An efficient, highly enantioenriched route to L-carnitine and α-lipoic acid via hydrolytic kinetic resolution

Article abstract of DOI:10.1055/s-2006-942363

A general and practical approach for the synthesis of C-4 chiral building blocks using Jacobsen's hydrolytic kinetic resolution technique to resolve terminal epoxides and diols in high enantiomeric excess and excellent yields is described. The utilization of these building blocks for the synthesis of biologically important natural products L-carnitine and α-lipoic acid is illustrated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942363

PAPER
1863
An Efficient, Highly Enantioenriched Route to L-Carnitine and a-Lipoic Acid
via Hydrolytic Kinetic Resolution
L-Carnitine
and
a
-
.
L
ipoic Acid
S
via
H
ydrolytic
u
K
inetic Res
b
olution has Bose,* Liyakat Fatima, Salla Rajender
Organic Chemistry Division III, Fine Chemicals Laboratory, Indian Institute of Chemical Technology, Hyderabad, India, 500 007
Fax +91(40)27160387; E-mail: dsb@iictnet.org; E-mail: dsb@iict.res.in
Received 30 November 2005; revised 19 December 2005
OH
2
OH
Abstract: A general and practical approach for the synthesis of
C-4 chiral building blocks using Jacobsen’s hydrolytic kinetic reso-
lution technique to resolve terminal epoxides and diols in high
enantiomeric excess and excellent yields is described. The utiliza-
tion of these building blocks for the synthesis of biologically impor-
tant natural products L-carnitine and a-lipoic acid is illustrated.
_
+
_
+
H3N
COO
Me3N
COO
1
H
S
COOH
S
3
Keywords: L-carnitine, a-lipoic acid, hydrolytic kinetic resolution,
terminal epoxide, enantioenriched
Figure 1
oxides are arguably the most important subclass of these
compounds, and no general and practical method exists
for their production in enantiomerically pure form. Termi-
nal epoxides are available inexpensively as racemic mix-
tures, and kinetic resolution is an attractive strategy for the
production of optically active epoxides, by an economical
and operationally simple method.
(R)- and (S)-Carnitine (3-hydroxy-4-trimethylaminobu-
tyric acid, 1) have attracted considerable attention in re-
cent years, owing to their interesting biological properties
and their use as pharmaceuticals.1–5 (R)-Carnitine 1, also
known as vitamin BT, plays an important role in the b-ox-
idation of fatty acids, acting as a carrier of fatty acids over
the mitochondrial membrane. Since fatty acid oxidation is
a critical step by which cells derive energy, carnitine is
important for cellular energetics. The antipode, S enantio-
mer of 1, acts as a competitive inhibitor of carnitine
acyltransferase6 causing depletion of carnitine. a-(R)-Li-
poic acid 3 is an important protein bound coenzyme and
growth factor found in animal tissues, plants, and micro-
organisms. It plays a major role in several biochemical
processes and has been identified as a crucial co-factor
with pyruvate dehydrogenase (PDH) and a-ketoglutarate
dehydrogenase (KGDH) multi-enzyme complexes re-
sponsible for the production of acetyl-CoA in metabolic
pathways7 (Figure 1). The increasing demand for this
class of compound is exemplified by numerous synthetic
routes including optical resolution, fermentation, the chi-
ron approach (asymmetric synthesis from natural prod-
ucts), and catalytic asymmetric synthesis, along with their
associated patents.8 There is still a need, however, for
straightforward syntheses that have significant practical
value.
[2-(Phenylmethoxy)ethyl]oxirane 4 has been extensively
used as a versatile C-4 chiral building block in the prepa-
ration of a variety of biologically important compounds
including compactin and milbemycin,10 1,3-polyols (mac-
rolide antibiotics)11 and most recently, (R)/(S)-S-adenos-
yl-1,8-diamino-3-thiooctane.12 Despite the extensive use
of this chiral epoxide, there is still no method for its prep-
aration in both high yields and enantiomeric purity. In this
paper, we wish to describe a more convenient synthesis of
the enantiomerically pure epoxides (R)- and (S)-4 by em-
ploying Jacobsen’s hydrolytic kinetic resolution (HKR),
as the key step, to resolve the terminal epoxides. The HKR
method uses readily accessible cobalt-based chiral salen
complex 5 as a catalyst and constitutes a very attractive
approach for the preparation of highly enantioselective
chiral epoxides and diols of high optical purity in excel-
lent yields.13 The salient features of HKR include the ac-
cessibility of racemic terminal epoxides and the use of
water as the reagent/nucleophile for epoxide ring-open-
ing, which allows access to highly enantioenriched (>99%
ee) products in close to theoretical yields. Also HKR is a
practical and scaleable reaction protocol involving low
loadings (0.2–2.0 mol%) of a recyclable catalyst and the
separation of the product from unreacted epoxide is sim-
ple due to large boiling point and polarity differences.
