An efficient synthesis of enantiomeric (S)-phosphocarnitine

Article abstract of DOI:10.1002/1099-0690(200208)2002:16<2758::AID-EJOC2758>3.0.CO;2-Q

Diethyl (S)-2,3-epoxypropylphosphonate [(S)-3] was transformed into (S)-phosphocarnitine [(S)-2] in the following sequence of reactions: a C-3 regioselective opening of the oxirane ring with magnesium bromide, quantitative bromide displacement with trimethylamine, and ester hydrolysis. The epoxide ring opening of 3 with HC1/EtOAc gave a 92:8 mixture of 3- and 2-chloro-substituted phosphonates, Reaction of (S)-3 with aqueous NMe3 gave diethyl 3-hydroxy-l-propenylphosphonate as a major product. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200208)2002:16<2758::AID-EJOC2758>3.0.CO;2-Q

FULL PAPER
An Efficient Synthesis of Enantiomeric (S)-Phosphocarnitine
[a]
[a]
Andrzej E. Wr o´ blewski* and Anetta Hałajewska-Wosik
Keywords: Kinetic resolution / Regioselectivity / Amino acids / Chiral auxiliaries / Conformation analysis
Diethyl (S)-2,3-epoxypropylphosphonate [(S)-3] was trans-
formed into (S)-phosphocarnitine [(S)-2] in the following se-
ture of 3- and 2-chloro-substituted phosphonates. Reaction of
(S)-3 with aqueous NMe gave diethyl 3-hydroxy-1-propen-
3
quence of reactions: a C-3 regioselective opening of the oxir- ylphosphonate as a major product.
ane ring with magnesium bromide, quantitative bromide dis-
placement with trimethylamine, and ester hydrolysis. The ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
epoxide ring opening of 3 with HCl/EtOAc gave a 92:8 mix-
2002)
Introduction
Results and Discussion
As already reported,[38] the racemic epoxyphosphonate 3
can be transformed in the presence of 0.2 mol % of (R,R)-
salen-Co -OAc [(R,R)-4] after 72 h into a mixture of (S)-
The importance of (R)-(Ϫ)-carnitine (1) in the oxidation
of fatty acids and other metabolic pathways has been recog-
nized in recent years.[ Increasing use of this compound
primarily as a dietary supplement has resulted in the elab-
oration of numerous synthetic procedures, including trans-
1]
III
(
(
Ϫ)-3 and diethyl (R)-(Ϫ)-2,3-dihydroxypropylphosphonate
5) (Scheme 1). Optically active (S)-3 was separated from
[2Ϫ6]
formations of homochiral starting materials,
asymmet-
the diol and the catalyst in 34% yield by distillation in va-
cuo. The absolute stereochemistries of the unchanged epox-
ide and the obtained diol were assigned by chemical cor-
[
7Ϫ14]
ric synthesis,
applications of enzymes and related
and also optical resolution of the ra-
[
15Ϫ22]
technologies
cemic carnitine or its precursors.[23,24]
[
39]
relation.
stereochemical outcome of the hydrolytic kinetic resolution
Furthermore, they are in agreement with the
[
40]
of other terminal epoxides catalysed by (R,R)-4.
Various analogues of carnitine have been synthesised in
order to study its mode of action and to reveal the struc-
tural features of binding sites.[
25Ϫ34]
Among them, phos-
phocarnitine (2), an analogue in which the carboxy group
has been replaced with a phosphoryl residue, has recently
[
35]
been obtained.
logical activity of several structurally diversified carnitine
Recent reports on the synthesis and bio-
[36]
analogues including phosphonates
duction of 3-substituted 2-oxopropylphosphonates
and Bakers yeast re-
The 94% ee of the unchanged epoxide (S)-3 was estab-
[
37]
31
has lished by the P NMR analysis of the derivative (S,S)-8
prompted us to disclose a new method for the preparation obtained after the transformations depicted in Scheme 2.
of (S)-2 based on Jacobsen’s hydrolytic kinetic resolution {NB The ee values reported have been corrected to take
(
HKR) of the racemic epoxyphosphonate 3. In this paper into account the 98.5% ee of the (S)-O-methylmandelic acid
[
41]
we give a full account of our synthesis of optically active [(S)-6] starting material. }The use of dibenzylamine led to
[
38]
(S)-3 and describe its transformation into phosphocarni- the exclusive opening of the epoxide ring at the less
[
42]
tine (S)-2.
hindered position to give (S)-3;
the reaction was com-
plete in 24 h.
Separation of the diol (R)-5 was achieved by further dis-
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, tillation of the residue left after recovery of (S)-3. The high
[
a]
Medical University of Ł o´ d z´ ,
boiling fraction contained minute quantities of the epoxide,
which were removed by column chromatography to give
pure diol (ee 86%) in 31% yield. This was the only way to
9
0-151 Ł o´ d z´ , Muszy n´ skiego 1, Poland
Fax: (internat.) ϩ48-42/678-8398
E-mail: aewplld@ich.pharm.am.lodz.pl
2758
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0816Ϫ2758 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 2758Ϫ2763

An Efficient Synthesis of Enantiomeric (S)-Phosphocarnitine
FULL PAPER
Scheme 1. Reagents and conditions: (a) (R,R)-salen-CoIII-OAc (0.2 mol %), H
O (0.55 equiv.)
