Enantioselective synthesis of (R)-(+)-α-lipoic acid via proline-catalyzed sequential α-aminoxylation and HWE olefination of aldehyde

Article abstract of DOI:10.1016/j.tetlet.2010.05.007

An efficient enantioselective synthesis of (R)-(+)-α-lipoic acid is described, in high optical purity (>97% ee), using l-proline-catalyzed sequential α-aminoxylation and Horner-Wadsworth-Emmons olefination of aldehyde as the key step.

Full text of DOI:10.1016/j.tetlet.2010.05.007

Tetrahedron Letters 51 (2010) 3587–3589
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Enantioselective synthesis of (R)-(+)-a-lipoic acid via proline-catalyzed
sequential
a
-aminoxylation and HWE olefination of aldehyde
*
Sharad P. Panchgalle, Ganesh F. Jogdand, Subhash P. Chavan, Uttam R. Kalkote
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient enantioselective synthesis of (R)-(+)-a-lipoic acid is described, in high optical purity (>97%
Received 26 March 2010
Revised 3 May 2010
Accepted 6 May 2010
Available online 10 May 2010
ee), using
L-proline-catalyzed sequential
a-aminoxylation and Horner–Wadsworth–Emmons olefination
of aldehyde as the key step.
Ó 2010 Elsevier Ltd. All rights reserved.
a
-Lipoic acid is an important growth factor for a variety of mi-
cro-organisms, and also a co-factor for the multi-enzyme complex
that catalyzes oxidative decarboxylation of
-keto acids.1 Reed and
co-workers reported the isolation of -lipoic acid in 1951 from li-
Mannich reaction,13 Diels–Alder cycloaddition,14 Michael addi-
tion,15 and -functionalization of aldehydes16 among many others.
a
a
Proline-catalyzed sequential transformations17 is an emerging re-
search field in organic synthesis.
a
ver residue.1 Although the chemical structure of
a
-lipoic acid was
Optically active
a-hydroxyaldehydes are important intermedi-
determined,1,2 its absolute configuration R was not known till Gol-
ates in organic synthesis.18 The more prominent, well-established
ding’s synthesis of complementary enantiomer from S-malic acid.3
methodsofenantioselectivea-oxygenationsincludetheuseofDavis
Since then a number of ( )-
a-lipoic acid syntheses have been doc-
oxaziridine,19a Sharpless dihydroxylation of enol ethers,19b manga-
nese-salen epoxidation of enol ethers,19c and Shi epoxidation of enol
umented in the literature.4 Lipoic acid and its derivatives are highly
active as anti-HIV and anti-tumor agents. The R-(+)-enantiomer is
more effective than the S-(ꢀ)-enantiomer in enhanced insulin-
stimulated glucose transport and non-oxidative and oxidative
glucose metabolism.5 In this context, the development of enantio-
selective methods for the preparation of enantiomerically pure
lipoic acid is of particular interest from the standpoint of pharma-
ceutical and organic chemistry. Several asymmetric syntheses of 1
have been reported, which include (i) the stereospecific synthesis
from chiral building blocks or using chiral auxilaries;6 (ii) the enzy-
matic reduction of prochiral ketones;7 (iii) the enzymatic resolu-
tion of racemic mixtures;8 (iv) the asymmetric organometallic
ethers.19d Recently,
L
-proline-catalyzed
hydes16 has also been found to be an excellent asymmetric method
for chiral -hydroxyaldehydes. The reaction has several advantages
a-aminoxylation of alde-
a
from a practical point of view, which include inexpensive and com-
mercially available proline as the catalyst, commercial availability of
both forms of proline, low catalyst loadings (5–20 mol %), and good
to excellent yield of enantiomerically enriched alcohols. In continu-
ation with our work of organocatalytic asymmetric synthesis of bio-
logically active compounds,20 in this Letter, we wish to report the
organocatalytic enantioselective approach to synthesis of (R)-(+)-
a
-lipoic acid by using a L-proline-catalyzed sequential aminoxyla-
catalytic methods.9 Recently,
was used for the synthesis of (R)-
L
-proline-catalyzed aldol reaction
-lipoic acid 1, but it involves
tion-HWE olefination reaction of aldehyde17d as the key step.
a
destroying one of the chiral centers.10 Some of these methods are
not amenable to scale up, due to large number of steps coupled
with low yields.