Chiral epoxides are versatile building blocks for the syn-
thesis of enantiomerically pure complex molecules.
Asymmetric epoxidation of olefins presents a powerful
strategy for the synthesis of enantiomerically enriched ep-
oxides. Great success has been achieved in the epoxida-
tion of allylic alcohols, unfunctionalized cis-olefins, and
conjugated trisubstituted olefins.9 However, terminal ep-
The substrate for HKR, racemic epoxide 4, was obtained
from the commercially available 3-buten-1-ol by benzyla-
tion with one equivalent of sodium hydride and benzyl
bromide in THF in 90% yield followed by epoxidation
with MCPBA in dichloromethane. Subsequent HKR of 4
SYNTHESIS 2006, No. 11, pp 1863–1867
x
x.
x
x
.
2
0
0
6
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-942363; Art ID: Z23505SS
© Georg Thieme Verlag Stuttgart · New York

1864
D. S. Bose et al.
PAPER
H
H
N
O
N
O
Co
t-Bu
t-Bu
OAc
t-Bu
t-Bu
(R,R)-5
OH
(R,R)-5
(0.5 mol%)
O
O
OH
+
H2O (0.55 equiv)
BnO
BnO
BnO
(S)-6
(R)-4 96% ee
+
(
)-4
Ph3P, DIAD
C6H6, reflux
O
BnO
(S)-4 94% ee
Scheme 1
with (R,R)-salen-Co(III)-OAc complex 5 (0.5 mol%) and bromide in the presence of sodium hydride and TBAI in
H2O (0.55 equiv) at ambient temperature afforded a mix- DMF. The next step was to elaborate the terminal olefin
ture of epoxide (R)-4 in 47% yield (98% optical yield) and into the corresponding acid function. Thus, compound 9
the 1,2-diol 6 in 43% yield (Scheme1). The diol 6 could was subjected to hydroboration–oxidation, using borane–
be recycled, via the Mitsunobu reaction with DIAD and DMS–hydrogen peroxide in THF to afford the primary al-
triphenylphosphine in refluxing benzene, to afford the cohol 10 in 88% yield. Oxidation of the primary alcohol
corresponding epoxide (S)-4 in 80% yield with 96% opti- to the carboxylic acid16 was achieved with a mixture of so-
cal yield. Both epoxides are expected to serve as good pre- dium chlorite and bleach, catalyzed by TEMPO and fol-
cursors for the synthesis of biologically interesting natural lowed by esterification with diazomethane to afford the
products. Although both epoxides have been synthesized ester 11. Removal of the benzyl group by hydrogenolysis
independently, by long synthetic routes,14,8e starting from gave the diol 12, which was converted to a-(R)-lipoic acid
chiral pool aspartic acid, malic acid etc., the present syn- 3, by the standard sequence of reactions.8i Mesylation of
thetic modification, to obtain both epoxides (R)- and (S)- diol 12 followed by disulfide displacement with a mixture
4 in just one or two steps from ( )-(4) ,was a significant of sodium sulfide and sulfur in DMF at 90 °C for 24 hours
improvement. Utilization of the C-4 chiral building blocks and finally saponification with potassium carbonate in
for the synthesis of L-carnitine 1 and a-(R)-lipoic acid 3 methanol and water yielded lipoic acid 3. The spectral
was then investigated.
data and optical rotation of 3 were in good agreement with
the reported data.
