A short and productive synthesis of (R)-α-Lipoic acid

Article abstract of DOI:10.1515/znb-1999-0514

(R)-α-Lipoic acid is synthesized in seven steps from the base chemicals methyl acetoacetate or Meldrum's acid and monomethyl adipate. The key steps are the introduction of the stereogenic center by fermentative or homogeneously catalyzed hydrogenation of 3-oxooctanedioic acid diester to (3S)-3-hydroxyoctanedioic acid diester and its regioselective reduction to (6S)-6,8-dihydroxyoctanoic acid ester. The overall yield of (R)-α-lipoic acid, starting from 3-oxooctanedioic acid diester, is 40%.

Full text of DOI:10.1515/znb-1999-0514

A Short and Productive Synthesis of (R)-«-Lipoic Acid
Gerhard Bringmanna, Daniela Herzberga, Geo Adamb,
Friedhelm Balkenhohlb, Joachim Paustb
a Institute for Organic Chemistry of the University of Würzburg,
Am Hubland, D-97074 Würzburg, Germany
b Main Laboratory of BASF AG, D-67056 Ludwigshafen, Germany
Z. Naturforsch. 54b, 655-661 (1999); received December 4. 1999
Lipoic Acid, Yeast Reduction, Enantioselective Hydrogenation, Regioselective Reduction
(R)-a-Lipoic acid is synthesized in seven steps from the base chemicals methyl acetoace-
tate or Meldrum’s acid and monomethyl adipate. The key steps are the introduction of the
stereogenic center by fermentative or homogeneously catalyzed hydrogenation of 3-oxo-
octanedioic acid diester to (3S)-3-hydroxyoctanedioic acid diester and its regioselective re-
duction to (6S)-6,8-dihydroxyoctanoic acid ester. The overall yield of (R)-a-lipoic acid, start-
ing from 3-oxooctanedioic acid diester, is 40%.
Results and Discussion
The 3-oxo diesters 4 have not been employed
before in lipoic acid syntheses. They can be pre-
pared in good yield and purity in the ways shown
in Scheme 2. Acylation of the calcium enolate of
methyl acetoacetate with methyl adipoyl chloride
yields dimethyl 3-oxooctanedioate (4, R = CH3)
[10]. Mixed 3-oxo diesters (4, R = alkyl) are ob-
tained by acylation of Meldrum's acid and subse-
quent alcoholysis [1 1 ].
Methods have been developed in recent years
for the enantioselective reduction of 3-oxo esters
which can also be used for the conversion of 4
to 3. The hydrogenation of 4 to 3 is carried out
chemically using the catalyst system Ru2C14 [(S)-
BINAP]2 xN Et3 [12]. The reaction proceeds par-
ticularly smoothly on addition of catalytic amounts
of acid [13]. The conversion and enantiomeric ex-
cess are 96% and 98% respectively.
(R)-a-Lipoic acid (1) occurs as a protein-bound
coenzyme in animal and vegetable tissue and also
in microorganisms [1], (R)- and (S)-a-Lipoic acid
differ considerably each other in biochemical and
pharmacological investigations [2]. For example, in
animal experiments, the (R)-enantiomer mainly
has an antiinflammatory action and the (S)-enan-
tiomer mainly an analgesic action. It is therefore
sensible to employ a-lipoic acid in enantiomer-
ically pure form.
The (R)-enantiomer of a-lipoic acid (1) can be
obtained in various ways, for example by chemical
[3] or enzymatic [4] cleavage of the racemic pro-
duct or of one of its precursors, with the aid of
chiral templates [5], from structural units of the
chiral pool [6 ], by enantioselective synthesis [7]
and by microbiological transformations [8 ].
The reduction of the 3-oxodiesters 4 also takes
place using baker’s yeast. A strong dependence of
the radical R is observed here both on the yield
and on the enantioselectivity of the reaction. The
results achieved with various esters under stand-
ard conditions are summarized in Table I. The re-
duction is preferably carried out with the isobutyl
ester (4, R = z-C4H9). After optimization of the
reaction conditions, 3 (R = z-C4H9) could be iso-
lated in 75% yield and with an (R/S) enantiomer
ratio of 97 to 3 [14]. A further 5% yield of the
product is obtained in the form of the free acid (3,
R = H). Ethanol has proven suitable as a carbon
source and solubilizer in the fermentative reduc-
tion [15].
