Synthesis of (2R,8′S,3′E)-δ-tocodienol, a tocoflexol family member designed to have a superior pharmacokinetic profile compared to δ-tocotrienol

Article abstract of DOI:10.1016/j.tet.2016.05.028

A group of side chain partially saturated tocotrienol analogues, namely tocoflexols, have been previously designed in an effort to improve the pharmacokinetic properties of tocotrienols. (2R,8′S,3′E)-δ-Tocodienol (1) was predicted to be a high value tocof

Full text of DOI:10.1016/j.tet.2016.05.028

Tetrahedron xxx (2016) 1e6
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Tetrahedron
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Synthesis of (2R,80S,30E)-
designed to have a superior pharmacokinetic profile compared to
-tocotrienol
d-tocodienol, a tocoflexol family member
d
Xingui Liu, Satheesh Gujarathi, Xuan Zhang, Lijian Shao, Marjan Boerma,
Cesar M. Compadre, Peter A. Crooks, Martin Hauer-Jensen, Daohong Zhou,
*
Guangrong Zheng
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A group of side chain partially saturated tocotrienol analogues, namely tocoflexols, have been previously
designed in an effort to improve the pharmacokinetic properties of tocotrienols. (2R,80S,30E)-
d
-Tocodienol
(1) was predicted to be a high value tocoflexol for further pharmacological evaluation. We now report
here an efficient eight-step synthetic route to compound 1 utilizing naturally-occurring -tocotrienol as
-to-
Received 11 March 2016
Received in revised form 9 May 2016
Accepted 10 May 2016
Available online xxx
d
a starting material (24% total yield). The key step in the synthesis is oxidative olefin cleavage of
cotrienol to afford the chroman core of 1 with retention of chirality at the C-2 stereocenter.
d
Keywords:
Tocotrienol
Ó 2016 Elsevier Ltd. All rights reserved.
Tocodienol
Oxidative olefin cleavage
CeC coupling
Desulfonylation
1. Introduction
Tocopherol is rapidly secreted from the liver into plasma because it
has the highest affinity for
In contrast, - and -tocotrienol are restrained in the liver due to
a
-TTP out of all vitamin E homologues.5
Tocotrienol, and its tocopherol counterpart belong to the vita-
g
d
min E family. Both tocotrienol and tocopherol have a-, b-, g-, and d-
homologues and share a common 6-hydroxychroman moiety, with
tocotrienol having an unsaturated farnesyl side chain that differs
from the saturated phytyl side chain in tocopherol (Fig. 1). Toco-
trienols have been shown to have many bioactivities that are often
not observed with tocopherols.1 Both tocopherols and tocotrienols
have been investigated for their use as potential radiation pro-
tectors. Among them,
g- and
d
-tocotrienol exhibit the most sig-
nificant radioprotective effects.2 However, both
g-
and d-
tocotrienol have low bioavailability and short plasma elimination
half-lives3 that limit their exposure in systemic circulation and
require that they be administered in large doses.2 The low bio-
availability and short half-live of
part, caused by their weak binding affinity to
protein ( -TTP). -TTP is a specific transport protein responsible for
transferring the vitamin E compounds out of the liver, where they
are subject to metabolism, into the systemic circulation.4
g- and
d-tocotrienol are, at least in
a-tocopherol transfer
a
a
a
-
* Corresponding author. Tel.: þ1 501 526 6787; fax: þ1 501 526 5945; e-mail
address: gzheng@uams.edu (G. Zheng).
Fig. 1. Structures of naturally occurring tocopherols and tocotrienols.
