EtOAc (2 x 10 mL). The combined organic layers are dried using anhydrous Na ₂ S04 _, filtered and concentrated to give the crude compound to which toluene (3 x 10 mL) is added and evaporated at 45 °C. The crude compound is purified by column chromatography (Eluent: EA/hexanes - 1 :4) to procure the desired γ-Tocotrienol (R)-14d as a colourless oil. Yield: 520 mg (85%)

1H NMR (CDC1 ₃ , 400 MHz): δ 6.38 (s, 1H), 5.20 - 5.00 (m, 3H), 4.20 (br s, 1H), 2.75 - 2.60 (m, 2H), 2.20 - 2.00 (m, 12H), 1.90 - 1.95 (m, 4H), 1.80 - 1.70 (m, 2H), 1.69 (s, 3H), 1.60 - 1.50 (m, 8H), 1.27 (s, 6H); LCMS (M+H): m/z calculated for C28H43O2 411.65, found 411.9

Example 4d: Alternate synthesis of key diol intermediate 8d, used for γ-tocotrienol

Step-1 : Synthesis of 2,7,8-Trimethyl-chroman-2-carboxylic acid ethyl ester (16d)

A suspension of 2,3-dimethyl phenol (10 g, 0.082 mol), paraformaldehyde (5.4 g, 0.180 mol), ethyl methacrylate (51.7 g, 0.409 mol), (n-Bu) ₂ NH (1.68 mL, 0.011 mol) and AcOH (2.76 mL, 0.041 mol) is taken together in an autoclave and purged with Ar for 20 min. The mixture is heated to 125°C overnight in the autoclave (internal pressure 12 kg/cm ₃ ). After the completion of reaction (TLC control), the reaction mixture is cooled to ambient temperature and transferred to a round bottomed flask. The residual contents are washed with EA (2 x 50 mL) and collected together with the crude mixture. The crude mixture is then evaporated to remove all the volatiles and is subjected to silica gel column chromatography to procure the desired ester as a pale-yellow oil.

Yield: 7.8 g (38%)

LCMS (M+H): m/z calculated for Ci ₄ Hi ₉ 0 ₃ 235.3, found 235.2

Step-2: Synthesis of 6-Bromo-2,7,8-trimethyl-chroman-2-carboxylic acid methyl ester (17d)

16d 17d

To a cold (0-5°C) stirred solution of ester 16d (1 g, 4.268 mmol) in dry DMF (4 mL, 4 V) N- bromosuccinimide (0.798 g, 4.481 mmol) is added in portions. After complete addition, the reaction mixture is slowly warmed up to 25°C and stirred for 2 h. After completion of the reaction,(TLC control; Eluent: 4:1, Hexanes/EtOAc), the reaction mixture is poured over ice- cold water, slowly and then stirred for 1 h. The precipitated solid is filtered and dried reduced pressure to yield bromo ester 17d as an off-white solid.

Yield: 1.2 g (92%)

LCMS (M+H): m/z calculated for Ci ₄ Hi ₈ Br0 ₃ 314.1, found 314.9

Step-3: Synthesis of 6-Hydroxy-2,7,8-trimethyl-chroman-2-carboxylic acid (19(i)d)

To a suspension of bromide 17d (1 g, 3.1934 mmol), Cu(acac) ₂ (78 mg, 0.319 mmol), KOH (1.07 g, 19.16 mmol) and amide ligand (98 mg, 0.319 mol), DMSO (8 mL) in water (2 mL). is added. The reaction mixture is degassed with argon for 20 min and stirred vigorously at 100°C for 18 h. After completion of reaction, the resulting reaction mixture is cooled to 25°C, filtered through Celite, diluted with water (5 V) and backwashed with MTBE (2 x 5 V). The aqueous layer is then acidified with Cone. HC1 to pH ~3 and extracted with EtOAc (3 x 5 V). The organic layer is washed with water (2 x 5 V), brine (2 x 5V). The organic layer is dried using anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The crude compound 19(i)d obtained is taken as such for the next step without any further purification.

Yield: 512 mg (68%);

LCMS (M-H): m/z calculated for Ci ₃ Hi ₅ 0 ₄ 235.2, found 235.0

Step-4: Synthesis of 2-Hydroxymethyl-2,7,8-trimethyl-chroman-6-ol (8d)

19(i)d 8d To a cold (0-5°C) solution of hydroxyl acid 19(i)d (500 mg, 2.12 mmol) in dry THF (3 mL), Red-AL (50% w/w in toluene, 12.7 mL, 6.35 mol) is added in portions at 0-5°C. After complete addition of Red-Al, the reaction mixture is slowly warmed up to 25°C and stirred for 1 h (TLC control). The reaction mixture is cooled to 0-5°C and carefully quenched with 6 N HC1 (3 V) and extracted with MTBE (3 x 5 V). The combined organic layers are dried using anhydrousNa ₂ S0 ₄ , concentrated and the crude compound is purified by column chromatography to get the desired product8d as an off-white solid.

Yield: 329 g (70%)

LCMS (M+H): m/z calculated for C13H19O3 223.2, found 223.1.

The procedure presented herein provides a solution for the large-scale preparation of tocotrienols by a facile, environmentally benign and industrially scalable method from inexpensive commercially available o-cresol derivatives. The intermediates of the procedure are highly stable and can be used directly for the synthesis of various tocotrienols. The method can replace the tedious and expensive extraction procedures from natural resources of tocotrienols.