Enantioselective synthesis of R-(+)-α and S-(-)-α-lipoic acid

Article abstract of DOI:10.1016/j.tetlet.2004.06.027

An efficient synthesis of α-lipoic acid from the readily available cis-2-butene-1,4-diol employing a Claisen orthoester rearrangement and Sharpless asymmetric dihydroxylation as the key steps, is described.

Full text of DOI:10.1016/j.tetlet.2004.06.027

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6027–6028
Enantioselective synthesis of R-(+)-a and S-())-a-lipoic acid
Subhash P. Chavan,* Cherukupally Praveen, G. Ramakrishna and U. R. Kalkote
Division of Organic Chemistry, Technology, National Chemical Laboratory, Pune 411008, India
Received 29 March 2004; revised 30 May 2004; accepted 7 June 2004
Abstract—An efficient synthesis of a-lipoic acid from the readily available cis-2-butene-1,4-diol employing a Claisen orthoester
rearrangement and Sharpless asymmetric dihydroxylation as the key steps, is described.
Ó 2004 Elsevier Ltd. All rights reserved.
R-(+)-a-Lipoic acid is the coenzyme associated with
a-ketoacid dehydrogenase.1 a-Lipoic acid was first iso-
lated by Reed et al. in 1950 and characterized as the
cyclic disulfide 5-[3-(1,2-dithiolanyl)]-pentanoic acid.1a;2
The absolute configuration of natural a-(+)-lipoic acid
was confirmed as R by the synthesis of its unnatural
())-antipode from S-malic acid by Golding and
co-workers3 Lipoic acid is an important and powerful
biological anti-oxidant that can directly scavenge free
radicals and protect cells from oxidative damage.4
Lipoic acid and its derivatives are highly active as anti-
HIV5 and anti-tumour agents.6 The R-(+)-enantiomer is
much more effective than the S-())-enantiomer at
enhancing insulin-stimulated glucose transport and
nonoxidative and oxidative glucose metabolism.7
COOH
COOH
S S
S S
2
1
S-(-)-Lipoic acid
R-(+)-Lipoic acid
O
COOC2H5
HO
O
OH OH
BnO
OH
BnO
4
8
5
Scheme 1. Retrosynthetic analysis for 1.
which would be derived from the allyl alcohol 4 by a
Claisen orthoester rearrangement and Sharpless asym-
metric dihydroxylation, to install the requisite chirality.
The biological properties of both the enantiomers of
a-lipoic acid have fostered significant interest in their
synthesis.8 The first asymmetric synthesis of (+)-lipoic
acid was reported by Elliot in which the rather expensive
(S,S)- pentane-2,4-diol was used as the starting material
and source of optical purity.9 Most of the syntheses of
lipoic acid employ a Chiron approach. Our synthesis of
a-lipoic acid comprises simple experimental procedures,
which readily provide either enantiomer of lipoic acid
starting from the readily available achiral precursor cis-
2-butene-1,4-diol.
Enantiomerically pure hydroxy lactone 5, the versatile
intermediate for our synthesis, obtained in four steps
from cis-2-butene-1,4-diol 3,10 was treated with triphen-
ylphosphine, iodine and imidazole to give the iodo lac-
tone 6. Reduction of the lactone using DIBAL-H at
)78 °C followed by an in situ two-carbon Wittig reac-
tion gave the unsaturated ester 7. Removal of the benzyl
protection, removal of iodine and reduction of the
double bond was achieved in one pot using W2 Raney
nickel in the presence of hydrogen at room temperature
and pressure for 24 h to give the diol 8. The diol 8, a well
known intermediate for the synthesis of (+)-lipoic acid,
was treated with mesyl chloride to deliver the dimesylate
9. The dimesylate on reacting with Na2S and elemental
sulfur in DMF at 90 °C for 24 h gave ethyl lipoate 10,
which on hydrolysis with 1M ethanolic KOH gave R-
(+)-a-lipoic acid. Having accomplished the synthesis of
natural R-(+)-lipoic acid we turned our attention to
Our retrosynthetic analysis, as shown in Scheme 1,
conceived the hydroxy lactone 5 as the key intermediate,
Keywords: Lipoic acid; cis-2-Butene-1,4-diol; Sharpless asymmetric
dihydroxylation; Claisen orthoester rearrangement.
* Corresponding author. Tel./fax: +91-20-5893614; e-mail: spchavan@
dalton.ncl.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.027