The published syntheses have a number of dis-
advantages, such as their many reaction steps as
well as expensive starting materials and reagents.
Consequently they are not carried out industrially.
We have developed the synthesis strategy for 1
shown in Scheme 1. The known (6 S)-6 ,8 -dihy-
droxyoctanoic acid ester (2) [9] was planned to be
prepared by regioselective reduction of (3S)-3-hy-
droxyoctanedioic acid diester (3), and this, in turn,
should be accessible by enantioselective reduction
of 3-oxooctanedioic acid diester (4).
* Reprint requests to Dr. J. Paust.
0932-0776/99/0500-0655 $06.00 © 1999 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
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656
G. Bringmann et al. ■A Short and Productive Synthesis of (R)-a-Lipoic Acid
Meldrum's acid
methyl acetoacetate
Pyr, CH2CI2
Ca(OH)2, CH2CI2
Y
oh
Ro.nJvr^O
{?
o
OH
ROH
NH3, H 2o
87%
88%
Scheme 1. Alternative routes to
3-oxooctanedioic acid diester (4).
4 (R=i-C4H9)
4 (R=CH3)
Table I. Yeast reduction of 4 to 3 under standardized
conditions (21 g of dried yeast, 30 g of sucrose and 3 g
of 4 in 1 1of water, 24 h, 36 °C).
R
Crude
yield (g)
4:3 (HPLC) (S)-3:(R)-3
RO
OH
2.8
1.6
2.2
2.1
2.3
1.8
2.5
1.3
0.3
1.9
65:35
12:88
9:91
18:82
20:80
28:72
30:70
35:65
85:15
50:50
60:40
65:35
88:12
65:35
50:50
70:30
c h 3
c 2h 5
/-c 3h 7
/7-C4H9
/-C4H9
S-C4H9
r-C4H9
(C H ,),-C H (C H ,)2
« -c 8h 17
c 6h 5
Complete hydrolysis
Complete hydrolysis
The regioselective reduction of the 3-hydroxy
diester 3 is carried out with sodium borohydride
in boiling tetrahydrofuran [16] and yields the en-
antiomerically pure methyl (6 S)-6 ,8 -dihydroxyoc-
tanoate (2) in 90% crude yield [9], In addition,
about 5% of (3S)-octane-l,3,8-triol is found. The
high regioselectivity of this reaction is based on
the precomplexation of the reductant at the free
hydroxyl group of the starting materials 3. Pure 2
of m.p. 51-52 °C and [a]o = -4.4° (c = 1, dichloro-
methane) is obtained in 82% yield by crystallization
from diisopropyl ether.
The (6 S)-dihydroxy ester 2 can be converted into
(R)-a-lipoic acid 1 in the ways shown in Scheme 3
via the dimesylate 5 [9] as an intermediate. Reaction
of 5 with potassium thioacetate in DMF and cleav-
age of the (6 R)-triester 6 with potassium hydroxide
s - s
Scheme 2. Key steps in the synthesis of (R)-lipoic acid
(1).
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G. Bringmann et al. • A Short and Productive Synthesis of (R)-ß-Lipoic Acid
657
Scheme 3. (R)-a-Lipoic acid (1), final
steps.
both from Merck DA. - Spray reagents: molybda-
tophosphoric acid and Cer(IV) sulfate in H20 /
yield (6 R)-dihydrolipoic acid (7), which can be
reacted to give 1 , for example using oxygen and
iron(III) chloride as a catalyst [17]. Based on 2, the
yield of 1 is 65%. Alternatively, 1 is obtained in two
stages, also in 65% yield, specifically by reaction of
5 with sodium disulfide in DMF [5, 18] and base-
or lipase-catalyzed hydrolysis of methyl (6 R)-a-
lipoate (8 ).
H2S 0 4; anisaldehyde in H2S 0 4/H 0A c/H 20.
-
Column chromatography: silica gel 0.040-
0.063 mm, Merck/DA.