2
Scheme 2. Reagents and conditions: (a) Bn
2
NH (1.1 equiv.), 60 °C, 20 h; (b) 6 (1.5 equiv.), 1,3-dicyclohexylcarbodiimide (DCC) (1.5
Cl
equiv.), 4-(dimethylamino)pyridine (DMAP) (0.1 equiv.), CH
2
2
obtain (R)-5 free from the catalyst. When the reaction mix- groups have reported full C-3 regioselectivity of the epoxide
tures formed in the hydrolytic kinetic resolution experi- opening in 3 using hydrogen chloride in chloroform.[43Ϫ45]
ments were subjected to column chromatography, fractions
containing (S)-3 and (R)-5 were contaminated with the
catalyst. The enantiomeric purity of (R)-5 was estimated by
3
1
P NMR spectroscopy after complete esterification with
(
(
S)-O-methylmandelic acid (6) to afford diester
Scheme 2).
9
Our strategy for the synthesis of phosphocarnitine (S)-2
is illustrated in Scheme 3.
Scheme 4. Reagents and conditions: (a) 3.8  HCl/EtOAc, 20 °C,
0.5 h
Attempts to open the epoxide ring in 3 with aqueous tri-
methylamine gave diethyl 3-hydroxy-1-propenylphosphon-
[
44,46,47]
ate (14)
as a major component (60%) of the crude
reaction mixture together with (S)-15 (ca. 20%) and several
unidentified products (Scheme 5).
Scheme 5. Reagents and conditions: (a) Me
3
N, 45% aqueous solu-
Scheme 3. Reagents and conditions: (a) MgBr
2
, diethyl ether; (b)
tion
4
3 2
5% Me N in ethanol/water; (c) 12  HCl, H O
The epoxide (S)-3 was reacted with MgBr in diethyl
In the presence of NMe in water/ethanol solution the
2
3
[
43]
ether
to afford the bromohydrin (R)-10. Complete C-3 bromohydrin (R)-10 was transformed quantitatively into
regioselectivity of the epoxide opening was established by the ammonium salt (S)-11. It is worth noting that the basi-
3
1
appearance of a P NMR signal at δ ϭ 29.06 ppm and city of the reaction mixture is not high enough to reconvert
3
1
31
identification of the diol (S)-5 (δ ϭ 30.7 ppm) as a minor (R)-10 to (S)-3, since the P NMR signal of 14 was not
P
(Ͻ 0.5%) impurity of the crude product. The ee of (R)-10 found in the spectrum of the crude product. The ammo-
in the reaction mixture (94%) and in the purified sample nium salt was isolated as an extremely hygroscopic solid.
3
1
(
99.9%) was estimated by P NMR spectroscopy after deri- Attempts to purify it by crystallisation led to contamination
vatisation with (S)-O-methylmandelic acid (6). with unidentified materials; however, column chromato-
As an alternative approach to introduce a good leaving graphy on silica gel afforded enantiomerically pure (S)-11
group at C-3 of the propylphosphonate framework, the ep- in 82% yield.
oxide ring opening in racemic 3 was studied with hydrogen
Hydrolysis of (S)-11 was accomplished with concentrated
chloride. Addition of 3.8  HCl/EtOAc led to the formation HCl under reflux to give (S)-2. After standard treatment
of a 92:8 mixture of 12 and 13 (Scheme 4). Other research with propylene oxide, the crude product was purified on
Eur. J. Org. Chem. 2002, 2758Ϫ2763
2759

A. E. Wr o´ blewski, A. Hałajewska-Wosik
FULL PAPER
silanized silica gel to give an amorphous white solid in 78%
yield, which was further crystallised from acetone/water.
Conclusions
An efficient synthesis of enantiomeric (S)-phosphocarnit-
ine was elaborated, which relies on the hydrolytic kinetic
resolution (HKR) of diethyl 2,3-epoxypropylphosphonate
using Jacobsen’s catalyst, followed by a fully C-3 regioselec-
tive opening of the highly enantiomerically enriched (ee
The 2-hydroxypropylphosphonates 5, 10, 11 and 12 exist
in [D]chloroform predominantly as their anti conformers 16
as can be judged from the large (15.5Ϫ16.9 Hz) values of
3
3
3
their J
couplings together with the J
and J
H1a-H2 H1b-
C,P
couplings of 3.9Ϫ6.2 Hz and 6.9Ϫ8.7 Hz, respectively.
H2
9
4%) epoxide with MgBr , bromide substitution with Me N
However, the 3-hydroxypropylphosphonate 13 can rotate
2
3
3
and ester hydrolysis. Replacement of the carboxyl group by
a phosphoryl residue reduces the conformational mobility
of the carnitine skeleton.
freely around the PϪC1 and C1ϪC2 bonds ( J
ϭ 7.2,
C,P
3
3
JH1a-H2 ϭ 7.5, J
ϭ 6.5 Hz). Based on these data we
H1b-H2
would like to emphasise the stabilising role of the intramo-
lecular
phonates.
hydrogen
bond
in
2-hydroxypropylphos-
[
48Ϫ50]
The stability of the anti conformer 16 can
Experimental Section
be additionally increased if one assumes the formation of
the hydrogen bond within a six-membered ring, which ad-
opts a chair conformation 17 with the C-2 substituents in
the equatorial positions.
