2,5,6,7,8-Pentasubstituted (S)- and (R)-[2-chroman-2-yl]ethanols as intermediates for the synthesis of α-tocopherol and its chiral analogs

Article abstract of DOI:10.1023/A:1015001401902

In the presence of lipase from the yeast Candida cylindracea, partial acetylation of (±)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl]ethanol with vinyl acetate gives S-(+)-acetate whose alkaline hydrolysis affords (5)-( - )-alcohol. Repeated enzymatic

Full text of DOI:10.1023/A:1015001401902

Russian Chemical Bulletin, International Edition, Vol. 50, No. 11, pp. 2121—2129, November, 2001
2121
2,5,6,7,8-Pentasubstituted (S)- and (R)-[2-chroman-2-yl]ethanols as
intermediates for the synthesis of α-tocopherol and its chiral analogs
V. N. Odinokov,a« A. Yu. Spivak,a G. A. Emel´yanova,a G. D. Gamalevich,b and E. P. Serebryakovb«
àInstitute of Petrochemistry and Catalysis, Bashkortostan Republic Academy of Sciences
and Ufa Scientific Center of the Russian Academy of Sciences,
141 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
Fax: +7 (347 2) 31 2750. E-mail: ink@anrb.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. E-mail: ser@cacr.ioc.ac.ru
In the presence of lipase from the yeast Candida cylindracea, partial acetylation of
(±)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl]ethanol with vinyl acetate gives
S-(+)-acetate whose alkaline hydrolysis affords (S)-(–)-alcohol. Repeated enzymatic acety-
lation of the "residual" alcohol up to ∼39% conversion afforded the R-enantiomer. The
enantiomeric alcohols were oxidized to (S)- or (R)-aldehydes having the same sign of [α]D as
the original alcohols. These alcohols were converted into S-(+)- and R-(–)-enantiomers of
the antioxidant MDL-73404, a hydrophilic analog of α-tocopherol.
Key words: (S)- and (R)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl]ethanols;
(S)- and (R)-[6-benzyloxy-2,5,7,8-tetramehylchroman-2-yl]acetaldehydes; (S)-2-[6-hydroxy-
2,5,7,8-tetramethylchroman-2-yl]ethanol; lipase from Candida cylindracea, enantioselec-
tive acylation; 2-{[6-hydroxy-2,5,7,8-tetramethylcroman-2-yl]ethy}trimethylammonium
p-toluenesulfonate, S- and R-enantiomers.
Natural α-tocopherol ((2R,4´R,8´R)-6-hydroxy-
2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman,
(R)-1) is an important inhibitor of lipid peroxidation in
vivo and a powerful cytoprotector.1,2 Although the activ-
ity of (R)-1 is only ∼1.4 times as high as that of synthetic
vitamin Å (a racemic mixture of all stereoisomers pos-
sible for this structure), the understanding of the impor-
tance of this lipophilic vitamin as a therapeutic and
preventive drug and a food additive, which has grown
rapidly during the last three decades, has led to intensive
search for industrially viable methods of the total synthe-
sis of enantiopure α-tocopherol (for reviews, see Refs 3
and 4). In particular, many effective and/or elegant
pathways to chroman derivatives of the type 2 containing
a functionalized substituent at C(2) appropriate for con-
struction of side chains of α-tocopherol and re-
lated compounds have been developed.3—11 (S)-(6-Ben-
zyloxy-2,5,7,8-tetramethylchroman-2-yl)acetaldehyde
((S)-3),10,12 2-(S)-2-[6-hydroxy-2,5,7,8-tetramethyl-
chroman-2-yl]ethanol ((S)-4),10,13 and (S)-2-[6-ben-
4″
R1O
1″
4a
HO
6
O
2´
2
8a
O
R
O
R
O
O
1
´
2
(S)-3
(R)-1: R =
–
(S)-10: R = [N+Me3]TsO
2: R = CHO, Cl, OMe, CH2CO2H, CH2CH2OTs, etc.
R1 = H, Ac, H2NCOCO, etc.
RO
OR1
O
(S)-4: R = H, R1 = H
(S)-5: R = H, R1 = Ac
(S)-6: R = Bn, R1 = H
(S)-7: R = Bn, R1 = Ac
(S)-4, (S)-5, (S)-6, (S)-7
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2026—2033, November, 2001.
1066-5285/01/5011-2121 $25.00 © 2001 Plenum Publishing Corporation

2122
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 11, November, 2001
Odinokov et al.
Table 1. Acylation of alcohol (±)-6 with vinyl acetate in the presence of lipase from the yeast Candida
cylindracea (CCL)
Run
T/°Ñ
(±)-6 : CCL
C (%)a
(+)-7
[α]D (CHCl3)
(+)-6
[α]D (CHCl3)
ratio, (w/w)
Yield (%)
Yieldb (%)
1
2
3
4
5
22±2
22±2
4±1
4±1
4±1
1 : 1
2 : 1
1 : 1
1 : 1
1 : 1
50—52
∼32
50
32
31
47.5
50.5
+5.9
+6.8
+18.5
+17.1
+16.3
43.5
66.5
65.4
49.7
44.8
+4.4
Not determined
Not determined
+16.2
> 32
> 47.5
> 50.5
+16.4
a Determined from the chemical yield of isolated pure (TLC, 1H NMR) acetate (+)-7.
b Recovery of the pure scalemic alcohol.
zyloxy-2,5,7,8-tetramethylchroman-2-yl]ethanol ((S)-6)14
are among the most promising intermediates for the
synthesis of (R)-1 and its biologically active analogs.
Homochiral intermediates (S)-3, (S)-4, and (S)-6
were first synthesized from the corresponding (S)-acid
(2, R = CH2CO2H, R1 = H), which in turn was
obtained from the corresponding racemate by classical
resolution of diastereomeric salts.12 A rational alterna-
tive to this approach is the synthesis of racemic phenolic
alcohol 4 ((±)-4) and its kinetic resolution into enanti-
omers using lipases, because simple methods are
known9,10 for the conversion of the "wrong" enantiomer
(R)-4 into (S)-4. Compound (±)-4 is easily obtained by
C-alkylation of trimethylhydroquinone (8) with 4-methyl-
5,6-dihydro-2H-pyran (9),15 which is a side product in
the production of isoprene by the Prins reaction.16 Phe-
nol (±)-4 has already been used for the synthesis of the
racemic antioxidant MDL-73404, which displays cardio-
protective activity,17 and later, for the synthesis of an
optically active form of MDL-73404, to which the
S-configuration at C(2) was assigned ((S)-10).10
was acylated with vinyl acetate in Et2O in the presence
of CCL (no reaction occurs in acetone at 0 or 22 °C,
Scheme 1), and the reaction products were separated by
column chromatography (Table 1). No products other
than (+)-acetate and the "residual" (+)-alcohol were
detected.
At both 22±2° and 4±1 °C, dextrorotatory acetate
and dextrorotatory "residual" alcohol were obtained. Judg-
ing by the sign and the magnitude of [α]D (for (S)-6 and
(R)-6 the [α]D25 values are –16.2 (CHCl3) 12 and +15.7
(CHCl3),19 respectively), the latter was assumed to be
alcohol (R)-6. Hence, S-configuration should be as-
signed to the isolated acetate (+)-7.
