Synthesis of an oxa-lipoic acid

Article abstract of DOI:10.1016/j.tetlet.2007.04.132

The synthesis of an oxa-lipoic acid is reported here for the first time. We have achieved the synthesis of the title compound starting from commercially available acrolein using a Michael addition and Knoevenagel condensation as key reactions.

Full text of DOI:10.1016/j.tetlet.2007.04.132

Tetrahedron Letters 48 (2007) 4533–4534
Synthesis of an oxa-lipoic acidI
D. Srinivasa Reddy,* P. Srinivas, D. Balasubrahmanyam and Javed Iqbal
Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
Received 1 March 2007; revised 19 April 2007; accepted 27 April 2007
Available online 1 May 2007
Abstract—The synthesis of an oxa-lipoic acid is reported here for the first time. We have achieved the synthesis of the title com-
pound starting from commercially available acrolein using a Michael addition and Knoevenagel condensation as key reactions.
Ó 2007 Elsevier Ltd. All rights reserved.
Lipoic acid (LA) 1, a naturally occurring octanoic acid
derivative, has a critical role in energy metabolism as
an essential co-factor for mitochondrial a-keto-acid
dehydrogenases.1 Besides its enzymatic role, LA has
been shown to act as a micronutrient with a range of
antioxidant and pharmacological properties.2 More
importantly, LA has been used for the treatment of dia-
betic complications and a recent study showed that LA
can be used as an anti-obesity drug.3 Despite its very
attractive biological properties, it suffers from poor bio-
availability. One of the reasons for its metabolic instabil-
ity is b-oxidation.4 Previous studies on metabolism have
shown that LA is subject to extensive b-oxidation and
major metabolites like bisnorlipoic acid and tetranorli-
poic acids were identified.4c Recently, 3-keto-lipoic acid,
an intermediate resulting from b-oxidation was detected
in human plasma after oral dosing in a healthy volun-
teer.4d To address this issue, the b-methylene unit can
be replaced with a group such as –CF2, N-alkyl, or an
oxygen atom. We have designed the title compound in
which we replaced the b-methylene group with an oxy-
gen atom (Fig. 1). Although, there are several reports
in the literature on the synthesis of 1 and its deriva-
tives,5,6 no reports on the synthesis of the oxa-lipoic acid
2 are documented. In this Letter, we disclose the first
synthesis of oxa-lipoic acid 2 starting from commercially
available acrolein and benzylmercaptan.
O
OH
lipoic acid (LA) 1
Protection from
S
S
β
-oxidation
O
O
OH
S
S
oxa-lipoic acid 2
Figure 1. Protection from b-oxidation: replacement of b-methylene
group with an oxygen atom.
to its sensitivity towards various reaction conditions; in
particular, it is prone to oxidation. Our synthesis began
with the reaction of acrolein 3 with benzylmercaptan to
give the aldehyde 4.7 Two-carbon homologation of com-
pound 4 was achieved by heating with malonic acid
monoethyl ester in the presence of piperidine and pyri-
dine mixture to furnish 5 in 62% yield.7 Addition of an-
other molecule of benzylmercaptan in a Michael fashion
resulted in compound 6.7 The alcohol 7, obtained by
LiAlH4 reduction of 6 was subjected to O-alkylation
with t-butyl bromoacetate under phase-transfer catalysis
to furnish the ether 8 in 81% isolated yield. Removal of
the t-butyl group in 8 by stirring with TFA in DCM
gave the corresponding acid 9 in quantitative yield.
The synthesis of oxa-lipoic acid 2 was achieved by con-
struction of the dithiolane ring using a known proce-
dure.6h,i Reductive removal of the benzyl groups with
sodium–ammonia followed by oxidation furnished the
oxa-lipoic acid as a viscous material in 50% isolated
We designed the synthesis of oxa-lipoic acid 2 such that
the dithiolane moiety was introduced at a later stage due
Keywords: Lipoic acid; b-Oxidation; Metabolism.
q DRL Publication No. 638.
*
Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304
5438; e-mail: dsreddy@drreddys.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.132

4534
D. S. Reddy et al. / Tetrahedron Letters 48 (2007) 4533–4534
COOEt
BnSH
BnSH
BnS
OEt
BnS
COOH
CHO
CHO
Et3N, DCM
96%
piperidine
82%
pip/py, 130 o
62%
C
O
3
4
5
O
O
50% aq. NaOH
PTC, benzene
BrCH2COOBut
81%
OEt
OH
LiAlH4
OBut
SBn SBn O
SBn SBn
THF
91%
SBn SBn
6
7
8
O
O
O
1. Na/NH3, THF
2. O2, FeCl3
50%
O
TFA
OH
OH
DCM
100%
SBn SBn
S
S
2
9
Scheme 1.
1
Study; Biewenga, G. P., Ed.; Academisch Proefschrift, Vrije
Universiteit: Amsterdam, 1997; pp 137–151.
yield over two steps. The spectral data (IR, H NMR,
13C NMR and MS) of the 2 were in agreement with
structure 28 (see Scheme 1).
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Hudson, A. T. J. Chem. Soc., Perkin Trans. 1 1988, 9; (e)
Laxmi, Y. R. S.; Iyengar, D. S. Synthesis 1996, 594; (f)
Adger, B.; Bes, M. T.; Grogan, G.; McCaque, R.; Pedrag-
osa, M. S.; Roberts, S. M.; Villa, R.; Wan, P. W. H.;
Willetts, A. J. Bioorg. Med. Chem. 1997, 5, 253; (g)
Upadhya, T. T.; Nikalje, M. D.; Sudalai, A. Tetrahedron
Lett. 2001, 42, 4891; (h) Chavan, S. P.; Praveen, Ch.;
Ramakrishna, G.; Kalkote, U. R. Tetrahedron Lett. 2005,
45, 6027, and references cited therein.
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In conclusion, the first synthesis of oxa-lipoic acid 2 was
achieved starting from acrolein and benzylmercaptan.
Compound 2 was designed to resist from b-oxidation,
which may help in improving the bioavailability of lipoic
acid 1 by retaining its biological activity.
Acknowledgements
We thank Dr. Reddy’s Laboratories Ltd for the support
and encouragement. Help from the analytical depart-
ment in recording spectral data is appreciated.
References and notes
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8. Spectral data of 2: IR (Neat): 1731 cmÀ1 1H NMR
;
(400 MHz, DMSO-d6): d 12.54 (s, 1H), 3.99 (s, 2H), 3.77–
3.71 (m, 1H), 3.54 (t, 2H, J = 6.4 Hz), 3.2–3.09 (m, 2H),
2.47–2.39 (m, 1H), 1.99–1.88 (m, 2H), 1.82–1.74 (m, 1H);
13C NMR (100 MHz, DMSO): d 171.6, 69.4, 67.4, 52.8,
40.7, 39.8, 38.2; MS (CI): 208 (M+).