Chemoenzymatic synthesis of both enantiomers of α-tocotrienol

Article abstract of DOI:10.1016/j.bmc.2006.03.035

The stereoselective acylation of the achiral chromanedimethanol derivative 1 by vinyl acetate in the presence of Candida antarctica lipase B gave the (S)-monoester 2 in high enantiomeric purity (ee ≥ 98%). Enzymatic hydrolysis of diesters of compound 1 failed to give (R)-monoester 2 in good yield and high ee. Thus, both enantiomers of α-tocotrienol were synthesized from the (S)-monoester 2.

Full text of DOI:10.1016/j.bmc.2006.03.035

Bioorganic & Medicinal Chemistry 14 (2006) 5389–5396
Chemoenzymatic synthesis of both enantiomers of a-tocotrienol
Robert Cheˆnevert,* Gabriel Courchesne and Nicholas Pelchat
De´partement de chimie, faculte´ des sciences et de ge´nie, Universite´ Laval, Que´bec, Canada G1K 7P4
Received 2 March 2006; accepted 20 March 2006
Available online 17 April 2006
Abstract—The stereoselective acylation of the achiral chromanedimethanol derivative 1 by vinyl acetate in the presence of Candida
antarctica lipase B gave the (S)-monoester 2 in high enantiomeric purity (ee P 98%). Enzymatic hydrolysis of diesters of compound
1 failed to give (R)-monoester 2 in good yield and high ee. Thus, both enantiomers of a-tocotrienol were synthesized from the
(S)-monoester 2.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
the efficiency of the translation of HMG-CoA reductase
mRNA.18,19 They also inhibit the oxidation of low den-
sity lipoproteins associated with cardiovascular diseas-
es.20 In addition, they have been shown to have
anticancer21,22 and neuroprotective properties.23,24
The term vitamin E is the generic descriptor for all
tocopherol and tocotrienol derivatives that qualitatively
exhibit the biological activity of a-tocopherol.1 This
vitamin occurs naturally in eight main isoforms: a, b,
c, and d-tocopherols, and four corresponding tocotrie-
nols (Fig. 1). Tocotrienols differ from tocopherols by
possessing a farnesyl (three double bonds) rather than
a saturated phytyl side chain. The a, b, c, and d-homo-
logues are defined by the methylation patterns of the
aromatic ring. Natural tocopherols and tocotrienols
share the same 2R configuration. The chiral 2-methylch-
roman moiety is found in several natural products such
as clusifoliol,2 rhododaurichromanic acid A,3 garcinoic
acid,4 cystoseirol,5 polyalthidin,6 siccanin,7 and d-
trans-tocotrienoloic acid.8 Also, synthetic 2-methylchro-
mans have significant biological activities; for example,
troglitazone is an antidiabetic agent9 and trolox deriva-
tives show antioxidant, antiarrhythmic, and anti-inflam-
matory activities.10–12
Compared with tocopherols, the synthesis of tocotri-
enols has received little attention. A stereoselective syn-
thesis of a-tocotrienol via fractional crystallization of an
intermediate acid with (S)-a-methylbenzyl amine25 and
a few syntheses of the racemic compounds have been
reported.26–28 Herein, we report the synthesis of both
enantiomers of a-tocotrienol via the enzymatic desym-
metrization of the achiral chromanedimethanol 1.29
2. Results and discussion
The substrate 1 (Scheme 1) was readily prepared on the
basis of the protocol described by Harada et al.30
A
modified procedure using Bu3SnCH2OCH2OCH3 as a
hydroxymethyl anion equivalent31 gave a better overall
yield. Esterification of 1 with vinyl acetate in the pres-
ence of Candida antarctica lipase B (CAL-B) in diethyl
ether gave monoester (S)-2 (60% yield, ee P 98%) and
the corresponding achiral diester 3 (27% yield).32
Replacement of diethyl ether by acetonitrile provided
a better yield of monoester (S)-2 (2, 87% yield; 3, 12%
yield) but a lower ee (90%).
Tocotrienols are plant constituents particularly abun-
dant in palm oil and cereal seeds.13,14 A variety of bio-
logical activities have been recently ascribed to
tocotrienols.15 They are lipid-soluble antioxidants that
protect membranes and cell components from the oxida-
tive stress mediated by free radicals.16,17 Tocotrienols
down-regulate cholesterol biosynthesis by increasing
HMG-CoA reductase degradation as well as decreasing
Diester 3 is easily recovered and recycled by chemical
hydrolysis of the ester groups. The enantiomeric compo-
sition of 2 was determined by reaction with (+)-a-meth-
oxy-a-trifluoromethyl-a-phenylacetic acid (MTPA) in
the presence of 1-[3-(dimethylamino)propyl]-3-ethyl-car-
Keywords: a-Tocotrienol; Vitamin E; Desymmetrization; Lipase.
Corresponding author. Tel.: +1 418 656 3282; fax: +1 418 656
7916; e-mail: robert.chenevert@chm.ulaval.ca
*
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.03.035

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R. Chenevert et al. / Bioorg. Med. Chem. 14 (2006) 5389–5396
5390
Figure 1. Structures of vitamin E natural main isoforms.