General: 1H NMR spectra were recorded with a Bruker DPX
(
250 MHz) spectrometer or with a Varian Mercury-300 spectro-
meter; chemical shifts are quoted in ppm with respect to TMS and
1
3
31
coupling constants in Hz. C and P NMR spectra were recorded
on a Bruker DPX spectrometer at 62.9 and 101.25 MHz, or a
Varian Mercury-300 machine at 75.5 and 121.5 MHz, respectively.
IR spectroscopic data were measured on an Infinity MI-60 FT-IR
spectrometer. Melting points were determined on a Boetius appar-
atus and are uncorrected. Elemental analyses were performed by
the Microanalytical Laboratory of this Faculty on a PerkinϪElmer
PE 2400 CHNS analyzer. Polarimetric measurements were con-
ducted on a PerkinϪElmer 241 MC apparatus.
The following absorbents were used: column chromatography,
Merck silica gel 60 (70Ϫ230 mesh); analytical TLC, Merck TLC
plastic sheets silica gel 60 F254. TLC plates were developed in ethyl
3 3
acetate/hexanes or CHCl /CH OH solvent systems. Visualization
of spots was effected with iodine vapours. All solvents were purified
by methods described in the literature.[
54]
Racemic 3 was prepared according to the literature procedure in
Conformational studies on carnitine (1) revealed that it
exists almost exclusively in a gauche conformation 18 about
the C3ϪC4 bond, while, about the C2ϪC3 bond, a 53:42:5
mixture of conformers 19, 20, 21 is present.[ These con-
clusions are based on the values of the vicinal couplings
H3-H4a (1.9 Hz), H3-H4b (9.1 Hz), H2a-H3 (7.3 Hz) and
3
1
[55,56]
6
0% yield (δ
P
ϭ 26.71 ppm).
Before the estimation of ee’s,
3
1
values and the separation of the P NMR resonances of diastereo-
isomeric (S)-O-methylmandelic acid derivatives were assigned using
racemic 3, 5, 10 and 11.
51]
Hydrolytic Kinetic Resolution of Racemic 3: A mixture of (R,R)-4
(46.1 mg, 0.076 mmol), toluene (0.6 mL) and acetic acid (9.4 µL,
0.15 mmol) was stirred in air at room temperature for 1 h. After
removal of the solvent, the brown residue was dried under vacuum.
The racemic epoxide (7.415 g, 38.2 mmol) was added to the catalyst
in one portion and the mixture was cooled in an ice-water bath.
Water (0.378 mL, 21.0 mmol, 0.55 equiv.) was added over 0.5 h.
After 1 h the bath was removed and the reaction mixture was
[
52]
H2b-H3 (6.0 Hz)
and were further supported by MM2
[
51]
calculations;
the conformational preferences of the re-
lated phosphocarnitine (2) are similar. However, values of
the H2-H3a and H2-H3b couplings (9.8 and 1.2 Hz, re-
spectively) suggest the existence of the gauche conformer
22. On the other hand, the conformational equilibrium of
equally populated species 23 and 24 is proposed, as the H2- stirred at room temperature for 72 h. Ethyl acetate (15 mL) was
H1a and H2-H1b couplings are almost the same (6.6 and added followed by MgSO (1 g). After removal of the drying agent
and the solvent, the crude product was distilled to give (S)-(Ϫ)-3
4
6
.8 Hz); the vicinal H2-P coupling (7.6 Hz) is in agreement
2
0
[53]
(2.557 g, 34%) as a colourless oil (b.p. 64Ϫ68 °C/0.05 Torr). [α]
D
ϭ
with the gauche arrangement of these nuclei.
2760
Eur. J. Org. Chem. 2002, 2758Ϫ2763

An Efficient Synthesis of Enantiomeric (S)-Phosphocarnitine
FULL PAPER
Ϫ3.3 (c ϭ 1.38, ethanol), ee 94%. 31P NMR (121.5 MHz, CDCl
δ ϭ 26.82 ppm.
3
2
): the ethereal solution of MgBr was cooled to 0 °C under argon
and a solution of (S)-3 (1.05 g, 5.40 mmol) in dry diethyl ether
2 mL) was introduced slowly. The reaction mixture was stirred at
Ϫ5 °C for 2 h and then quenched with cold saturated aqueous
NH Cl (20 mL). The organic phase was separated, and the water
phase was extracted with diethyl ether (3 ϫ 5 mL). The organic
extracts were combined, dried over MgSO and concentrated. The
(
0
Further distillation afforded a fraction (b.p. 100Ϫ130 °C/0.05 Torr)
identified by 31P NMR spectroscopy as a 9:91 mixture of (S)-3 and
4
(
(
R)-5 (2.674 g). After chromatography on a silica gel column (R)-5
2
0
D
2.500 g, 30%) was obtained as a very viscous colourless oil. [α] ϭ
4
[39]
Ϫ13.5 (c ϭ 1.75, ethanol), ee 86% {ref. [α]
D
ϭ Ϫ12.2 (c ϭ 4.1,
crude product was chromatographed on silica gel with chloroform/
methanol (100:1, v/v) to give (R)-10 (1.18 g, 79%) as a colourless
oil which solidified at low temperatures, but melted before reaching
ethanol)}. IR (film): ν˜ ϭ 3375, 2985, 2932, 2913, 1224, 1031, 967
Ϫ1
1
3
3
cm . H NMR (300 MHz, CDCl ): δ ϭ 1.347 and 1.344 (2t, J ϭ
2
2
3
7
.0, 6 H, CH
3
), 1.95 (ddAB, J ϭ 19.2, JAB ϭ 15.3, J ϭ 3.9, 1
20
2
1
7
0 °C. [α]
D 3
ϭ ϩ12.4 (c ϭ 4.12, CHCl
). IR (film): ν˜ ϭ 3333, 2915,
2
2
3
H, 1b-H), 2.05 (ddAB, J ϭ 16.6, JAB ϭ 15.3, J ϭ 8.7, 1 H, 1a-
H), 3.54 (dAB, JAB ϭ 11.4, J ϭ 5.6, 1 H, 3b-H), 3.70 (ddAB,
AB ϭ 11.4, J ϭ 3.6, J ϭ 1.4, 1 H, 3a-H), 4.0Ϫ4.2 (m, 5 H) ppm.
