Chirality induction and chiron approaches to enantioselective total synthesis of α-lipoic acid

Article abstract of DOI:10.1016/j.tet.2015.04.090

Abstract An efficient, short and convenient asymmetric synthesis of (R)-(+)-lipoic acid in seven steps from chiral hydroxy aldehyde with 32.5% overall yield is described. Synthesis of S and R enantiomers of α-lipoic acid from cis-1,4-butene diol derived chiral lactone is reported with 34 % overall yield. The present synthesis involves use of simple reaction conditions making it a convenient synthesis.

Full text of DOI:10.1016/j.tet.2015.04.090

Accepted Manuscript
Chirality induction and chiron approaches to enantioselective total synthesis of α-
lipoic acid
Subhash P. Chavan, Kailash P. Pawar, Ch. Praveen, Niteen B. Patil
PII:
S0040-4020(15)00600-6
10.1016/j.tet.2015.04.090
TET 26693
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 December 2014
Revised Date: 22 April 2015
Accepted Date: 24 April 2015
Please cite this article as: Chavan SP, Pawar KP, Praveen C, Patil NB, Chirality induction and chiron
approaches to enantioselective total synthesis of α-lipoic acid, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.04.090.
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Graphical Abstract
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Chirality induction and chiron approaches to
enantioselective total synthesis of α-lipoic acid
Subhash P. Chavan,* Kailash P. Pawar, Ch. Praveen and Niteen B. Patil
Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune -411008, India.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Chirality induction and chiron approaches to enantioselective total synthesis of α-
lipoic acid
Subhash P. Chavan,* Kailash P. Pawar, Ch. Praveen and Niteen B. Patil
a Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune -411008, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient, short and convenient asymmetric synthesis of (R)-(+)-lipoic acid in 7 steps from
chiral hydroxy aldehyde with 32.5% overall yield is described. Synthesis of S and R enantiomers
of α-lipoic acid from cis-1,4-butene diol is reported with 34% overall yield. The present
synthesis involves use of simple reaction conditions making it a convenient synthesis.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Sharpless asymmetric dihydroxylation
Chiral pool
Chirality induction
Lipoic acid
Enantioselective
at biointerface for biosensors and biological applications.5 It is a
biological antioxidant which can scavenge free radicals and protect
cells from oxidative damage.6 It can act as antitumour agent.7 It is
an important growth factor and also a cofactor for the multi
enzyme complex that catalyses decarboxylation of β-keto acids.8 It
is useful in treatment of cancer, inflammation, ischemia-
reperfusion injury and as an antiaging agent.9 Moreover, α-lipoic
acid is used in treatment of alcoholic liver diseases,10 mushroom
poisoning,11 metal poisoning,12 diabetes and neurodegenerative
disorders.13 These significant biological activities of (+)-α-lipoic
acid 1a are of great commercial importance which has made it an
attractive target for synthetic organic chemists for decades and in
the process many synthetic endeavours have been reported.14
1. Introduction
α-Lipoic acid 1 was first isolated by Reed et al. in 1950.1 It is the
cyclic disulfide of 6,8-di-mercapto-n-caprylic acid. Both the
antipodes of lipoic acid were obtained by resolution method in
1954, wherein it was also established that (R)-(+)-α-lipoic acid 1a
shows more bioactivity than (S)-(-)-α-lipoic acid 1b.2 Golding et
al. determined the absolute configuration by synthesizing
complementary enantiomer from S-malic acid.3 (R)-(+)-α-Lipoic
acid 1a is vital cofactor widely distributed in many plants and
animals. It exhibits wide variety of various biological and
pharmaceutical activities. It has been reported to show inhibition
of HIV-I replication in T-cells and HeLa-CD+ at 37-70 µg/mL
concentration.4 Recently, it is also observed that lipoic acid glycol-
conjugates show control on nonspecific adsorption of blood serum 2. Results and discussion
S
S
S
S
This group has been actively engaged in devising novel
synthetic methodologies towards α-lipoic acid 1.14v,x,y,z,aa The
synthesis of racemic lipoic acid from cyclohexanone reported by
this group required 11 steps14y while the other route required 9
steps.14z Though these syntheses involved interesting chemistry
and are novel synthetic routes, it was realised that there is scope
for improvement and one needs to avoid some of the critical
reaction conditions which may not be viable at higher scale, by
devising alternate routes using chiral pool approach and chirality
induction approach where our emphasis was on the use of simple,
practical and environmentally benign reaction condtions. Also,
one of our aims was to develop shorter route as compared to our
prior syntheses and a scope to be carried out at larger scale. In
accordance with our plan and goal we herein report the details of
asymmetric synthesis of both the antipodes of lipoic acid from cis-
OH
OH
O
O
(R)-(+)-α−Lipoic acid 1a
α−Lipoic acid 1
S
S
OH
O
(S)-(-)-α−Lipoic acid 1b
Figure1. Structures of racemic and chiral lipoic acid.
