Approaches to the preparation of 4-benzyloxy-2-(α,α,α- D3)methylphenol, a building block for labeled δ-tocopherol, and a new synthesis of R,R,R-5-D3-α-tocopherol

Article abstract of DOI:10.1002/ejoc.200400535

Different routes are described for the synthesis of 4-benzyloxy-2-D ₃-phenol, a key building block in the preparation of D ₃-δ-tocopherol. Conditions for the improvement of Minami's reduction are also given, allowing a straightforward route to the title compound and a new synthesis of R,R,R-5-D₃-α-tocopherol in good yields, starting from widely available R,R,R-α-tocopherol. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400535

FULL PAPER
Approaches to the Preparation of 4-Benzyloxy-2-(α,α,α-D3)methylphenol,
a Building Block for Labeled δ-Tocopherol, and a New Synthesis of
R,R,R-5-D3-α-Tocopherol
Francesco Mazzini,[a] Alessandro Mandoli,[a] Piero Salvadori,*[a] Thomas Netscher,[b] and
Thomas Rosenau[c]
Keywords: Natural products / Tocopherols / Deuterium labeling / Chroman ring / Reduction
Different routes are described for the synthesis of 4-
R,R,R-5-D3-α-tocopherol in good yields, starting from widely
benzyloxy-2-D3-phenol, a key building block in the prepara- available R,R,R-α-tocopherol.
tion of D3-δ-tocopherol. Conditions for the improvement of
Minami’s reduction are also given, allowing a straightfor-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ward route to the title compound and a new synthesis of Germany, 2004)
Introduction
metry,[4Ϫ6] which are being used more and more for the
characterization of such complex matrices.
As the building of the chroman and aliphatic side-chain
systems has already been reported in various and efficient
ways,[7] the key point in planning a trideuteromethyl δ-to-
copherol synthesis in either a racemic or a stereoiso-
merically pure form can be envisaged in the preparation of
a D3-hydroquinone derivative properly protected on the
oxygen in the 4-position.
Here we describe a very easy and high yielding procedure
for the synthesis of 2-D3-4-benzyloxyphenol (1) that dra-
matically improves our previous preparation of 8-D3-δ-to-
copherol.[8] Moreover, we report the application of the same
simple route for an alternative synthesis of 5-D3-α-tocoph-
erol.
Vitamin E is the most important fat-soluble, chain-break-
ing antioxidant. The term vitamin E covers all tocol and
tocotrienol derivatives that exhibiting the biological activity
of α-tocopherol.[1] There is growing interest in a deep and
thorough study of α-tocopherol lower homologues,[2] γ- and
δ-tocopherol. Despite their much lower plasma concen-
tration and bioactivity compared to α-tocopherol, it is im-
portant to have a full understanding of their unique proper-
ties that are not shared by α-tocopherol, and which may be
very important to human health. The strong interest in
these biologically relevant compounds prompted the
development of a synthesis of their labeled analogues to
greatly help in in vivo studies on the metabolic mechanism
and allow very accurate evaluation of their content in bio-
logical and food matrices. The utilization of stable isotope-
labeled analogues greatly facilitates the carrying out of such
studies.[3] In fact, it is a powerful tool in terms of both
specificity and sensitivity, acting as a probe in the body and
as an internal standard for accurate quantitative determi-
nation by specific techniques such as mass spectro-
Results and Discussion
In reporting the first synthesis of D3-δ-tocopherol,[8] we
described the difficulties encountered in attempting the
preparation of the labeled methylhydroquinone derivative 1.