Enzymatic acylation of alcohol (±)-6 at 4±1 °C up
to the conversion C > 32% followed by chromatographic
separation of the product mixture afforded acetate 7
with [α]D22 +18.5 (CHCl3) (specimen (S)-7(À), Table 1,
run 3). Alkaline hydrolysis of this acetate (LiOH in
aqueous MeOH) gave rise to alcohol (S)-6 with
22
[α]D –17.1 (CHCl3). The total yield of (S)-6 over two
steps was 30.4% based on (±)-6, or, in other words,
60.8% of its content in the racemate.
Upon oxidation with pyridinium chlorochromate,
the resulting specimen of alcohol (S)-6 was converted
Results and Discussion
22
into aldehyde (S)-3 with [α]D –15.1 (CHCl3). Al-
We have developed a chemo-enzymatic synthesis of
aldehyde (S)-3 from compounds 8 and 9 using the most
readily available microbial lipase, the lipase from
the yeast Candida cylindracea (CCL). It had been
shown previously18 that (±)-3,7-dimethyloctanol and
(±)-7-methoxy-3,7-dimethyloctanol where, alike with
alcohol 6, the reaction center and asymmetric center are
separated by two methylene groups, can be converted,
on treatment with vinyl acetate in the presence of CCL,
into the corresponding (S)-acetates and "residual"
(R)-alcohols with high enantioselectivity (ee 92—98%)
and good yields. This served as the basis for the present
study.
Chemo-enzymatic synthesis of enantiomeric chirons 6
and 3. The reaction of dihydropyran 9 with trimethyl-
hydroquinone 8 in the presence of AlCl3
pound (±)-4, the phenolic hydroxyl of which was selec-
tively protected by benzylation (PhCH2Cl in the K2CO3
(solid)/DMF system). The resulting compound (±)-6
though this configuration has previously been assigned12
22
to an aldehyde with [α]D +15.16 or +16.2 (CHCl3),
prepared by treating precursor 2 (R = CH2CO2Me,
R´ = Bn)* with Bui2AlH, the above transformations
suggest that dextrorotatory acetate 7 has most probably
S configuration.
The scalemic alcohol fraction isolated upon enzy-
matic acylation of (±)-6 at 4±1 °C (specimen (R)-6(À),
run 3) was purified from unconsumed alcohol (S)-6 by
repeated enzymatic acylation under the same condi-
* Previously,14 a specimen of (R)-1 with the same characteris-
tics (including [α]D) as natural α-tocopherol had been pre-
pared from alcohol (S)-(–)-6 by a reliable route; therefore, the
true configuration at C(2) in the chroman fragment in both
compounds is beyond doubt. However, aldehyde (+)-3 was
used only in the synthesis of α-tocotriånol,12 whose identifica-
tion with a specimen of natural origin was less certain due to
the absence of reliable [α]D values for this compound.
15
gave com-

Synthesis of α-tocopherol analogs
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 11, November, 2001 2123
Scheme 1
tions. The yield of the acetate fraction ((S)-7(Â)) was
39% calculated in relation to alcohol (R)-6(A) and the
yield (recovery) of the enantiomerically enriched alco-
hol (R)-6(B) with [α]D22 +17.35 (CHCl3) was 59%. The
total yield of this alcohol (specimen (R)-6(Â)) from
(±)-6 after two operations of enzymatic kinetic resolu-
tion was 38.5% (77% of the content of the R-enantiomer
in the racemate).
HO
+
OH
O
9
8
Oxidation of alcohol (R)-6(Â) with ÐCC smoothly
resulted in the dextrorotatory aldehyde with [α]D21 +16.0
(CHCl3), whose 1H and 13C NMR spectra were the
same as the spectrum of aldehyde (S)-3 synthesized by
us (see above). In order to exclude any probability of
inversion of configuration at C(2) during oxidation of
the alcohol, the dextrorotatory aldehyde ((R)-3, by its
origin) was reduced by NaBH4. The resulting alcohol
a (67%)
RO
OH
O
21
(R)-6 (specimen C) had [α]D +16.0 (CHCl3).* Obvi-
(±)-4 (R = H)
(±)-6 (R = Bn)
b (59.3%)
ously, neither inversion at C(2), nor considerable loss of
åå took place in the oxidation of (R)-6. Standard acety-
lation of specimen (R)-6(C) furnished acetate (R)-7
c (C > 32%)
22
with [α]D –15.5 (CHCl3).
These correlations between enantiomeric alcohols 6,
their acetates 7, and aldehydes 3 showed that the acety-
lation of alcohols (R)-6 and (S)-6 is accompanied by
inversion of the sign of the specific rotation of the product.
An analogous effect has been observed previously in the
replacement of the OH group of (S)-6 by a more
electronegative OTs group;14 this might also be mani-
BnO
BnO
OH
OAc
O
O
(R)-(+)-6(A)
c (C > 39%)
(S)-(+)-7(A)
d (95%)
* Both in this case and in the case of alkaline hydrolysis of
acetate (S)-7 with LiOH in aqueous MeOH, the [α]D for the
resulting specimens of alcohol (S)-6 was somewhat lower than
it might be expected on the basis of [α]D of the initial acetate.
The [α]D value of alcohol is also affected by the duration of
the contact of (S)-7 with the base. Alkaline hydrolysis of a
(59%)
(39%)
BnO
OH
(R)-(+)-6(B)
(S)-(+)-7(B)
22
O
specimen of (S)-7 with [α]D +18.5 carried out for 1 h gave a
e (87.5%)
22
specimen of alcohol (S)-6 with [α]D
–17.1, whereas a
specimen of (S)-7 with [α]D +17.1 was converted into speci-
BnO
(S)-(–)-6
e (79%)
23
O
men (S)-6 with [α]D
–16.85 after alkaline hydrolysis for
0.5 h; alkaline hydrolysis of (S)-7 with [α]D +16.3 for 1 h gave
alcohol (S)-6 with [α]D –15.5. Although the deviation from
O
H
20
proportionality for the [α]D values of the initial acetate and
the corresponding alcohol differ little from the standard error
of measurements, the noted tendency may point to possible
alkaline racemization at C(2) in chroman (S)-6. Its driving
forces are probably the energy difference between the bicyclic
alkoxide anion and delocalized phenoxide anion and the ease
of formation and opening of the oxetane ring in rotamers I and
II caused by spatial proximity.
(R)-(+)-3
(S)-(–)-3
f (90%)
BnO
OAc
g (95%)
(R)-(+)-6(C)
O
BnO
BnO
2´
–
(R)-(–)-7
O
3´
S
O
Reagents and conditions:
a. AlCl3/DCE, ∆; b. BnCl—K2CO3/DMF, ∼20 °C;
c. H2C=CHOAc—CCL (cat.)/Et2O 3—5 °C, 10 h;
–
O
O
I
d. LiOH/MeOH—H2O, ∼20 °C; e. PCC/CH2Cl2, ∼20 °C;
f. NaBH4/MeOH; g. Ac2O—DMAP/Py—Et2O, ∼20 °C.
BnO
BnO
–
2´
O
Note. The chemical yields for enzymatic reactions are given in
weight percent relative to the introduced substrate ((±)-4 for
the first resolution and scalemic alcohol (R)-4(A) for the
second one).