1-O-Isobutyl 8-O-methyl 3-oxooctanedioate (4):
117.6 g (0.8 mol) of Meldrum’s acid and 129 ml
(0.16 mol) of pyridine are added at 0 °C to 650 ml
of dichloromethane. This solution is treated at
0 °C with 148 g (0.82 mol) of methyl adipoyl chlo-
ride in the course of about 90 min and is stirred at
room temperature for 4 h. After addition of
150 ml (1.6 mol) of isobutanol, dichloromethane is
distilled off to an internal temperature of 60 °C
(about 400 ml) and the reaction mixture is then
refluxed for 3 h.
To work up, the dichloromethane distillate is
added again at 25 °C, and the mixture is treated
with 700 ml of water and acidified to pH 1.5
using conc. sulfuric acid (about 58 g). The or-
ganic phase is washed twice with 300 ml of 5 per-
cent sulfuric acid and twice with 300 ml of water
and evaporated under reduced pressure: residue
216.6 g, GC purity [B] 92.5 area% corresponding
to 96.9% yield. The crude product is separated
from low-boiling and high molecular weight by-
products in a countercurrent film evaporator.
Degassing: 137 °C, 1 mbar, 150 ml/h; residue
195.3 g. Distillation: 180 °C, 1 mbar, 100 ml/h, dis-
Experimental
Analytical apparatus and equipment: melting
point: HWS SGV 500 PLUS, not corrected. - In-
frared spectra: Bruker IFS 8 8 . - Nuclear magnetic
resonance spectra: Bruker AMX 360 (360 MHz
'H , 90.5 MHz 13 C). - Mass spectra: Finnigan
MAT 90 (relative intensities of the signals in per-
cent based on the base peak). - Specific rotations:
Perkin-Elmer 243 B (25 °C, r = 589 nm). - Ele-
mental analyses: C, H, N: Leco 1000; O: Leco
RO 478; S: Carlo Erba NA 1500. - Gas chroma-
tography: HP 5890/series II Plus; A: DB 1 701,
30 m, 50 °C
103 kPa, integrator HP 3396 series II; B: CP-SIL/
5.50 m, 50 °C 240 °C (7.5 °C/min), 240 °C -»
240 °C (10 °C/min), FID, He
300 °C (30 °C/min), FID, integrator HP Chem.
Station Version A.03.34, He 172 kPa. - Distilla-
tion equipment: countercurrent thin-layer evapo-
rator (0.026 m2) with wiper blades and condenser;
micro short-path distillation apparatus (Schott/ tillate 191.8 g, GC [B] 95.5 area% corresponding
Mainz) with rotary oil pump. - Thin-layer chro- to 88.9% yield.
matography: HPTLC aluminum foils silica gel 60
Dimethyl 3-oxooctanedioate
(4. R = C //?):
F254 and TLC aluminum foils silica gel 60 F254,
233.4 g (3.15 mol) of calcium hydroxide is sus-
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G. Bringmann et al. • A Short and Productive Synthesis of (R)-tt-Lipoic Acid
658
The biomass is separated and washed twice with
pended in 1.6 1of dichloromethane. 348 g (3 mol)
of methyl acetoacetate is added within 1 h and the 2 1each of 50 percent ethanol. About 12 1of clear
mixture is stirred for 0.5 h. 607.5 g (3.45 mol) of runnings are obtained, which are extracted once
with 5 1 and twice with 2.5 1of ethyl acetate. The
methyl adipoyl chloride is then added within 2 h
ethyl acetate phase is washed with 5.5 1of 2.5 per-
and the mixture is then refluxed for 2 h. After
cooling to 25 °C, a solution of 168.6 g (3.15 mol) cent sodium hydroxide solution and twice with 4 1
portions of water and concentrated on a rotary
evaporator (50 °C, 30 mbar). Residue: 285.4 g, GC
surface area% (B) after silylation (MSTFA) 80%
of ammonium chloride in
to flow into the reaction mixture which is then ad-
justed to pH 9 by addition of aqueous ammonia.
1
1 of water is allowed
After 3 h, it is acidified to PH < 1 using concen- corresponding to 80% yield.
