Simplistic expedient and practical synthesis of (±)-α-lipoic acid

Article abstract of DOI:10.1055/s-2005-861867

Synthesis of α-lipoic acid has been achieved by a simple sequence of reactions. The synthesis highlights the use of α-chloroesters in a Reformatsky reaction. The intermediate keto acid is an intermediate from which both isomers of lipoic acid can be prepared. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-861867

PAPER
1297
Simplistic Expedient and Practical Synthesis of ( )-a-Lipoic Acid
Simplistic Exp
u
edient
a
nd P
b
ractical
S
ynt
h
hesis of
(
)
a
a
-Lipoic
A
c
s
id h P. Chavan,* K. Shivsankar, K. Pasupathy
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
E-mail: spchavan@dalton.ncl.res.in
Received 10 November 2004; revised 7 January 2005
group using thionyl chloride and pyridine gave exclusive-
ly compound 4. The reasons as to why the elimination
gave exclusively the endocyclic product are under study.
DIBAL-H reduction of the ester to alcohol followed by
protection using benzoyl chloride gave 6. The benzoate 6
on ozonolysis followed by Jones oxidation gave ketoacid
7, which on reduction with NaBH4 in MeOH gave hy-
droxy acid 8. The hydroxy acid 8 thus obtained was ester-
ified and treated with sodium methoxide to give diol 9,
which is a key intermediate in the synthesis of lipoic acid.
The diol 9 was efficiently converted to lipoic acid follow-
ing the reported protocol.12
Abstract: Synthesis of a-lipoic acid has been achieved by a simple
sequence of reactions. The synthesis highlights the use of a-chlo-
roesters in a Reformatsky reaction. The intermediate keto acid is an
intermediate from which both isomers of lipoic acid can be pre-
pared.
Key words: Reformatsky reaction, a-chloroesters, a-lipoic acid,
ozonolysis
a-Lipoic acid (1,2-dithiolane-3-pentanoic acid) and its re-
duced form dihydrolipoic acid (6,8-dimercapto-octanoic
acid) are physiologically occurring substances.1,2
Figure 1
Lipoic acid has been shown to possess antioxidant abili-
ties against attack by free radical4 as well as an inhibitory
effect against HIV replication.5 Interplay between lipoic
acid and gluathione in the guardianship against lipid per-
oxidation and metal toxicity has also been demonstrated.
Moreover, lipoic acid is used to a great extent in the treat-
ment of various diseases such as alcoholic liver diseases,8
mushroom poisoning,9 metal poisoning,6 diabetes, and
neurodegenerative disorders.11 The simplicity and useful-
ness of lipoic acid have attracted many groups around the
world. Several reports have also been published on the
biosynthesis of lipoic acid.23 Still lipoic acid remains a fa-
vorite molecule as seen in recent publications.12–23 Previ-
ous syntheses of lipoic acid involve either complex routes,
complex intermediates, or harsh reaction conditions.
Scheme 1
Our strategy involved in the synthesis of lipoic acid is
based on a modified Reformatsky reaction that we devel-
oped.24 The synthesis of lipoic acid is to highlight the use-
fulness of this methodology. Reformatsky reaction on
cyclohexanone followed by elimination of hydroxyl
Highlights of this synthesis are the use of ethyl chloroac-
etate for the Reformatsky reaction using simple condi-
tions. Earlier reports of Reformatsky using chloroacetate
involve the use of highly activated zinc25 or zinc-copper
SYNTHESIS 2005, No. 8, pp 1297–1300
x
x
.
x
x
.2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-861867; Art ID: Z20804SS
© Georg Thieme Verlag Stuttgart · New York

1298
S. P. Chavan et al.
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couple26 for the reaction. Another point to be noted here is
that enantioselecetive reduction of the carbonyl of 7 can
be achieved using Baker’s yeast; a similar system has
been reported by Gopalan et al.20
and reaction was quenched with a sat. solution of potassium sodium
tartrate. The temperature of the reaction mixture was allowed to rise
to r.t. It was filtered through celite, concentrated in vacuo, and pu-
rified by flash column chromatography to furnish 1.75 g (81%) of 5
as a colorless liquid; bp 85 °C (7 torr) [lit. 85 °C (7 torr)].
IR (neat): 3350, 2924, 1439 cm–1.
1H NMR: d = 1.2–2.0 (m, 8 H), 2.25 (t, 2 H, J = 6 Hz), 3.6 (t, 2 H,
J = 6 Hz), 5.5 (m, 1 H).