O
HO
S
S
O
OH OH
O
OEt
OPMB
The area of asymmetric organocatalysis is rapidly developing
and attracts scientific community around the world. In the recent
years organocatalytic asymmetric synthesis has provided several
new methods for obtaining chiral building blocks.11 In this context,
proline, the only natural amino acid with a secondary amine func-
tionality, an abundant, inexpensive amino acid available in both
enantiomeric forms, has emerged as a ‘universal catalyst’.11 Proline
has high utility, especially in enantioselective aldol reaction,12
OH
OEt
4
4
1
2
3
4
OH
OH
O
OPMB
OH
OPMB
6
5
* Corresponding author. Tel.: +91 20 25902578; fax: +91 20 25902629.
E-mail address: ur.kalkote@ncl.res.in (U.R. Kalkote).
Scheme 1. Retrosynthetic analysis of (R)-(+)-a-lipoic acid 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.007

3588
S. P. Panchgalle et al. / Tetrahedron Letters 51 (2010) 3587–3589
O
HO
c
OH
OEt
a
b
d
OH
OH
O
OPMB
OPMB
OPMB
6
5
4
3
O
O
O
TBDMSO
TBDMSO
TBDMSO
f
OEt
OEt
OEt
OH
e
OPMB
OPMB
OPMB
7
8
9
S
S
OH OH
S
g
h
S
i
OEt
OEt
O
O
O
2
10
1
Scheme 2. Reagents and conditions: (a) 4-methoxybenzyl chloride, NaH, THF/DMF (1:1), 0 °C to rt overnight, 79%; (b) IBX, DMSO, rt, 2 h, 94%; (c) (i) PhNO, L-proline, DMSO,
rt, 20 min then triethylphosphonoacetate, LiCl, DBU, CH3CN, 0 °C, 45 min; (ii) 10% Pd/C, H2, EtOAc, 4 h, 58% (for two steps); (d) TBDMSCl, imidazole, 4-DMAP, CH2Cl2, 0 °C to rt
overnight, 89%; (e) DIBAL-H (2 M in toluene), CH2Cl2, ꢀ78 °C, 2 h then triethylphosphonoacetate, LiCl, DBU, CH3CN, 0 °C, 45 min, 82%; (f) 10% Pd/C, H2, EtOAc, rt, 4 h, 94%; (g)
TiCl4, CH2Cl2, 0 °C, 1 h, 87%; (h) MeSO2Cl, Et3N, CH2Cl2, 0 °C, 4 h then Na2S, sulfur, DMF, 80 °C, 24 h, 85%; (i) 1 M ethanolic KOH, rt, 24 h, 76%.
From retrosynthetic analysis (Scheme 1), it was envisaged that
the key intermediate 3 could be derived from the aldehyde 4 using
complex reaction mixture instead of the desired dihydroxy ester
11 (Scheme 3). We obtained similar results for Wittig reaction at
lower temperatures. If this reaction would have worked then this
synthesis would have been much shorter than the present
synthesis.
The analytical data of all new compounds are in good agree-
ment with proposed structures23 and that of 1 is in good agree-
ment with the literature data.24
L
-proline-catalyzed sequential
a-aminoxylation and HWE olefin-
ation to install required chirality.
Our approach started with commercially available butane-1,4-
diol 6 as illustrated in Scheme 2. The mono hydroxyl protection
of 6 with p-methoxybenzyl chloride and NaH gave alcohol 5 in
79% yield. Alcohol 5 was oxidized with IBX to aldehyde 4 in 94%
yield and subsequently subjected to modified MacMillan proto-
In conclusion, we have achieved a short and efficient synthesis
col17d (sequential
L
-proline-catalyzed
a
-aminoxylation-HWE olef-
of (R)-(+)-
catalyzed sequential a
a
-lipoic acid (overall yield 16.6%) by employing proline-
-aminoxylation-HWE olefination of alde-
ination) and then hydrogenation to obtain chiral
3 in 58% yield over two steps. The enantiopurity of
c
c
-hydroxy ester
-hydroxy ester
hyde. Excellent yields, simple and environmentally friendly proce-
dures, and easy availability of the starting materials are some of
the salient features of this approach.