The crude product is separated from low-boiling
trated hydrochloric acid. The dichloromethane
phase is washed with two portions (1 1 ) of water
and with 0.5 1 of 2 N hydrochloric acid and the
crude product is isolated by evaporation at re-
duced pressure; 644 g, GC [B] 81 area% corre-
sponding to 77% yield. Further purification is car-
ried out by distillation in a countercurrent film
evaporator; degassing: 110 °C, 0 . 2 mbar, 150ml/h,
residue 512 g; distillation: 160 °C, 0.2 mbar, distil-
late 481 g corresponding to 71% yield.
IR (film): v (cm -1) 1739, 1719. - 'H-NMR
(400.1 MHz), DCC13: d = 1.64 (m, 4H), 2.33 (t, J =
7 Hz, 2H), 2.60 (t, J = 7 Hz, 2H), 3.49 (s, 2H), 3.65
(s, 3H), 3.72 (s, 3H); enol form (8 %): 5.01 (s, 1H),
12.00 (s, 1H). - 13 C-NMR (100.6 MHz, DCC13):
d = 22.9, 24.2, 33.7, 42.5, 49.0 (5 t, C-5, 6 , 7, 4, 2),
51.5 (q, OCH3) 52.2 (q, OCH3) 167.8 (s, C-l),
173.7 (s, C-8 ), 202.5 (s, C-3); enol form: 24.3, 25.7
and high-boiling impurities by continuous distilla-
tion in a countercurrent thin-layer evaporator.
Degassing: 130 °C, 0.2 mbar, distillate I: 6 g, resi-
due: 177 g; distillation: 160 °C, 0.2 mbar, distillation
II: 160.8 g, residue: 11 g. GC area% (B) of distillate
II: 88.3% corresponding to 71% yield; ee>97%
after l9F-NMR analysis of the Mosher ester.
Dimethyl (3S)-3-hydroxyoctanedioate (3, R -
C //?): All operations are carried out in an argon
atmosphere with rigorous exclusion of oxygen. Tri-
ethylamine is freshly distilled; methanol and the
starting material are saturated with argon before
the reaction.
Di[2,2'-bis(diphenylphosphino)-l,r-binaphthyl]-
tetrachlorodirutheniumtriethylamine
adduct
(Ru2 Cl4 [(S)-BINAP]2 xN Et3): 45.55 mg (0.162
mmol) of di-//-chloro(?74-l,5 -cyclooctadiene)ruthe-
(2 t, C-5.6 ), 33.8, 34.6 (2 t, C-4.7), 51.1, 51.7 (2 q, nium(II) (RuCl2COD)2, 121.5 mg (0.195 mmol) of
(S)-2,2'-bis(diphenylphosphino-l,l'-binaphthyl-
((S)-BINAP) and 0.18 ml (about 1.8 mmol) of tri-
ethylamine are dissolved in 7.5 ml of toluene. The
solution is refluxed for 3 h, cooled to room tem-
perature and the solvent is evaporated in vacuo
(30 °C, 8 mbar).
2 0CH-,), 89.0 (d, C-2), 173.1, 173.9 (2 s, C-1.8),
178.4 (s, C-3). - MS (El, 70 eV), m/e (%): 217 (15)
(MH+), 216 (10)(M+); 185 (41)(M+-O C H 3), 184
(60)(M+-C II3OH), 153 (42), 143 (67) (M+-
CH2C 0 7CH3), 116 (90), 111 (100), 101 (70, 59
(80), 55 (75).
The residue is taken up in 15 ml of a solution of
216 g (1 mol) of dimethyl 3-oxooctanedioate (4,
R = CH3) in 600 ml of methanol and refluxed for
30 min. After cooling to room temperature, the
catalyst solution is added to the remaining solu-
tion of the starting material in methanol, 0.25 ml
of 1 M sulfuric acid is added and the mixture is
hydrogenated in a 2 1 stainless steel autoclave hav-
ing a glass insert (12 h, 80 °C, 30 bar of hydrogen).
The autoclave contents are concentrated on a ro-
tary evaporator (50 °C, 30 mbar; residue 233 g).
The crude product can be purified by distillation
in a countercurrent film evaporator. Degassing/
distillation: heating jacket 120 °C/160 °C, 0.1 mbar;
cooling jacket 30 °C/40 °C; residue: 213 g/4 g; dis-
tillate 3 g/205 g. According to silylation (MSTFA)
and GC analysis (B), a sample of the distillate has
a purity of 96%. The enantiomeric purity can be
determined by means of ‘H-NMR spectroscopy by
complexation with TFAE (OCH3) and is >96%.