Ϫ1
1
3
3
221, 1027 cm . H NMR (300 MHz, CDCl : δ ϭ 1.35 (t, J ϭ
.0, 6 H, CH ), 2.08 (ddAB, J ϭ 17.1, JAB ϭ 15.3, J ϭ 8.3, 1
3
H, 1b-H), 2.16 (ddAB, J ϭ 18.6, JAB ϭ 15.3, J ϭ 4.2, 1 H, 1a-
H), 3.49 (ddAB, JAB ϭ 10.3, J ϭ 5.4, J ϭ 1.3, 1 H, 3b-H), 3.52
ddAB, JAB ϭ 10.3, J ϭ 5.4, J ϭ 1.3, 1 H, 3a-H), 3.80 (d, J ϭ
.0, 1 H, OH), 4.08Ϫ4.25 (m, 5 H) ppm. C NMR (75.5 MHz,
2
3
2
2
3
2
3
4
J
2
2
3
13
3
C NMR (75.5 MHz, CDCl
3
): δ ϭ 16.51 (d, J ϭ 6.0, CH
3
), 29.93
), 66.77
2
3
4
1
2
(
(
(
d, J ϭ 140.0, C-1), 62.03 and 62.19 (2d, J ϭ 6.3, CH
2
2
3
4
3
(
4
d, J ϭ 15.5, C-3), 67.29 (d, 2J ϭ 3.4, C-2) ppm. P NMR
3
31
13
121.5 MHz, CDCl ): δ ϭ 30.78 ppm.
3
3
1
CDCl
3
): δ ϭ 16.46 (d, J ϭ 6.3, CH
3
), 31.69 (d, J ϭ 139.7, C-1),
3
2
3
6
2
3
8.74 (d, J ϭ 16.6, C-3), 61.99 and 62.20 (2d, J ϭ 6.4, CH
2
),
): δ ϭ
P (275.08): calcd. C 30.56, H 5.86; found C
Alternatively, from the racemic epoxide 3 (2.60 g, 14.0 mmol) and
water (0.138 mL, 7.70 mmol, 0.55 equiv.) in the presence of (R,R)-
2
31
6.15 (d, J ϭ 3.1, C-2) ppm. P NMR (121.5 MHz, CDCl
9.06 ppm. C 16BrO
0.58, H 5.60.
3
7
H
4
4
5
(17 mg, 0.028 mmol), a 52:48 mixture of (S)-(Ϫ)-3 and (R)-(Ϫ)-
was obtained after 19 h. Column chromatography on silica gel
with chloroform/methanol mixtures (20:1 and 10:1, v/v) gave (S)-
Reaction of Racemic 3 with 3.8  HCl/EtOAc: Diethyl 2,3-epoxy-
propylphosphonate (3) (1.00 g, 5.15 mmol) was dissolved at room
temperature in 2.7 mL of 3.8  HCl/EtOAc. After disappearance
of 3 (TLC) the solvent was evaporated in vacuo (0.1 Torr) and the
residue (1.406 g) was analysed by H, C, C(apt) and P NMR
spectroscopy. This material was chromatographed on a silica gel
column with chloroform/methanol (50:1, v/v) to give 12 as a col-
ourless oil (0.684 g, 58%) and various mixtures of 12 and 13, in-
cluding the most polar fraction of 12 and 13 (33:67) (47 mg).
3
1
3
(1.21 g, 44%) contaminated with traces of the catalyst (δ
P
ϭ
2
6.68 ppm) and (R)-5 (0.90 g, 30%), as a very viscous almost col-
20
ourless oil. [α]
D
ϭ Ϫ17.8 (c ϭ 4.3, ethanol).