Scheme 1. Reagents and conditions: (a) Candida antarctica lipase B, vinyl acetate, Et20, 2 h; (b) MsCl, Et3N, CH2Cl2; (c) NaBH4, DMSO, 115 ꢁC;
(d) NaH, BnBr, THF; (e) (COC1)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC.
bodiimide hydrochloride (EDC) and 4-dimethylamino-
pyridine (DMAP), followed by 19F NMR (376 MHz)
analysis of the resulting diastereoisomeric esters
(Mosher’s ester). The next step is the conversion of the
primary alcohol to a methyl group. Sodium borohydride
in polar aprotic solvents provides an effective source of
nucleophilic hydride for the reductive displacement of
functional leaving groups. Thus, monoester (S)-2 was
treated with two equivalents of mesyl chloride in the
presence of triethylamine to give dimesylate (R)-4 in
87% yield (Scheme 1). Reduction of (R)-4 with NaBH4
in DMSO provided chromanol (R)-5 in 82% yield. Selec-
tive benzylation of the phenol function with benzyl bro-
mide afforded (R)-6 in 80% yield. The enantiomeric
excess of (R)-6 was further checked by 19F NMR analy-
sis of the MTPA derivative. This procedure proved that
there is complete retention of configuration (ee P 98%)
in the previous steps. The absolute configuration of (R)-
6 was determined by its transformation (Swern’s oxida-
tion, 97% yield) into known chroman-2-carboxalde-
hyde.33–35 This chemical correlation proved that the
enzymatic acylation of 1 provided monoester 2 with
the (S) configuration.
and enantioselectivity under various conditions. This
enzymatic hydrolysis, like many desymmetrizations, is
coupled with a subsequent kinetic resolution.36 Thus,
hydrolysis of 8a–c first give the chiral monoesters 9a–c
but these products are also substrates for the hydrolase,
resulting in the production of achiral diol 10. This sec-
ond hydrolysis lowers the yield of monoesters but
increases their ee by kinetic resolution. The diesters
and the monoesters are similar substrates and the en-
zymes usually have a preference for the same stereogenic
center, thus removing the minor enantiomer. For in-
stance, the hydrolysis of esters 8b,c in water-saturated
diisopropyl ether (DIPE) in the presence of CAL-B gave
monoesters with fair ee (85%) but the yield was low
(16%) and the main product was the achiral diol 10.
Thus, the opposite enantiomer (S)-6 leading to the nat-
urally occurring (R)-a-tocotrienol was synthesized from
the same starting material (S)-2 (Scheme 3). Protection
of both hydroxyl groups of (S)-2 with tert-butyldimeth-
ylsilyl ethers followed by the removal of the acetate moi-
ety of (R)-11 with ethylmagnesium bromide provided
(R)-12 in high yield. Preparation and reduction of tosyl-
ate (S)-13 gave protected chromanol (S)-14. Deprotec-
tion of silyl ethers with TBAF and selective
benzylation of (S)-5 provided (S)-6. The enantiomeric
purity of (S)-6 (ee P 98%) was confirmed by 19F
NMR analysis of the MTPA derivative.
Chromane derivative (R)-6 leads to (S)-a-tocotrienol,
the non-natural enantiomer, after the introduction of
the side chain. As enzymes usually show the same enan-
tioselectivity for acylation and deacylation reactions, the
hydrolysis of diesters 8a–c (Scheme 2) appeared attrac-
tive since it would produce the monoesters 9a–c of
opposite configuration. However, the hydrolysis of
diesters 8a–c proved to be inefficient in terms of yield
The coupling of chromanol (S)-6 with the farnesyl side
chain was accomplished using the reaction sequence
depicted in Scheme 4. The anion of known sulfone

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R. Chenevert et al. / Bioorg. Med. Chem. 14 (2006) 5389–5396
5391
Scheme 2.
Scheme 3. Reagents: (a) TBSCl, imidazole, CH2Cl2; (b) EtMgBr, THF; (c) TsCl, Et3N, DMAP, CH2Cl2; (d) LiEt3BH, THF; (e) TBAF, AcOH,
THF; (f) BnBr, NaH, DMF.
Scheme 4. Reagents and conditions: (a) Tf2O, Et3N, CH2Cl2, ꢀ10 ꢁC; (b) nBuLi, THF/HMPA, ꢀ78 ꢁC; (c) PdCl2(dppp), LiBHEt3, THF, ꢀ10 ꢁC;
(d) Li, EtNH2/Et20, ꢀ78 ꢁC.
1637,38 generated by treatment with n-butyllithium in the
presence of hexamethylphosphoramide (HMPA) was
subjected to alkylation with triflate (S)-15 to give prod-
uct (S)-17 as a mixture of diastereoisomers in 60% yield.