13C NMR: d = 22.5 (t), 23.0 (t), 25.4 (t), 28.3 (t), 41.3 (t), 60.4 (t),
123.7 (d), 134.3 (s).
All solvents were distilled before use. Petroleum ether refers to the
fraction boing in the range of 60–80 °C. All melting points and boil-
ing points are uncorrected. IR spectra were recorded on a Perkin-
1
Elmer IR spectrophotometer model 683B or 1605 FTIR. H NMR
and 13C NMR spectra were recorded on Bruker AC 200, MSL 300
and DRX 500 instruments using TMS as an internal standard. Mass
spectra were recorded at an ionization energy of 70 eV on a Finni-
gan MAT-1020 automated GC/MS instrument.
2-Cyclohex-1-en-1-ylethyl Benzoate (6)
2-Cyclohex-1-en-1-ylethanol (5; 1.00 g, 8.0 mmol) was placed in a
100 mL round bottom flask with a guard tube and addition funnel
attached. Anhyd CH2Cl2 (40 mL) was added followed by Et3N (962
mg, 9.6 mmol). The reaction was cooled to 0 °C in an ice-bath. BzCl
(1.226 mg, 8.8 mmol) was added dropwise. The reaction was
quenched with water (5 mL) and the product was extracted with
CH2Cl2 (2 × 20 mL). The organic phase was washed with NaHCO3
solution (2%, 3 × 20 mL). The organic phase was dried, filtered, and
concentrated in vacuo to furnish 680 g (92%) of 6 as a colorless oil.
IR (neat): 3063, 2930, 2672, 1685, 1595, 1419 cm–1.
1H NMR: d = 1.2–2 (m, 8 H), 2.25 (t, 2 H, J = 6 Hz), 4.2 (t, 2 H,
J = 6 Hz), 5.5 (m, 1 H), 7.38–7.52 (m, 3 H), 8.00–8.05 (m, 2 H).
Ethyl (1-Hydroxycyclohexyl)acetate (3)27
Zn (830 mg, 12.8 mmol) was placed in a 50-mL two-necked round
bottom flask attached with a reflux condenser and septum. The re-
action vessel was evacuated and flushed with argon. Anhyd ben-
zene–Et2O (1:1, 15 mL) was added with vigorous stirring. Ethyl
chloroacetate (750 mg, 6.12 mmol) was added dropwise, followed
by a crystal of I2 to initiate the reaction. Cyclohexanone (500 mg,
5.1 mmol) was added dropwise after 15 minutes and the reaction
was refluxed at 80 °C. The progress of the reaction was monitored
by TLC (EtOAc–petroleum ether, 1:10) and was quenched after 6 h
by the addition of HCl (10%, 5 mL). The compound was extracted
with Et2O (2 × 20 mL), washed with dil. HCl (5 mL), and water
(2 × 10 mL). The combined organic layers were dried over anhyd
Na2SO4, filtered, and concentrated under vacuum. Chromatography
furnished 616 mg (65%) of 3 as a colorless oil.
13C NMR: d = 22.2 (t), 22.8 (t), 25.2 (t), 28.4 (t), 37.1 (t), 63.3 (t),
123.7 (d), 129.3 (d), 129.4 (d), 132.4 (d), 133.6 (s), 146.5 (s), 166.0
(s).
MS: m/z = 230 (M+).
IR (CHCl3): 3518, 2934, 2861, 1716, 1447, 1401, 1372, 1332, 1196,
1128, 1031 cm–1.
8-(Benzoyloxy)-6-oxooctanoic Acid (7)
1H NMR: d = 1.20 (t, 3 H, J = 7 Hz), 1.30–1.80 (m, 10 H), 2.40 (s,
2 H), 3.80 (br, 1 H), 4.10 (q, 2 H, J = 7 Hz).
13C NMR: 13.9 (q), 21.7 (2 × t), 25.4 (t), 37.2 (2 × t), 45.4 (t), 59.9
(t), 69.5 (s), 172.1 (s).
2-Cyclohex-1-en-1-ylethyl benzoate (6; 500 mg, 2.2 mmol) was
placed in a 100-mL round bottomed flask. Anhyd CH2Cl2 (30 mL)
was added and the reaction mixture was cooled to –78 °C and O3
was bubbled through until the blue color persisted indicating the
end of the reaction. O2 was passed through the mixture for an addi-
tional 10 min, followed by N2 for a further 10 min. Me2S (2 mL) was
added and the temperature of the reaction mixture was allowed to
reach r.t. H2O (10 mL) was added to the reaction mixture and the or-
ganic layer was separated, dried, filtered, and concentrated under
vacuum. The crude product thus obtained was subjected to the Jones
oxidation at 0 °C in acetone (10 mL). The reaction was quenched
with i-PrOH (4 mL) and filtered through celite and concentrated in
vacuo to furnish 488 mg (85%) of 7 as a white solid; mp 57.5–
58 °C.