http://dx.doi.org/10.1016/j.tet.2016.05.028
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
X. Liu et al. / Tetrahedron xxx (2016) 1e6
their low affinity for
elimination half-lives of
a
-TTP. As a result, the estimated apparent
-tocotrienol (t1/2¼4.3 h) and -tocotrienol
The syntheses of aldehyde C (3-chromanylpropanals) type
g
d
building blocks, including the corresponding 3-chromanylpropanols
and 3-chromanylpropanoic acids, in optically pure forms have been
reported.8 There are also a variety of reported enantioselective ap-
proaches to the synthesis of the chiral chroman core of vitamin E, i.e.,
chromanylmethanols,9 which could serve as a precursor for the
synthesis of aldehyde C. However, most of these syntheses are low-
yielding, multistep procedures. Given the potential utility of C as
(t1/2¼2.3 h) in humans are 4.5- and 8.7-fold shorter, respectively,
than
a
-tocopherol (t1/2¼20 h).3
The crystal structures of naturally occurring (2R,40R,80R)-
a-to-
copherol bound to a
-TTP reveal that the C40eC90 fragment of the
saturated phytyl side chain in the a-tocopherol molecule is bent
into a U-shape.6 It is difficult for the C40eC90 fragment in the far-
nesyl chain of tocotrienol to take up the same shape because of the
a key intermediate for the synthesis of d-tocotrienol analogues with
modifications on the side chain, we decided to search for an alter-
native but simpler and more efficient method to this compound. As
relatively high rigidity caused by the presence of the
double bonds, which compromises the incorporation of toco-
trienols into the binding pocket of -TTP. These observations
prompted us to design more flexible analogues with enhanced
bendability in their side chains by saturating
30 and/or 70 double
bonds in the -tocotrienol molecule. This group of ‘flexible’
tocotrienol analogues was collectively termed tocoflexols, from
which (2R,80S,30E)-
-tocodienol (1, Fig. 2) was identified as a com-
pound with the highest affinity for -TTP through a vigorous
molecular dynamics-based screening program.7 Herein, we de-
D
30 and
D
70
a
d-tocotrienol is readily available from natural sources, we envisioned
that C could be synthesized by oxidative cleavage of the double
D
D
bonds of naturally occurring optical pure d-tocotrienol.
d
d-
Commercially available DeltaGoldÒ, a tocopherol free vitamin E
supplement obtained in an enriched form from annatto oil, con-
d
tains 67%
source of
DeltaGoldÒ using silica gel based flash column chromatography
d-tocotrienol and 7.5%
g
-tocotrienol, and was used as the
a
d-tocotrienol. The isolation of
d-tocotrienol from
scribe the synthesis of compound 1 from naturally-occurring
tocotrienol.
d-
was straightforward and afforded 3.5 g of
d-tocotrienol in a pure
form from 6.0 g of the mixture.10
The 6-OH group of d-tocotrienol was then protected as a silyl
ether moiety and the resulting TBS-protected product 2 was sub-
mitted to olefin oxidative cleavage (Table 1). Compound 2 was
treated with OsO4 (5 mol %) and NaIO4 (9 equiv) in THF/H2O at room
temperature; the consumption of the starting material and in-
termediates was monitored by GCeMS and TLC. Initial screening of
reaction conditions revealed that the ratio of the two solvents, THF
and H2O, was an important factor for the progress of the reaction,
and a 3:1 ratio of THF/H2O afforded the best result (Table 1, entry 1).
A relatively low reaction concentration (0.05e0.1 M) of 2 was
necessary for the progress of the reaction, likely due to the low
solubility of both 2 and NaIO4 in the solvent mixture. Disappoint-
ingly, only low yields of aldehyde 3 (10e17% yield) were obtained
from these reactions.11 No improvement was seen in the yield of 3
using various solvents (1,4-dioxane, diethyl ether, acetone, and t-
butanol were examined) or by adding 2,6-lutidine.12
Fig. 2. Structures of
simulated docking of 1 in the binding cavity of
d
-tocotrienol and (2R,80S,30E)-
d
-tocodienol (1) (left); and
a-TTP (right).
When the ratio of THF/H2O was changed to 1:1, a significant
amount of unreacted starting material (2) still remained (TLC and
GCeMS analyses) after 48 h, likely due to the low solubility of 2 in
the solvent mixture (Table 1, entry 2). A decrease in the proportion
of H2O in the solvent mixture by changing the ratio of THF/H2O to
10:1 resulted in a relatively rapid disappearance of 2. However, only
trace amounts of 3 were detected and the major product was the
olefin dihydroxylation product (with three pairs of 1,2-diols) due to
the low solubility of NaIO4 in the reaction mixture (entry 3). We
reasoned that the sluggish reaction was caused by the very differ-
ent solubilities of 2 and NaIO4 in the reaction media, and the low
yields were probably caused by the long reaction time and the
relatively unstable nature of aldehyde 3 in the reaction mixture.