No attempt was made to separate these diastereoisomers
since the newly formed stereogenic center is eliminated
in the next step. In a previous paper, we reported the
removal of the phenylsulfonyl and benzyl groups in
one step via dissolving-metal reduction with lithium in
ethylamine. Unfortunately, we have since discovered
that this method leads to some loss of the stereochemical
integrity of the double bonds. The contaminant isomers

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R. Chenevert et al. / Bioorg. Med. Chem. 14 (2006) 5389–5396
5392
are not easily separable by standard chromatographic
techniques. In an alternative method, desulfonylation
of the allylic sulfone (S)-17 with LiBHEt3 catalyzed by
PdCl2(dppp) proceeded without migration of the double
bond.39–41 Natural a-tocotrienol (R)-19 was obtained by
debenzylation of (R)-18. Though this second method is
longer by one step, it provides pure a-tocotrienol. The
same sequence was applied for the transformation of
(R)-6 into non-natural (S)-a-tocotrienol. The prepara-
tion and chiral phase HPLC analysis of a-tocotrienol
methyl ethers according to a known procedure con-
firmed the stereochemical (RS, E/Z) purity of the syn-
thetic enantiomers.42
6H), 2.09 (s, 3H), 2.15 (s, 3H), 2.63 (t, J = 6.9 Hz, 2H),
4.14 (d, J = 11.4 Hz, 2H), 4.23 (d, J = 11.4 Hz, 2H), 4.25
(s, 1H); 13C NMR (CDCl3) d 11.08, 11.50, 12.00, 19.41,
20.65, 24.56, 64.26, 73.94, 116.88, 118.29, 121.31,
122.75, 144.09, 145.31, 170.48; HRMS (CI, NH3) calcd
for C18H24O6 (M+ ) 336.1573. Found 336.1577.
4.3. Mesylate (R)-4
Monoacetate (S)-2 (91 mg, 0.31 mmol) was dissolved in
anhydrous dichloromethane (5 mL) cooled to 0 ꢁC under
a dry argon atmosphere. Anhydrous triethylamine
(130 lL, 0.933 mmol) and methanesulfonyl chloride
(70 lL, 0.904 mmol) were added and the solution was
stirred at room temperature for 1 h. The solution was
diluted with ethyl acetate and washed successively with
3 N aq HCl, sat. aq NaHCO3, and brine. The organic
layer was dried (MgSO4) and evaporated. The crude
product was purified by flash chromatography
In conclusion, both enantiomers of a-tocotrienol 19
have been prepared from the same starting material
(S)-2, which was obtained by enzymatic desymmetriza-
tion of prochiral chromanedimethanol 1.43,44
(CH2Cl2/ethyl acetate, 97:3) to give mesylate (R)-4
23
D
(c 1.52, CHCl3); IR (KBr) 3000, 2920, 1730, 1450,
4. Experimental
(133 mg, 94%) as a white solid. Mp. 125 ꢁC; ½aꢁ ꢀ1.39
;
1340, 1220, 1160, 1040, 955, 815 cmꢀ1 1H NMR
4.1. General methods
(CDCl3) d 2.00 (dd, J = 12.7 and 6.8 Hz, 2H), 2.07 (s,
3H), 2.10 (s, 3H), 2.20 (s, 3H), 2.23 (s, 3H), 2.65 (t,
J = 6.8 Hz, 2H), 3.02 (s, 3H), 3.24 (s, 3H), 4.16 (d,
J = 11.7 Hz, 1H), 4.25 (d, J = 11.7 Hz, 1H), 4.28 (d,
J = 10.9 Hz, 1H), 4.31 (d, J = 10.9 Hz, 1H); 13C NMR
(CDCl3) d 11.79, 13.53, 14.34, 19.14, 20.59, 23.63,
37.40, 38.67, 63.47, 68.82, 74.45, 117.44, 123.93, 127.47,
129.53, 140.39, 148.30, 170.18; HRMS (CI, NH3) calcd
for C18H26O9S2 (M+) 450.1018. Found 450.1021.
Infrared spectra were recorded on a Bomem MB-100
spectrometer. Optical rotations were measured using a
JASCO DIP-360 digital polarimeter (c as g of compounds
per 100 mL). Flash chromatography was carried out
using 40–63 lm (230–400 mesh) silica gel. NMR spectra
were recorded at 400 MHz (1H), 376 MHz (19F), and
100 MHz (13C) on a Varian Inova AS400 spectrometer.
Candida antarctica lipase B was purchased from Boehrin-
ger–Mannheim (Chirazymeꢂ L-2, c.-f. C2; 5 U/mg).
4.4. Compound (R)-5
4.2. Enzymatic desymmetrization of chromanedi-
methanol 1
Mesylate (R)-4 (69.5 mg, 0.152 mmol) and sodium boro-
hydride (54.4 mg, 1.438 mmol) were dissolved in anhy-
drous dimethylsulfoxide (2 mL) under dry argon
atmosphere. The solution was stirred at 115 ꢁC for
20 h. The solution was cooled to 0 ꢁC, water was added
(1 mL), and the solution was stirred for 15 min. Then, a
saturated aqueous solution of NaHCO3 (2 mL) was add-
ed and the mixture was stirred for 10 min. The aqueous
phase was extracted with ethyl acetate. The organic
phase was dried over MgSO4 and evaporated. The crude
product was purified by flash chromatography (CH2Cl2/
Compound 1 (216 mg, 0.86 mmol) was dissolved in
diethyl ether (30 mL) on powdered molecular sieves
(3A, 200 mg). Lipase B from Candida antarctica
(26 mg) and vinyl acetate (400 lL, 4.30 mmol) were then
added and the mixture was stirred at room temperature.