____________________
*Corresponding author. Tel.: +91 020 25902286; fax: +91 020 25902629;
e-mail: sp.chavan@ncl.res.in

2
Tetrahedron
ACCEPTED MANUSCRIPT
1
butene-1,4-diol in 10 steps14v where chirality induction approach and at 1778 cm-1 for the γ-lactone carbonyl functionality. The H-
was used and enantiospecific synthesis of R-enantiomer of lipoic NMR spectrum revealed disappearance of proton signals in the
acid was achieved by chiron approach.
olefinic region and the proton signals corresponding to the ethyl
group. This indicated that dihydroxylation and in situ cyclization
had taken place in one pot.15 The enantiopurity of the
hydroxylactone was estimated to be in excess of 94% using chiral
HPLC analysis (Chiralcel OD, 80:20, hexane:i-PrOH, 1 mL /min,
254 nm). Treatment of the hydroxy lactone 6 with PPh3, iodine and
imidazole in anhydrous toluene at 70 oC for 3 h smoothly delivered
the iodolactone 5 (Scheme 3). Having accomplished the synthesis
of compound 5, our next concern was to reduce it to lactol and
two-carbon homologation to give the required compound 4.
Accordingly, iodolactone 5 was reduced using DIBAL-H at–78 oC,
The retrosynthetic analysis for the enantioselective synthesis of
R-(+)-lipoic acid is depicted (Scheme 1). It was envisaged that a
simple basic hydrolysis could be used to form 1a from the ethyl
lipoate 2a and this in turn should be available from diol ester 3a.
The diol ester 3a could be obtained from the iodo lactone 5,
through intermediate 4, which could be easily prepared in one step
from the hydroxy lactone 6. The stereocenters of 6 can be installed
by Sharpless asymmetric dihydroxylation reaction of (E)-ethyl 6-
S
S
S
S
O
OBn OH
I
COOH
COOEt
O
COOEt
HO
a
O
b
I
O
1
COOEt
e
2a
4
BnO
5
BnO
6
OBn OBn
OH OH
OMs OMs
d
OH OH
COOEt
c
I
COOEt
4
COOEt
f
3a
11
3a
OH
O
O
S
S
O
HO
S
S
I
O
COOEt
HO
COOH
6
2a
BnO
5
BnO
1a
7
Scheme 3. a) PPh3, I2, Im, toluene, 70 oC, 3 h, 94%; b) i) DIBAL-H, CH2Cl2, -
Scheme 1. Retrosynthetic analysis
78 oC, 1 h; ii) Ph3PCHCOOC2H5, rt, 24 h, 96%; c) W 2 Raney nickel, H2, rt, 24
(benzyloxy)hex-4-enoate 10. The (E)-ethyl 6-(benzyloxy)hex-4-
enoate 10 could be readily obtained from cis-2-butene-1,4-diol 7
by a known procedure earlier utilized by us.15
o
h, 84%; d) CH3SO2Cl, Et3N, CH2Cl2, 0 C, 4 h, 92%; e) Na2S.7H2O, S, DMF,
90 oC, 24 h, 72%; f) 1 M Ethanolic KOH, rt, 24 h, 75%.