R
–
O
O
O
II

2124
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 11, November, 2001
Odinokov et al.
fested to a minor extent in the transition from alcohol 6
to aldehyde 3. The difference between molecular ro-
that this aldehyde was (S)-3. However, as follows from
our work, this is most likely (R)-3.*
tations of the acetate and the alcohol {∆[M]D
=
Synthesis of both enantiomers of the antioxidant
MDL-73404. Both enantiomers of (±)-10 were synthe-
sized from chirons (R)-6 and (S)-6, prepared by a single
acylation of alcohol (±)-6 to a conversion of > 50.5%
(see Table 1, run 5). The starting alcohol (S)-6 used in
[α]D(ace)•MWace/100 – [α]D(alc)•MWalc/100} is 126.8°
in the (S)-series and –114.8° in the (R)-series, i.e., the
average |∆[M]D| value is ∼120°. So great |∆[M]D| values
are usually found in molecules with heteroatoms at the
asymmetric C-atom.20
23
this synthesis had [α]D –15.5 (CHCl3).
Enzymatic acylation of phenol (±)-4 with vinyl ac-
etate in Et2O at 4 °C occurs slowly, unlike that of
alcohol (±)-6. The only reaction product obtained at
16—18 °C (yield 17%) had an [α]D of +17.2 (CHCl3)
and was identified as (S)-5 based on 1H and 13C NÌR
spectra. The alkaline hydrolysis of (S)-5 yielded levoro-
tatory alcohol (S)-4, which was identical with phenol
(±)-4 as regards the NMR and UV spectra and TLC
data, while the sign of [α]D was the same as that of a
specimen of (S)-4 synthesized from (R)-mevalono-
lactone13 and with that of the product of hydrogenolytic
debenzylation of alcohol (S)-6 prepared in this study.*
This confirmed the correctness of the configuration
assigned to levorotatory phenol (S)-4. Since the synthe-
sis of chiron (S)-5 using this method was ineffective, we
did not investigate the synthetic application of (S)-5.
At the beginning, the synthesis was performed in
four steps by analogy with the route described previ-
ously17 for the transformation of synthon (±)-4 into
(±)-10. The overall yield of (R)-{2-[6-hydroxy-2,5,7,8-
tetramethylchroman-2-yl]ethyl}trimethylammonium
p-toluenesulfonate (R)-10 from (R)-6 was only 8%,
because of the low yield of (R)-2,5,7,8-tetramethyl-
2-(2-bromoethyl)chroman in the first step of the syn-
thesis, i.e., in the reaction of alcohol (R)-6 with
Ph3P•Br2, which yielded benzyl bromide as the major
product. Similar transformations of alcohol (S)-6 gave
salt (S)-(+)-10 in an overall yield of 6.5%.
The synthesis comprising the conversion of alcohols
(R)-6 or (S)-6 into the corresponding toluenesulfonates
((R)-11, (S)-11) and their reaction with trimethylamine
appeared to be more efficient. Indeed, the modeling of
this route using (±)-6 gave racemic (±)-12 in an overall
yield of 40.6% (Scheme 2). However, a combination of
the two above approaches proved to be the method of
choice for the synthesis of MDL-73404 enantiomers.
HO
OH
CCL/H2C=CHOAc
16—18 °C, 120 h
O
Scheme 2
(±)-4
BnO
OTs
a
b
(±)-6
92.3%
49.5%
HO
OAc
O
O
(±)-11
LiOH/MeOH
(S)-(+)-5
BnO
+
–
NMe3TsO
O
H2—Pd(C)/EtOH
(S)-(–)-6
(S)-(–)-4
(±)-12
In a previous study,10 the acylation of (±)-4 in the
presence of lipase from Pseudomonas sp. up to a ∼64%
conversion gave the dextrorotatory "residual" alcohol,
which was assumed to have the S configuration. This
assignment was based on the conversion of the alcohol
(after 6-O-benzylation and oxidation) into aldehyde with
Reagents and conditions:
a. TsCl/Py, 8—10 °C, 48 h;
b. NMe3 (10 equiv.)/DMF, 20 °C, 48 h.
* Paradoxically, the reference compounds (S)-(+)-3 12 and
(S)-(–)-6 14 were first synthesized from a common chiral
precursor (2, R = CH2CO2H, R´ = H) by pathways that rule
out, in all probability, the inversion at C(2) in the chroman
nucleus. However, to the best of our knowledge, to the
[α]D +16.2 (CHCl3). It has been taken for granted12
25
* The specimen of (S)-4 obtained by a stereocontrolled route
from (R)-mevalonic acid had [α]D –4.06 (MeOH)13. Alco-
exclusion of one ambiguous work,10 direct oxidation of
27
19
hol (S)-4 that we prepared by alkaline hydrolysis of monoacetate
(S)-(–)-6 14 or (R)-(+)-6
to aldehydes has not been re-
20
(S)-(+)-5 had [α]D –10.4 (c 0.3, MeOH).
ported.

Synthesis of α-tocopherol analogs
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 11, November, 2001 2125
Tosylation of alcohol (R)-6, the subsequent reaction
of p-toluenesulfonate (R)-11 with Me2NH in DMF, and
quaternization of the resulting amine (R)-13 by methyl
p-toluenesulfonate proceeded with more than >90%
yields to produce the O-benzyl derivative of (R)-10
((R)-12). Hydrogenolysis of (R)-12 yielded crystalline
(+)-MDL-73404 specimens and, correspondingly, the
initial alcohols (R)-6 and (S)-6 had ee of ∼90%.
It is noteworthy that Mizuguchi and coworkers at-
tributed the S configuration to the dextrorotatory enan-
tiomer of phenol 4 {[α]D23 +19.2 (CHCl3) for ee >99%10
or [α]D26 +14.3 (CHCl3) for ee 71%9}. The S configura-
tion was also assigned to the levorotatory enantiomer of
MDL-73404 prepared therefrom.10 The chemical corre-
lation of chirons (S)-4 and (S)-6 synthesized in the
present work does not support this assignment.
23
salt (R)-10, [α]D –5.23 (MeOH), in an overall yield of
80.8% (Scheme 3).
Scheme 3
*
*
*
a
(R)-(+)-6
91.7%
The CCL-catalyzed acetylation of alcohols (±)-6
and (R)-6(A) allows one to obtain enantiomeric
2-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)etha-
nols having ee of ∼90%, i.e., at the same level as in the
case of previously synthesized specimens of (S)-6 14 and
(R)-6.19 The correlation of the signs of [α]D to configu-
rations of enantiomeric 2-(chroman-2-yl)ethanols, their
acetates, and the corresponding aldehydes as well as the
inversion of [α]D upon the transitions of (R)-6 to (R)-10
and (S)-6 to (S)-10 attest to the necessity of careful
approach to the determination of absolute configura-
tions of this type of compounds. Preparation of both
enantiomers of the antioxidant MDL-73404 is a pre-
requisite for the study of the dependence of their bio-
logical activities on the absolute configuration.
BnO
X
O
(R)-11 (X = OTs)
b (92%)
(R)-13 (X = NMe2)
c (95.5%)
–
(R)-12 (X = [NMe3]+TsO
d
(91.4%)
(R)-(–)-10
(Σ = 80.8%)
Experimental
BnO
OTs
a
(S)-(–)-6
The 1H and 13C NMR spectra were recorded on a Bruker
92.4%
O
AM-300 spectrometer (operating at 300.13 and 75 ÌHz for 1
H
and 13C, respectively) using CDCl3 as the solvent (unless
stated otherwise). The UV spectra (λ/nm; ε) were recorded on
a Specord UV-VIS instrument (Karl Zeiss) in EtOH. The [α]D
values were determined on a JASCO-DIP 360 polarimeter.