The reaction was monitored by thin layer chromatogra-
phy and quenched by filtration of the enzyme (2 h). The
volatiles were evaporated and the crude product was
purified by flash chromatography (CH2Cl2/ethyl acetate,
9:1) to give monoacetate (S)-2 (150 mg, 60%) and diac-
etate 3 (114 mg, 39%) as white solids.
ethyl acetate, 95:5) to give (R)-5 (29.4 mg, 82%) as a
white solid. Mp. 126.5–127.5 ꢁC, lit.33 127–129 ꢁC; ½aꢁ
23
D
ꢀ1.8 (c 1.45, EtOH); lit.33 [a]D 1.54 (c 1.89, EtOH) for
22
Compound (S)-2: mp 139 ꢁC; ½aꢁ ꢀ15.6 (c 1.53,
the S enantiomer; IR (KBr) 3400, 2900, 1440, 1405,
D
CHCl3); IR (KBr) 3400, 2920, 2900, 1700, 1400, 1250,
1
1245, 1155, 1080, 1030, 885 cmꢀ1; H NMR (CDCl3) d
1040, 930, 800 cmꢀ1
;
1H NMR (CDCl3) d 1.93 (m,
1.24 (s, 3H), 1.74 (dt, J = 13.3 and 5.5 Hz, 1H), 2.01
(dt, J = 13.3 and 8.4 Hz, 1H); 2.13 (s, 3H), 2.14 (s,
3H), 2.18 (s, 3H), 2.30 (t, J = 6.1 Hz, 1H), 2.67 (m,
2H), 3.65 (m, 2H), 4.72 (s, 1H); 13C NMR (CDCl3) d
11.22, 11.74, 12.13, 20.16, 20.32, 27.76, 69.21, 74.94,
117.20, 118.91, 121.50, 122.39, 144.79, 145.00.
2H), 2.09 (s, 3H), 2.10 (s, 6H), 2.15 (s, 3H), 2.22 (br s,
1H), 2.63 (t, J = 6.4 Hz, 2H), 3.67 (m, 2H), 4.16 (d,
J = 11.5 Hz, 1H), 4.22 (d, J = 11.5 Hz, 1H); 13C NMR
(CDCl3) d 11.11, 11.63, 12.02, 19.50, 20.68, 24.08,
63.64, 64.49, 75.52, 117.31, 118.54, 121.37, 122.48,
144.17, 145.32, 170.96; HRMS (EI) calcd for
C16H22O5 (M+) 294.1467. Found 294.1470.
4.5. Compound (R)-6
Compound 3: mp 111 ꢁC; IR (KBr) 3550, 2960, 1730,
To a solution of (R)-5 (425.0 mg, 1.798 mmol) in anhy-
drous THF (20 mL) cooled to 0 ꢁC under dry argon
atmosphere was added sodium hydride (62.7 mg,
1
1455, 1390, 1240, 1040, 940, 910, 850 cmꢀ1; H NMR
(CDCl3) d 1.95 (t, J = 6.9 Hz, 2H), 2.07 (s, 3H), 2.08 (s,

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R. Chenevert et al. / Bioorg. Med. Chem. 14 (2006) 5389–5396
5393
2.613 mmol) and the mixture was stirred for 10 min.
Benzyl bromide (300 lL, 2.522 mmol) was added and
the mixture was allowed to reach room temperature
and stirred for 20 h. The mixture was diluted with dieth-
yl ether (60 mL) and washed successively with 3 N aq
HCl, saturated aq NaHCO3, and brine. The organic
layer was dried over MgSO4 and the solvents were re-
moved in vacuo. The crude product was purified by flash
chromatography (petroleum ether/diethyl ether 65:35) to
21.17, 24.21, 26.02, 26.32, 63.58, 65.54, 75.92, 117.80,
122.96, 123.77, 126.42, 144.77, 145.44, 171.16; HRMS
(CI, NH3) calcd for C28H50O5Si2 (M+), 522.3197. Found
522.3203.
4.8. Compound (R)-12
To a solution of (R)-11 (716 mg, 1.369 mmol) in dry
THF (36 mL) was added ethylmagnesium bromide
(1 M solution in THF, 6.85 mL, 6.85 mmol) and the
solution was stirred at room temperature for 1.5 h. A
saturated aqueous solution of NH4Cl (20 mL) was slow-
ly added and the mixture was extracted with ethyl ace-
tate (3· 30 mL). The organic phase was washed with
brine, dried over MgSO4, and concentrated. The crude
product was purified by flash chromatography (hex-
give (R)-6 (470.0 mg, 80%) as a white solid. Mp 72–
22
D
IR (KBr) 3380, 2900, 1440, 1400, 1360, 1245, 1145,
74 ꢁC (lit.33 mp 66–69.5 ꢁC); ½aꢁ 1.1 (c 1.05, CHCl3);
1075, 1040, 895 cmꢀ1 1H NMR (CDCl3) d 1.25 (s,
;
3H), 1.75 (m, 1H), 1.93 (br s, 1H), 2.03 (m, 1H), 2.12
(s, 3H), 2.19 (s, 3H), 2.24 (s, 3H), 2.67 (m, 2H), 3.61
(d, J = 11.3 Hz, 1H), 3.67 (d, J = 11.3 Hz, 1H), 4.70 (s,
2H), 7.37 (m, 3H), 7.51 (d, J = 7.2 Hz, 2H); 13C NMR
(CDCl3) d 11.80, 11.92, 12.78, 20.09, 20.49, 27.62,
69.25, 74.67, 75.27, 117.52, 122.83, 126.12, 127.63,
127.73, 128.15, 128.38, 137.82, 147.21, 148.57.