The dihydroxylation step was completed in 24 h when the reaction
was conducted in a 10:1 ratio of THF/H2O (entry 3). Olefin dihy-
droxylation of 2 afforded three pairs of 1,2-diols, which should
provide sufficient solubility in a polar solvent system that can
dissolve NaIO4. We envisaged that such homogeneous or near ho-
mogeneous reaction mixture would result in rapid cleavage of the
1,2-diol products. Thus, we tried the reaction in a two-step one-pot
fashion by initial treatment of 2 with OsO4 (5 mol %) and N-meth-
ylmorpholine-N-oxide (NMO, 4 equiv) in a 10:1 ratio mixture of
THF/H2O to form the tris-dihydroxylation product, followed by
addition of H2O (to a final 1:1 ratio of THF/H2O) and NaIO4 to the
reaction mixture. Under these conditions, compound 3 was ob-
tained in a significantly improved conversion (38% after conversion
to the alcohol) (entry 4). Further investigation of the reaction
revealed that a procedure developed by Nicolaou et al.,13 involving
PhI(OAc)2 as an oxidative cleaving agent of 1,2-diols, afforded the
2. Results and discussion
Our retrosynthetic strategy is outlined in Scheme 1. A discon-
nection at the C50eC60 bond of (2R,80S,30E)-
-tocodienol (1) would
d
lead to segments A and B, which can be coupled through various
alkylation methods. Segment B can be derived from commercially
available R-(þ)-citronellol, while segment A can be derived from
aldehyde C via a HornereWadswortheEmmons (HWE) olefination
reaction to form the E-double bond.
Scheme 1. Retrosynthetic approach to (2R,80S,30E)-
d-tocodienol (1).
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X. Liu et al. / Tetrahedron xxx (2016) 1e6
3
Table 1
Screening of reaction conditions for the oxidative cleavage reaction
Entry
Conditions
Time (h)
Yield
1
2
3
4
OsO4 (5 mol %), NaIO4 (9 equiv), THF/H2O (3:1)
OsO4 (5 mol %), NaIO4 (9 equiv), THF/H2O (1:1)
OsO4 (5 mol %), NaIO4 (9 equiv), THF/H2O (10:1)
24
48
24
24
10e17%a
n.d.b
Tracec
i) OsO4 (5 mol %), NMO (4 equiv), THF/H2O (10:1);
ii) NaIO4 (4 equiv), THF/H2O (1:1)d
i) OsO4 (5 mol %), NMO (4 equiv), 2,6-lutidine (6 equiv), acetone/H2O (10:1);
ii) PhI(OAc)2 (4 equiv), acetone/H2O (10:1)e
12
15
2
38%a
62%f
5
a
Yields were based on the corresponding alcohol.
n.d.¼not determined.
b
c
d
e
f
The major product was olefin dihydroxylation product containing three pairs of 1,2-diols.
One-pot reaction, NaIO4 and H2O were added directly to the reaction mixture.
One-pot reaction, PhI(OAc)2 was added directly to the reaction mixture.
Yield of purified 3.
best results. Aldehyde 3 was isolated in 62% yield (entry 5) and the
enantiopurity at C-2 was retained with >95% ee based on chiral
HPLC analysis.14
conditions, no g-alkylation product was observed. It is noteworthy
that no coupling product was formed in the absence of HMPA.
HMPA is known to facilitate carbanion formation and to strongly
coordinate lithium cation, thereby increase the reactivity of the
carbanion.18 The subsequent reductive cleavage of the sulfone
group of 15 using sodium amalgam to form 10 occurred in 66%
yield. Removal of the TBS-group with TBAF/THF led to the final
product 1 in quantitative yield.
It has been reported that Kotake’s Pd-mediated desulfonylation
procedure usually affords high yields.16d,16e,19 However, the sulfone
group required to be at the allylic position. Accordingly, chloride 13
was converted to sulfone 16 (87% yield), which was then coupled
with bromide 9 to furnish 17 in 84% yield (Scheme 3). The sulfone
group of 17 was removed smoothly by treating with super-hydride
(LiBHEt3) in the presence of catalytic amount of Pd(dppp)Cl2.
However, the desulfonylation reaction afforded an inseparable
mixture of 10 and its three isomers, presumably 30Z-isomer of 10
and 40E/Z mixture of double isomerized product.20
Aldehyde 3 was then converted into 5 through a HWE olefina-
tion procedure using triethyl 2-phosphonopropionate (4) under the
treatment of sodium hydride (88% yield, 9:1 E/Z selectivity based on
GCeMS analysis) (Scheme 2). DIBAL-H reduction of ester 5 gave the
corresponding alcohol 6 (89% yield), which was converted into
acetate 7 in quantitative yield. Coupling of compound 7 with (R)-
(ꢀ)-citronellyl bromide (9) was attempted under conditions re-
ported by Gosmini et al.15 Surprisingly, 7 remained unchanged
during the course of the reaction, while a model coupling reaction
between 2-methylallyl acetate and 9 worked as expected. Alter-
natively, a coupling reaction between tosylate 8 and Grignard re-
agent 11, derived from 6 and 9, respectively, proceeded smoothly to
the desired product 10 with good regioselectivity (
on GCeMS analysis). Unfortunately, removal of the
product 12 from the product mixture was unsuccessful.
a
:
g
g
92:8 based
-alkylation
Scheme 2. Synthesis of intermediates 7/8 and attempts for the formation of 10.