Column chromatography was carried out using SiO2 (Silica
gel 60, Fluka) and TLC analysis was done with Silica gel/TLC
(S)-11
(S)-11
b
(S)-13
(S)-12
c
d
cards (Fluka). The specific activity of the lipase from Candida
(S)-(+)-10
–1
cylindracea (CCL, Fluka) was 2.3—2.4 u mg
.
(Σ = 88.3%)
2-[(±)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-yl]etha-
nol ((±)-4). Alkene 9 (706 mg, 7.2 mmol) was slowly added to
a mixture of trimethylhydroquinone 8 (906 mg, 6 mmol) and
anhydrous AlCl3 (0.8 g, 6 mmol) in 6 mL of anhydrous
1,2-dichloroethane. The mixture was stirred under reflux for
15 min, cooled, poured into ice water, and allowed to stand in
the cold for 12 h. The crystals that precipitated were filtered
off and washed with cold Et2O to give 1 g (67%) of alcohol
(±)-4, m.p. 135—136 °C (from a CH2Cl2—hexane mixture).
1H NMR (DMSO-d6), δ: 1.10 (s, 3 H, 2-CH3); 1.55—1.75
(m, 4 H, C(3)H2, C(1´)H2); 1.91 (s, 3 H, Ar—CH3); 1.94 (s,
3 H, Ar—CH3); 1.98 (s, 3 H, Ar—CH3); 2.42 (t, 2 H, C(4)H2,
J = 6.3 Hz); 3.43—3.63 (m, 2 H, C(2´)H2). 13C NMR
(DMSO-d6), δ: 12.11, 12.18, 13.17 (3 Ar—CH3); 20.68 (C(4));
24.48 (2-CH3); 32.15 (C(3)); 41.60 (C(1´)); 57.40 (C(2´));
73.75 (C(2)); 117.30 (C(8a)); 120.97 (C(5)); 121.63 (C(8));
123.23 (C(7)); 144.94 (C(4a)); 145.58 (C(6)). UV, λmax/nm (ε):
225 (11000) and 287 (3100).
Reagents and conditions: a. TsCl/Py, 8—10 °C, 48 h;
b. HNMe2 (10 equiv.)/DMF, 20 °C, 24 h;
c. TsOMe/DMF, 20 °C, 24 h;
d. H2—Pd(C)/EtOH, ∼20 °C.
The 1H NMR spectroscopic data for (R)-10 were in
qualitative agreement with the data published for opti-
cally active10 and racemic17 compounds with structure
10. The same route was used to transform alcohol (S)-6
into crystalline salt (S)-10, [α]D23 +5.25 (MeOH), in an
overall yield of 88.3%.
Previously, the dextrorotatory enantiomer of
25
MDL-73404 with [α]D –5.8° (MeOH) has been pre-
pared from the dextrorotatory enantiomer of alcohol 4
with ee 99% (data from enantioselective GLC).10 Com-
parison of the [α]D of our specimens of (R)-10 and
(S)-10 with the above [α]D shows that our (–)- and
2-[(±)-6-Benzyloxy-2,5,7,8-tetramethylchroman-2-
yl]ethanol ((±)-6). Calcined K2CO3 (2.72 g, 19.7 mmol) and

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Odinokov et al.
benzyl chloride (2.6 mL, 20.6 mmol) were added to a solution
of phenol (±)-4 (1.86 g, 7.44 mmol) in 15.3 mL of anhydrous
DMF. The reaction mixture was stirred for 36 h and poured
into ice water, the products were extracted with EtOAc, the
extract was washed with brine, dried (MgSO4), concentrated,
and chromatographed on a column (elution with Et2O—hex-
ane, 1 : 10) to give 1.5 g (59.3%) of alcohol (±)-6, m.p.
64—69 °C (from an Et2O—hexane mixture). 1H NMR, δ: 1.35
(s, 3 H, 2-CH3); 1.78—2.50 (m, 4 H, C(3)H2 and C(1´)H2);
2.14 (s, 3 H, Ar—CH3); 2.23 (s, 3 H, Ar—CH3); 2.27 (s, 3 H,
Ar—CH3); 2.67 (t, 2 H, C(4)H2, J = 7.1 Hz); 3.86—4.02
(m, 2 H, C(2´)H2); 4.74 (s, 2 H, PhCH2O); 7.35—7.50
(m, 5 H, Ar—H). 13C NMR, δ: 11.89 (Ar—CH3); 11.95
(Ar—CH3); 12.79 (Ar—CH3); 20.36 (C(4)); 23.24 (2-CH3);
31.62 (C(3)); 41.91 (C(1´)); 58.98 (C(2´)); 74.63 (C(2));
75.41 (PhCH2O); 117.38 (C(8a)); 122.61 (C(8)); 126.18
(C(7)); 127.63 (C(2″)/C(6″)); 127.72 (C(4′′)); 128.09 (C(5));
128.35 (C(3″)/C(5″)); 137.74 (C(1″)); 147.10 (C(4a));
148.52 (C(6)).
(S)-(+)-2-(2-Acetoxyethyl)-6-benzyloxy-2,5,7,8-tetra-
methylchroman ((S)-7). Freshly distilled vinyl acetate (85 µL,
0.92 mmol) and CCL powder (260 mg) were added to a
solution of alcohol (±)-6 (260 mg, 0.76 mmol) in 3 mL of
anhydrous Et2O. The reaction mixture was magnetically stirred
in a sterilized two-neck flask at 4±1 °C, the course of the
reaction was monitored by TLC (system I: benzene—EtOAc,
5 : 1). After 10 h, the reaction mixture was filtered through a
porous glass filter No. 3, the precipitate was washed with
anhydrous Et2O, and the combined organic filtrate was con-
centrated at 40 °C (30 Torr). The residue (a mixture of the
acetate with nonconsumed alcohol) was fractionated on
rated in vacuo, 1.5 mL of water was added to the viscous
residue, and the emulsion was extracted with EtOAc (4½5 mL).
The extract was dried (Na2SO4) and concentrated in vacuo
(40 °C, 25 Torr), and the oily residue (86 mg) was
chromatographed on a column with 12 g of SiO2 in a ben-
zene—EtOAc gràdient. Elution with a benzene—EtOAc mix-
ture (50 : 50) gave a pure (TLC, system I) colorless oil with
Rf 0.36, which solidified on storage into a finely crystalline
22
mass with m.p. 55—58 °C and [α]D –17.1 (c 0.65, CHCl3)
(Ref. 14: [α]D –16.2 (CHCl3)). Yield 79 mg (95% based on
acetate (S)-7(A), 30.4% based on the starting alcohol (±)-6
and, correspondingly, 60.8% of the theoretical content in the
racemate). The 1H and 13C NMR spectra of the resulting
specimen of (S)-6 were almost indistinguishable from the
corresponding spectra of alcohol (±)-6.
Similar hydrolysis of a specimen of (S)-7 with [α]D23 +16.3
(c 0.4, CHCl3) prepared in run 5 (Table 1) resulted in alcohol
23
(S)-6 with [α]D –15.5 (c 0.4, CHCl3), yield 96%.