Thus, hydrogenolysis of the benzyl ether on chiral ep-
oxide (R)-4 gave the required epoxy alcohol 7 in 85% In summary, we have demonstrated a very simple and
yield (Scheme 2). Conversion of 7 into the corresponding practical method for the synthesis of enantiomerically
(3R)-(–)-4-amino-3-hydroxybutyric acid (GABOB),8
a
pure (R)-carnitine and a-(R)-lipoic acid using Jacobsen’s
well-known neuromodulator, was accomplished in a HKR technique as the key step and source of chirality.
straightforward manner in two steps. The primary alcohol The extension of the synthetic methodology described to
in compound 7 was oxidized to the corresponding carbox- other biologically active compounds, employing the ver-
ylic acid and subsequent nucleophilic opening of the ep- satile intermediate 4, is being investigated in our laborato-
oxy acid with a solution of concentrated ammonium ry.
hydroxide furnished 2. Methylation of enantiomerically
pure (R)-2 was carried out under basic conditions to yield
O
a
b,c
O
(R)-carnitine 18a in 65% yield.
OH
OBn
7
(R)-4
Upon re-examination of the structure of a-(R)-lipoic acid
3, we realized that (R)-[2-(benzyloxy)ethyl]oxirane (4)
could be an ideal precursor (Scheme 3). Thus, the re-
giospecific opening of epoxide (R)-4 with but-3-enylmag-
nesium bromide (3 equiv) in THF containing 10 mol%
lithium tetrachlorocuprate15 at –78 °C furnished 1-benzyl-
oxyoct-7-en-3-ol (8) in 90% yield. The hydroxy group in
8 was protected as benzyl ether by reaction with benzyl
OH
OH
+
+
_
d
_
Me3N
COO
H3N
COO
2
1
Scheme 2 Synthesis of (R)-carnitine 1. Reagents and conditions: (a)
H2, Pd/C, EtOH; (b) RuCl3, NaIO4; (c) concd NH4OH; (d) MeI, base.
Synthesis 2006, No. 11, 1863–1867 © Thieme Stuttgart · New York

PAPER
L-Carnitine and a-Lipoic Acid via Hydrolytic Kinetic Resolutions
1865
OH
O
b
a
BnO
BnO
BnO
BnO
(R)-4
(S)-8
OBn
OBn
c
d
OH
BnO
9
10
OBn
OH
e
CO2Me
HO
CO2Me
11
12
f
(R)- Lipoic Acid 3
Scheme 3 Synthesis of (R)-lipoic acid 3. Reagents and conditions: (a) CH2=CHCH2CH2MgBr, Li2CuCl4 (cat.), THF, –78 °C to r.t.; (b) NaH,
BnBr, DBAI, DMF, 85%; (c) BH3·DMS, MeCO2Na, H2O2, THF, 88%; (d) (i) NaClO2, TEMPO, NaOCl; (ii) CH2N2, Et2O; (e) H2, Pd/C, EtOH
(f) (i) MsCl, Et3N/CH2Cl2 (ii) Na2S, S, DMF, 90 °C, 24 h (iii) K2CO3, MeOH, H2O.
1H NMR spectra were recorded on a Varian FT 200 MHz (Gemini)
spectrometer. Chemicals shifts are reported in ppm relative to TMS
as an internal standard. Mass spectra (EI) were recorded at 70 eV on
a Finnigan Mat 1020B mass spectrometer. Melting points were re-
corded on a Büchi 535 and are uncorrected. Optical rotations were
measured on a Jasco DIP 360 digital polarimeter. Elemental analy-
ses were performed on elemental analyzer Vario EL. Column chro-
matography was carried out using 60–120 mesh silica gel. TLC was
performed on Merck 60 F-254 silica gel plates. Reagents and sol-
vents were of analytical grade or were purified by standard proce-
dures prior to use, and petroleum ether (PE) refers to the fraction
with bp 60–80 °C.
1H NMR (CDCl3): d = 1.6–2.0 (m, 2 H), 2.35 (br s, 1 H), 2.42–2.68
(m, 1 H), 2.7–3.1 (m, 2 H), 3.73 (t, J = 6.0 Hz, 2 H).
