PAPER
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.
References
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1H NMR: d = 1.2–1.75 (m, 8 H), 2.32 (t, J = 6 Hz, 2 H), 2.9 (m, 1
H), 3.73 (s, 3 H), 3.76–3.87 (m, 2 H).
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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IR (CHCl3): 2932, 1735, 1435 cm–1
1985, 26, 2535.
1H NMR: d = 1.3–1.7 (m, 6 H), 1.75–1.8 (m, 1 H), 2.23 (t, 2 H, J = 8
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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R. Tetrahedron Lett. 2004, 45, 6027; and the references cited
therein.
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-
Synthesis 2005, No. 8, 1297–1300 © Thieme Stuttgart · New York