(R)-(+)-2-[6-Benzyloxy-2,5,7,8-tetramethylchroman-2-
yl]ethanol ((R)-6). The alcohol fraction recovered from enzy-
matic acetylation of (±)-6 at 4 °C (specimen (R)-6(A), 170 mg,
0.5 mmol)) was dissolved in 2 mL of anhydrous Et2O. Vinyl
acetate (56 µL, 0.6 mmol) and CCL powder (170 mg) were
added to the solution. The mixture was stirred for 10 h at 4 °C,
the degree of conversion being monitored by TLC, and worked
up as described for the synthesis of acetate (S)-7. Column
chromatography on SiO2 using a benzene—EtOAc gradient
gave initially 74.6 mg (39% based on (R)-6(A)) of TLC-pure
acetate (scalemic mixture of S- and R-enantiomers, specimen
(S)-7(B)) and then pure "residual" alcohol (R)-6(B), a color-
22
less oil with Rf 0.36 (system I) and [α]D +17.35 (c 0.7,
a
column with SiO2 with an adsorbent
:
adsorbate ra-
CHCl3), which gradually transformed into fine crystals with
25
tio of 40 (w/w) using benzene—EtOAc gradient
:
1
a
m.p. 52—55 °C; Ref. 19: m.p. 51—56 °C, [α]D
+15.68
(100 : 0 → 50 : 50) as the eluent to give pure acetate (S)-7
(specimen (7A)) as a colorless solid with m.p. 55—59 °C,
Rf 0.77 (system I) and [α]D +18.5 (c 0.8, CHCl3). Yield
93.5 mg (32%). Further elution gave 170 mg (65.4%) of a
chromatographically pure fraction of the nonconsumed alco-
hol. No other products were detected by either TLC or
1H NMR; the material balance of the reaction corresponded to
a degree of conversion of about 31—33%.
On trituration with a drop of EtOH, acetate (S)-7 was
transformed into fine crystals with the same m.p. 1H NMR, δ:
1.35 (s, 3 H, 2-CH3); 1.85—1.95 (m, 4 H, C(3)H2, C(1´)H2);
2.08 (s, 3 H, COCH3); 2.13 (s, 3 H, Ar—CH3); 2.18 (s, 3 H,
Ar—CH3); 2.24 (s, 3 H, Ar—CH3); 2.65 (t, 2 H, C(4)H2,
J = 6.5 Hz); 4.32 (m, 2 H, CH2OÀñ); 4.75 (s, 2 H, PhCH2O);
7.40—7.55 (m, 5 H, Ar—H). 13C NMR (δ: 11.90 (Ar—CH3);
12.01 (Ar—CH3); 12.88 (COCH3); 12.90 (Ar—CH3); 20.42
(C(4)); 24.81 (2-CH3); 31.95 (C(3)); 52.34 (C(1´)); 73.59
(CH2OAc); 74.73 (C(2)); 117.02 (C(8a)); 123.12 (C(8)); 126.21
(C(7)); 127.69 (C(2″)/C(6″)); 127.81 (C(4″)); 128.44 (C(5),
C(3″)/C(5″)); 146.90 (C(4a)); 148.77 (C(6)); 201.75 (COCH3).
UV, λmax/nm (ε): 230 (11400), 280 (2100), 287 (2350).
Acylation of alcohol (±)-6 (0.5 g, 1.46 mmol) in Et2O
(10 mL) with vinyl acetate (2 mmol) at 4 °C over a period of
17 h gave products whose yields and [α]D values are given in
Table 1 (run 5).
(CHCl3). The yield was 100 mg (59% based on (R)-6(A),
38.5% based on the initial alcohol (±)-6 and, correspondingly,
77% of the content in the racemate).
(R)-(+)-[6-Benzyloxy-2,5,7,8-tetramethylchroman-
2-yl]acetaldehyde ((R)-3). Alcohol (R)-6(B) (100 mg,
0.294 mmol) was added in one portion at 20 °C under argon to
a vigorously stirred suspension of ÐCC (88.5 mg, 0.41 mmol)
in anhydrous CH2Cl2 (2 mL). The reaction mixture was stirred
for 2 h, then, without dilution with Et2O, the supernatant was
decanted from the black precipitate and filtered through a pad
of SiO2 (3½1.7 cm), which was washed with anhydrous CH2Cl2
(9 mL) and Et2O (3½5 mL). The combined solutions were
filtered and concentrated (40 °C (bath), 25 Torr) to give 90 mg
of a TLC-homogeneous light-colored oil with Rf 0.78 (sys-
tem I). Column chromatography on SiO2 using
a ben-
zene—EtOAc gradient (10 : 0 → 8 : 2) gave aldehyde (R)-3 as
a colorless oil, which slowly solidified on storage to give an
21
amorphous material, m.p. 76—81 °C and [α]D +16.0 (c 0.9,
CHCl3). Yield 87 mg (87.5%). 1H NMR, δ: 1.45 (s, 3 H,
2-CH3); 1.90—2.0 (m, 2 H, C(3)H2); 2.12 (s, 3 H, Ar—CH3);
2.20 (s, 3 H, Ar—CH3); 2.25 (s, 3 H, Ar—CH3); 2.55—2.80
(m, 4 H, C(4)H2 and C(1´)H2); 4.75 (s, 2 H, PhCH2O);
7.35—7.60 (m, 5 H, Ar—H); 9.96 (t, 1 H, CH=O, J = 1.5 Hz).
13C NMR, δ: 11.90 (Ar—CH3); 12.01 (Ar—CH3); 12.90
(Ar—CH3)); 20.43 (C(4)); 24.81 (2-CH3); 31.95 (C(3)); 52.34
(C(1´)); 73.58 (C(2)); 74.73 (PhCH2O); 117.02 (C(4a)); 123.11
(C(8)); 127.69 (C(7)); 127.83 (C(2″)/C(6″)); 128.45 (C(4″));
128.09 (C(5)); 128.35 (C(3″)/C(5″)); 137.81 (C(1″)); 146.05
(C(8a)); 148.77 (C(6)); 201.78 (CH=O). UV, λmax/nm (ε):
230 (sh, 11200), 360 (sh, 890). The spectroscopic data and the
characteristics of the resulting aldehyde (R)-3 are similar to
those reported for the dextrorotatory aldehyde having the same
(S)-(–)-2-[6-Benzyloxy-2,5,7,8-tetramethylchroman-2-
yl]ethanol ((S)-6). A solution of acetate (S)-7(A) (93 mg,
0.24 mmol) in 1.2 mL of ÌåOH was added to a solution of
LiOH (6.2 mg, 0.26 mmol) in 0.8 mL of water. The reaction
mixture was stirred for 1 at 20 °C until the initial acetate
completely disappeared (TLC monitoring, system I) and neu-
tralized to ðH 7.0 with glacial ÀñOH. The solvent was evapo-

Synthesis of α-tocopherol analogs
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 11, November, 2001 2127
structure (Ref. 12: m.p. 85—90 °C, [α]D25 from +16.2 (CHCl3)
to +15.16 (CHCl3) for the analytical specimen) but prepared
by a different route.
Subsequent elution with benzene—EtOAc (1 : 1) and pure
EtOAc resulted in the recovery of 75 mg of nonconsumed
compound 4 (Rf 0.36 in system II) containing no visible
impurities (TLC). The 1H NMR spectrum practically coin-
cided with that of (±)-4.