Protection of the phenolic group in the 4-position of the
hydroquinone ring is required to avoid the formation of 5-
and 7-monomethyl regioisomers and possible double-alky-
lation products[9] in the subsequent condensation step with
isophytol for the construction of the chroman ring (Fig-
ure 1). Benzyl would be a good protective group for this
purpose because of its stability in the condensation reac-
tion[9] and the mild conditions used for its subsequent re-
moval, but our previous attempts to perform the reduction
of methyl 5-benzyloxy-2-hydroxy benzoate to 1, via the cor-
[a]
`
Dipartimento di Chimica e Chimica Industriale, Universita di
Pisa,
Via Risorgimento 35, 56126 Pisa, Italy
Fax: (internat.) ϩ 39-050-2219-918-260
E-mail: psalva@dcci.unipi.it
[b]
[c]
Research and Development, DSM Nutritional Products,
P.O. Box 3255, 4002 Basel, Switzerland
Fax: (internat.) ϩ 41-061-687-2201
E-mail: thomas.netscher@dsm.com
Institute of Chemistry, University of Agricultural Sciences,
Muthgasse 18, 1190 Vienna, Austria
Fax: (internat.) ϩ 43-1-36006-6059
E-mail: thomas.rosenau@boku.ac.at
4864
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400535
Eur. J. Org. Chem. 2004, 4864Ϫ4869

Approaches to the Preparation of 4-Benzyloxy-2-(α,α,α-D3)methylphenol
FULL PAPER
responding benzylic alcohol as an intermediate, gave very (9aϪd) of the commercially available hydroquinone mono-
poor results.[8]
benzyl ether 8 were prepared and subjected to several alky-
lation runs, using nBuLi or tBuLi as the metallating agent
and CD3I as the electrophile. In the best case 70% conver-
sion of 9d into the trideuteromethyl derivative was achieved,
but, in general, the separation of the desired product from
the unchanged starting material was not possible. However,
we succeeded in preparing pure
1
by using
a
bromineϪlithium exchange at low temperature on the bro-
minated derivative 9e.[12] Addition of a slight excess (1.4
equivalents) of nBuLi followed by the prompt addition of
six equivalents of CD3I gave compound 1 in 79% overall
yield from 8b, after removal of the MOM group and purifi-
cation by column chromatography (Scheme 2).
Figure 1. Retrosynthesis of ring-labeled δ-tocopherol
In reinvestigating this route, we became interested in a
paper by Versteeg et al. where the trapping of methanesul-
fonates analogous to 5 as the corresponding bromide was
briefly mentioned.[10] Therefore, 5 was prepared from the
acid 2 and reacted with MeSO2Cl, 2,6-lutidine and excess
LiBr to afford a mixture of chlorinated and brominated
products 6a and 6b, respectively. This mixture proved to be
unstable on standing, but its immediate reduction by
LiAlD4 provided, after deprotection, the desired hydro-
quinone 1 in 72% overall yield from 5 (Scheme 1).
Scheme 2. Preparation of 1 by directed metallation (DMG ϭ di-
recting metallation group)
Although the two routes just described were already satis-
factory, we eventually found a much more effective route to
1 based on the report by Minami and Kijima of the re-
duction of salicylic acids to the corresponding 2-meth-
ylphenols.[13] According to this method, the salicylic acid is
converted upon reaction with ethyl chloroformate into a
bis-ethoxycarbonyl derivative, whose treatment with so-
dium borohydride in aqueous THF directly affords the 2-
methylphenol in moderate to good yields. The latter step
is supposed to proceed through an initial reduction of the
carboxylic site of the mixed anhydride moiety to the corre-
sponding benzyloxy anion, followed by migration of the re-
sidual carbonate group from the phenolic to the alcoholic
oxygen atom. Subsequent cleavage of the benzylic CϪO
bond of the resulting phenoxide derivative would then pro-
vide a highly reactive o-quinone methide, whose reduction
by the borohydride eventually leads to the methylphenol
product.[14]
Scheme 1. i) NaH, DMF then BnBr, 86%; ii) NaH, DMF then
MOMCl, quant.; iii) LiAlD4, THF, 86%; iv) MeSO2Cl, 2,6-lutidine,
excess LiBr, THF, 85%; v) LiAlD4, THF, 90%; vi) MeOH, cat. p-
TsOH, 50 °C, 3 h, 95%
Preliminary experiments on 3 carried out according to
this protocol (Scheme 3) revealed that, while the formation
of the intermediate bis-carbonate 10 was quantitative, only
Although most of the steps of this route proceed in high a 50% yield of the desired methylphenol was obtained un-
yields, we also considered the use of a directed metallation der Minami’s original reduction conditions (4 equiv.
strategy[11] in order to shorten the synthesis of 1. For NaBH4, H2O/THF 1:1 as solvent). At first, we supposed
this purpose, N,N-diisopropylcarbamoyl, N,N-diethylcarb- that hydrolysis of the mixed anhydride 10 back to the acid
amoyl, methyl and methoxymethyl (MOM) derivatives could take place in the basic aqueous medium. Therefore,
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FULL PAPER
Scheme 3. i) ClCO2Et, Et3N, 0 °C, 2 h; ii) NaBD4, 8 equiv., D2O/
Scheme 4. i) Br2, hexane, room temp., 3 h; ii) Ac2O, AcOH,
CH2Cl2, H2SO4 cat., room temp., overnight, 82% over 2 steps; iii)
THF, 0 °C, 3 h, 89%; iii) ZnCl2, 1.5 equiv., iBuOAc, aq. HClcat
,
isophytol, 72%; iv) 5% Pd/C, H2, EtOAc, overnight, quant.