C10 H 16 O5 (216.2)
Calcd
C 55,55 H 7.46 0 36.99%,
Found C 55.20 H 7.80 0 37.20%.
1-O-Isobutyl 8-O-methyl (3S)-3-hydroxyoctane-
dioate (3, R = i-C4H9): 9.2 1of drinking water is in-
troduced into a 10 1 fermenter containing 90 g of
sodium chloride and the solution autoclaved at
120 °C for 20 min. 0.3 Vvm of nitrogen are then
passed into the fermenter gas space, the temper-
ature is kept at 37 °C and 200 ml of ethanol and
500 g of dried yeast (Gist Brocades) are added at
350 rpm. The pH is kept at 6.0 ± 0.2 using 2 M
NaOH. After an initial fermentation phase of
45 min, 300 g of 3 are added and the mixture is
stirred for 5 -7 days under 0.3 Vvm of nitrogen.
The starting material and product concentrations
are checked daily by means of GC. The fermenta-
tion is stopped at a starting material concentration
of < 1 g/1 .
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G. Bringmann et al. ■A Short and Productive Synthesis of (R)-a-Lipoic Acid
659
1021, 954. - !H-NMR (400 MHz, CDC13): (3 =
[ö]d = +14.3° (c = 1.1, dichloromethane). - IR
(film) v = 3507 cm- 1 (br., O -H ), 2952 (m, C -H ), 1.30-1.75 (m, 8 H, 3-, 4-, 5-, 7-CH2), 2.35 (t, J =
1737 (s, C=0), 1438, 1367, 1257, 1199, 1173, 1097, 7 Hz, 2H, 2-CH2), 3.67 (s, 3H, C 0 2CH3), 3.78 (m,
1012. - 'H-NMR (400 MHz, CDC13): d = 1.50 (m, 3H, 6 -H, 8 -CH2), 4.20 (m, 1H, OH), 4.27 (m, 1H,
4H, 5-, 6 -CH2), 1.67 (m, 2H, 4-CH2, 2.35 (t, 7 = OH). - 1 3 C-NMR (100.6 MHz, CDC13): 6 = 24.9,
25.1 (2 t, C-3.4), 34.0 (t, C-2), 37.2 (t, C-5), 38.7 (t,
1H, OH), 3.65 (s, 3H, C 0 2CH,), 3.70 (s, 3H, C-7), 51.6 (q, OCH3 ), 60.5 (t, C-8 ), 70.4 (d, C-6 ),
C 0 2 CH,), 4.01 (m, 1H, 3H). 1 3 C-NMR 174.5 (s, C-l). - MS (El, 70 EV), m/e (%): 145
8 Hz, 2H, 7-CH2), 2.47 (m, 2H, 2-CH2), 3.32 (s,
-
(100 MHz, CDC13): (3= 24.8, 25.1 (2 t, C-5,6 ), 33.9 (26), 141 (12), 123 (9), 116 (28), 113 (57), 87 (100);
(t, C-7), 36.2 (t, C-4), 41.4 (t, C-2), 51.5, 51.7 (2 q, MS (Cl, 70 eV), m/e (%): 191 (100) [MH+], 117
2 OCH3 ), 67.7 (d, C-3), 173.2, 174.1 (2 s, C-l,8 ). -
MS (EI, 70 eV); m/e (%): 169 (16, 155 (10), 145
(29), 137 (45), 116 (69), 103 (55), 87 (100), 59 (15),
43 (28); MS (CI, 70 eV); m/e (%): 219 (100)
(MH+).
(60) [MH+- H 20].
C9H 180 4 (190.2)
Calcd
C 56.83 H 9.54 0 33.65%,
Found C 56.80 H 9.40 0 33.50%.
C10 H 1 8 -O 5 (218.2)
In the same manner, 3 (R = /-C4H9) can also be
reduced to 2 using sodium borohydride. To deter-
mine the purity of the ethyl acetate solution a sam-
ple is evaporated and analyzed by gas chromatog-
raphy (B) using an internal standard: 89% 2, 5%
2-isobutyl ester. The yield of crystalline 2 is 72%.