6028
S. P. Chavan et al. / Tetrahedron Letters 45 (2004) 6027–6028
I
O
O
COOC2H5
b)
COOC2H5
c)
OH
OH
a)
ref 10
O
O
I
HO
OH OH
OH
BnO
BnO
BnO
8
7
6
5
3
COOH
COOC2H5
COOC2H5
f)
d)
e)
S
S
S
S
OMs OMs
1
10
9
Scheme 2. Reagents and conditions: (a) PPh3, I2, imidazole, 70 °C, 3 h, 94%; (b) DIBAL-H, DCM, )78 °C, 1 h, Ph3PCHCOOC2H5, 24 h; rt, 96%;
(c) W2 Raney nickel, H2, rt, 24 h, 84%; (d) CH3SO2Cl, Et3N, DCM, 0 °C, 4 h, 92%; (e) Na2S, S, DMF, 90 °C, 24 h, 72%; (f) 1 M ethanolic KOH, rt,
24 h, 75%.
6. Bingfham, P. M.; Zarchar Z. PCT Int. Appl. WO 0024,
synthesize unnatural S-())-lipoic acid. Accordingly we
734, 2000; Chem. Abstr. 2000, 132, 3081921.
7. Streeper, R. S.; Henriksen, E. J.; Tritschler, H. J. Am. J.
Physiol. 1997, 273(1 pt 1), E185–191.
8. (a) Brookes, M. H.; Golding, B. T.; Hudson, A. T.
prepared the enantiomer of hydroxy lactone 5 by using
AD-mix-b and then applying the same sequence of
reactions as used to synthesize R-(+)-a-lipoic acid. The
physical and spectroscopic data of all the synthetic
materials are in good agreement with the proposed
structures and those of 1 and 2 are in good agreement
with the literature data11 (Scheme 2).
J. Chem. Soc., Perkin Trans. 1 1988, 9–12; (b) Rao, A. V.
R.; Gurjar, M. K.; Garyali, K.; Ravindranathan, T.
Carbohydr. Res. 1986, 148, 51–55; (c) Rao, A. V. R.;
Mysorekar, S. V.; Gurjar, M. K.; Yadav, J. S. Tetrahedron
Lett. 1987, 28, 2183–2186; (d) Page, P. C. B.; Rayner, C.
In summary both R-(+)-a-and S-())-a-lipoic acid were
M.; Sutherland, I. O. J. Chem. Soc., Chem. Commun. 1986,
1408–1409; (e) Menon, R. B.; Kumar, M. A.; Ravindra-
nathan, T. Tetrahedron Lett. 1987, 28, 5313–5314; (f)
Laxmi, Y. R. S.; Iyengar, D. S. Synthesis 1996, 594–596;
(g) Adger, B.; Bes, M. T.; Grogan, G.; McCaque, R.;
Pedragosa, M. S.; Roberts, S. M.; Villa, R.; Wan, P. W.
H.; Willetts, A. J. Bioorg. Med. Chem. 1997, 5, 253–261;
(h) Upadhya, T. T.; Nikalje, M. D.; Sudalai, A. Tetrahe-
dron Lett. 2001, 42, 4891–4893, and references cited
therein.
synthesized efficiently in 34% overall yield in 8 steps
from the allyl alcohol 4, which in turn was obtained
from the readily available cis-2-butene-1,4-diol as the
common achiral precursor. The synthesis of other bio-
logically active compounds from the versatile interme-
diate 5 are being investigated in our laboratory.
9. Elliott, J. D.; Steele, J.; Johnson, W. S. Tetrahedron Lett.
1985, 26, 2535–2538.
Acknowledgements
10. Chavan, S. P.; Praveen, C. Tetrahedron Lett. 2004, 45,
421–423.