NMO,
4 equiv., CH3CN, room temp., overnight, 92%; iv)
NH2SO3H, NaClO2, 1,4-dioxane/H2O, room temp., 50 min, 96%;
v) KOH 2 m, MeOH, 50 °C, 2 h, 93%; vi) a. ClCO2Et, Et3N, 0 °C,
2 h, quant. b. NaBD4, 8 equiv., D2O/THF, 0 °C, 3 h, 72%
we tried changing the solvent to a mixture of THF and
MeOH, but under these conditions only methyl ester and
ethyl carbonate derivatives were obtained. Thus, water
seems to play an essential role in the reaction, as noted
before by Mitchell.[14] In a further experiment, the dropwise
addition of water to a suspension of THF and NaBH4 af-
forded the methylphenol 1 in 35% yield, together with the
corresponding benzylic alcohol in 45% yield. While this was
still unsatisfactory from a synthetic point of view, the for-
mation of the latter product nonetheless offered a clue to
the low to moderate yields reported in Minami’s paper for
most of the substrates. A possible interpretation is that the
postulated o-quinone methide intermediate undergoes at-
tack by water instead of reduction by the borohydride.
Hence, in order to steer the reaction towards the formation
of the methylphenol product, we investigated the effect of
increasing the amount of reducing agent, by carrying out
several experiments in THF/H2O (1:1), with between five
and ten equivalents of NaBH4. Under these conditions the
yields of product increased starting from six equivalents,
reaching a maximum of 89% with eight equivalents. No
further improvements were observed with larger amounts
of NaBH4. Having optimized the procedure, the reduction
step of 10 was repeated with NaBD4 in THF/H2O or, more
effectively, in THF/D2O to prevent H/D scrambling. With
this route, 1 could be prepared with an excellent 98% iso-
tope purity (GC-MS) and 77% overall yield from 2, through
three easy and highly efficient steps.
Conclusions
Different approaches have been explored for the prep-
aration of labeled 4-benzyloxy-2-methylphenol (1), which is
a key building block in the synthesis of deuterated δ-toc-
opherol. In particular, after optimization of Minami’s orig-
inal procedure for the reduction of salicylic acids to 2-meth-
ylphenols, a very simple high yielding and scalable route
was set up, allowing the preparation of 1 in three steps from
commercially available hydroxysalicylic acid (2). Conse-
quently, the synthesis of labeled rac-δ-tocopherol was dra-
matically improved compared with our previously reported
route.[8] The modified Minami protocol also proved effec-
tive with other salicylic acid systems, providing a valid
alternative for the preparation of R,R,R-5-D3-α-tocopherol,
starting from widely available α-tocopherol.
Experimental Section
All reactions were performed under an inert atmosphere (Ar or
1
N2). H and 13C NMR spectra were recorded on a Varian Gemini
200 spectrometer (200 MHz and 50.3 MHz, respectively), in CDCl3
or CD3OD solution with Me4Si or CHCl3 as internal standards. 2H
NMR spectra were recorded on a Varian VXR 300 spectrometer
(46 MHz for 2H) in CHCl3 with CDCl3 as internal standard.
Chemical shifts are expressed on the δ scale (ppm). The APCI mass
spectra were acquired on a PerkinϪElmer Sciex API III Plus mass
spectrometer. GC/MS analyses were recorded on a Saturn 2000
GC-MS/MS Varian Chromatography System mass spectrometer
After acid-catalyzed condensation of 1 with isophytol,
mild Pd/C debenzylation smoothly provided rac-D3-δ-toc- connected to a 3800 Varian gas chromatograph equipped with a
DB-5 capillary column (30 m ϫ 0.25 mm, 0.25 µm film thickness).
Optical purity was checked by chiral HPLC analyses performed
using a Jasco PU-980 system equipped with a Jasco 821-FP fluori-
metric detector (λex ϭ 298 nm, λem ϭ 345 nm) on a Chiralcel OD-
H column (hexane/2-propanol, 200:1). Commercial reagents and
solvents were purchased from Aldrich, Fluka, or Merck, and puri-
fied by standard methods when necessary. THF was distilled from
Na/K alloy before use. Hexane was distilled from Na. LiAlD4 (96
atom-% D), NaBD4 (98 atom-% D), D2O (99.8 atom-% D)and
CD3I (Ն 99.5 atom-% D) were purchased from Aldrich.
2R,4ЈR,8ЈR-α-Tocopherol (Covitol F1490) was purchased from
opherol 12, without any loss of the level of deuteration
(Scheme 3).
Finally, the excellent results achieved in the modified Mi-
nami reduction prompted us to apply the same procedure
to the easily accessible γ-tocopherol-5-carboxylic acid 16.[15]
Following a known sequence, α-tocopherol of natural origin
was converted into 16, by benzylic bromination and a two-
step oxidation,[16Ϫ18] and 16 was then reduced with NaBD4
to the enantiomerically pure R,R,R-5-D3-α-tocopherol 17
in 72% yield from 16 (Scheme 4).