1
13
13
31
General Procedures for the Estimation of eeЈs. a) Epoxides (S)-3: A
mixture of the epoxide (40.0 mg, 0.21 mmol) and dibenzylamine
(
45.0 mg, 0.23 mmol, 1.1 equiv.) in an argon-filled flask was kept
at 60 °C for 20 h. After cooling under argon to room temperature,
CH Cl (2 mL) was added followed by (S)-6 (53.0 mg, 0.32 mmol,
.5 equiv.), DCC (66.0 mg, 0.32 mmol, 1.5 equiv.) and DMAP
2.6 mg, 0.021 mmol, 0.1 equiv.). The reaction mixture was stirred
for 72 h at room temperature. 1,3-Dicyclohexylurea (DCU) was fil-
tered off, washed with a small amount of cold CH Cl , and the
solution was concentrated. The residue was dissolved in CDCl
2
2
1
(
Diethyl 3-Chloro-2-hydroxypropylphosphonate (12): 1H NMR
3
2
(
3
300 MHz, CDCl ): δ ϭ 1.35 (t, J ϭ 7.0, 6 H), 2.07 (ddAB, J ϭ
2
3
2
1
7.1, JAB ϭ 15.3, J ϭ 8.4, 1 H, 1b-H), 2.16 (ddAB, J ϭ 19.1,
AB ϭ 15.3, J ϭ 3.9, 1 H, 1a-H), 3.61 (ddAB, JAB ϭ 10.8, J ϭ
.4, J ϭ 1.3, 1 H, 3b-H), 3.63 (ddAB, JAB ϭ 10.8, J ϭ 5.4, J ϭ
.3, 1 H, 3a-H), 4.06Ϫ4.29 (m, 5 H) ppm. C NMR (75.5 MHz,
): δ ϭ 16.51 (d, J ϭ 6.3, CH
9.30 (d, J ϭ 16.9, C-3), 62.18 and 62.39 (2d, J ϭ 6.4, CH
d, J ϭ 3.7, C-2) ppm. P NMR (121.5 MHz, CDCl
2
2
2
3
2
3
J
3
4
2
3
4
5
1
3
1
(
0.6 mL) and the solution was analysed by P NMR spectroscopy.
No P NMR signals of the unchanged epoxide or unchanged
amino alcohol were found in the spectra. P NMR (121.5 MHz,
CDCl ): δ ϭ 27.13 [(S,S)-8] and 27.59 ppm [(R,S)-8].
1
3
3
1
3
1
CDCl
4
(
3
3
), 30.88 (d, J ϭ 140.6, C-1),
3
1
3
2
2
), 66.65
): δ ϭ 29.29.
3
2
31
3
b) Diol (R)-5: (S)-6 (70.0 mg, 0.42 mmol, 3.0 equiv.), DCC
87.0 mg, 0.42 mmol, 3.0 equiv.) and DMAP (3.7 mg, 0.03 mmol,
.2 equiv.) were added to a solution of (R)-5 (30.0 mg, 0.14 mmol)
in CH Cl (1.5 mL). The reaction mixture was stirred at room tem-
perature for 72 h. After removal of DCU, the solution was concen-
Diethyl 2-Chloro-3-hydroxypropylphosphonate (13): (NMR spectro-
scopic data taken from spectra of a 33:67 mixture of 12 and 13).
(
0
1
3
H NMR (300 MHz, CDCl
ddAB, J ϭ 19.2, JAB ϭ 15.5, J ϭ 6.5, 1 H, 1b-H), 2.41 (ddAB,
3
): δ ϭ 1.35 (t, J ϭ 7.2, 6 H), 2.36
2
2
2
2
3
(
2
2
3
3
31
31
J ϭ 18.5, JAB ϭ 15.5, J ϭ 7.5, 1 H, 1a-H), 3.27 (brt, J ഠ 5.0,
trated and the residue was analysed by P NMR spectroscopy.
NMR (121.5 MHz, CDCl ): δ ϭ 25.02 [(R,S,S)-9] and 24.95 ppm
(S,S,S)-9].
P
1
4
1
H, OH), 3.87 (brt, 3J ഠ 4.6, 2 H, 3-H), 4.08Ϫ4.22 (m, 4 H),
.24Ϫ4.35 (m, 1 H, 2-H) ppm. C NMR (75.5 MHz, CDCl
6.67 (d, J ϭ 6.0, CH
2), 62.52 and 62.56 (2d, J ϭ 6.5, CH
3
1
3
3
): δ ϭ
[
3
1
3
), 32.60 (d, J ϭ 138.5, C-1), 56.78 (s, C-
2
3
c) Secondary Alcohols (R)-10 and (S)-11: The procedure described
above for the diol was followed using (R)-10 or (S)-11 (0.15 mmol),
2
), 67.09 (d, J ϭ 7.2, C-3)
3
1
ppm. P NMR (121.5 MHz, CDCl
3
): δ ϭ 26.60 ppm.
(
S)-6 (1.5 equiv.), DCC (1.5 equiv.) and DMAP (0.1 equiv.) in
CH Cl (1.5 mL).
S)-O-Methylmandelic acid esters of (R)-10: 31P NMR
(
S)-3-(Diethoxyphosphoryl)-2-hydroxy-N,N,N-trimethylpropyl-
ammonium Bromide [(S)-11]: Ethanol (2 mL) was added to a mix-
ture of (R)-10 (0.942 g, 3.40 mmol) and 45% aqueous Me
2
2
(
(
(
3
N
121.5 MHz, CDCl
S)-O-Methylmandelic acid esters of (S)-11: P NMR (121.5 MHz,
): δ ϭ 23.42 (S,S) and 23.75 ppm (R,S).
3
): δ ϭ 24.80 (R,S) and 25.10 ppm (S,S).