ane/ethyl acetate, 85:15) to give (R)-12 (636 mg, 97%)
23
D
3468, 2983, 2955, 2928, 2857, 1641, 1257, 1091,
as a colorless oil. ½aꢁ 8.13 (c 6.16, CHCl3); IR (neat)
1
835 cmꢀ1; H NMR (CDCl3) d 0.05 (s, 3H), 0.07 (s,
3H), 0.12 (s, 6H), 0.91 (s, 9H), 1.05 (s, 9H), 1.93–1.97
(m, 2H), 2.05 (s, 1H), 2.07 (s, 3H), 2.08 (s, 3H), 2.10
(s, 3H), 2.50–2.65 (m, 2H), 3.59 (d, J = 9.6 Hz, 1H),
3.69–3.76 (m, 3H); 13C NMR (CDCl3) d ꢀ5.35, ꢀ3.10,
12.35, 13.66, 14.55, 18.37, 18.83, 20.09, 24.11, 26.04,
26.32, 64.96, 66.34, 76.58, 118.16, 122.68, 123.99,
126.40, 144.86, 145.37; HRMS (CI, NH3) calcd for
C26H48O4Si2 (M+) 480.3091. Found 480.3082.
4.6. Compound (R)-7
To a solution of oxalyl chloride (200 lL, 2.29 mmol) in
dichloromethane (2 mL) was added dimethylsulfoxide
(250 lL, 3.52 mmol) at ꢀ78 ꢁC under dry argon atmo-
sphere. After stirring for 15 min, alcohol (R)-6
(115 mg, 0.35 mmol) in dichloromethane (3 mL) was
added and, after 90 min, triethylamine (650 lL,
4.66 mmol). After stirring for an additional 3 h at
ꢀ78 ꢁC, the solution was allowed to warm to room tem-
perature. Ethyl acetate was added and the organic layer
was washed with 3 N aq HCl, saturated aqueous NaH-
CO3, and brine. The organic layer was dried over
MgSO4 and evaporated. Flash chromatography (hex-
ane/ethyl acetate, 95:5) afforded aldehyde (R)-7
4.9. Compound (S)-13
To a solution of (R)-12 (616 mg, 1.323 mmol), triethyl-
amine (1.29 mL, 9.26 mmol) and 4-dimethylaminopyri-
dine (50 mg) in dry dichloromethane (45 mL) was
added p-toluenesulfonyl chloride (1.26 g, 6.61 mmol)
and the solution was stirred at room temperature for
12 d. The solution was diluted with diethyl ether
(100 mL) and the organic phase was washed with 1 N
aq HCl, saturated aq NaHCO3, and brine. The organic
phase was then dried over MgSO4 and evaporated.
(110.7 mg, 97%) as a white solid. Mp 58–59 ꢁC, lit.33
22
56–61 ꢁC; ½aꢁ ꢀ13.5 (c 1.21, CHCl3), lit.34 ꢀ10.9 (c
D
0.39, CHCl3, R enantiomer), lit.45 12.5 (c 2.8, CHCl3,
S enantiomer). The spectroscopic data of 7 were identi-
cal to those reported in the literature.33–35
Flash chromatography (hexane/ethyl acetate, 75:25)
23
provided (S)-13 (719 mg, 86%) as a colorless oil. ½aꢁ
D
4.7. Compound (R)-11
ꢀ1.49 (c 4.47, CHCl3); IR (neat) 3431, 3065, 3031,
2857, 1598, 1462, 1367, 1253, 1178, 1095, 835 cmꢀ1
;
To a solution of monoacetate (S)-2 (446 mg, 1.52 mmol)
in dry dimethylformamide (10 mL) were added tert-bu-
tyl-dimethylsilyl chloride (701 mg, 4.65 mmol) and imid-
azole (528 mg, 7.75 mmol) and the mixture was stirred
at room temperature for 24 h. The mixture was diluted
with water and the aqueous phase was extracted with
diethyl ether (3· 20 mL). The combined organic layers
were washed with brine, dried over MgSO4, and evapo-
rated. Flash chromatography (hexane/ethyl acetate,
1H NMR (CDCl3) d ꢀ0.007 (s, 3H), ꢀ0.01 (s, 3H),
0.11 (s, 6H), 0.84 (s, 9H), 1.04 (s, 9H), 1.82-1.89 (m,
2H), 1.98 (s, 3H), 2.00 (s, 3H), 2.07 (s, 3H), 2.43 (s,
3H), 2.45-2.48 (m, 2H), 3.56 (d, J = 10.0 Hz, 1H), 3.62
(d, J = 10.0 Hz, 1H), 4.06 (s, 2H), 7.29 (d, J= 7.6 Hz,
2H), 7.75 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3) d
ꢀ5.38, ꢀ5.34, ꢀ3.13, 12.16, 13.57, 14.53, 18.34, 18.83,
19.67, 21.86, 23.75, 25.98, 26.31, 63.41, 69.96, 75.69,
117.41, 122.96, 123.79, 126.52, 128.18, 129.97, 132.90,
144.91, 145.02; HRMS (CI, NH3) calcd for C33H54O6S-
Si2 (M+) 634.3179. Found 634.3187.