4866
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Approaches to the Preparation of 4-Benzyloxy-2-(α,α,α-D3)methylphenol
FULL PAPER
Henkel. All other commercial reagents were used without further
purification. Column chromatography was performed on silica gel
60 (70Ϫ230 mesh and 230Ϫ400 mesh). TLC was performed on
room temp. for 4 h. Water was then added and the THF evaporated
off. The mixture was extracted with Et2O (3 ϫ 100 mL), the com-
bined organic extracts were subsequently washed to neutrality with
silica gel MachereyϪNagel Alugram Sil G/UV254 (0.20 mm). All water, dried over Na2SO4 and concentrated to dryness. Purification
yields given refer to isolated yields.
by column chromatography (Hex/EtOAc, 4:1) afforded a mixture
of 6a and 6b (4.32 g; Br/Cl ϭ 77:23 by NMR) in 85% yield with
respect to 5. H NMR (CDCl3/TMS): δ ϭ 3.5 and 3.51 (s, H3CO-
5-Benzyloxy-2-hydroxybenzoic Acid (3): A solution of 2 (9.24 g,
60 mmol) in DMF was added dropwise (30 mL) to a suspension of
dry NaH (3.35 g, 132 mmol, 2.2 equiv.) in DMF (50 mL). After
stirring for 2 h at room temperature, a solution of benzyl bromide
(7.13 mL, 60 mmol, 1 equiv.) in DMF (15 mL) was added dropwise.
After 2 h TLC (Hex/EtOAc/AcOH, 3:1:0.005) confirmed complete
conversion of the starting acid. Water was added, the reaction mix-
ture acidified to pH 3 with 1 m HCl and extracted with Et2O (3 ϫ
100 mL). The combined organic extracts were subsequently washed
to neutrality with water, dried over Na2SO4 and finally concen-
trated under reduced pressure. Recrystallization of the crude prod-
uct from CHCl3 (60 mL) afforded 6.45 g of 3 as a white solid. A
further 3.71 g were obtained from a second recrystallization from
CHCl3 (15 mL). The residue was purified by column chromatogra-
phy (Hex/EtOAc/AcOH, 4:1:0.005) to give a further 1.7 g. Overall
yield of 3: 86%. 1H NMR (CDCl3/TMS): δ ϭ 5.06 (s, 2 H, PhCH2),
6.95 (d, J ϭ 9.2 Hz, 1 H, ArH), 7.21 (dd, J1 ϭ 3.2, J2 ϭ 9.0 Hz,1
H, ArH) 7.3Ϫ7.45 (m, 6 H, ArH), 9.98 (s, 1 H, OH) ppm. 13C
NMR (CDCl3): δ ϭ 70.9, 110.7, 113.8, 118.9, 126.5,127.6, 128.1,
128.6, 136.6, 151.3, 157, 174.2 ppm.
1
CH2OArX), 5.01 and 5.02 (s, PhCH2), 5.18 and 5.2 (s, CH3O-
2
CH2OAr), 6.85Ϫ7.5 (m, ArH) ppm. H NMR (CHCl3): δ ϭ 4.51
(s, ArCD2Br), 4.63 (s, ArCD2Cl) ppm.
4-Benzyloxy-1-methoxymethoxy-2-(D3)methylbenzene (7) from 6a/
6b: A solution of 6a/6b (3.22 g) in dry THF (15 mL) was added
dropwise to a stirred suspension of LiAlD4 (940 mg, 24.6 mmol,
2.5 equiv.) in dry THF (20 mL). After 4 h, TLC (Hex/EtOAc, 20:1)
confirmed the end of the reaction. The mixture was neutralized
with water and NH4Cl, and the THF evaporated off. The aqueous
layer was filtered and extracted with Et2O (3 ϫ 100 mL), and the
combined organic extracts were subsequently washed to neutrality
with water and dried over Na2SO4. Evaporating to dryness afforded
1
7 (2.25 g, 90% yield) as a yellow oil. H NMR (CDCl3/TMS): δ ϭ
3.56 (s, 3 H, H3COCH2OAr), 5.06 (s, 2 H, PhCH2), 5.19 (s, 2 H,
CH3OCH2OAr), 6.82 (dd, J1 ϭ 3.1, J2 ϭ 8.8 Hz, 1 H, ArH), 6.91
(d, J ϭ 3.2 Hz, 1 H, ArH), 7.05 (d, J ϭ 8.8 Hz, 1 H, ArH),
7.35Ϫ7.55 (m, 5 H, ArH) ppm. 2H NMR (CHCl3): δ ϭ 2.30 (s,
ArCD3) ppm.