(S)-(–)-[6-Benzyloxy-2,5,7,8-tetramethylchroman-2-
yl]acetaldehyde ((S)-3). Levorotatory aldehyde (S)-3 was pre-
pared from 50 mg of alcohol (S)-6 using the above-described
procedure as a finely crystalline white material with m.p.
(S)-(–)-2-[6-Hydroxy-2,5,7,8-tetramethylchroman-2-
yl]ethanol ((S)-4). À. A solution of LiOH (4 mg) in a mixture
of 0.2 mL of water and 0.8 mL of ÌåOH was added at 20 °C
to a solution of acetate (S)-5 (17 mg) in 0.2 mL of ÌåOH.
After 30 min, the reaction mixture was neutralized with glacial
ÀñOH to ðH 7.0. Subsequent work-up was the same as
described for the synthesis of alcohol (S)-6. Column chroma-
tography on SiO2 in a benzene—EtOAc gradient gave com-
pound (S)-4 as a colorless oil with Rf 0.36 (system II) and
[α]D –10.4 (c 0.4, MeOH) or –14.1 (c 0.3, CHCl3), cf.
25
70—80 °C and [α]D –15.1 (c 0.65, CHCl3). Yield 39.3 mg
(79%). The spectroscopic data of (S)-3 virtually coincided with
those of the specimen of (R)-3 described above.
(R)-(–)-2-(2-Acetoxyethyl)-6-benzyloxy-2,5,7,8-tetra-
methylchroman ((R)-7). A solution of aldehyde (R)-3 (82 mg,
0.25 mmol) in 2 mL of ÌåOH was added at 0 °C to a solution
of NaBH4 (4.9 mg, 0.128 mmol) in 1.5 mL of ÌåOH chilled
to 0 °C, and the reaction mixture was magnetically stirred for
1.5 h without further cooling until the initial (R)-3 disappeared
(TLC). Methanol was evaporated in vacuo, the residue was
partitioned between 0.2 mL of water and 0.3 mL of Et2O, and
the aqueous layer was additionally extracted with ether
(3½0.5 mL). The combined extract was dried (Na2SO4) and
concentrated in vacuo. The residue was chromatographed on a
column with SiO2 to isolate pure alcohol (R)-6(C) with Rf 0.36
20
Ref. 13: [α]D –4.06 (MeOH). On prolonged storage under
argon, the oil turned into a solid with m.p. 126—131 °C (lit.:
13
m.p. 137
or 153 °C15). Yield 13.2 mg (90%). The 1H NMR
spectrum of alcohol (S)-4 was virtually identical with
that of (±)-4.
B. Hydrogenolysis of alcohol (S)-6 (34 mg, 0.1 mmol) in
5 mL of EtOH over 5% Pd/C (50 mg) was carried out for 4 h.
The catalyst was filtered off and washed with EtOH (2 mL),
and the filtrates were combined and concentrated in vacuo.
The residue was chromatographed twice on a column with
SiO2. Elution with benzene—EtOAc (1 : 1) gave 23 mg of
compound (S)-4 as a colorless oil with Rf 0.36 (system II) and
20
and [α]D +15.99 (c 0.6, CHCl3). Yield 74.3 mg (90%). This
specimen did not differ, judging by 1H NMR spectra, from
specimens (R)-6(Â) and (S)-6; however, according to TLC
data (system I), it contained traces of an impurity with a
greater Rf.
20
Freshly distilled Àñ2O (29 µL 0.28 mmol), pyridine (23 µL,
0.28 mmol), and DMAP (3 mg) were added to a solution of
alcohol (R)-6(C) (70 mg, 0.21 mmol) in 2.5 mL of anhydrous
Et2O. The reaction mixture was stirred for 2 h at ∼20 °C,
allowed to stand for 16 h, washed with saturated aqueous
solutions of CuSO4 and NaHCO3 and with water, dried
(Na2SO4), and concentrated in vacuo. The residue (oil, 76 mg)
was chromatographed on a column with SiO2 in a ben-
zene—EtOAc gradient. Elution with benzene—EtOAc (9 : 1)
gave TLC-pure (Rf 0.77) acetate (R)-7 as a colorless oil, which
[α]D –10.9 (c 0.25, MeOH) or –16.4 (c 0.2, CHCl3). The
1H NMR spectrum of the product was identical with those of
(±)-4 and the above-mentioned specimen of (S)-4.
(R)-6-Benzyloxy-2,5,7,8-tetramethyl-2-[2-tosyloxy-
ethyl]chroman ((R)-11). Alcohol (R)-6 (31.2 mg, 0.09 mmol)
and TsCl (39 mg, 0.21 mmol) were dissolved in 0.3 mL of
pyridine and the solution was allowed to stand for 48 h at 4 °C.
The reaction mixture was worked up by a known procedure,14
and the residue (45 mg) was chromatographed on a column
with SiO2. Elution with a benzene—EtOAc mixture (4 : 1)
gave 42.5 mg (93%) of a chromatographically pure thick oil
with Rf 0.73 (system I). 1H NMR, δ: 1.25 (s, 3 H, 2-CH3);
1.81 (t, 2 H, C(3)H2); 1.97, 2.15, 2.20 (all s, 3½3 H, Ar—CH3);
2.05 (m, 2 H, C(1´)H2); 2.45 (s, 3 H, Ar—CH3); 2.57 (t, 2 H,
C(4)H2, J = 6.5 Hz); 4.30 (m, 2 H, C(2´)H2); 4.71 (s, 2 H,
ArOCH2Ph); 7.3—7.5 (m, 7 H, Ar—H); 7.78 (d, 2 H, J = 8 Hz,
a part of an À2Â2 system of toluenesulfonate).
22
slowly became a solid with m.p. 50—55 °C and [α]D –15.33
(c 0.55, CHCl3). Yield 74.3 mg (95%). The 1H and 13C NMR
spectra of this compound virtually coincided with the spectra
of acetate (S)-7.
(S)-(+)-2-(2-Acetoxyethyl)-6-hydroxy-2,5,7,8-tetra-
methylchroman ((S)-5). Vinyl acetate (36 µL, 0.4 mmol) and
CCL powder (0.1 g) were added to a solution of phenol (±)-4
(0.1 g, 0.294 mmol) in 2 mL of anhydrous Et2O. The mixture
was stirred at 16—18 °C, the degree of conversion being
monitored by TLC. In a benzene—EtOAc mixture (5 : 2,
system II), the starting (±)-4 had Rf 0.36, and the only
product had Rf 0.83. The product accumulated over the reac-
tion time from 7 to 24 h, no changes being observed during the
subsequent 96 h. The reaction mixture was worked-up as
described in the synthesis of acetate (S)-7. Elution of the
column with benzene—EtOAc (4 : 1) gave pure monoacetate
(S)-5 as a colorless oil, which slowly solidified into an amor-
phous mass with [α]D21 +17.20 (c 0.18, CHCl3). Yield 19.9 mg
(17%). 1H NMR, δ: 1.35 (s, 3 H, 2-CH3); 1.80—2.02 (m, 4 H,
C(3)H2, C(1´)H2); 2.07 (s, 3 H, Ar—CH3); 2.12 (s, 6 H,
Ar—CH3, COCH3); 2.18 (s, 3 H, Ar—CH3); 2.65 (t, 2 H,
C(4)H2 J = 6); 4.38 (m, 2 H, CH2OÀñ). 13C NMR, δ: 11.04
(Ar—CH3); 11.35 (Ar—CH3); 11.86 (Ar—CH3); 11.90
(Ar—CH3); 12.28 (COCH3); 20.63 (C(4)); 23.81 (2-CH3);
32.08 (C(3)); 37.86 (C(1´)); 60.98 (CH2OAc); 73.24 (C(2));
118.67 (C(8a)); 121.35 (C(8)); 128.88 (C(7)); 144.94 (C(4a));
145.05 (C(6)); 171.27 (COCH3). UV, λmax/nm (ε): 230 (10900),
280 (2010), 286 (2210).