(R)-Dihydrolipoic acid (7): 29.5 g (150 mmol) of
methyl (6 S)-6 ,8 -dihydroxyoctanoate (2) and 60.6 g
(600 mmol) of triethylamine in 400 ml of dichloro-
Calcd C 55.03 H 8.31 0 36.65%,
Found C 54.50 H 8.30 0 36.70%.
Methyl (6S)-6,8-dihydroxyoctanoate (2): A solu-
tion of 218 g (1 mol) of dimethyl (3S)-3-hydroxy-
octanedioate (3, R = CH3) in 1.251 of tetrahy-
drofuran is introduced into a 3 1 high-grade steel
reactor (stirrer, thermometer, distillation attach-
ment), treated with 23.6 g (0.6 mol) of sodium
borohydride and refluxed for 3 h. After cooling to
room temperature, the reaction mixture is acidi-
fied by metering in a 1 M solution of hydrogen
chloride in methanol to PH 5. 1 1 of solvent mix-
ture is then distilled off at 45-50 °C, 300 mbar.
After addition of 1 1 of methanol each time, this
distillation is repeated a further two times*.
1.2 1of ethyl acetate and 150 ml of ethyl acetate
phase from the preceding batch are added to the
residue and the solution is washed twice with
300 ml of water. Small amounts of 2 are isolated
from the aqueous phases by washing with 150 ml
of ethyl acetate and added to the following batch
before washing with water.
The ethyl acetate solution is evaporated and the
residue is taken up in 660 ml of diisopropyl ether
with warming to 50 °C. After cooling to 25 °C and
addition of seed crystals, the temperature is re-
duced by about 10 °C/h, the mixture is stirred at
-10 °C for 1 h, the resulting crystals are isolated
in a cooled pressure filter and the product is dried
in a stream of nitrogen: 155.8 g, 82%, m.p. 51.5-
52.5 °C. - [a]o = -4.42° (c = 1.1, dichloromethane
[6 ]) - IR (KBr): v = 3363 cm- 1 (s, O -H ), 2942 (m,
C -H ), 1735 (s, C=0), 1442,1224,1192,1172,1055,
methane are dissolved in a
1
1 high-grade steel
reactor (thermometer, dropping funnel, distilla-
tion attachment with 2 0 cm packed column) and
51.6 g (450 mmol) of methanesulfonyl chloride are
added at 0 °C within 1.5 h. The mixture is allowed
to react at 0 °C for 1 h, 300 ml of water are added
and the lower phase is separated off. The aqueous
phase is re-extracted with 150 ml of dichlorometh-
ane. The combined dichloromethane phases are
washed twice with 150 ml of 1 M hydrochloric acid
and twice with 150 ml of water and dried by azeo-
tropic distillation. The residual dichloromethane is
distilled off with simultaneous addition of 300 ml
of cyclohexane up to a transition temperature of
80 °C.
A sample of the cyclohexane solution is evapo-
rated in vacuo for determining the purity of and
characterization [6 ] of the methyl (6 S)-6 ,8 -dimeth-
ylsulfonyloxyoctanoate: crude yield quantitative,
yellow oil. [a]o = +17.6° (c=1.2, dichlorometh-
ane). - 'H-NMR (250 MHz, CDC13): <3= 1.30-1.88
(m, 6 H, 3-, 4-, 5-CH2), 2.09 (m, 2H, 7-CH2), 2.30 (t,
J = 7 Hz, 2H, 2-CH2), 3.05 (s, 3H, CH3S 0 2), 3.10 (s,
3H, CH3 S 02), 3.57 (s, 3H, C0 2 CH3), 4.32 (t, J =
7 Hz, 2H, 8 -CH2), 4.85 (m, 1H, 6 -H).
150 ml of dimethylformamide and 22.3 g (200
mmol) of potassium thioacetate are introduced into
a
1
1 high-grade steel reactor (thermometer, drop-
ping funnel, distillation attachment) and treated at
50 °C/200 mbar with 35 ml (about 75 mmol) of a so-
* The last portions of distillate are free from trimethyl
borate according to GC analysis (B).