4-Benzyloxy-2-bromo-1-methoxymethoxybenzene (9e): Compound
8b was prepared following the procedure reported by Dodsworth
et al.[19] Its MOM derivative 9e was obtained as described for the
preparation of 4 in 98% yield. H NMR (CDCl3/TMS): δ ϭ 5.00
(s, 2 H, PhCH2), 3.51 (s, 3 H, H3COCH2OAr), 4.99 (s, 2 H,
Methoxymethyl 5-Benzyloxy-2-methoxymethoxybenzoate (4):
A
solution of 3 (4.88 g, 20 mmol) in DMF (30 mL) was added drop-
wise to a suspension of dry NaH (1.26 g, 50 mmol, 2.5 equiv.) in
DMF (20 mL). After stirring for 1 h at room temperature, a solu-
tion of MOMCl (3.8 mL, 50 mmol, 2.5 equiv.) in DMF (15 mL)
was added dropwise, and the resulting mixture was stirred over-
night. Complete conversion of the starting phenol was confirmed
by TLC (Hex/EtOAc, 7:1). Water was added (50 mL) and the reac-
tion mixture extracted with Et2O (3 ϫ 100 mL). The combined
organic extracts were subsequently washed to neutrality with water
and dried over Na2SO4. Evaporation to dryness gave 4 (6.6 g, ഠ
100%) as yellow oil. 1H NMR (CDCl3/TMS): δ ϭ 3.51 (s, 3 H,
H3COCH2OAr), 3.53 (s, 3 H, H3COCH2OCO), 5.03 (s, 2 H,
PhCH2), 5.17 (s, 2 H, CH3OCH2OAr), 5.44 (s, 2 H, CH3OCH2-
OCO), 7.1Ϫ7.6 (m, 8 H, ArH) ppm.
1
PhCH2), 5.15 (s, 2 H, CH3OCH2OAr), 6.85 (dd, J1 ϭ 3.0, J2
ϭ
9.0 Hz, 1 H, ArH), 7.04 (d, J ϭ 9.0 Hz, 1 H, ArH), 7.19 (d, J ϭ
3.0 Hz, 1 H, ArH), 7.35Ϫ7.42 (m, 5 H, ArH) ppm. 13C NMR
(CDCl3): δ ϭ 56.3, 70.7, 96.1, 113.6, 114.8, 118.1, 119.6, 127.3,
128.1, 128.5, 136.5, 148.3, 154.1 ppm.
4-Benzyloxy-1-methoxymethoxy-2-(D3)methylbenzene (7) from 9e:
A solution of nBuLi (1.9 mL, 4.2 mmol, 2.2 m in hexane) was added
to a solution of 9e (970 mg, 3 mmol) in dry THF (15 mL) at Ϫ78
°C. Immediately afterwards a solution of CD3I (1.12 mL, 18 mmol,
6 equiv.) in dry THF (10 mL) was added. After 2 h, GC analysis
showed a 97% conversion of the starting material and formation
of 7 in 90% yield.
5-Benzyloxy-2-methoxymethoxy-(α,α-D2)benzyl Alcohol (5): A solu-
tion of 4 (6.56 g) in dry THF (20 mL) was added dropwise at 0 °C
to a stirred suspension of LiAlD4 (1.4 g, 36.8 mmol) in dry THF
(15 mL). The mixture was then warmed to room temp. and stirred
for 3 h. TLC (Hex/EtOAc, 3:1) showed the complete conversion of
reagent. The mixture was neutralized with water and NH4Cl, and
the THF evaporated off. The aqueous layer was filtered and ex-
tracted with Et2O (3 ϫ 100 mL), and the combined organic extracts
were subsequently washed to neutrality with water and dried over
Na2SO4. The solution was concentrated in vacuo to give 5 (4.72 g,
86% yield) as a pale-yellow solid. 1H NMR (CDCl3/TMS): δ ϭ 2.8
(br. s, 1 H, OH), 3.49 (s, 3 H, H3COCH2OAr), 5.03 (s, 2 H,
PhCH2), 5.12 (s, 2 H, CH3OCϪH2OAr), 6.83 (dd, J1 ϭ 3.2, J2 ϭ
9.2 Hz, 1 H, ArH), 6.9Ϫ7.06 (m, 2 H, ArH), 7.3Ϫ7.46 (m, 5 H,
4-Benzyloxy-(2-D3)methylphenol (1) from 7: The crude mixture of
7 was dissolved in MeOH (25 mL), a catalytic amount of p-TsOH
was added and the reaction was heated to 50 °C for 3 h. After
evaporating the solvent, the residue was purified by column chro-
matography (Hex/EtOAc, 5:1) to afford 1 in 82% yield from 9e.