31
(2.20 mL, 16.7 mmol, 5 equiv.) to get a homogenous solution,
which was kept at 20 °C for 23 h. Volatiles were evaporated and
the oily residue was subjected to column chromatography on silica
gel (80 g) with chloroform/methanol (10:1, v/v) (800 mL) to give
CDCl
3
Diethyl (R)-3-bromo-2-hydroxypropylphosphonate (10): A solution
of ethylene dibromide (2.07 g, 11.0 mmol) in dry diethyl ether
2
0
D
(S)-11 (0.924 g, 82%) as a colourless oil. [α] ϭ Ϫ16.4 (c ϭ 2.27,
(
2 mL) was added dropwise to magnesium (0.29 g, 12.0 mmol) at a ethanol). IR (film): ν˜ ϭ 3406, 2986, 2914, 1643, 1480, 1222, 1026
Ϫ1
1
3
rate sufficient to maintain the diethyl ether at reflux. After 2 h of
refluxing, more diethyl ether (20 mL) was added with a cannula,
3
cm . H NMR (300 MHz, CDCl ): δ ϭ 1.35 (t, J ϭ 7.1, 6 H),
2.19 (ddAB, J ϭ 18.0, JAB ϭ 15.5, J ϭ 6.9, 1 H, 1b-H), 2.25
2
2
3
Eur. J. Org. Chem. 2002, 2758Ϫ2763
2761

A. E. Wr o´ blewski, A. Hałajewska-Wosik
FULL PAPER
2
2
3
[10]
(
3
ddAB, J ϭ 18.0, JAB ϭ 15.5, J ϭ 6.3, 1 H, 1a-H), 3.47 (s, 9 H),
S. Sakuraba, H. Takahashi, H. Takeda, K. Achiwa, Chem.
Pharm. Bull. 1995, 43, 738Ϫ747.
H. C. Kolb, Y. L. Bennani, K. B. Sharpless, Tetrahedron: Asym-
metry 1993, 4, 133Ϫ141.
M. Kitamura, T. Ohkuma, H. Takaya, R. Noyori, Tetrahedron
Lett. 1988, 29, 1555Ϫ1556.
2
3
2
.70 (dd, J ϭ 13.3, J ϭ 10.1, 1 H, 3b-H), 4.03 (d, J ϭ 13.3, 3a-
[
[
[
11]
12]
13]
3
3
3
3
H), 4.14 (dq, J ϭ 7.7, J ϭ 7.1, 4 H), 4.70 (ddddd, J ϭ 10.5, J ϭ
1
H, OH) ppm. C NMR (75.5 MHz, CDCl
6
3
3
3
3
0.1, J ϭ 6.9, J ϭ 6.3, J ϭ 6.1, 1 H, 2-H), 5.55 (d, J ϭ 6.1, 1
13
3
3
): δ ϭ 16.65 (d, J ϭ
1
2
.3, CH
3
), 31.94 (d, J ϭ 138.0, C-1), 55.08, 62.13 (d, J ϭ 2.0, C-
H. Takeda, S. Hosokawa, M. Aburatani, K. Achiwa, Synlett
2
3
2
), 62.70 and 62.78 (2d, J ϭ 6.6, CH
2
), 70.64 (d, J ϭ 15.5, C-3)
): δ ϭ 27.23 ppm. H NMR
1
991, 193Ϫ194.
31
1
ppm. P NMR (121.5 MHz, CDCl
3
[14]
[15]
[16]
R. Pellegata, I. Dosi, M. Villa, G. Lesma, G. Palmisano, Tetra-
hedron 1985, 41, 5607Ϫ5613.
D. Ditullio, D. Anderson, C-S. Chen, C. J. Sih, Bioorg. Med.
Chem. 1994, 2, 415Ϫ420.
N. Kasai, K. Sakaguchi, Tetrahedron Lett. 1992, 33,
3
2
(
1
300 MHz, CD
3
OD): δ ϭ 1.35 (t, J ϭ 7.1, 6 H), 2.14 (dd, J ϭ
3
8.4, J ϭ 6.3, 2 H, 1-H), 3.25 (s, 9 H), 3.50 and 3.52 (ddAB part
2
3
3
of ABX system,
JAB ϭ 13.6, J ഠ 6.8, J ഠ 5.7, 2 H, 3ab-H),
3
3
3
3
4
5
.1Ϫ4.2 (m, 4 H), 4.55 (ddtd, J ϭ 12.0, J ϭ 6.8, J ϭ 6.3, J ഠ
.7, 1 H, 2-H) ppm. 13C NMR (75.5 MHz, CD
OD): δ ϭ 16.94 (d,
1211Ϫ1212.
3
[
[
[
17]
18]
19]
3
1
H. Seim, H. P. Kleber, Appl. Microbiol. Biotechnol. 1988, 27,
538Ϫ544.
D. Bianchi, W. Cabri, P. Cesti, F. Francalanci, M. Ricci, J. Org.
Chem. 1988, 53, 104Ϫ107.
C. Fuganti, P. Grasselli, P. F. Seneci, S. Servi, P. Casati, Tetra-
hedron Lett. 1986, 27, 2061Ϫ2062.
C. Fuganti, P. Grasselli, Tetrahedron Lett. 1985, 26, 101Ϫ104.
A. Gopalan, C. J. Sih, Tetrahedron Lett. 1984, 25, 5235Ϫ5238.
B. N. Zhou, A. S. Gopalan, F. VanMiddlesworth, W. R. Shieh,
C. J. Sih, J. Am. Chem. Soc. 1983, 105, 5925Ϫ5926.
R. Voeffray, J.-C. Perlberger, L. Tenud, J. Gosteli, Helv. Chim.
Acta 1987, 70, 2058Ϫ2064.