Alcohol 7 (0.5 g, 5.7 mmol) was added slowly to a vigorously
stirred solution of NaIO4 (3.33 g, 15.5 mmol), in CH3CN–H2O–
CCl4 (1:1:1, 10 mL) and RuCl3·(H2O)n (8.0 mg). The reaction mix-
ture was then stirred for 1 h. The heterogenous mixture was filtered
and the aqueous and organic phases partitioned. The aqueous phase
was extracted several times with THF (3 × 5 mL). The combined or-
ganic phases were treated with excess concentrated NH4OH (2 mL)
and the resulting solution was warmed on a steam bath for 24 h. The
reaction mixture was then concentrated to give a tan solid which
was purified by ion-exchange chromatography on Dowex 50W-X8
(200–400 mesh H+ form), eluting first with H2O and then 2 N
NH4OH to yield 2 as a white crystalline solid (400 mg, 60%); mp
211–213 °C (dec.) (Lit.8b 216–217 °C dec.); [a]D25 –20.5 (c 1.8,
H2O) {Lit.8d [a]D25 –21.06 (c 2.2, H2O)}.
(R)- and (S)-[2-(Benzyloxy)ethyl]oxirane (4)
A stirred solution of ( )-4 (8.0 g, 44.94 mmol) and (R,R)-salen
Co(III)–OAc catalyst 5 (145 mg, 0.225 mmol) was cooled to 0 °C,
then H2O (0.45 mL, 25.0 mmol) was added dropwise over a period
of 45 min. The reaction mixture was then stirred at r.t. for 5 h, dilut-
ed with EtOAc, dried (Na2SO4), and concentrated. The brown resi-
due was chromatographed (EtOAc–hexane, 1:9); the first fraction
eluted contained (R)-4 and the second fraction eluted afforded (S)-
diol (6) (3.8 g, 43%). Subsequently, 6 (3.5 g, 17.85 mmol), Ph3P
(7.0 g, 26.7 mmol), and DIAD (5.16 mL, 26.75 mmol) in benzene
(50 mL) were heated under reflux for 20 h. The solvent was re-
moved, Et2O (80 mL) was added, and the Ph3PO precipitate was re-
moved by filtration. The filtrate was concentrated and the resulting
residue was purified by column chromatography (EtOAc–hexane,
1:9) to give (S)-4 (2.55 g, 80%); [a]D –13.9 (c 2.0, CHCl3)
[Lit.14b –14.5 (c 2.51, CHCl3)].
1H NMR (D2O): d = 2.38 (d, J = 6.0 Hz, 2 H), 2.90 (dd, J = 12.8, 9.6
Hz, 1 H), 3.17 (dd, J = 13.4, 3.0 Hz, 1 H), 4.25–4.15 (m, 1 H).
Anal. Calcd for C4H9NO3: C, 40.34; H, 7.56; N, 11.76. Found: C,
40.37; H, 7.58; N, 11.73.
(3R)-4-Trimethylamino-3-hydroxybutyric Acid [R-Carnitine]
(1)
Methylation of (3R)-2 (200 mg, 1.68 mmol) was carried out by the
reported method8a to furnish (R)-1 (175 mg, 65% yield) as a clear
colorless gum, which was recrystallized from i-PrOH; mp 193–195
25
°C (Lit.8a mp 197–198 °C); [a]D25 –22.6 (c 1.0, H2O) {Lit.8a [a]D
–23.7 (c 0.86, H2O)}; 95% ee.
1H NMR (D2O): d = 2.23 (s, 9 H), 2.49–2.35 (m, 2 H), 3.44–3.42
(R)-[2-(Benzyloxy)ethyl]oxirane (4)
(m, 2 H), 4.60–4.52 (m, 1 H).
[a]D +16.6 (c 3.0, CHCl3) [Lit.14b +16.9 (c 2.51, CHCl3)].
Anal. Calcd for C7H15NO3·0.7H2O: C, 51.79; H, 9.39; N, 8.62.
Found: C, 51.72; H, 9.37; N, 8.57.
1H NMR (CDCl3): d = 1.69–1.95 (m, 1 H), 2.50 (dd, J = 5.0, 2.7 Hz,
1 H), 2.75 (pseudo t, J = 4.5 Hz, 1 H), 3.01–3.07 (m, 2 H), 3.59 (t,
J = 6.1 Hz, 2 H), 4.51 (s, 2 H), 7.30–7.39 (m, 5 H).
13C NMR (CDCl3): d = 33.3, 47.4, 50.3, 67.5, 73.4, 127.8, 128.7,
138.7.