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660
G. Bringmann et al. • A Short and Productive Synthesis of (R)-a-Lipoic Acid
lution of methyl (6 S)-6 ,8 -dimethanesulfonyloxyoc-
tanoate in cyclohexane. Cyclohexane largely distills (film): v = 2934 cm“ 1 (m, C -H ), 2860 (w, C -H ),
[a]o = -15.3 (c = 0.91. dichloromethane). - IR
off during this procedure.
1706 (s, C=0), 1412, 1284, 1089, 937, 742. - 'H-
NMR (400 MHz, CDC13): <3= 1.33 (d, J = 10 Hz,
IH, C H -SH ), 1.40 (t, 7= 8 Hz. 1H. CH.SH),
1.45-1.70 (m, 6 H, 3-, 4-, 5-CH2), 1.77 (m, 1H,
7-H), 1.90 (m, 1H, 7-H), 2.40 (t, J= 6 Hz, 2H,
2-CH2), 2.71 (m, 2H. 8 -CH2), 2.94 (m, 1H, 6 -H),
The mixture is stirred at 50 °C for 4 h, 600 ml of
water are added and it is extracted three times with
200 ml of w-hexane. The hexane phases are washed
with 2 0 0 ml of water and concentrated in a counter-
current film evaporator (200 mbar, 50 °C); the crude
yield of methyl (6 R)-6 ,8 -diacetyldihydrolipoate is II.02 (1H, C 0 2H).
-
1 3 C-NMR (100 MHz,
quantitative.
CDC13): (3= 22.3 (t, C-8 ), 24.2 and 26.4 (1 t, C-3
and C-4), 33.9 (t, C-2), 38.6 (t, C-5), 39.2 (d, C-6 ),
42.7 8 t, C-7), 180 (s, C-l). - MS (El, 70 eV), m/e
(%): 208 (70) [M+], 206 (15) [M+-2H], 95 (82), 87
A sample is purified by column chromatography
for characterization (silica gel, hexane/methyl
/-butyl ether 4/1): colorless liquid. [a]o = -6.16
(c = 0.62, dichloromethane).
-
IR (film): v = (85), 81 (100), 73 (70), 67 (55), 55 (54) [C4H7+],
2930 c m ( w , C -H ), 1738 (s, C=0), 1691 (s, C=0), 45 (54), 41 (65) [C3 H5+],
1436, 1355, 1199, 1173, 1135, 1114, 952, 630. - 'H-
NMR (400 MHz, CDC13): d = 1.40 (m, 2H, CH2),
1.62 (m, 4H, CH2 -C H 7), 1.80 (m, 1H, 7-H), 1.86 (m,
1H, 7-H), 2.32 (m, 8 H, 2S -C O -C H 3 and 2-CH2),
2.90 (m, 2H, 8 -CH2), 3.56 (m, 1H, 6 -H), 3.66 (s, 3H,
C 0 2CH3). - 13 C-NMR (100 MHz, CDC13): (3= 24.6
C8H 160 2 S2 (208.3)
Calcd
C 46.12 H 7.74 0 15.36 S 30.78%,
Found C 45.40 H 7.60 0 15.40 S 30.60%.
(R)-a-Lipoic acid (1): 520 ml of water and 11 g
(t, C-3), 26.2 (t, C-4), 26.5 (t, C-8 ), 30.5, 30.7 (2 q, 2 (about 50 mmol) of crude (R)-dihydrolipoic acid
S-CO-CH3), 33.8 (t, C-2), 34.4 (t, C-7), 34.7 (t, C-5), are introduced into a
1 high-grade steel reactor
43.4 (d, C-6 ), 51.4 (q, OCH3), 173.8 (s, C-l), 195.3, (thermometer, gas inlet tube, 2 0 cm packed col-
195.4 (2 s, 2 S-C O -C H ,). - MS (El, 70 eV), m/e
(%): 263 (57) [M+-C O -C H 3], 233 (10), 221 (30), of light and treated with 2 M sodium hydroxide
1
umn with distillation attachment) with exclusion
solution (about 33 g) to pH 9. 0.3 ml of a 10%
Fe(III) chloride solution is added, and the solution
is gassed intensively with air until the color
changes from gray-black to yellow-green (about
189 (75), 43 (100): MS (Cl, 70 eV), m/e (%): 307
(100) [MH+], 247 (19).