J ϭ 6.0, CH
3
), 33.01 (d, J ϭ 139.7, C-1), 55.22 (three lines of
1
2
3
equal intensity, J ϭ 3.5, CH ), 63.28 (d, J ϭ 2.9, C-2), 63.74 and
2
3
31
6
(
(
3.82 (2d, J ϭ 6.1, CH
121.5 MHz, CD OD): δ ϭ 28.57 ppm. C10
370.22): calcd. C 32.44, H 7.80, N 3.78; found C 32.51, H 7.90,
2
), 71.62 (d, J ϭ 15.2, C-3) ppm. P NMR
3
H
25BrNO P·2H O
4
2
N 3.56.
[20]
[
[
21]
22]
Phosphocarnitine [(S)-2]: A mixture of (S)-11 (0.580 g, 1.74 mmol)
and conc. HCl (9.3 mL) was refluxed for 5 h. Volatiles were evapor-
ated, the residue was dried under vacuum and then dissolved in
ethanol (5.4 mL). The precipitate formed after dropwise addition
of propylene oxide (5.4 mL) was filtered off and chromatographed
on a silanized silica gel [Kieselgel 60 silanisiert (70Ϫ230 mesh)
Merck Art. 7719 was used] column with water to give (S)-2
[23]
[24]
[25]
[26]
R. N. Comber, W. J. Brouillete, J. Org. Chem. 1987, 52,
2
311Ϫ2314.
T. L. Hutchison, A. Saeed, P. E. Wolkowicz, J. B. McMillin,
W. J. Brouillette, Bioorg. Med. Chem. 1999, 7, 1505Ϫ1511.
I. Bernabei, R. Castagnani, F. De Angelis, E. De Fusco, F.
Giannessi, D. Misiti, S. Muck, N. Scafetta, M. O. Tinti, Chem.
Eur. J. 1996, 2, 826Ϫ831.
R. Castagnani, F. De Angelis, E. De Fusco, F. Giannessi, D.
Misiti, D. Meloni, M. O. Tinti, J. Org. Chem. 1995, 60,
8318Ϫ8319.
(0.270 g, 78%) as a white amorphous powder. Crystallisation from
2
0
water/acetone gave a white solid. M.p. 270 °C (decomp.). [α]
Ϫ17.4 (c ϭ 1.15, water). IR (KBr): ν˜ ϭ 3393, 2922, 2851, 1474,
D
ϭ
Ϫ1
1
2
1
067, 985 cm . H NMR (300 MHz, D
2
O): δ ϭ 1.76 (ddAB, J ϭ
[
[
27]
28]
2
3
2
1
6.6, JAB ϭ 14.8, J ϭ 6.6, 1 H, 1a-H), 1.78 (ddAB, J ϭ 16.7,
2
3
2
J
AB ϭ 14.8, J ϭ 6.8, 1 H, 1b-H), 3.25 (s, 9 H), 3.43 (dAB, JAB ϭ
3
2
3
1
3
1
1
3.8, J ϭ 9.8, 1 H, 3a-H), 3.64 (dAB, JAB ϭ 13.8, J ϭ 1.2, 1 H,
W. J. Brouillette, A. Saeed, A. Abuelyaman, T. L. Hutchison,
P. E. Wolkowicz, J. B. McMillin, J. Org. Chem. 1994, 59,
3
3
3
3
3
b-H), 4.52 (brm, J ϭ 9.8, J ϭ 7.6, J ϭ 6.8, J ϭ 6.6, J ϭ 1.2,
H, 2-H) ppm. 13C NMR (62.9 MHz, D
O): δ ϭ 32.93 (d, J ϭ
1
2
4297Ϫ4303.
1
25.9, C-1), 52.35 (three lines of equal intensity, J ϭ 3.6), 61.67
C-2), 69.36 (d, J ϭ 12.0, C-3) ppm. P NMR (121.5 MHz, D
[29]
[30]
D. R. Bingham, J. R. Neergaard, B. V. R. Sasry, H. E. Smith,
Med. Chem. Res. 1991, 1, 130Ϫ 135.
G. Cardillo, M. Orena, M. Penna, S. Sandri, C. Tomasini, Syn-
lett 1990, 543Ϫ544.
S. Shinagawa, T. Kanamaru, S. Harada, M. Asai, H. Okazaki,
3
31
(
2
O):
δ ϭ 17.8 ppm. HRMS (FABϩ) C H17NO P (m/z): calcd. 198.0895;
found 198.0898.
6 4
[31]
J. Med. Chem. 1987, 30, 1458Ϫ 1463.
P. M. Woster, W. J. Murray, J. Med. Chem. 1986, 29, 865Ϫ868.
C. A. Hosmer, R. N. Comber, W. J. Brouillete, J. Org. Chem.
[
[
32]
33]
Acknowledgments
We thank Mrs Małgorzata Pluskota for her skilled experimental
contributions. Financial support from the Medical University of
Ł o´ d z´ (502-13-597 and 503-302-4) is gratefully acknowledged.
1
985, 50, 3627Ϫ3631.
[34]
[35]
C. R. Degenhardt, J. Org. Chem. 1980, 45, 2763Ϫ2766.
E. Tadeusiak, B. Krawiecka, J. Michalski, Tetrahedron Lett.
1
999, 40, 1791Ϫ1792.