(S)-1-Benzyloxyoct-7-en-3-ol (8)
Mg (1.5 g, 62.5 mmol), 4-bromo-1-butene (8.1 g, 60 mmol), and a
few drops of 1,2-dibromoethane in anhyd THF (25 mL) were gently
warmed until the reaction commenced. The reaction mixture was
then stirred at r.t. for 1 h and then cooled to –78 °C. A solution
Li2CuCl4 (0.09 g, 0.4 mmol) in THF was introduced into the reac-
tion mixture. After stirring for 1 h, (R)-4 (3.1 g, 17.5 mmol) in THF
(15 mL) was added dropwise. The mixture was stirred at –78 °C for
an additional 3 h and then allowed to warm to r.t. overnight. The re-
action was quenched with a cold sat. aq solution of NH4Cl (10 mL).
The organic layer was separated and the aqueous layer extracted
with Et2O (2 × 25 mL). The combined organic layer was washed
with brine (10 mL), dried (Na2SO4), and concentrated under re-
duced pressure. The crude residue was chromatographed (EtOAc–
Anal. Calcd for C11H14O2: C, 74.13; H, 7.92. Found: C, 74.10; H,
7.95.
(3R)-4-Amino-3-hydroxybutyric Acid (GABOB) (2)
A stirred solution of (R)-4 (1.5 g, 8.42 mmol) in EtOH (10 mL) was
hydrogenated over 5% Pd/C (150 mg) under 1 atm of H2 pressure.
After 5 h the reaction mixture was filtered through celite and the fil-
trate was concentrated to afford 7 (630 mg, 85%) as a colorless oil,
which was used in the next step without purification.
Synthesis 2006, No. 11, 1863–1867 © Thieme Stuttgart · New York

1866
D. S. Bose et al.
PAPER
PE, 1:2) to give 8 (3.7 g, 90%) as a light yellow oil; [a]D +5.5 (c 0.5,
(1.83g, 30 mL), the temperature was maintained at <20 °C. The pH
of the aqueous layer should be 8.5–9.0. After stirring for 0.5 h at r.t.,
MTBE (30 mL) was added. The organic layer was separated and
discarded. A further portion of MTBE (45 mL) was added, and the
aqueous layer was acidified to pH 3–4 with 2.0 N HCl (15 mL). The
organic layer was separated, washed with H2O (2 × 25 mL) and
brine (25 mL), and then concentrated to give the crude carboxylic
acid, which was esterified by dissolution in a solution of CH2N2 (ex-
cess) in Et2O and the resulting solution was left to stand overnight.
The crude methyl ester was purified by column chromatography
(EtOAc–PE, 1:5) to give 11 (1.75 g, overall yield: 80%) as an oil;
[a]D +20.5 (c 0.5, CHCl3).
CHCl3).
1H NMR (CDCl3): d = 1.28–1.51 (m, 4 H), 1.59–1.61 (m, 2 H),
1.98–2.01 (m, 2 H), 2.85 (br s, 1 H), 3.52–3.54 (m, 2 H), 3.61–3.64
(m, 1 H), 4.42 (s, 2 H), 5.1–5.85 (m, 3 H), 7.23 (s, 5 H).
MS (CI): m/z (%) = 91 (100), 107 (81), 131 (18), 159 (47), 235 [54,
(M + 1)].
Anal. Calcd for C15H22O2: C, 76.88; H, 9.46. Found: C, 76.95; H,
9.49.
(S)-6,8-Dibenzyloxyoct-1-ene (9)
1H NMR (CDCl3): d = 1.22–1.58 (m, 6 H), 1.72–1.74 (m, 2 H), 2.21
(t, J = 7.3 Hz, 2 H), 3.45–3.48 (m, 3 H), 4.42 (d, J = 8.3 Hz, 1 H),
4.45 (d, J = 8.3 Hz, 1 H).
To a solution of alcohol 8 (2.35 g, 10.0 mmol) in anhyd DMF (15
mL) was added TBAI (7.49 g, 20.0 mmol) followed by NaH (60%
wt in mineral oil, 0.36 g, 15.0 mmol) at 0 °C under a N2 atmosphere.