To avoid the formation of 12, we turned our effort to a sulfone
3. Conclusions
based CeC coupling method (Scheme 3).16 Corey-Kim chlorina-
tion17 of 6 afforded 13 in 98% yield. Reacting of 13 with the anion
obtained on treatment of sulfone 14 with nBuLi in THF/HMPA fur-
In summary, we have developed an efficient synthesis of
(2R,80S,30E)-
d-tocodienol (1), a
d-tocotrienol analogue designed to
nished 15 in 83% yield as
a diastereoisomers. Under these
have improved pharmacokinetic properties. A novel strategy,
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4
X. Liu et al. / Tetrahedron xxx (2016) 1e6
Scheme 3. Sulfone based coupling reaction for synthesis of compound 1.
involving an oxidative olefin cleavage of naturally-occurring
d
-
1.27 (s, 3H), 0.98 (s, 9H), 0.17 (s, 6H); 13C NMR (100 MHz, CDCl3)
147.7, 146.5, 135.2, 135.1, 131.4, 127.0, 124.5, 124.4, 124.3, 120.9,
120.2, 117.3, 75.4, 39.9, 39.8, 31.6, 26.9, 26.7, 25.9, 25.8, 24.2, 22.6,
22.3, 18.3, 17.8, 16.2, 16.1 (2C), 16.0, ꢀ4.3; MS (EI) m/z 510.5 (Mþ);
HRMS (ESI/APCI) m/z calcd for C33H55O2Si [MþH]þ 511.3966, found
511.3957.
tocotrienol, was employed for the generation of the chroman core
of 1. The aldehyde intermediate from the olefin cleavage reaction is
a key building block for the synthesis of tocotrienol analogues,
which are of great interest in the search for new radiation pro-
tective agents. Preliminary studies showed that 1 was equally po-
d
tent as an antioxidant when compared to its parent compound, d-
tocotrienol (see Supplementary data). Further investigations on the
biological properties of 1 and its potential to be considered as
a clinical candidate are currently ongoing in our laboratory.
4.3. 3-[2,8-Dimethyl-6-tert-butyldimethylsiloxychroman-
2(S)-yl]propanal (3)
To a solution of compound 2 (170 mg, 0.33 mmol) in acetone/
water (4 mL/0.19 mL) was added N-methylmorpholine-N-oxide
(NMO) (155 mg, 1.32 mmol), 2,6-lutidine (181 mg, 2 mmol), and
OsO4 (2% aqueous solution, 0.21 mL, 0.016 mmol). The final ace-
tone/water ratio was 10:1. After stirring at room temperature for
15 h, (diacetoxyiodo)benzene (425 mg, 1.50 mmol) was added and
the resulting mixture was allowed to stir at room temperature for
2 h before being quenched with saturated aqueous Na2SO3 (5 mL).
The mixture was extracted with ethyl acetate (3ꢂ10 mL) and the
combined organic layers were washed with brine (10 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude product was chromatographed on silica (hex-
anes/ethyl acetate 20:1) to afford compound 3 (71 mg, 62%) as
4. Experimental section
4.1. General
DeltaGoldÒ was obtained from American River Nutrition, Inc.
Dry THF, CH2Cl2, and DMF were obtained via a solvent purification
system by filtering through two columns packed with activated
ꢀ
alumina and 4 A molecular sieve, respectively. All other reagents
and solvents obtained from commercial sources were used without
further purification. If dry and air-free conditions were required,
reactions were performed in oven-dried glassware (130 ꢁC) under
a positive pressure of argon. Flash chromatography was performed
using silica gel (230e400 mesh) as the stationary phase. Reaction
progress was monitored by thin layer chromatography (silica-
coated glass plates) and visualized under UV light and after expo-
sure to iodine vapor, and by GCeMS. NMR spectra were recorded in
CDCl3 at 400 MHz for 1H NMR, and 100 MHz for 13C NMR. Chemical
a colorless oil: 1H NMR (400 MHz, CDCl3)
d 9.80 (s, 1H), 6.46 (d,
J¼2.4 Hz, 1H), 6.37 (d, J¼2.4 Hz, 1H), 2.69e2.75 (m, 2H), 2.60e2.64
(m, 2H), 2.00e2.11 (m, 4H), 1.86e1.92 (m, 1H), 1.72e1.81 (m, 2H),
1.23 (s, 3H), 0.97 (s, 9H), 0.15 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
202.6, 148.0, 145.9, 127.0, 120.7, 120.4, 117.4, 74.5, 38.7, 32.4, 31.7,
shifts
d
are given in ppm using tetramethylsilane as an internal
25.9, 23.7, 22.4, 18.2, 16.3, ꢀ4.3. MS (EI) m/z 348.2 (Mþ); HRMS (ESI/
standard. Multiplicities of NMR signals are designated as singlet (s),
broad singlet (br s), doublet (d), doublet of doublets (dd), triplet (t),
quartet (q), and multiplet (m). HRMS were recorded on an Agilent
LCTOF spectrometry unit run in the ESI/APCI mode (Mass Spec-
trometry Facility, University of California Riverside).