85:15) afforded compound (R)-11 (755 mg, 95%) as a
23
D
2929, 2885, 2857, 1748, 1462, 1252, 1094, 947,
colorless oil. ½aꢁ 6.03 (c 7.16, CHCl3); IR (neat) 2954,
1
837 cmꢀ1; H NMR (CDCl3) d 0.03 (s, 3H), 0.05 (s,
4.10. Compound (S)-14
3H), 0.13 (s, 6H), 0.89 (s, 9H), 1.05 (s, 9 H), 1.84–2.02
(m, 2H), 2.06 (s, 6H), 2.09 (s, 3H), 2.10 (s, 3H), 2.57
(t, J = 6.8 Hz, 2H), 3.60 (d, J = 10.0 Hz, 1H), 3.71 (d,
J = 10.0 Hz, 1H), 4.19 (d, J = 11.2 Hz, 1H), 4.23 (d,
J = 11.2 Hz, 1H); 13C NMR (CDCl3) d ꢀ5.35, ꢀ5.33,
ꢀ3.12, ꢀ3.09, 12.15, 13.63, 14.55, 18.40, 18.83, 19.99,
To a solution of (S)-13 (272 mg, 0.428 mmol) in dry
THF (15 mL) was added lithium triethylborohydride
(1 M solution in THF, 1 mL, 1 mmol) at 0 ꢁC under a
dry argon atmosphere. The solution was stirred at room
temperature for 4 h and then at reflux for 12 h. Then,

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R. Chenevert et al. / Bioorg. Med. Chem. 14 (2006) 5389–5396
5394
after mixture was allowed to cool down at room temper-
ature, a saturated aqueous solution of NaHCO3 was
added, and the mixture was stirred for 10 min. The solu-
tion was diluted with ethyl acetate (50 mL) and washed
with saturated aqueous NaHCO3 (20 mL) and brine
(20 mL). The organic layer was dried (MgSO4) and
evaporated. Flash chromatography (hexane/ethyl ace-
d 11.61, 11.89, 12.76, 19.62, 20.96, 27.66, 72.77, 74.65,
79.46, 116.50, 120.68, 123.32, 126.05, 127.63, 127.76,
128.38, 128.68, 137.69, 146.40, 148.95; HRMS (CI,
NH3) calcd for C22H25F3O5S (M+) 458.1375. Found
458.1367.
4.14. Compound (S)-17
tate, 9:1) provided alcohol (R)-12 (95 mg, 46%) and
23
D
CHCl3); IR (neat) 2955, 2928, 2896, 2857, 1462, 1413,
(S)-14 (71 mg, 36%) as a yellow oil. ½aꢁ 1.46 (c 1.41,
To a solution of sulfone 16 (676 mg, 2.0 mmol) in THF
(6 mL) and HMPA (1.7 mL) cooled to ꢀ78 ꢁC under a
dry argon atmosphere was added dropwise a solution of
n-butyllithium (1.6 M in hexane, 0.95 mL, 1.50 mmol)
and the mixture was stirred for 30 min. A solution of
triflate (S)-15 (560 mg, 1.22 mmol) in dry THF (9 mL)
was added dropwise and the solution was stirred at
ꢀ78 ꢁC for 8 h, then at room temperature for 10 h.
The solution was diluted in diethyl ether, washed with
brine, dried over MgSO4, and evaporated. The crude
product was purified first by flash chromatography on
silica gel (hexane/ethyl acetate, 9:1), then by column
chromatography on C-18 reverse-phase (acetonitrile/
water, 95:5) to give the mixture of diastereoisomers
(S)-17 (0.786 g, 60%) as a yellow oil. IR (neat) 3030,
2925, 2855, 1453, 1373, 1304, 1254, 1146, 1085, 999,
1
1252, 1092, 946, 836 cmꢀ1; H NMR (CDCl3) d 0.04
(s, 3H), 0.07 (s, 3H), 0.13 (s, 6H), 0.91 (s, 9H), 1.06 (s,
9H), 1.26 (s, 3H), 1.73–1.80 (m, 1H), 1.92–1.99 (m,
1H), 2.07 (s, 3H), 2.08 (s, 3H), 2.11 (s, 3H), 2.54–2.58
(m, 2H), 3.53 (d, J = 9.6 Hz, 1H), 3.59 (d, J = 9.6 Hz,
1H); 13C NMR (CDCl3) d ꢀ5.23, ꢀ5.19, ꢀ3.11,
ꢀ3.09, 12.23, 13.66, 14.56, 18.48, 18.84, 20.77, 22.43,
26.10, 26.35, 28.49, 68.61, 75.34, 117.94, 122.77,
123.77, 126.11, 144.37, 146.11; HRMS (CI, NH3) calcd
for C26H48O3Si2 (M+) 464.3142. Found 464.3148.
4.11. Compound (S)-5
To a solution of (S)-14 (409 mg, 0.881 mmol) in dry
THF (15 mL) was added glacial acetic acid (0.416 mL,
7.27 mmol) and the solution was stirred for 5 min under
a dry argon atmosphere. Then, n-tetrabutylammonium
fluoride (2.04 g, 7.8 mmol) was added and the solution
was stirred for 72 h at room temperature. The reaction
was quenched by addition of brine (10 mL) and the
product was extracted with ethyl acetate (3· 30 mL).