4-Benzyloxy-(2-D3)methylphenol (1) from 3: ClCO2Et (1.08 mL,
11.3 mmol, 2.6 equiv.) was added to a solution of 3 (1.06 g,
4.3 mmol) and Et3N (1.6 mL, 11.3 mmol, 2.6 equiv.) in THF
(45 mL) at 0 °C and the mixture stirred for 3 h at this temperature.
The resulting white precipitate was filtered off and washed with
THF (15 mL). The combined filtrates were concentrated to small
volume, re-diluted with THF (15 mL) and carefully added to a
solution of NaBD4 (1.32 g, 34.7 mmol, 8 equiv.) in D2O (15 mL)
at 0 °C. The white suspension was allowed to warm to room temp.
and stirred overnight. TLC (Hex/EtOAc/AcOH, 3:1:0.005) showed
complete conversion of the starting acid. The mixture was neu-
tralized with 1 m HCl and the THF evaporated off. The aqueous
2
ArH) ppm. H NMR (CHCl3): δ ϭ 4.63 (s, benzylic D) ppm. 13C
NMR (CDCl3): δ ϭ 56.0, 61.2 (m), 70.3, 95.4, 114.3, 115.2, 115.8,
127.3, 127.7, 128.4, 131.5, 137, 149, 153.8 ppm.
5-Benzyloxy-2-methoxymethoxy-(α,α-D2)benzyl Bromide/Chloride
Mixture (6a/6b): LiBr (13 g, 150 mmol, 10 equiv.), 5 (4.11 g,
15 mmol), 2,6-lutidine (3.48 mL, 30 mmol,
(2.34 mL, 30 mmol, 2 equiv.) and dry THF (60 mL) were stirred at
2
equiv.), MsCl layer was extracted with Et2O (3 ϫ 100 mL), and the combined
organic extracts were subsequently washed to neutrality with water
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FULL PAPER
and dried over Na2SO4. The solution was concentrated in vacuo to
give 1 (840 mg, 89% yield) as a pale-yellow solid. M.p. 85Ϫ88 °C.
1H NMR (CDCl3/TMS): δ ϭ 4.55 (br. s, 1 H, OH), 4.99 (s, 2 H,
Na2SO3 (150 mg) was added to destroy the unreacted NaClO2 and
any HOCl formed during the reaction. Water was then added and
the aqueous phase was extracted with Et2O (3 ϫ 50 mL). The com-
bined organic extracts were subsequently washed to neutrality with
PhCH2), 6.68 (m, 2 H, ArH), 6.78 (m, 1 H, ArH), 7.35Ϫ7.45 (m,
2
5 H, ArH) ppm. H NMR (CH3Cl): δ ϭ 2.2 (s, ArCD3) ppm. 13C water, dried over Na2SO4 and concentrated to dryness to give pure
NMR (CDCl3): δ ϭ 16.3, 71.0, 113.3, 115.7, 118.1, 125.2, 127.7,
15 (485 mg, 96% yield), without further purification, as a yellow
128.1, 128.8, 137.2, 148.3 ppm. APCI-MS (in MeOH): m/z ϭ 218 oil. 1H NMR (CDCl3/TMS): δ ϭ 0.95Ϫ1.6 [m, 36 H, C(2a)H3 and
[M ϩ Hϩ]. C14H11D3O2 (217.3): calcd. C 77.39, H 7.88; found C
77.18, H 7.65; 98% isotope purity by GC mass spectrometry.
C16H33 chain], 1.7 (m, 2 H, ArCH2CH2), 2.01 (s, 3 H, ArCH3), 2.1
(s, 3 H, ArCH3), 2.28 (s, 3 H, CH3CO), 2.9 (t, J ϭ 6.2 Hz, 2 H,
ArCH2CH2), 9.2 (br. s, 1 H, ArCO2H) ppm. 13C NMR (CDCl3):
δ ϭ 12.8, 12.9, 19.6, 19.7, 20.6, 21.1, 22.5, 22.7, 24, 24.4, 24.7, 27.9,
30.6, 32.7, 37.2, 37.3, 39.3. 40.1, 76, 118.3, 121.5, 128.9, 130.3,
140.5, 150, 170.1, 171.9 ppm.