The reaction mixture was stirred for a few minutes and then BnBr
(3.42 g, 2.37 mL, 20.0 mmol) was added. After stirring at r.t. for 2
h, the reaction mixture was quenched with a sat. aq solution of
NH4Cl (20 mL), and the mixture was extracted with Et2O (2 × 25
mL). The combined organic phases were washed with H2O (5 mL),
brine (5 mL), dried (Na2SO4), and concentrated under reduced pres-
sure. The residue was purified by column chromatography (EtOAc–
PE, 1:4) to give 9 (2.76 g, 85%) as a colorless oil; [a]D +19.5 (c 0.5,
CHCl3).
MS (EI): m/z (%) = 91 (100), 108 (10), 141 (27), 181 (11), 264 (8),
371 [10, (M + 1)].
Anal. Calcd for C23H30O4: C, 74.56; H, 8.16. Found: C, 74.61; H,
8.19.
(S)-Methyl 6,8-Dihydroxyoctanoate (12)
To a solution of 11 (1.0 g, 2.69 mmol) in EtOH (3 mL) was added
a suspension of 5% Pd/C (100 mg) in EtOH (2 mL). The mixture
was placed in a Parr apparatus and hydrogenated at 50 psi for 5 h.
The solution was filtered through Celite and the filtrate was concen-
trated under reduced pressure to give a viscous residue. The residue
was dissolved in Et2O (15 mL), dried (Na2SO4), and re-evaporated
to afford the dihydroxy ester 12 as a colorless oil (0.44 g, 87%); [a]D
–3.5 (c 1.0, CHCl3).
1H NMR (CDCl3): d = 1.48–1.51 (m, 4 H), 1.75–1.77 (m, 2 H),
2.01–2.03 (m, 2 H), 3.49–3.52 (m, 3 H), 4.40 (s, 2 H, OCH2Ph), 4.39
(d, J = 8.3 Hz, 1 H, CHHPh), 4.45 (d, J = 8.3 Hz, 1 H, CHHPh),
4.95–5.89 (m, 3 H, CH=CH2), 7.23 (s, 10 H).
MS (CI): m/z (%) = 91 (100), 107 (21), 127 (8), 181 (6), 215 (2), 325
[10, (M + 1)].
1H NMR (CDCl3): d = 1.49–1.51(m, 8 H), 2.25 (t, J = 7.3 Hz, 2 H),
3.65 (s, 3 H), 3.32–3.35 (m, 3 H), 4.50 (s, 2 H).
Anal. Calcd for C22H28O2: C, 81.44; H, 8.70. Found: C, 81.37; H,
8.75.
MS (CI, NH3): m/z (%) = 130 (3), 141 (21), 163 (11), 174 (17), 191
[100, (M + 1)].
(S)-6,8-Dibenzyloxyoctan-1-ol (10)
To a stirred solution of alkene 9 (2.5 g, 7.7 mmol) in anhyd THF (15
mL) was added a solution of 2 M BH3·DMS (4.6 mL, 9.22 mmol)
at 0 °C under a N2 atmosphere. After stirring for 2 h at r.t., MeOH
(5 mL) was carefully introduced at 0 °C to decompose excess
BH3·DMS, followed by the addition of 1 M aq NaOEt (30 mL) and
30% H2O2 (14.0 mL). The reaction mixture was then stirred at r.t.
for 2 h. The solvent was removed under vacuum, diluted with H2O
(2 mL), and extracted with CHCl3 (2 × 100 mL). The combined ex-
tracts were washed with brine (5 mL), dried (Na2SO4), and concen-
trated. The resulting residue was purified by column
chromatography (EtOAc–PE, 1:9) to afford 10 (2.32 g, 88%) as a
colorless liquid; [a]D +21.3 (c 0.5, CHCl3).
Anal. Calcd for C9H18O4: C, 58.82; H, 9.54. Found: C, 58.88; H,
9.48.
a-(R)-Lipoic Acid (3)
Mp 44–46 °C (Lit.8a 46–48 °C); [a]D +101 (c 1.0, C6H6) [Lit.8a +104,
(c 0.88, benzene)].
1H NMR (CDCl3): d = 1.50–1.53 (m, 2 H), 1.67–1.70 (m, 6 H),
1.86–1.88 (m, 1 H), 2.35 (t, J = 7.3 Hz, 2 H), 2.92–2.95 (m, 1 H),
3.06–3.08 (m, 2 H), 3.47–3.49 (m, 1 H), 11.05 (br s, 1 H).