The organic phase was dried over MgSO4 and evaporat-
ed. The crude product was purified by flash chromatog-
raphy (CH2Cl2/ethyl acetate, 9:1) to give (S)-5 (208 mg,
1
854 cmꢀ1; H NMR (CDCl3) d 1.13 (s, 3H), 1.18 (s,
3H), 1.23 (s, 3H), 1.30 (s, 3H), 1.58 (s, 6H), 1.66 (s,
3H), 1.70–2.07 (m, 30 H), 2.10 (s, 3H), 2.13 (s, 3H),
2.18–2.19 (s, 3H), 2.49–2.59 (m, 4H), 4.04–4.08 (m,
1H), 4.12–4.16 (m, 1H), 4.66 (s, 4H), 4.99–5.08 (m,
4H), 5.16 (d, J = 9.6 Hz, 2H), 7.23–7.55 (m, 14 H),
7.60 (t, J = 7.4 Hz, 2H), 7.75 (d, J = 7.2 Hz, 2H), 7.83
(d, J = 7.6 Hz, 2H); 13C NMR (CDCl3) d 12.12, 12.19,
13.08, 13.10, 16.23, 16.75, 17.93, 20.59, 20.71, 24.32,
24.43, 25.94, 26.28, 26.90, 32.13, 32.41, 37.20, 37.65,
39.92, 40.03, 40.07, 61.33, 61.81, 74.04, 74.19, 74.91,
117.23, 117.28, 119.06, 119.10, 122.84, 123.15, 123.70,
123.74, 124.41, 126.30, 127.91, 127.95, 128.02, 128.04,
128.32, 128.68, 128.77, 128.92, 129.20, 129.68, 131.62,
133.50, 133.63, 135.82, 135.87, 137.84, 137.95, 138.11,
138.14, 144.46, 145.14, 147.26, 147.46, 148.64, 148.73;
HRMS (CI, NH3) calcd for C42H54O4S1 (M+)
654.3743. Found 654.3752.
quantitative). ½aꢁ23 1.61 (c 2.25, EtOH). The spectroscop-
D
ic data were identical for both enantiomers.
4.12. Compound (S)-6
Benzylation of (S)-5 gave (S)-6 in 80% yield according to
23
the procedure described above. ½aꢁ ꢀ1.55 (c 2.09,
D
CHCl3). The spectroscopic data of (S)-6 were identical
for both enantiomers.
4.15. Compound (R)-18
4.13. Compound (S)-15
To a solution of sulfone (S)-17 (1.684 g, 2.56 mmol) and
PdCl2(dppp) (151 mg, 0.256 mmol) in dry THF (70 mL)
cooled to 0 ꢁC under dry argon atmosphere was added
dropwise a solution of lithium triethylborohydride
(1 M in THF, 7.7 mL, 7.7 mmol). The mixture was stir-
red at 0 ꢁC for 5 h and then at room temperature over-
night. The mixture was diluted with ether and washed
successively with 1 M aq KCN, brine, and water. The
organic layer was dried (MgSO4), and evaporated. The
crude product was purified by flash chromatography
(pure hexane to hexane/AcOEt, 95:5) to give (R)-18
To a solution of (S)-6 (152.3 mg, 0.467 mmol) and anhy-
drous triethylamine (100 lL, 0.718 mmol) in dry dichlo-
romethane (4.6 mL) cooled to ꢀ10 ꢁC under argon
atmosphere was added trifluoromethanesulfonic anhy-
dride (100 lL, 0.594 mmol). The solution was stirred
at ꢀ10 ꢁC for 30 min. The solution was diluted with eth-
yl acetate and washed with 3 N aq HCl, saturated aq
NaHCO3, and brine. The organic layer was dried over
MgSO4 and the solvents were removed in vacuo. The
crude product was purified by flash chromatography
(hexane/diethyl ether, 93:7) to give (S)-15 (131.9 mg,
(1.00 g, 76%) as a colorless oil. ½aꢁ23 4.76 (c 0.63, CHCl3);
D
23
D
62%) as a white solid. Mp 90–92 ꢁC; ½aꢁ ꢀ3.56 (c
IR (neat) 3089, 3065, 3033, 2968, 2924, 2855, 1458, 1368,
1248, 1159, 1090 cmꢀ1; 1H NMR (CDCl3) d 1.25 (s, 3H),
1.53–1.65 (m, 11H), 1.67 (s, 3H), 1.73–1.87 (m, 2H),
1.93–1.99 (m, 4H), 2.01–2.07 (m, 4H), 2.10–2.16 (m,
8H), 2.21 (s, 3H), 2.59 (t, J = 6.74 Hz, 2H), 4.68 (s,
2H), 5.05–5.17 (m, 3H), 7.33 (t, J = 7.03 Hz, 1H), 7.39
1
2.14, CHCl3); H NMR (CDCl3) d 1.38 (s, 3H), 1.87
(m, 1H), 2.01 (m, 1H), 2.12 (s, 3H), 2.19 (s, 3H), 2.24
(s, 3H), 2.68 (t, J = 6.8 Hz, 2H), 4.45 (d, J = 10.2 Hz,
1H), 4.51 (d, J = 10.2 Hz, 1H), 4.71 (s, 2H), 7.40
(m, 3H), 7.52 (d, J = 6.9 Hz, 2H); 13C NMR (CDCl3)

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R. Chenevert et al. / Bioorg. Med. Chem. 14 (2006) 5389–5396
5395
(t, J = 7.03 Hz, 2H), 7.90 (d, J = 7.03 Hz, 2H); 13C
NMR (CDCl3) d 12.06, 12.22, 13.09, 16.11, 16.23,
17.92, 20.90, 22.45, 24.08, 25.95, 26.82, 26.98, 31.60,
39.91, 39.93, 39.95, 74.80, 74.93, 117.77, 123.18,
124.42, 124.59, 124.63, 126.21, 127.93, 127.99, 128.18,
128.68, 131.48, 135.18, 135.33, 138.26, 148.08, 148.39;