followed by in situ treatment with two-carbon Wittig ylide to
afford the unsaturated ester 4 in 96% yield. The trans olefin was
obtained as a major product along with the small amount of cis
olefin. Since, the next step was the reduction of double bond, no
attempt was made to separate them. The next immediate concern
was the transformation of iodo ester 4 into the corresponding diol
The synthesis starts from cis-2-butene-1, 4-diol 7, a relatively
inexpensive starting material. As shown (Scheme 2), the
commercially available cis-2-butene-1,4-diol 7 was isomerized in
to 3-butene-1,2-diol 8 by refluxing in water in the presence of
catalytic amount of HgSO4 and conc. H2SO4 (cat).15 Selective
mono protection of the primary hydroxyl group as its benzyl ether
was achieved in 69% yield by using one equivalent each of sodium ester 3a. The removal of the benzyl group, removal of iodine and
hydride and benzyl bromide in anhydrous THF. In an another
method primary hydroxyl group was selectively protected by
refluxing 3-butene-1,2-diol 8 in anhydrous benzene by using 1.1
reduction of the double bond were efficiently achieved in a single
step using W2 Raney nickel under an atmosphere of H2 at room
temperature and normal pressure for 24 h to deliver the diol ester
3a. The diol 3a is the well known intermediate for the synthesis of
R-(+)-lipoic acid and was converted in to the final target molecule
by a series of reactions. Accordingly, treatment of diol 3a with
OH
OH
a
HO
HO
HO
c
b
MsCl and Et3N in anhydrous CH2Cl2 at
corresponding dimesylate in 92% yield. The dimesylate 11 on
0
oC provided
BnO
7
8
9
reaction with sodiun sulfide nonahydrate and sulfur in anhydrous
DMF at 90 C for 24 h afforded ethyl lipoate 2a in 72% yield.
O
O
o
d
HO
BnO
O
BnO
O
Finally, hydrolysis of ethyl lipoate 2a with 1 M KOH solution in
ethanol at room temperature for 24 h afforded R-(+)-lipoic acid 1a
in 75% yield. The synthetic lipoic acid thus obtained showed the
10
6
25
D
Scheme 2. a) Cat. HgSO4, cat. H2SO4, H2O, 61%; b) NaH, BnBr THF, rt, 2 h,
69% or KOH, BnCl, benzene, 64% c) CH3C(OEt)3, cat. propionic acid, 140 oC,
2 h, 94%; d) AD-mix-α, t-BuOH-H2O (1:1), 0 oC, 24 h, 93%, 94% ee.
equivalent of KOH and 1 equivalent of benzyl chloride for 6 h to
afford monobenzyl ether 9 in 64% yield. Monoprotected allyl
rotation [α] : +106.29 (c=1, benzene) which was in good
agreement with the literature data.14 In a similar way we also
prepared the unnatural antipode S-(α)-lipoic acid.
The same sequence of reactions was followed for the synthesis
of S isomer 1b except the use of AD-mix-β in place of AD-mix-α
in the crucial dihydroxylation reaction, which fixes the desired
stereochemistry of the resultant compound. The spectral data were
the same as described for R-(+)-lipoic acid, except the sign of
alcohol
9
was subjected to Johnson-Claisen orthoester
rearrangement using triethyl orthoacetate in the presence of
catalytic amount of propionic acid at 140 C to afford (E)-ethyl 6-
o
(benzyloxy)hex-4-enoate 10 in 94% yield. Having the compound
10 in hand, the next concern was the stereoselective synthesis of
hydroxy lactone 6 with the desired stereochemistry. The product
(E)-ethyl 6-(benzyloxy)hex-4-enoate 10 was subjected to
Sharpless asymmetric dihydroxylation using AD-mix-α. The IR
spectrum of 6 showed absorption at 3434 cm-1for hydroxyl group
25
optical rotation [α] : -102 (c = 0.9, benzene).
D

3
o
imidazole in xylene at 80 C for 3 h in 73% yield. The iodo
In continuation of our work on lipoic acid, we also achieved
enantiospecific synthesis of (+)-α-lipoic acid 1a by chiron
approach using inexpensive reagents, renewable raw materials and
environmentally benign reaction conditions.