Ethyl Cyclohex-1-en-1-ylacetate (4)28
Ethyl 1-(hydroxycyclohexyl)acetate (3; 2.05 g, 11.07 mmol) in an-
hyd CH2Cl2 (60 mL) was placed in a 100-mL two-necked round
bottom flask with an addition funnel and a guard tube attached. An-
hyd pyridine (1.050 g, 13.12 mmol) was added and the reaction
mixture was cooled to 0 °C using an ice-salt mixture. After 10 min,
SO2Cl2 (1.447 g, 12.3 mmol) was added dropwise over 10 min. The
progress of the reaction was monitored by TLC using EtOAc–petro-
leum ether (1:19). The reaction mixture was stirred for 30 min,
quenched with ice-cold water (5 mL), and CH2Cl2 (20 mL) was add-
ed. The reaction mixture was washed with dilute HCl (5%, 2 × 15
mL), water (2 × 20 mL), and NaHCO3 (5%, 15mL). The organic
layer was dried over anhyd Na2SO4, filtered, and concentrated in
vacuo. Chromatography (EtOAc–petroleum ether, 1:20) gave 1.60
g (86%) of 4 as a colorless oil.
IR (CHCl3): 3438, 3020, 2956, 1713, 1414 cm–1.
1H NMR: d = 1.65 (m, 4 H), 2.4 (t, 2 H, J = 7 Hz), 2.51 (t, 2 H, J = 7
Hz), 2.87 (t, 2 H, J = 6 Hz), 4.59 (t, 2 H, J = 6 Hz), 7.4–7.6 (m, 3
H), 8.0 (d, 2 H, J = 8 Hz).
13C NMR: d = 23.1(t), 24.3 (t), 33.9 (t), 41.7 (t), 42.9 (t), 60.1 (t),
128.5 (d), 129.8 (d), 130.24 (s), 133.2 (d), 166.5 (s), 179.1 (s), 207.3
(s).
IR (CHCl3): 3411, 2936, 1736, 1457, 1370, 1300, 1159, 1032 cm–1.
1H NMR: d = 1.21 (t, 3 H, J = 7 Hz), 1.32–2.11 (m, 8 H), 2.90 (s, 2
H), 4.10 (q, 2 H, J = 7 Hz), 5.51 (m, 1 H).
Anal. Calcd for C15H18O5: C, 64.75; H, 6.47. Found: C, 64.60;
H, 6.49.
2-Cyclohex-1-en-1-ylethanol (5)29
8-(Benzoyloxy)-6-hydroxyoctanoic Acid (8)30
Ethyl cyclohex-1-en-1-ylacetate (4; 2.84 g, 17 mmol) was placed in
a 100-mL dry two-necked round bottom flask with a two-way stop-
cock and a septum. The round bottom flask was flushed with argon,
anhyd CH2Cl2 (50 mL) was added, and the mixture was cooled to
–78 °C in a cryostat. DIBAL-H (3 M, 17 mL, 51.0 mmol) was added
dropwise with constant stirring and stirring was continued for 3 h
and then a further 2 h at 0 °C. The reaction was monitored by TLC
8-(Benzoyloxy)-6-oxooctanoic acid (7; 500 mg, 1.9 mmol) was
placed in a single neck round bottom flask. MeOH (10 mL) was
added and reaction mixture was cooled to 0 °C in an ice-bath.
NaBH4 (135 mg, 3.6 mmol) was added slowly. The progress of the
reaction was monitored by TLC (EtOAc–petroleum ether, 3:7). The
reaction was quenched by the addition of a sat. solution of NH4Cl (2
mL). The solution was filtered and the product extracted with
Synthesis 2005, No. 8, 1297–1300 © Thieme Stuttgart · New York

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Simplistic Expedient and Practical Synthesis of ( )-a-Lipoic Acid
1299
EtOAc (2 × 20 mL). The organic layer was dried over anhyd
Na2SO4, filtered, and concentrated in vacuo. Chromatography fur-
nished 453 mg (90%) of 8.
IR (CHCl3): 3446, 2934, 1711, 1599 cm–1.