(S)-6-Benzyloxy-2,5,7,8-tetramethyl-2-[2-tosyloxyethyl]-
chroman ((S)-11) was prepared in the same way as toluene-
sulfonate (S)-11 from 62.4 mg of alcohol (S)-6 and 78 mg of
TsCl. The yield of the toluenesulfonate characterized by Rf
(0.73, system I) was 92.4%.
(R)-6-Benzyloxy-2-(2-dimethylaminîethyl)-2,5,7,8-tetra-
methylchroman ((R)-13). A flow of Me2NH generated by
treating a saturated aqueous solution of [Ìå2NH2]Cl with
KOH and dried successively with BaO and Na2SO4 was bubbled
into a tared flask with anhydrous DMF (10 mL) at 5 °C When
the weight gain reached 0.38 g, 1.0 mL (∼37.5 mg of Me2NH,
0.83 mmol) of the resulting solution was withdrawn, and
p-toluenesulfonate (R)-11 (41.2 mg, 0.083 mmol) in anhydrous
DMF (0.2 mL) was added to the solution. The reaction
mixture was kept at 4 °C for 48 h. Excess Me2NH and the
solvent were removed in vacuo (60 °C, 10 Torr), the poorly
soluble residue was suspended in 1 mL of water, the suspen-
sion was acidified with HCl to ðH 2, and the organic impuri-
ties were extracted with Et2O (3½3 mL). The aqueous phase
was brought to ðH 11 at 10 °C by adding solid NaOH and
extracted with Et2O (5½3 mL). The extract was dried (Na2SO4)

2128
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 11, November, 2001
Odinokov et al.
and concentrated in vacuo to give amine (R)-13 as a colorless
oil. Yield 29 mg (92%). 1H NMR, δ: 1.27 (s, 3 H, 2-CH3);
1.85 (m, 4 H, C(3)H2, C(1´)H2); 2.10, 2.17, 2.22 (all s,
p-Toluenesulfonate (±)-11 was prepared by the reaction of
alcohol (±)-6 (2.17 g, 6.38 mmol) with TsCl (1.37 g, 7.15 mmol)
in 20 mL of anhydrous Py (0—4 °C, 48 h). The usual
3½3 H, Ar—CH3); 2.29 (s,
H, C(2´)H2); 2.57 (m,
6
H, N(CH3)2); 2.60 (m,
work-up gave 2.32 g (74%) of p-toluenesulfonate (±)-11
2
2
H, NCH2); 2.61 (t, H,
2
(oil), whose 1H NMR and Rf coincided with those for
(R)- and (S)-11.
C(4)H2, J = 6.5 Hz); 4.70 (s, 2 H, OCH2Ph); 7.4—7.5
(m, 5 H, Ph).
A flow of trimethylamine generated by treatment of a
saturated aqueous solution of [Ìå3NH]Cl with KOH and
dried by passing over BaO and Na2SO4 was bubbled into a
tared flask with anhydrous DMF (10 mL) at 0—5 °C. When
the weight gain reached 1.07 g, 1.0 mL (∼106 mg Me3N,
∼1.8 mmol) of the resulting solution was withdrawn and
p-toluenesulfonate (±)-11 (110 mg, 0.83 mmol) in dry DMF
(2 mL) was added to the solution. The mixture was kept at
4 °C for 44 h. Excess Me3N and DMF were removed in vacuo,
and the residue (colorless oil) was triturated and washed with
anhydrous Et2O (5½4 mL); concentration of the extract gave
nonconsumed sulfonate (±)-11 (51 mg, 0.41 mmol). On tritu-
ration with 2 or 3 drops of Et2O, the reaction product (60 mg,
49.5%) turned into crystals with m.p. 205—208 °C (dec.). The
1H NMR spectrum of salt (±)-12 virtually coincided with the
spectra of (R)-12 and (S)-12.
(S)-6-Benzyloxy-2-(2-dimethylaminîethyl)-2,5,7,8-tetra-
methylchroman ((S)-13) was prepared in the same way as
amine (R)-13 from p-toluenesulfonate (S)-11 (61.3 mg) and
Me2NH (55.8 mg) in DMF. Yield 43.5 mg (95.5 mg). The
1H NMR spectrum coincided with that of (R)-13.
(R)-{2-[6-Benzyloxy-2,5,7,8-tetramethylchroman-2-
yl]ethyl}trimethylammonium p-toluenesulfonate ((R)-12). A
mixture of amine (R)-13 (28 mg, 0.076 mmol) and methyl
p-toluenesulfonate (28.2 mg, 0.152 mmol) in 2.5 mL of freshly
distilled DMF was allowed to stand for 24 h at 20—22 °C,
DMF and the main portion of the methylating reagent were
evaporated in vacuo (70 °C (bath), 3 Torr), the residue was
triturated and washed with anhydrous Et2O (5½3 mL) to
remove traces of TsOMe. The white precipitate was crystal-
lized from a MeCN—Et2O mixture to give pure salt (R)-12
with m.p. 218—220 °C (dec.). Yield 40.5 mg (96.5%). 1H NMR,
δ: 1.25 (s, 3 H); 1.80 (m, 2 H, C(3)H2); 2.06—2.08 (coales-
cence of s, 3 H + m, 2 H, Ar—CH3, C(1´)H2); 2.12 (s, 3 H);
2.18 (s, 3 H); 2.35 (s, 3 H, SO2C6H4CH3); 2.60 (t, 2 H,
C(4)H2, J = 6.5 Hz); 3.32 (s, 9 H, N+CH3); 3.52 (m,
2 H, C(2´)H2); 4.72 (s, 2 H, OCH2Ph); 7.12 (d, 2 H,
The authors are grateful to M. I. Struchkova and
A. V. Ignatenko (Institute of Organic Chemistry of the
RAS) for recording NMR spectra. Trimethylhydro-
quinone was kindly provided by V. I. Gunar (All-Rus-
sian Research Institute of Vitamins).
JAB
= 8 Hz); 7.25—7.55 (m, 5 H, Ph); 7.73 (d, 2 H,
The work was supported by the Russian Foundation
for Basic Research (Project No. 99-03-32992), the State
Program for the Support of Prominent Scientific
Schools (Project No. 00-15-97347), and the Inte-
grated Program of Scientific Research of the RAS for
2001—2002.
JAB = 8 Hz, —C6H4—).
(S)-{2-[6-Benzyloxy-2,5,7,8-tetramethylchroman-2-
yl]ethyl}trimethylammonium p-toluenesulfonate ((S)-12) was
prepared in the same way as the R-enantiomer from amine
(S)-13 (43.5 mg, 0.188 mmol) and methyl toluenesulfonate
(44 mg, 0.24 mmol) in 3 mL of DMF. Yield 64 mg (97.7%).