13C NMR (75 MHz): d = 24.4, 28.8, 33.7, 34.6, 38.3, 40.3, 56.2,
180.0.
1H NMR (CDCl3): d = 1.25–1.62 (m, 6 H), 1.70–1.72 (m, 2 H), 2.85
(br s, 1 H), 3.45–3.48 (m, 5 H), 4.41 (s, 4 H), 4.41 (d, J = 8.3 Hz, 1
H), 4.43 (d, J = 8.3 Hz, 1 H), 7.23 (s, 10 H).
MS (EI): m/z (%) = 81 (100), 95 (7), 105 (25), 123 (64), 155 (17),
173 (12), 206 (70, M+).
Anal. Calcd for C8H18O2S2: C, 46.55; H, 6.85; S, 31.1. Found: C,
46.8; H, 6.9; S, 31.15.
MS (CI): m/z (%) = 18 (100), 91 (59), 108 (6), 127 (38), 145 (4), 181
(6), 235 (8), 343 [40, (M + 1)].
Anal. Calcd for C22H30O3: C, 77.15; H, 8.83. Found: C, 77.22; H,
8.92.
Acknowledgment
L. F. and S. R. thank CSIR, New Delhi for financial support.
(S)-Methyl 6,8-Dibenzyloxyoctanoate (11)
A mixture of alcohol 10 (2.0 g, 5.8 mmol), TEMPO (63.54 mg, 0.40
mmol), MeCN (200 mL), and sodium phosphate buffer (22 mL,
0.67 M, pH 6.7) was heated to 35 °C. Then NaClO2 (80%, 1.05 g,
11.66 mmol) in H2O (6 mL) and NaOCl (5.25%, 1.06 mL, 2.0
mol%) in H2O (2.9 mL) were added simultaneously over 2 h (Cau-
tion! Do not mix NaOCl and NaClO2 before adding to the reaction
mixture). The mixture was stirred at 35 °C until the reaction was
complete, then cooled to r.t., H2O (45 mL) was added, and the pH
adjusted to 8.0 with 2.0 N NaOH (6 mL). The reaction was
quenched by pouring the mixture into a cold aq solution of Na2SO3
References
(1) L-Carnitine and its Role in Medicine: From Function to
Therapy; Ferrari, R.; Di Mauro, S.; Sherwood, G., Eds.;
Academic Press: San Diego, 1992.
(2) (a) De Simone, C.; Famularo, G. Carnitine Today; Springer-
Verlag: Heidelberg, 1997. (b) Engel, A. G. In Carnitine
Biosynthesis Metabolism and Functions; Frenkel, R. A.;
McGarry, J. D., Eds.; Academic Press: New York, 1980,
271.
Synthesis 2006, No. 11, 1863–1867 © Thieme Stuttgart · New York

PAPER
L-Carnitine and a-Lipoic Acid via Hydrolytic Kinetic Resolutions
1867
(3) Tomsen, J. H.; Sug, A. L.; Yap, V. U.; Patel, A. K.; Karrase,
Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York, 1999,
Chap. 18, 2. (b) Jacobsen, E. N. Asymmetric Catalytic
Epoxidation of Unfunctionalized Olefins, In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York,
1993, 159–202. (c) Collman, J. P.; Zhang, X.; Lee, V. J.;
Uffelman, E. S.; Brauman, J. I. Science (Washington, D.C.)
1993, 261, 1404. (d) Katsuki, T. Asymmetric Epoxidation of
Unfunctionalized Olefins and Related Reactions, In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New
York, 2000, 287–325. For recent reviews, see: (e) Porter,
M. J.; Skidmore, J. Chem.Commun. 2000, 1215.
(f) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Synth. Org.
Chem. Jpn. 2002, 60, 94.
T. J.; De Flice, S. L. Am. J. Cardiol. 1979, 33, 300.
(4) Chapoy, P. R.; Angelini, C.; Brown, W. J.; Stiff, J. E.; Shug,
A. L.; Cederbaum, S. D. N. Engl. J. Med. 1980, 303, 1389.
(5) Guarnieri, G.; Ranieri, F.; Toigo, G.; Vasile, A.; Cinam, M.;
Rizzoli, V.; Morachiello, M.; Campanacci, L. Am. J. Clin.