3 was 97%, determined by chiral HPLC analysis.21 In order to avoid
interference of hydroxyl group during chain elongation, it was pro-
tected with TBDMSCl and imidazole to obtain silyl ether 7 in 89%
yield. The ester 7 was then reduced to aldehyde with DIBAL-H at
Acknowledgments
ꢀ78 °C and subjected to HWE olefination to obtain
a,b-unsaturated
S.P.P. thanks UGC, New Delhi, for financial assistance in the
form of fellowship. The authors are thankful to Mrs. S. S. Kunte
for chiral HPLC analysis.
ester 8 in 82% yield. The ,b-unsaturated ester 8 on hydrogenation
a
with 10% Pd/C afforded saturated ester 9 in 94% yield. The next task
was deprotection of p-methoxybenzyl ether and silyl ether. For the
purpose of deprotection of both the protecting groups, we sub-
jected ester 9 to TiCl4 in CH2Cl2 at 0 °C for 30 min and obtained
dihydroxy ester 2 in 87% yield. The dihydroxy ester 2, a well known
References and notes
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with Na2S and elemental sulfur in DMF at 80 °C afforded ethyl lip-
oate 10. Ethyl lipoate 10 on hydrolysis using 1 M ethanolic KOH
furnished the target (R)-(+)-
To reduce the number of steps and to increase the efficacy of
synthesis we subjected aldehyde
to Hayashi’s protocol16a
-proline-catalyzed
a-lipoic acid 1 in 76% yield.
4
(
L
a-aminoxylation) followed by Wittig reac-
tion22 with (E)-methyl-4-(triphenylphosphoranylidene)but-2-eno-
ate and the resultant material after workup was subjected to Pd/C-
catalyzed hydrogenation. But to our disappointment it resulted in a
O
HO
a, b, c
OMe
O
OH
11
OPMB
4
Scheme 3. Reagents and conditions: (a) PhNO,
(E)-methyl-4-(triphenylphosphoranylidene)but-2-enoate, CH2Cl2, rt, 12 h; (c) 10%
L
-proline, CH3CN, ꢀ20 °C, 24 h; (b)
Pd/C, H2, EtOAc, 6 h.

S. P. Panchgalle et al. / Tetrahedron Letters 51 (2010) 3587–3589
3589
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21. Chiral HPLC analysis at 230 nm, tR = 17.37 min, tS = 18.79 min on Chiralcel OD-
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phase with 0.5 mL/min flow rate.
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22. Buchta, E.; Andree, F. Chem. Ber. 1960, 93, 1349.
23. All new compounds were characterized and gave satisfactory analytical data.
Compound 3: yellow oil, ½a D25
ꢀ41.6 (c 1.12, CHCl3); ee >97%; IR (CHCl3) mmax
ꢂ
3453, 2997, 1733 cmꢀ1 1H NMR (200 MHz, CDCl3): d ppm 1.24 (t, 3H), 1.69–
;
1.81 (m, 4H), 2.36–2.50 (m, 2H), 3.12 (br s, 1H), 3.58–3.63 (m, 1H), 3.66–3.71
(m, 1H), 3.76–3.83 (m, 1H), 3.79 (s, merged, 3H), 4.11 (q, 2H), 4.43 (s, 2H), 6.85
(d, J = 8.54, 2H), 7.22 (d, J = 8.54, 2H); 13C NMR (50 MHz, CDCl3): d = 14.1, 30.5,
32.1, 36.3, 55.2, 60.3, 68.7, 70.5, 72.9, 113.7, 129.3, 129.8, 159.2, 174.0 ppm.
Elemental Anal. Calcd for C16H24O5: C, 64.84; H, 8.16. Found: C, 64.79; H, 8.14.