HRMS (CI, NH3) calcd for C36H51O2 (MH)+
515.3889. Found 515.3882.
10. Chabrier, P. E.; Auguet, M.; Spinnewyn, B.; Auvin, S.;
´
Cornet, S.; Demerle-Pallardy, C.; Guilmard-Favre, C.;
Marin, J. G.; Pignol, B.; Gillard-Roubert, V.; Roussi-
lot-Charnet, C.; Schulz, J.; Viossat, I.; Bigg, D.;
Moncada, S. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
10824.
11. Moulin, C.; Duflos, M.; Le Baut, G.; Grimaud, N.;
Renard, P.; Caignard, D. H. Eur. J. Med. Chem. 1998, 33,
321.
12. Koufaki, M.; Calogeropoulou, T.; Rekka, E.; Chryselis,
M.; Papazafiri, P.; Gaitanaki, C.; Makriyannis, A. Bioorg.
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4.16. (R)-a-Tocotrienol 19
13. Panfili, G.; Fratianni, A.; Irano, M. J. Agric. Food Chem.
2003, 51, 3940.
14. Cahoon, E. B.; Hall, S. E.; Ripp, K. G.; Ganzke, T. S.;
Hitz, W. D.; Coughlan, S. J. Nat. Biotechnol. 2003, 21,
1082.
To a solution of (R)-18 (219 mg, 0.426 mmol) in diethyl
ether (11 mL) cooled to ꢀ78 ꢁC under a dry argon atmo-
sphere was added ethyl amine (11 mL) and then lithium
(81 mg, 11.65 mmol). The mixture was stirred at ꢀ78 ꢁC
for 3 h. The reaction was quenched by the addition of
saturated aqueous NH4Cl (3 mL) and methanol
(3 mL). The solvents were evaporated and the residue
was dissolved in diethyl ether. The organic layer was
washed with brine, dried (MgSO4) and evaporated.
The crude material was purified by flash chromatogra-
15. Schaffer, S.; Muller, W. E.; Eckert, G. P. J. Nutr. 2005,
135, 151.
¨
16. Niki, E.; Noguchi, N. Acc. Chem. Res. 2004, 37, 45.
17. Yoshida, Y.; Niki, E.; Noguchi, N. Chem. Phys. Lipids
2003, 123, 63.
18. Pearce, B. C.; Parker, R. A.; Deason, M. E.; Dischino, D.
D.; Gillespie, E.; Qureshi, A. A.; Volk, K.; Wright, J. J. K.
J. Med. Chem. 1994, 37, 526.
19. Qureshi, A. A.; Sami, S. A.; Salser, W. A.; Khan, F. A.
Atherosclerosis 2002, 161, 199.
20. Qureshi, A. A.; Bradlow, B. A.; Salser, W. A.; Brace, L. D.
J. Nutr. Biochem. 1997, 8, 290.
21. Iqbal, J.; Minhajuddin, M.; Beg, Z. H. Eur. J. Cancer
Prev. 2003, 12, 447.
22. Takahashi, K.; Loo, G. Biochem. Pharmacol. 2004, 67,
315.
23. Khanna, S.; Roy, S.; Ryu, H.; Bahadduri, P.; Swaan, P.
W.; Ratan, R. R.; Sen, C. K. J. Biol. Chem. 2003, 278,
43508.
24. Asakada, F.; Hashino, A.; Kume, T.; Katsuki, H.;
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Helv. Chim. Acta 1976, 59, 290.
phy (hexane/ethyl acetate, 95:5) to yield (R)-a-tocotrien-
23
D
2.47, CHCl3); IR (neat) 3465, 2968, 2925, 2855, 1450,
ol (0.150 g, 83%) as a solid. Mp 30–31 ꢁC; ½aꢁ ꢀ4.12 (c
1
1376, 1257, 1166, 1088, 928 cmꢀ1; H NMR (CDCl3) d
1.25 (s, 3H), 1.48–1.67 (m, 14H), 1.80 (m, 2H), 1.96
(m, 4H), 2.02–2.16 (m, 12H), 2.21 (s, 3H), 2.61 (t,
J = 6.74 Hz, 2H), 4.17 (br s, 1H), 5.13 (m, 3H); 13C
NMR (CDCl3) d 11.49, 11.99, 12.42, 16.10, 16.21,
17.90, 20.95, 22.43, 23.93, 25.92, 26.80, 26.96, 31.77,
39.72, 39.90, 39.92, 74.49, 117.51, 118.68, 121.22,
122.84, 124.41, 124.60, 131.48, 135.16, 135.25, 144.77,
145.68.
Acknowledgment
26. Pearce, B. C.; Parker, R. A.; Deason, M. E.; Qureshi, A.
A.; Wright, J. J. K. J. Med. Chem. 1992, 35, 3595.
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1983, 31, 4341.
The authors thank the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC) for financial
support and a postgraduate scholarship to G.C.
28. Mayer, H.; Metzger, J.; Isler, O. Helv. Chim. Acta 1967,
50, 1376.
29. For a preliminary account on the synthesis of the non-
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