11. All new compounds were characterized and gave satisfac-
C.P. and G.R. thank CSIR (New Delhi) for research
fellowships. Funding from YSA (CSIR, New Delhi) to
S.P.C. is gratefully acknowledged.
24
tory spectral data. Compound 5: ½aꢀ +40.59 (c ¼ 1,
D
CHCl3). 1H NMR (200 MHz, CDCl3) d ppm: 2.25 (2H,
m), 2.48 (2H, m), 2.69 (1H, m), 3.59 (2H, m), 3.84 (1H, m),
4.57 (3H, m), 7.33 (5H, m). 13C NMR (50 MHz, CDCl3) d:
23.37, 28.11, 70.57, 71.60, 73.14, 79.87, 127.51, 128.13,
24
D
References and notes
137.47, 177.75 ppm. Compound 6: ½aꢀ )19.77 (c ¼ 1,
CHCl3). 1H NMR (200 MHz, CDCl3) d ppm: 2.04 (1H,
m), 2.42 (1H, m), 2.49 (2H, m), 3.72 (1H, dd, J ¼ 10:56,
5.87 Hz), 3.83 (1H, dd, J ¼ 10:56, 5.08 Hz), 4.31 (1H, m),
4.55 (3H, m), 7.32 (5H, m). 13C NMR (50 MHz, CDCl3) d:
1. (a) Reed, L. J.; Gunsalus, I. C.; De Busk, B. G.;
Hornberger, C. S., Jr. Science 1951, 114, 93–94; (b)
Schmidt, U.; Grafen, P.; Altland, K.; Goedde, H. W. Adv.
Enzymol. 1969, 32, 423–469; (c) Sigel, H. Angew. Chem.,
Int. Ed. Engl. 1982, 21, 389–400.
2. (a) Reed, L. J.; Gunsalus, I. C.; Schnakenberg, G. H. F.;
Soper, Q. F.; Boaz, H. E.; Kern, S. F.; Parke, T. V. J. Am.
Chem. Soc. 1953, 75, 1267–1270; (b) Reed, L. J.; DeBusk,
B. G.; Hornberger, C. S.; Gunsalus, I. C. J. Am. Chem.
Soc. 1953, 75, 1271–1273.
3. Brookes, M. H.; Golding, B. T.; Howes, D. A.; Hudson,
A. T. J. Chem. Soc., Chem. Commun. 1983, 1051–1053,
The same group has completed a synthesis of the natural
enantiomer.
4. Bast, A.; Haenen, G. R. M. M. Biochim. Biophys. Acta
1988, 963, 558–561.
27.60, 28.44, 33.96, 71.38, 72.88, 78.80, 127.43, 128.24,
24
D
137.25, 175.66 ppm. Compound 7: ½aꢀ )24.67 (c ¼ 1,
1
CHCl3). H NMR (200 MHz, CDCl3) d ppm: 1.29 (3H, t,
J ¼ 7:05 Hz), 1.70 (1H, m), 1.90 (1H, m), 2.38 (2H, m),
2.97 (1H, br), 3.65–3.91 (3H, m), 4.20 (3H, m), 4.56 (2H,
s), 5.8 (1H, dt, J ¼ 15:65, 1.57 Hz), 6.96 (1H, dt,
J ¼ 15:65, 6.65 Hz), 7.32 (5H, m). 13C NMR (50 MHz,
CDCl3) d: 14.08, 27.98, 33.86, 37.75, 59.84, 72.49, 72.89,
73.22, 121.45, 127.48, 127.74, 128.25, 137.00, 148.14,
166.11 ppm.
24
Compound 1: mp: 48 °C, ½aꢀ +106.29 (c ¼ 0:1, benzene).
D
1H NMR (200 MHz, CDCl3) d ppm: 1.52 (2H, m), 1.68
(4H, m), 1.91 (1H, m), 2.37 (2H, t, J ¼ 7:05 Hz), 2.63 (1H,
m), 3.18 (2H, m), 3.55 (1H, m), 12.45 (1H, br). 13C NMR
(50 MHz) d: 24.44, 28.74, 33.88, 34.65, 38.48, 40.21, 56.20,
179.85 ppm.
5. Baur, A.; Harrer, T.; Penkert; Jahn, G.; Kalden, J. R.;
Fleckenstein, B. Klin Wocheschr 1991, 69, 722–724, Chem.
Abstr. 1992, 116, 207360.