6-O-Benzyl-(8-D3)-(all-rac)-δ-tocopherol (11): A solution of isophy-
tol (0.48 mL, 1.37 mmol) in iBuOAc (5 mL) was added dropwise
very slowly (over 3 h) to a stirred mixture of 1 (200 mg, 0.91 mmol),
0.5 mL of aq. HCl (Ͼ36.5%) and anhydrous ZnCl2 (190 mg,
1.37 mmol, 1.5 equiv.) in iBuOAc (5 mL) at 50 °C. The reaction
mixture was stirred for a further 3 h at 50 °C and then allowed to
cool to room temp. After workup by extraction with toluene/water,
the resulting crude brownish mixture was saponified by stirring for
4.5 h at room temp. with methanolic 1 m KOH (12 mL). The mix-
ture was then acidified with 2 m HCl, and the MeOH evaporated
off. Water (10 mL) was added and the mixture extracted with Et2O
(3 ϫ 30 mL). The combined organic extracts were subsequently
washed to neutrality with water, dried over Na2SO4 and concen-
trated to dryness. After purification by flash chromatography (Hex/
EtOAc, 9:1), 11 (320 mg, 72% yield) was obtained as a brown-yel-
(2R,4ЈR,8ЈR)-γ-Tocopherol-5-carboxylic Acid (16): A solution of
KOH in MeOH (10 mL, 2 m) was added to 15 (490 mg, 0.97 mmol).
The solution was heated to 50 °C for 2 h, then the MeOH was
evaporated off and water added. The aqueous phase was extracted
with Et2O (3 ϫ 50 mL). The combined organic extracts were sub-
sequently washed to neutrality with water, dried over Na2SO4 and
concentrated to dryness to give pure 16 (420 mg, 93% yield), with-
1
out further purification, as a yellow semi-solid. H NMR (CDCl3/
TMS): δ ϭ 0.95Ϫ1.6 [m, 36 H, C(2a)H3 and C16H33 chain], 1.7 (m,
2 H, ArCH2CH2), 2.01 (s, 3 H, ArCH3), 2.1 (s, 3 H, ArCH3), 3.05
(t, J ϭ 6.2 Hz, 2 H, ArCH2CH2), 9.8 (br. s, 1 H, ArOH), 11.1 (br.
s, 1 H, ArCO2H) ppm. 13C NMR (CDCl3): δ ϭ 11.8, 13.0, 19.6,
19.7, 20.9, 22.6, 22.7, 23.6, 24, 24.4, 24.8, 27.9, 30.9, 31.4, 32.6,
32.8, 37.2, 37.3, 37.4, 39.3. 39.6, 74.6, 106.7, 119, 124, 136.1, 144.8,
155.9, 176.8 ppm.
1
low oil. H NMR (CDCl3/TMS): δ ϭ 0.7Ϫ1.9 [m, 38 H, C(3)H2,
C(2a)H3 and C16H33 chain], 2.7 [t, J ϭ 7.0, 2 H, C(4)H2], 5.0 (s, 2
H, PhCH2), 6.5 (d, J ϭ 3.1 Hz, 1 H, ArH), 6.7 (d, J ϭ 3.2 Hz, 1
H, ArH), 7.3Ϫ7.5 (m, 5 H, ArH) ppm. 2H NMR (CHCl3): δ ϭ
2.11 [s, C(8)D3] ppm. APCI-MS (in MeOH): m/z ϭ 497 [M ϩ 1].
(8-D3)-(all-rac)-δ-Tocopherol (12): A suspension of 11 (150 mg,
0.3 mmol) and 5% palladium on carbon (160 mg) in EtOAc (6 mL)
was stirred overnight under an atmosphere of hydrogen. After fil-
tering through celite, the filtrate was concentrated in vacuo afford-
ing 12 (120 mg, ഠ100% yield) as a pale-yellow dense liquid. 1H
NMR (CDCl3/TMS): δ ϭ 0.7Ϫ1.9 [m, 38 H, C(3)H2, C(2a)H3 and
C16H33 chain], 2.65 [t, J ϭ 7.0, 2 H, C(4)H2], 4.4 (br. s, 1 H, OH),
6.38 [d, J ϭ 2.6 Hz, 1 H, C(5)H], 6.47 [s, 1 H, C(7)H] ppm; no
aromatic 8-methyl proton signal at δ ϭ 2.09 ppm was detectable.
2H NMR (CHCl3): δ ϭ 2.08 [s, C(8)D3] ppm. 13C NMR (CDCl3):
δ ϭ 147.8, 146.0, 127.1, 121.3, 115.8, 112.5, 75.5, 40.1, 39.4,
37.3Ϫ37.6, 32.8, 32.7, 31.4, 28, 24.8, 24.4, 24, 22.7, 22.6, 22.5, 21,
19.5Ϫ19.7 ppm. APCI-MS (in MeOH): m/z ϭ 406 [M ϩ Hϩ], 140.