APCI) m/z calcd for C20H33O3Si [MþH]þ 349.2194, found 349.2178.
4.4. Ethyl 5-[2,8-dimethyl-6-tert-butyldimethylsiloxychro-
man -2(R)-yl]-2-methylpent-2(E)-enoate (5)
To a suspension of NaH (60%, 83 mg, 2.1 mmol) in THF (1.5 mL)
was added triethyl 2-phosphonopropionate (0.27 mL, 1.26 mmol)
dropwise at 0 ꢁC. After stirring at 0 ꢁC for 30 min, a solution of
compound 3 (400 mg, 1.15 mmol) in THF (2 mL) was added drop-
wise. The resulting mixture was allowed to stir at the same tem-
perature for 1 h before being quenched with saturated aqueous
NH4Cl (5 mL). The mixture was extracted with ethyl acetate
(3ꢂ10 mL) and the combined organic layers were washed with
water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude
product was chromatographed on silica (hexanes/ethyl acetate
15:1) to afford compound 5 (352 mg, 88%, double configuration
assigned by NOESY) as a colorless oil: 1H NMR (400 MHz, CDCl3)
4.2. tert-Butyl{[2,8-dimethyl-2(R)-(4,8,12-trimethyltrideca-
3E,7E,11-trien-yl)chroman-6-yl]oxy}dimethylsilane (2)
To a solution of d-tocotrienol (400 mg, 1.0 mmol) in CH2Cl2
(10 mL) at 0 ꢁC was added imidazole (172 mg, 2.5 mmol) and TBSCl
(183 mg, 1.2 mmol) and the resulting mixture was stirred at room
temperature for 5 h. The reaction mixture was partitioned between
ethyl acetate (30 mL) and water (30 mL). The aqueous layer was
extracted with ethyl acetate (2ꢂ10 mL), and the combined organic
layers were washed with water (20 mL) and brine (20 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude product was chromatographed on silica (hex-
anes/ethyl acetate 30:1) to afford compound 2 (470 mg, 92%) as
d
6.78 (t, J¼7.2 Hz, 1H), 6.46 (s, 1H), 6.37 (s, 1H), 4.18 (q, J¼7.2 Hz,
a colorless oil: 1H NMR (400 MHz, CDCl3)
(d, J¼2 Hz, 1H), 5.13 (m, 3H), 2.70 (t, J¼6.4 Hz, 2H), 2.07e2.16 (m,
9H), 1.98 (m, 4H), 1.73e1.81 (m, 2H), 1.69 (s, 3H), 1.54e1.66 (m, 11H),
d
6.47 (d, J¼2 Hz,1H), 6.37
2H), 2.68e2.73 (m, 2H), 2.33 (q, J¼7.6 Hz, 2H), 2.11 (s, 3H), 1.82 (s,
3H),1.72e1.88 (m, 3H),1.62e1.67 (m,1H),1.27e1.30 (m, 6H), 0.97 (s,
9H), 0.16 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 168.3, 147.8, 146.2,
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X. Liu et al. / Tetrahedron xxx (2016) 1e6
5
142.2, 127.9, 127.0, 120.8, 120.3, 117.4, 75.0, 60.5, 38.5, 31.7, 25.9,
(100 MHz, CDCl3)
d
139.3, 133.7, 131.8, 129.4, 128.2, 124.2, 54.6, 36.5,
24.0, 23.1, 22.5, 18.3, 16.2, 14.4, 12.3, ꢀ4.3; MS (EI) m/z 432.4 (Mþ);
HRMS (ESI/APCI) m/z calcd for C25H40O4NaSi [MþNa]þ 455.2588,
found 455.2606.
31.6, 29.2, 25.8, 25.3, 19.2, 17.8; MS (EI) m/z 280.1 (Mþ); HRMS (ESI/
APCI) m/z calcd for C16H25O2S [MþH]þ 281.1570, found 281.1566.