Compound 7: yellow oil; ½a D25
ꢂ
ꢀ68.3 (c 1.21, CHCl3); 1H NMR (500 MHz, CDCl3):
d ppm 0.07 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.27 (t, J = 7.15 Hz, 3H), 1.74–1.79
(m, 3H), 1.81–1.87 (m, 1H), 2.37 (t, J = 7.70 Hz, 2H), 3.52 (t, J = 6.33 Hz, 2H),
3.83 (s, 3H), 3.89–3.94 (m, 1H), 4.14 (q, 2H), 4.44 (q, 2H), 6.89 (d, J = 8.53, 2H),
7.27 (d, J = 8.53, 2H); 13C NMR (125 MHz, CDCl3): d = ꢀ4.6, ꢀ4.5, 14.1, 17.9,
25.8, 29.7, 32.0, 36.7, 55.2, 60.2, 66.5, 68.2, 72.6, 113.7, 129.2, 130.5, 159.0,
173.8 ppm. Compound 8: colorless oil; ½a D25
ꢂ
ꢀ29.71 (c 1.19, CHCl3); 1H NMR
(200 MHz, CDCl3): d ppm 0.05 (s, 6H), 0.88 (s, 9H), 1.29 (t, J = 7.19 Hz, 3H),
1.57–1.64 (m, 1H), 1.70–1.83 (m, 3H), 2.20–2.26 (m, 1H), 2.34–2.40 (m, 1H),
3.52 (t, J = 7.78 Hz, 2H), 3.82 (s, 3H), 3.88–3.92 (m, 2H), 4.19 (q, 2H), 4.42 (dd,
J = 9.79, 11.54 Hz, 2H), 5.81 (d, J = 15.56 Hz, 1H), 6.90 (d, J = 8.53 Hz, 2H), 6.99
(dt, J = 6.77, 15.56 Hz, 1H), 7.26 (d, J = 8.53 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d = ꢀ4.6, 14.2, 18.0, 25.8, 29.7, 32.0, 36.8, 55.2, 60.1, 66.5, 68.6, 72.6, 113.7,
121.1, 129.2, 130.4, 149.2, 159.0, 173.8 ppm. Compound 9: yellow oil; ½a D25
ꢂ
ꢀ41.5 (c 0.95, CHCl3); 1H NMR (200 MHz, CDCl3): d ppm 0.04 (s, 6H), 0.87 (s,
9H), 1.26 (t, J = 7.32 Hz, 3H), 1.34–1.43 (m, 2H), 1.54–1.85 (m, 5H), 2.25–2.40
(m, 2H), 3.50 (t, J = 6.57 Hz, 2H), 3.81 (s, 3H), 3.85–3.89 (m, 1H), 4.10 (q,
J = 7.32 Hz, 2H), 4.41 (dd, J = 2.53, 11.62 Hz, 2H), 6.86 (d, J = 8.72 Hz, 2H), 7.24
(d, J = 8.72 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = ꢀ4.6, 14.2, 18.0, 25.8, 29.7,
32.0, 34.3, 36.8, 37.1, 55.2, 60.1, 66.8, 69.1, 72.6, 113.7, 129.2, 130.6, 159.0,
173.7 ppm; LC–MS: m/z = 461.17 (M++Na).
24. Analytical data for (R)-(+)-a-lipoic acid: yellow solid; mp 48 °C; [a]D +103.18 (c
0.86, benzene); IR (CHCl3) mmax 3018, 2934, 1701 cmꢀ1;1H NMR (400 MHz,
CDCl3): d ppm 1.43–1.56 (m, 2H), 1.66–1.76 (m, 4H), 1.88–1.96 (m, 1H), 2.38 (t,
J = 7.28 Hz, 2H), 2.43–2.51 (m, 1H), 3.09–3.22 (m, 2H), 3.35–3.61 (m, 1H); 13C
NMR (100 MHz, CDCl3): d = 24.3, 28.6, 33.7, 34.5, 38.4, 40.1, 56.2, 179.5 ppm.
Elemental Anal. Calcd for C8H14O2S2: C, 46.57; H, 6.84; S, 31.8. Found: C, 46.49;
H, 6.89; S, 31.79.
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