[36]
F. Giannessi, P. Chiodi, M. Marzi, P. Minetti, P. Pessotto, F.
De Angelis, E. Tassoni, R. Conti, F. Giorgi, M. Mabilia, N.
Dell’Uomo, S. Muck, M. O. Tinti, P. Carminati, A. Arduini,
J. Med. Chem. 2001, 44, 2383Ϫ2386.
[
[
[
1]
2]
3]
C. De Simone, G. Famularo, Carnitine Today Springer-Verlag,
Heildelberg, 1997.
[
[
37]
38]
C. Yuan, K. Wang, Z. Li, Heteroatom Chem. 2001, 12,
G. Wang, R. I. Hollingsworth, Tetrahedron: Asymmetry 1999,
5
51Ϫ556.
1
0, 1895Ϫ1901.
A. E. Wr o´ blewski, A. Hałajewska-Wosik, Tetrahedron: Asym-
M. Kabat, A. R. Daniewski, W. Burger, Tetrahedron: Asym-
metry 1999, 10, 2663Ϫ2665.
metry 2000, 11, 2053Ϫ2055.
E. Baer, H. Basu, Can. J. Biochem. 1969, 47, 955Ϫ960.
E. N. Jacobsen, Acc. Chem. Res. 2000, 33, 421Ϫ431.
A. E. Wroblewski, D. G. Piotrowska, Tetrahedron: Asymmetry
2000, 11, 2615Ϫ2624.
C. Verbruggen, S. De Craecker, P. Rajan, X.-Y. Jiao, M. Bor-
loo, K. Smith, A. H. Fairlamb, A. Haemers, Bioorg. Med.
Chem. Lett. 1996, 6, 253Ϫ258.
A. M. M. M. Phillips, M. J. Mphahlele, A. M. Modro, T. A.
Modro, A. Zwierzak, Phosphorus, Sulfur, Silicon Relat. Elem.
1992, 71, 165Ϫ174.
[
[
[
39]
40]
41]
[
[
4]
5]
M. Bols, I. Lundt, C. Pedersen, Tetrahedron 1992, 48, 319Ϫ324.
F. D. Bellamy, M. Bondoux, P. Dodey, Tetrahedron Lett. 1990,
´
3
1, 7323Ϫ7326.
K. Bock, I. Lundt, C. Pedersen, Acta Chem. Scand., Ser. B
983, B37, 341Ϫ344.
[
6]
[
[
42]
43]
1
[
[
7]
8]
R. P. Jain, R. M. Williams, Tetrahedron 2001, 57, 6505Ϫ6509.
M. Marzi, P. Minetti, G. Moretti, M. O. Tinti, F. De Angelis,
J. Org. Chem. 2000, 65, 6766Ϫ6769.
C. E. Song, J. K. Lee, S. H. Lee, S. Lee, Tetrahedron: Asym-
metry 1995, 6, 1063Ϫ1066.
[
9]
2762
Eur. J. Org. Chem. 2002, 2758Ϫ2763

An Efficient Synthesis of Enantiomeric (S)-Phosphocarnitine
FULL PAPER
[
[
[
[
[
44]
45]
46]
47]
48]
[51]
[52]
[53]
B. V. Ryabov, B. I. Ionin, A. A. Petrov, Zh. Obshch. Khim. 1988,
8, 969Ϫ983.
T. A. Modro, M. J. Mphahlele, Org. Mass Spectrom. 1992,
7, 47Ϫ49.
G. Just, P. Potvin, G. H. Hakimelahi, Can. J. Chem. 1980, 58,
780Ϫ2783.
A. Rakov, A. V. Alekseev, Zh. Obshch. Khim. 1973, 43,
76Ϫ278.
D. G. Genov, R. A. Kresinski, J. C. Tebby, J. Org. Chem. 1998,
3, 2574Ϫ2585.
W. J. Colucci, R. D. Gandour, E. A. Moobery, J. Am. Chem.
Soc. 1986, 108, 7141Ϫ7147.
G. Agostini, F. Coletta, A. Gambaro, S. Castellano, Spectro-
chim. Acta Part A 1979, 35, 733Ϫ737.
W. G. Bentrude, W. N. Setzer, Phosphorus-31 NMR Spectro-
scopy in Stereochemical Analysis (Eds.: J. G. Verkade, L. D.
Quin), VCH, Deerfield, 1987, chapter 11.
5
2
2
[
[
54]
55]
2
D. D. Perrin, W. L. F. Armarego, Purification of Laboratory
Chemicals, 3rd, ed., Pergamon Press, Oxford, 1988.
C. E. Griffin, S. K. Kundu, J. Org. Chem. 1969, 34, 1532Ϫ1539.
I. Rico, A. Bou, J. Lalo, J. P. Maffrand, D. Frehel, New. J.
Chem. 1989, 13, 507Ϫ510.
6
[
[
49]
50]
[56]
D. G. Genov, J. C. Tebby, J. Org. Chem. 1996, 61, 2454Ϫ2459.
˙
R. Gancarz, R. Latajka, B. Małuszek, E. Zyma n´ czyk-Duda, P.
Kafarski, Magn. Reson. Chem. 2000, 38, 197Ϫ200.
Received March 26, 2002
[O02169]
Eur. J. Org. Chem. 2002, 2758Ϫ2763
2763