Nutr. 1980, 33, 1489.
(6) (a) Vary, T. C.; Neely, J. R. Am. J. Physiol. 1982, 242,
H585. (b) Bressler, R.; Brendel, K. J. Biol. Chem. 1966, 241,
4092.
(7) (a) Sigel, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 389.
(b) Yadav, J. S.; Mysorekar, S. V.; Garyali, K. J. Sci. Ind.
Res. 1990, 49, 400; and references cited therein.
(8) For previous synthesis of L-Carnitine and (R)-(–)-GABOB:
(a) Kaneko, T.; Yoshida, R. Bull. Chem. Soc. Jpn. 1962, 35,
1153. (b) Jung, M. E.; Shaw, T. J. J. Am. Chem. Soc. 1980,
102, 6304. (c) Rossiter, B. E.; Sharpless, K. B. J. Org.
Chem. 1984, 49, 3707. (d) Takano, S.; Yanase, M.;
Sekiguchi, Y.; Ogasawara, K. Tetrahedron Lett. 1987, 28,
1783. (e) Van der Eycken, E.; De Wilde, H.; Deprez, L.;
Vande Walle, M. Tetrahedron Lett. 1987, 28, 4759.
(f) Lohray, B. B.; Reddy, A. S.; Bhushan, V. Tetrahedron:
Asymmetry 1997, 7, 2411. (g) Gopalan, A. S.; Sih, C. J.
Tetrahedron Lett. 1984, 25, 5235. (h) Wang, G.;
(10) Majewski, M.; Clive, D. L. J.; Anderson, P. C. Tetrahedron
Lett. 1984, 25, 2101.
(11) Nakata, T.; Suenga, T.; Oishi, T. Tetrahedron Lett. 1989, 30,
6525.
(12) Liu, C.; Coward, J. K. J. Med. Chem. 1991, 34, 2094.
(13) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
N. Science (Washington, D.C.) 1997, 277, 936. (b) Schaus,
S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307. (c) Larrow, J. F.; Hemberger,
K. E.; Jasmin, S.; Kabir, H.; Morel, P. Tetrahedron:
Asymmetry 2003, 14, 3589. (d) Song, Y.; Yao, X.; Chen, H.;
Bai, C.; Hu, X.; Zheng, Z. Tetrahedron Lett. 2002, 43, 6625.
(e) Bose, D. S.; Narsaiah, A. V. Bioorg. Med. Chem. 2005,
13, 627. (f) Bose, D. S.; Narsimha Reddy, A. V.; Chavhan,
S. W. Synthesis 2005, 2345.
(14) (a) Frick, J. A.; Klassen, J. B.; Bathe, A.; Abramson, J. M.;
Rapoport, H. Synthesis 1992, 621. (b) Liu, C.; Coward, J. K.
J. Org. Chem. 1991, 56, 2262.
(15) Fouquet, G.; Schlosser, M. Angew. Chem., Int Ed. Engl.
1974, 13, 82.
Hollingsworth, R. I. Tetrahedron: Asymmetry 1999, 10,
1895. (i) Jain, R. P.; Williams, R. M. Tetrahedron 2001, 57,
6505. (j) Bose, D. S.; Gurjar, M. K. Synth. Commun. 1989,
19, 3313. For the synthesis of a-(R)-lipoic acid, see:
(k) Elliott, J. D.; Steele, J.; Johnson, W. S. Tetrahedron Lett.
1985, 26, 2535. (l) Page, P. C. B.; Rayner, C. M.;
Sutherland, I. O. J. Chem. Soc., Chem. Commun. 1986,
1408. (m) Fadnavis, N. W.; Babu, R. L.; Vadivel, S. K.;
Deshpande, A. A.; Bhalarao, U. T. Tetrahedron: Asymmetry
1998, 9, 4109. (n) Chavan, S. P.; Praveen, C.; Ramakrishna,
G.; Kalkote, U. R. Tetrahedron Lett. 2004, 45, 6027.
(9) For leading reviews, see: (a) Jacobsen, E. N.; Wu, M. H. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
(16) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64,
2564.
Synthesis 2006, No. 11, 1863–1867 © Thieme Stuttgart · New York