4.5. 5-[2,8-Dimethyl-6-tert-butyldimethylsiloxychroman-
2(R)-yl]-2-methylpent-2(E)-en-1-ol (6)
4.8. tert-Butyl{[2,8-dimethyl-2(R)-(4,8S,12-trimethyltrideca-
3E,11-dien-yl)chroman-6-yl]oxy}dimethylsilane (10)
To a solution of compound 5 (260 mg, 0.6 mmol) in CH2Cl2
(3 mL) at ꢀ40 ꢁC was added DIBAL-H (1.2 M in toluene, 1.25 mL,
1.5 mmol) dropwise. After stirring at the same temperature for
1.5 h, the reaction was quenched with three drops of MeOH and
diluted with CH2Cl2 (10 mL), then poured into saturated Rochelle
salt solution (10 mL). The resulting mixture was stirred at room
temperature overnight. The aqueous phase was extracted with
ethyl acetate (2ꢂ10 mL) and the combined organic layers were
washed with brine (10 mL), dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The crude product was
chromatographed on silica (hexanes/ethyl acetate 5:1) to afford
compound 6 (235 mg, 89%) as a colorless oil: 1H NMR (400 MHz,
To a solution of compound 14 (56 mg, 0.20 mmol) in THF/HMPA
(3 mL/0.5 mL) at ꢀ78 ꢁC was added n-BuLi (1.6 M in hexane, 125
mL,
0.24 mmol) dropwise. The resulting bright orange-red colored
mixture was allowed to stir at ꢀ78 ꢁC for 1 h. Compound 12 (82 mg,
0.20 mmol) in THF (0.5 mL) was added dropwise and the resulting
mixture and the reaction was allowed to warm up to room tem-
perature. After turning into a colorless solution (about 1 h at room
temperature), the reaction was quenched with saturated aqueous
NH4Cl (5 mL) and extracted with ethyl acetate (3ꢂ10 mL). The
combined organic layers were washed with brine (10 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude product was chromatographed on silica (hex-
anes/ethyl acetate 20:1) to afford compound 15 (108 mg, 83%) as
a mixture of two diastereomers which were used directly to next
step. Compound 15 (50 mg, 0.077 mmol) was then dissolved in THF/
MeOH (2:5, 4 mL) and NaHPO4 (54 mg, 0.38 mmol) was added at
CDCl3)
d
6.46 (d, J¼2 Hz, 1H), 6.37 (d, J¼2 Hz, 1H), 5.42 (t, J¼2.8 Hz,
1H), 3.98 (s, 2H), 2.67e2.72 (m, 2H), 2.14e2.21 (m, 2H), 2.12 (s, 3H),
1.65e1.82 (m, 6H), 1.54e1.60 (m, 1H), 1.46 (br s, 1H), 1.27 (s, 3H),
0.97 (s, 9H), 0.16 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 147.7, 146.4,
134.9, 126.9, 126.4, 120.9, 120.3, 117.4, 75.2, 69.1, 39.4, 31.6, 25.9,
24.2, 22.6, 21.9, 18.3, 16.2, 13.6, ꢀ4.3; MS (EI) m/z 390.3 (Mþ); HRMS
(ESI/APCI) m/z calcd for C23H38O3NaSi [MþNa]þ 413.2482, found
413.2491.
0
ꢁC followed by sodium amalgam (5%, 354 mg, 0.77 mmol). After
stirring at the same temperature for 2 h, water (10 mL) was added
and the reaction was quenched by adding 1.0 M HCl dropwise to pH
7. The resulting mixture was extracted with ethyl acetate (3ꢂ10 mL)
and the combined organic phases was washed with saturated
aqueous NaHCO3 (15 mL), water (15 mL), and brine (15 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude product was chromatographed on silica (hex-
anes/ethyl acetate 30:1) to afford compound 10 (26 mg, 66%) as
4.6. 1-Chloro-5-[2,8-dimethyl-6-tert-butyldimethylsilox-
ychroman-2(R)-yl]-2-methyl-2(E)-pentene (13)
To a solution of N-chlorosuccinimide (60 mg, 0.9 mmol) in
CH2Cl2 (3 mL) at 0 ꢁC was added dimethyl sulfide (66
mL, 0.9 mmol)
dropwise. The resulting white suspension was stirred at 0 ꢁC for
30 min then a solution of compound 6 (117 mg, 0.3 mmol) in CH2Cl2
(0.5 mL) was added dropwise. The resulting mixture was allowed to
stir at 0 ꢁC for 30 min before being quenched with water. The
aqueous phase was extracted with CH2Cl2 (2ꢂ5 mL) and the com-
bined organic layers were washed with water (10 mL) and brine
(10 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude product was chromatographed
on silica (hexanes/ethyl acetate 10:1) to afford compound 13
a colorless oil: 1H NMR (400 MHz, CDCl3)
d
6.46 (d, J¼2 Hz, 1H), 6.37
(d, J¼2 Hz,1H), 5.13e5.10 (m, 2H), 2.69e2.60 (m, 2H), 2.12e2.09 (m,
5H), 1.95e1.90 (m, 3H), 1.78e1.74 (m, 2H),1.69 (s, 3H), 1.68e1.61 (m,
1H), 1.60 (s, 3H), 1.57 (s, 3H), 1.55e1.45 (m, 1H), 1.32e1.26 (m, 4H),
1.26 (s, 4H), 1.26e1.22 (m, 1H), 1.20e1.00 (m, 2H), 0.97 (s, 9H), 0.86
(d, J¼6.4 Hz, 3H), 0.16 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 147.7,
146.5, 135.7, 131.1, 127.0, 125.2, 124.2, 121.0, 120.2, 117.4, 75.4, 40.1,
39.9, 37.3, 36.7, 32.5, 31.6, 29.9, 25.9, 25.7, 25.5, 24.2, 22.6, 22.3,19.8,
18.3,17.8,16.2,15.9, ꢀ4.3; MS (EI) m/z: 512.4 (Mþ); HRMS (ESI/APCI)
m/z calcd for C33H57O2Si [MþH]þ 513.4122, found 513.4134.