1H NMR: d = 1.25–2.01 (m, 8 H), 2.30 (t, 2 H, J = 6 Hz), 3.75 (m,
1 H), 4.34–4.57 (m, 2 H), 7.07 (br s, 1 H), 7.40–7.60 (m, 3 H), 8.00
(d, 2 H, J = 8 Hz).
phy over silica gel (petroleum ether–EtOAc, 8:1) gave 0.120 g
(70%) of 1.
1H NMR: d = 1.30–1.98 (m, 7 H), 2.37 (t, 2 H, J = 6.8 Hz), 2.42–
2.55 (m, 1 H), 3.04–3.22 (m, 2 H), 3.48–3.60 (m, 1 H), 8.10 (br s, 1
H).
13C NMR: d = 24.2 (t), 28.5 (t), 33.7 (t), 34.4 (t), 38.3 (t), 40.0 (t),
56.1 (d), 180.0 (s).
13C NMR: d = 24.8 (t), 25.2 (t), 34.1 (t), 36.5 (t), 37.1 (t), 62.4 (t),
68.6 (t), 128.5 (d), 129.8 (d), 130.4 (s), 133.1 (d), 167.1 (s), 178.7
(s).
Acknowledgment
Authors KS and KP thank CSIR, New Delhi for fellowships.
Methyl 6,8-Dihydroxyoctanoate (9)12
8-(Benzoyloxy)-6-hydroxyoctanoic acid (8; 500 mg, 1.9 mmol) was
dissolved in Et2O (10 mL) and cooled to 0 °C. Diazomethane (ca. 7
equiv) in Et2O was added to the compound and the reaction mixture
was left over-night. The reaction mixture was then concentrated and
the crude product was placed in a 50-mL 2-neck round bottom flask
with a two-way stopcock and a stopper attached. Anhyd MeOH (10
mL) was added to the compound followed by NaOMe (15 mg). The
reaction was left for 3–4 h and then quenched with acidic resin (IR
120) till the reaction medium was neutral. The reaction mixture was
then filtered and concentrated in vacuo. After chromatography 340
mg (91%) of 9 was obtained as a colorless oil.
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13C NMR: d = 24.4 (t), 24.7 (t), 33.6 (t), 37.0 (t), 38.1 (t), 51.1 (t),
(8) Marshell, A. W.; Graul, R. S.; Morgan, M. Y.; Sherlock, S.
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71.3 (d), 173.7 (s).
Methyl Lipoate (10)12
Methyl 6,8-dihydroxyoctanoate (9; 300 mg, 1.58 mmol) was placed
in a two-necked round bottom flask with a two-way stopcock and a
septum attached. Anhyd CH2Cl2 (10 mL) was added followed by
Et3N (319 mg, 3.16 mmol). The reaction was cooled to 0 °C.
MeSO2Cl (463 mg, 3.16 mmol) was added dropwise. The progress
of the reaction was monitored by TLC. The reaction was quenched
with water (5 mL) and the organic layer was washed with aq
NaHCO3 (2%, 10 mL). The organic layer was dried over anhyd
Na2SO4, filtered, and concentrated under vacuum. The crude com-
pound was used directly in the next reaction. Finely ground
Na2S·H2O (410 mg, 1.7 mmol) and sulfur (54 mg, 1.7 mmol) were
dissolved in anhyd DMF (5 mL). The mixture was heated at 80 °C
for 24 h and then stirred at r.t. for 1 h. The reaction mixture was
poured into ice-cold water (15 mL) and was extracted with EtOAC
(3 × 20 mL) The combined organic extracts were dried over anhyd
Na2SO4, filtered, and evaporated under reduced pressure to furnish
257mg (74%) of 10 as a yellow oil.
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Hz), 2.35–2.50 (m, 1 H), 3.03–3.22 (m, 2 H), 3.43–3.60 (m, 1 H),
3.57 (s, 3 H).
13C NMR: d = 24.63 (t), 28.71 (t), 33.75 (t), 34.6 (t), 38.45 (t), 40.1
(t), 51.4 (q), 56.2 (d), 173.5 (s).
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Lipoic Acid (1)12
Aq KOH (0.1 M, 12 mL) was added to methyl lipoate (10; 0.220 g,
1 mmol) in MeOH (5 mL) and the mixture was stirred at r.t. in the
dark for 24 h. The MeOH was evaporated, the mixture was washed
with Et2O (15 mL) and the aq layer was acidified carefully with HCl
(6 N) to pH 2. The product was extracted with Et2O (2 × 20 mL), the
combined organic layers were dried over anhyd Na2SO4, filtered
and concentrated. The purification of the residue by chromatogra-
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S. P. Chavan et al.
PAPER
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Synthesis 2005, No. 8, 1297–1300 © Thieme Stuttgart · New York