C1 3 H22 0 4S2 (306.4)
Calcd
C 50.95 H 7.24 0 20.88 S 20.93%, 3 h) and acidified with concentrated hydrochloric
Found C 50.80 H 7.30 0 20.90 S 20.90%. acid to pH 1. It is extracted twice with 200 ml of
dichloromethane, the combined phases are
46 g (about 140 mmol) of crude methyl (6 R)- washed twice with 2 0 0 ml of water and the dichlo-
6 ,8 -diacetyldihydrolipoate and 160 g (about romethane solution is dried by azeotropic distilla-
1.4 mol) of 50% strength potassium hydroxide so- tion. The residual dichloromethane is distilled off
lution are intensively stirred for 6 h in a
grade steel reactor at room temperature with rig- ane up to a transition temperature of 80 °C. The
hot cyclohexane solution is filtered through 15 g
1
1 high-
with simultaneous addition of 2 0 0 ml of cyclohex-
orous exclusion of oxygen and the mixture is then
diluted with 500 ml of water. The mixture is acidi- of silica gel and the filtrate is cooled to 5 °C in the
fied while cooling with concentrated hydrochloric course of 6 h in the reactor after seeding with 1 .
acid (pH 1) and the product is extracted three The crystals are filtered off with suction, washed
times with 2 0 0 ml portions of dichloromethane. with cold cyclohexane and dried in a vacuum dry-
ing oven (30 mbar, 30 °C). 8.5 g of 1 of m.p. 49-
The dichloromethane phases are washed twice
with 2 0 0 ml of water and concentrated on a rotary 50 °C are obtained, GC purity (B) 98%. The yield
evaporator (50 °C, 50 mbar). 32.5 g of crude (R)- is 74% based on methyl (6 S)-6 ,8 -dihydroocta-
dihydrolipoic acid (7) is obtained as a residue.
The crude product can be purified by short-path
distillation: degassing/distillation: heating jacket
100 °C/100 °C, cooling jacket 20 °C/40 °C, pressure
1 mbar/0.03 mbar, distillate 1.5 g/28.1 g, residue
29.1g/0.8g. Purity according to GC 97%, 0.2%
noate (2).
[a]o = +117 (c = 1.81, benzene, [6 ]). - IR (KBr):
v —3032 cm“ 1 (br., O -H ), 2926 (m, C -H ), 1701
(s, C=0), 1425, 1409, 1305,1286,1248,1205, 932. -
'H-NMR (360 MHz, CDC13): (3= 1.50 (m, 2H,
CH2), 1.69 (m, 4H, CH2 -C H 2), 1.92 (m, 1H, 7-H),
(R)-a-lipoic acid; ee (MSTFA) 99.6%. The yield 2.38 (t, J = 7 Hz, 2H, 2-CH2), 2.47 (m, 1H, 7-H),
3.15 (m, 2H, 8 -CH2), 3.58 (m, 1H, 6 -H), 11.55 (1H,
of (R)-dihydrolipoic acid (7) is 85.7% based on
methyl (6 S)-6 ,8 -dihydroxyoctanoate.
CO?H). - ,3 C-NMR (90.6 MHz, CDC13): (3= 24.3
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661
G. Bringmann et al. • A Short and Productive Synthesis of (R)-ß-Lipoic Acid
(t, C-3), 28.6 (t, C-4), 33.8 (t, C-2), 34.5 (t, C-5),
38.5 (t, C-8 ), 40.2 (t, C-7), 56.2 (d, C-6 ), 180.1 (s,
C-l). - MS (EI, 70 eV), m /e (% ): 206 (100) [M+],
173 (15) [M+-SH ], 155 (19) [M+-SH -H zO], 141
(9) [M+-S H -S ], 123 (59) [M+-S H -S -H zO], 105
(17), 95 (60), 81 (73), 55 (37), 41 (40).
C8H 14 0 2S2 (206.3)
Calcd C 46.57 H 6.84 0 15.51 S 31.08%,
Found C 46.60 H 6.80 0 15.30 S 30.90%.
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