(120 mg, 98%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
d 6.46 (d,
J¼2 Hz, 1H), 6.37 (d, J¼2 Hz, 1H), 5.55 (t, J¼7.2 Hz, 1H), 4.00 (s, 2H),
2.65e2.75 (m, 2H), 2.16e2.22 (m, 2H), 2.11 (s, 3H), 1.64e1.81 (m,
6H), 1.52e1.60 (m, 1H), 1.26 (s, 3H), 0.97 (s, 9H), 0.16 (s, 6H); 13C
NMR (100 MHz, CDCl3)
d
147.8, 146.3, 131.8, 131.0, 126.9, 120.9,
4.9. (2R,80S,30E)-
d-Tocodienol (1)
120.3,117.4, 75.1, 52.6, 39.1, 31.7, 25.9, 24.1, 22.6, 22.5,18.5, 16.2,14.1,
ꢀ4.3; MS (EI) m/z 408.3/410.3 (Mþ); HRMS (ESI/APCI) m/z calcd for
To a solution of compound 10 (13 mg, 0.025 mmol) in THF (3 mL)
was added TBAF (10 mg, 0.038 mmol) at 0 ꢁC. After stirring at the
same temperature for 15 min, the reaction mixture was partitioned
between ethyl acetate (10 mL) and water (5 mL). The aqueous layer
was extracted with ethyl acetate (2ꢂ5 mL), and the combined or-
ganic layers were washed with water (3 mL) and brine (3 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude product was chromatographed on silica (hex-
anes/ethyl acetate 15:1e10:1) to afford 1 (10 mg, 100%) as a color-
C
23H38O2Si35Cl [MþH]þ 409.2324, found 409.2317.
4.7. (R)-[(3,7-Dimethyloct-6-en-1-yl)sulfonyl]benzene (14)
To a solution of 8-bromo-2,6-dimethyloct-2-ene (300 mg,
1.29 mmol) in DMF (5 mL) was added sodium benzenesulfinate
(253 mg, 1.54 mmol) at room temperature. The resulting mixture
was stirred overnight. Ethyl acetate (40 mL) was added and the
resulting mixture was washed with water (20 mL) and brine
(20 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude product was chromatographed
on silica (hexanes/ethyl acetate 5:1) to afford compound 14
(310 mg, 81%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
less oil: 1H NMR (400 MHz, CDCl3)
d
6.48 (d, J¼2.8 Hz, 1H), 6.38 (d,
J¼2.8 Hz,1H), 5.11 (m, 2H), 4.18 (br s,1H), 2.65e2.74 (m, 2H), 2.12 (s,
3H), 2.08e2.13 (m, 2H), 1.85e1.98 (m, 3H), 1.60e1.80 (m, 2H), 1.68
(s, 3H), 1.62e1.66 (m, 1H), 1.60 (s, 3H), 1.58 (s, 3H), 1.52e1.56 (m,
1H), 1.18e1.38 (m, 9H), 1.04e1.17 (m, 2H), 0.85 (d, J¼6.8 Hz, 3H); 13
C
d
7.55e7.92 (m, 5H), 5.02 (t, J¼7.2 Hz, 1H), 3.01e3.14 (m, 2H),
NMR (100 MHz, CDCl3) d 147.8, 146.2,135.7, 131.1, 127.5, 125.2,124.2,
1.87e1.96 (m, 2H),1.66e1.78 (m,1H),1.66 (s, 3H),1.46e1.61 (m, 5H),
1.22e1.31 (m,1H), 1.11e1.18 (m,1H), 0.85 (d, J¼6.4 Hz, 3H); 13C NMR
121.4, 115.7, 112.7, 75.5, 40.1, 39.9, 37.3, 36.7, 32.5, 31.5, 25.9, 25.7,
25.5, 24.2, 22.6, 22.3, 19.8, 17.8, 16.2, 15.9; MS (EI) m/z 398.3 (Mþ);
Please cite this article in press as: Liu, X.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.028

6
X. Liu et al. / Tetrahedron xxx (2016) 1e6
HRMS (ESI/APCI) m/z calcd for C27H43O2 [MþH]þ 399.3258, found
8. (a) Uria, U.; Vila, C.; Lin, M.-Y.; Rueping, M. Chem.dEur. J. 2014, 20,
ꢁ
~
13913e13917; (b) Lecea, M.; Hernandez-Torres, G.; Urbano, A.; Carreno, M. C.;