M.p. 219—221 °C (MeCN—Et2O, dec.). The 1H NMR spec-
trum was identical with that described above. Found (%):
C, 69.23; H, 7.92; S, 5.59. C32H43NO5S. Calculated (%):
C, 69.4; H, 7.8; S, 5.8.
References
(R)-{2-[6-Hydroxy-2,5,7,8-tetramethylchroman-2-
yl]ethyl}trimethylammonium p-toluenesulfonate ((R)-10). Salt
(R)-12 (40.5 mg, 0.073 mmol) was dissolved in 3 mL of EtOH
and subjected to hydrogenolysis over 5% Pd/C (60 mg) (22 °C,
750 Torr) for 5 h until visible absorption of H2 ceased. The
catalyst was filtered off and washed with EtOH, and the
filtrates were concentrated in vacuo to give 31 mg (91.4%) of a
white powder with m.p. 181—184 °C (dec.). recrystallization
1. (a) Vitamin E: Biological, Hematological and Clinical As-
pects, Eds. B. Lubin and L. J. Machlin, Ann. N. Y. Acad.
Sci., 1982, 393, 506 pp.; (b) M. J. Kelly, in Progress of
Medicinal Chemistry, Eds. G. P. Ellis and G. B. West,
Elsevier, Amsterdam, 1988, 25, p. 249.
2. (a) L. J. Machlin, in Handbook of Vitamins, Eds. L. J.
Machlin, Marcel Dekker, New York, 1991, 2nd ed. p. 99;
(b) T. Netscher, in Lipid Synth. Manuf., Ed. F. D. Gunstone,
Academic Press, Sheffield, UK, 1999, p. 250.
3. (a) G. Saucy and N. Cohen, in New Synthetic Methodol-
ogy and Biologically Active Substances. (Proc. 1st Int.
Kyoto Conf. New Aspects Org. Chem.), Ed. Z. Yoshida,
Kodansha—Elsevier, Tokyo—Amsterdam, 1981, p. 155;
(b) G. Solladie, in Studies in Natural Products Chemistry.
Vol. 4. Stereoselective Synthesis (Part C), Ed. Atta-ur-
Rahman, Elsevier, Amsterdam, 1989, p. 489.
from MeCN—Et2O (∼4 : 1) gave crystals with m.p. 204—208 °C
(dec.) and [α]D 23 –5.23 (c 0.21, MeOH), lit10
:
m.p.
23
205—208 °C, [α]D –5.8 (MeOH). 1H NMR (DMSO-d6) δ:
1.20 (s, 3 H, 2-CH3); 1.76 (m, 2 H, C(3)H2); 2.00 (s, 3 H);
2.02 (signal overlap s, 3 H, and m, 2 H); 2.06 (s, 3 H); 2.35 (s,
3 H, SO2C6H4CH3); 2.55 (m, 2 H, C(4)H2); 2.70 (narr.s, 1 H,
OH); 3.05 (s, 9 H, N+CH3); 3.45 (m, 2 H, C(2´)H2); 7.12 and
7.45 (both d, 2 H, C6H4, JAB = 8 Hz).
(S)-{2-[6-Hydroxy-2,5,7,8-tetramethylchroman-2-
yl]ethyl}trimethylammonium p-toluenesulfonate ((S)-10) was
prepared by hydrogenolysis of salt (S)-12 (34 mg, 0.06 mmol)
over 5% Pd/C (52 mg) in 4 mL of EtOH for 5 h. Recrystalli-
zation from MeCN—Et2O gave crystals of (S)-12 with m.p.
4. T. Netscher, Chimia, 1996, 50, 563.
5. (a) L. F. Tietze and J. Goerlicher, Synthesis, 1997, 877;
(b) L. F. Tietze and J. Goerlicher, Liebigs Ann./Recueil,
1977, 2221; (c) L. F. Tietze and J. Goerlicher, Synthesis,
1998, 873.
6. E. Mizuguchi and K. Achiwa, Chem. Pharm. Bull., 1997,
45, 1209.
23
207—208 °C and [α]D +5.25 (c 0.2, MeOH). Yield 27.1 mg
(96%). Found (%): C, 64.63; H, 7.83. C25H37NO5S. Calcu-
lated (%): C, 64.8; H, 8.0.
(±)-{2-[6-Benzyloxy-2,5,7,8-tetramethylchroman-2-
yl]ethyl}trimethylammonium p-toluenesulfonate ((±)-12).
7. R. A. Outten, P. Bohrer, R. V. Mueller, H. Schneider,
A. Ruettimann, and T. Netscher, Chemicke Listy, Sympo-
sia, 1999, 93, S49.

Synthesis of α-tocopherol analogs
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 11, November, 2001 2129
8. (a) E. Mizuguchi, M. Takemoto, and K. Achiwa, Tetra-
hedron: Asymmetry, 1993, 4, 1961; (b) E. Mizuguchi and
K. Achiwa, Tetrahedron: Asymmetry, 1993, 4, 2303.
9. E. Mizuguchi, T. Suzuki, and K. Achiva, SYNLETT,
1996, 743.
10. E. Mizuguchi, T. Suzuki, and K. Achiwa, SYNLETT,
1994, 929.
11. Ger. Offen. DE 19852903 (2000); C.A., 2000, 132, 321017.
12. J. W. Scott, F. T. Bizarro, D. R. Parrish, and G. Saucy,
Helv. Chim. Acta, 1976, 59, 290.
13. S. Takano, Y. Shimazaki, and K. Ogasawara, Heterocycles,
1990, 31, 917.
14. N. Cohen, W. F. Eichel, R. J. Lopresti, C. Neukom, and
G. Saucey, J. Org. Chim., 1976, 41, 3505.
15. Y. Fujita, M. Shiono, K. Ejiri, and K. Saita, Chem. Lett.,
1985, 1399.
17. J. M. Grisar, M. A. Petty, F. N. Bolkenius, J. Dow,
J. Wagner, E. R. Wagner, K. D. Haegele, and W. De Jong,
J. Med. Chem., 1991, 34, 257.
18. G. D. Gamalevich, and E. P. Serebryakov, Izv. Akad.
Nauk, Ser. Khim., 1997, 175 [Russ. Chem. Bull., 1997, 46,
171 (Engl. Transl.)].
19. N. Cohen, C. G. Scott, C. Neukom, R. J. Lopresti,
G. Weber, and G. Saucy, Helv. Chim. Acta, 1981, 64, 1158.
20. E. A. Braude and F. C. Nachod, Determination of Organic
Structures by Physical Methods, Academic Press, New York,
1955, p. 73.
21. N. Cohen, J. W. Scott, F. T. Bizarro, R. J. Lopresti, W. F.
Eichel, G. Saucy, and H. Mayer, Helv. Chim. Acta, 1978,
61, 837.
22. N. Cohen, R. J. Lopresti, and G. Saucy, J. Am. Chem.
Soc., 1979, 101, 6710.
16. E. P. Serebryakov, Zh. Vsesoyuz. Khim. ob-va im. D. I.
Mendeleeva, 1991, 36, 476 [Mendeleev Chem. J., 1991, 36,
No. 4 (Engl. Transl.)].
Received July 25, 2001
in revised form August 16, 2001