Isotope purity of 98% by GC-MS (TMS derivative).
(2R,4ЈR,8ЈR)-(5-D3)-(2R,4ЈR,8ЈR)-α-tocopherol (17): ClCO2Et
(0.22 mL, 2.26 mmol, 2.6 equiv.) was added to a solution of 16
(400 mg, 0.87 mmol) and Et3N (0.32 mL, 2.26 mmol, 2.6 equiv.) in
THF (10 mL) at 0 °C and the mixture stirred for 3 h at 0 °C. The
resulting white precipitate was filtered off and washed with THF
(10 mL). The combined filtrates were concentrated to small vol-
ume, re-diluted with THF (10 mL) and carefully added to a solu-
tion of NaBD4 (295 mg, 6.97 mmol, 8 equiv.) in D2O (10 mL) at 0
°C. The white suspension was allowed to warm to room temp. and
stirred overnight. TLC (Hex/EtOAc/AcOH, 3:1:0.005) showed
complete conversion of the starting acid. The mixture was neu-
tralized with 1 m HCl and the THF evaporated off. The aqueous
layer was extracted with Et2O (3 ϫ 30 mL), and the combined or-
ganic extracts were subsequently washed to neutrality with water
and dried over Na2SO4. The solution was concentrated in vacuo,
giving 17 (270 mg, 72% yield) as yellow oil. 1H NMR (CDCl3/
TMS): δ ϭ 0.7Ϫ1.9 [m, 38 H, C(3)H2, C(2a)H3 and C16H33 chain],
2.11 and 2.18 [s, 3 H, C(8)CH3 and s, 3 H, CH3C(7)], 2.6 [t, J ϭ
7.0 Hz, 2 H, C(4)H2], 4.2 (br. s, 1 H, OH) ppm. 2H NMR (CHCl3):
δ ϭ 2.08 [s, C(5)CD3] ppm. 13C NMR (CDCl3): δ ϭ 146.1, 145,
122.9, 121.3, 119.2, 117.3, 74.8, 40.3, 39.5, 37.8Ϫ38.1, 33.2, 33.1,
32.1, 28.4, 25.2, 24.9, 24.4, 23.2, 23.1, 21.8, 21.2, 20.4Ϫ20, 12.8,
12.2 ppm. APCI-MS (positive ion mode; in MeOH): m/z ϭ 433
[Mϩ]. Isotope purity of 98.5% by GC-MS (TMS derivative). Op-
tical purity assessed by chiral HPLC.
6-O-Acetyl-5-formyl-(2R,4ЈR,8ЈR)-γ-tocopherol (14): NMO (1.14 g,
9.7 mmol, 4 equiv.) was added to a solution of 13[15] (1.34 g,
2.41 mmol) in dry acetonitrile (20 mL). After stirring for 5 h at
room temp., the solvent was evaporated and the crude residue puri-
fied by column chromatography (Hex/EtOAc, 15:1) to afford 14
1
(1.17 g, 92% yield) as a dense, yellow oil. H NMR (CDCl3/TMS):
δ ϭ 0.95Ϫ1.6 [m, 36 H, C(2a)H3 and C16H33 chain], 1.7 (m, 2 H,
ArCH2CH2), 2.02 (s, 3 H, ArCH3), 2.1 (s, 3 H, ArCH3), 2.3 (s, 3
H, CH3CO), 3.05 (t, J ϭ 6.2 Hz, 2 H, ArCH2CH2), 10.26 (s, 1 H,
ArCHO) ppm. 13C NMR (CDCl3): δ ϭ 12.9, 13.0, 19.6, 19.7, 20.4,
20.9, 22.5, 22.6, 23.8, 24.7, 27.9, 30.5, 30.7, 32.6, 32.7, 37.2, 37.3,
37.4, 39.3. 39.9, 75.8, 120.5, 122.8, 128.2, 136.6, 145.0, 149.8, 169.6,
189.9 ppm.
6-O-Acetyl-(2R,4ЈR,8ЈR)-γ-tocopherol-5-carboxylic
Acid
(15):
NH2SO3H (160 mg. 1.6 mmol, 1.6 equiv.) and water (7 mL) were
added to a solution of 14 (490 mg, 1 mmol) in 1,4-dioxane (20 mL).
After stirring for 20 min, NaClO2 (180 mg, 1.4 mmol, 1.4 equiv.)
and water (5 mL) were added. After stirring for a further 30 min,
Acknowledgments
The University of Pisa and Centro di Eccellenza AMBISEN are
acknowledged for financial support.
4868
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4864Ϫ4869

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Received July 28, 2004
Eur. J. Org. Chem. 2004, 4864Ϫ4869
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© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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