Colobert, F. Org. Lett. 2010, 12, 580e583; (c) Rein, C.; Demel, P.; Outten, R. A.;
Netscher, T.; Breit, B. Angew. Chem., Int. Ed. 2007, 46, 8670e8673; (d) Jung, M. E.;
MacDougall, J. M. Tetrahedron Lett. 1999, 40, 6339e6342.
399.3262.
Acknowledgements
^
9. (a) Chenevert, R.; Courchesne, G. Tetrahedron Lett. 2002, 43, 7971e7973; (b)
Fuchs, M.; Simeo, Y.; Ueberbacher, B. T.; Mautner, B.; Netscher, T.; Faber, K. Eur. J.
Org. Chem. 2009, 833e840; (c) Couladouros, E. A.; Moutsos, V. I.; Lamp-
ropoulou, M.; Little, J. L.; Hyatt, J. A. J. Org. Chem. 2007, 72, 6735e6741; (d)
This work was supported financially by the National Institute of
General Medical Sciences of the National Institutes of Health under
grant number P20 GM109005. We thank Dr. Barrie Tan and
American River Nutrition, Inc. for providing DeltaGoldÒ.
^
Chenevert, R.; Courchesne, G.; Pelchat, N. Bioorg. Med. Chem. 2006, 14,
5389e5396; (e) Spivak, A. Y.; Shafikov, R. V.; Odinokov, V. N. Arkivoc 2011,
67e75; (f) Sugai, T.; Watanabe, N.; Ohta, H. Tetrahedron: Asymmetry 1991, 2,
371e376; (g) Hyatt, J. A.; Skelton, C. Tetrahedron: Asymmetry 1997, 8, 523e526;
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Supplementary data
10. Alternatively, DeltaGoldÒ was treated directly with TBSCl in CH2Cl2 to form
TBS-protected tocotrienols, which were then subjected to column separation.
Supplementary data (Reaction procedures and GCeMS spectra
for 10 from 6 and 16; 1H and 13C NMR spectra of compounds 1, 2, 3,
5, 6, 10, 13, and 16; antioxidant data) associated with this article can
be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2016.05.028.
However, the separation between TBS-d- and TBS-g-tocotrienol proved to be
very difficult.
11. Aldehyde 3 was inseparable from other components in the reaction mixture. To
determine the reaction yields, the crude product was treated with NaBH4/EtOH
to afford the corresponding primary alcohol, which was readily isolated by
column chromatography in 10e17% yield (two steps).
12. Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 19, 3217e3219.
13. Nicolaou, K. C.; Adsool, V. A.; Hale, R. H. Org. Lett. 2010, 12, 1552e1555.
14. The ee was determined on the corresponding primary alcohol of 3 by HPLC
using a Chiralcel OD-H column.
15. Qian, X.; Auffrant, A.; Felouat, A.; Gosmini, C. Angew. Chem., Int. Ed. 2011, 123,
10586e10589.
16. (a) Grieco, P. A.; Masaki, Y. J. Org. Chem. 1974, 39, 2135e2136; (b) Terao, S.; Kato,
K.; Shiraishi, M.; Morimoto, H. J. Chem. Soc., Perkin Trans. 1 1978, 1101e1110; (c)
Sato, K.; Miyamoto, O.; Inoue, S.; Yamamoto, T.; Hirasawa, Y. J. Chem. Soc., Chem.
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20. The ratio between 10 and the combined amount of three isomers is about 60:
40 based on GCeMS analysis.
Please cite this article in press as: Liu, X.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.028