ACCEPTED MANUSCRIPT
group in this iodoester 12 was removed using Raney Ni in
methanol under hydrogen atmosphere to provide deiodinated ester
16 in 94% yield. The acetal group in ester 16 was subsequently
deprotected with PTSA in methanol to obtain 1,3-diol 3b in 90%
yield.19 The 1,3-diol 3b was mesylated using methanesulphonyl
chloride and triethylamine in DCM. The dimesylate derivative
thus obtained was directly treated with sodium sulphide in DMF at
We planned our synthesis of (+)-α-lipoic acid 1a as outlined in
retrosynthetic analysis (Scheme 4). (+)-α-Lipoic acid 1a can be
S
S
OH OH
o
80 C to convert it into lipoate ester 2b in 81% yield. The lipoate
COOH
COOMe
ester 2b thus obtained was hydrolyzed using KOH in ethanol to
afford (+)-α-lipoic acid 1a in 77% yield. The spectral data of (+)-
α-lipoic acid 1a was in good agreement with reported one.14
1a
3b
3. Conclusion
O
O
O
O
COOMe
In conclusion, both the R-(+)-α and S-(-)-α antipodes of lipoic
acid were synthesized in 34% overall yield in 8 steps from the cis-
2-butene-1,4-diol derived (E)-ethyl 6-(benzyloxy)hex-4-enoate 10.
The synthesis involved Sharpless asymmetric dihydroxylation as
the chirality inducing tool. Thus, we have developed a new, short
synthetic route for the total synthesis of (+)-α-lipoic acid 1a from
hydroxy aldehyde 14 in 7 steps. The key reactions involved in
synthesis are Wittig reaction, iodination and hydrogenation which
are simple, requiring inexpensive reagents. This work reports short
reaction sequence, simple and practical reaction conditions for
synthesis of lipoic acid without compromising overall yield. Also,
present work decribes use of inexpensive reagents and renewable
raw materials which have merits over previous reports from this
group and provides scope for scale up and minimization of number
of purification steps which is highly desirable while performing
reactions at a higher scale.
COOMe
I
12
OH
13
O
O
O
OH
14
Scheme 4. Retrosynthetic analysis.
accessed from 1,3-diol 3b by straight forward chemical
transformations, which in turn can be obtained from iodo
compound 12 by deiodination followed by deprotection. The iodo
compound 12 can be easily accessed from unsaturated hydroxy
ester 13 by saturation of double bonds followed by iodination.
Unsaturated hydroxy ester 13 could be synthesized from chiral
template of hydroxy aldehyde 14 by Wittig reaction. Synthesis of
hydroxy aldehyde 14 from D-glucose is well documented.16
4. Experimental section
All reagents and solvents were used as received from the
manufacturers. Melting points are recorded using Buchi B-540
melting point apparatus in capillary tubes and are uncorrected and
the temperatures are in centigrade scale. IR spectra were recorded
on a Perkin-Elmer Infrared Spectrophotometer Model 68B or on a
1
Perkin-Elmer 1615 FT Infrared spectrophotometer. H (200 and
400 MHz) and 13C (50 and 100 MHz) NMR spectra were recorded
on Bruker and Bruker Advance 400 spectrometers, using a 2:1
mixture of CDCl3 and CCl4 as solvent. The chemical shifts (δ
ppm) and coupling constants (Hz) are reported in the standard
fashion with reference to chloroform, δ 7.26 (for 1H) or the central
line (77.0 ppm) of CDCl3 (for 13C). In the 13C NMR spectra, the
natures of the carbons (C, CH, CH2, or CH3) were determined by
recording the DEPT-135 spectra. The following abbreviations
were used to explain the multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet. The reaction progress was
monitored by the TLC analysis using thin layer plates precoated
with silica gel 60 F254 (Merck) and visualized by fluorescence
quenching or iodine or by charring after treatment with p-
anisaldehyde and also 2,4-DNP. Merck’s flash silica gel (230-400
mesh) was used for column chromatography.
Scheme 5. a) Ph3P=CH-CH=CHCOOMe, DCM, 5 h, 87%; b) H2, Pd/C,
MeOH, 2 h, 97%; c) Ph3P, I2, Im, xylene, 70 oC, 6 h, 73%; d) TEA, H2, Raney
Ni, MeOH, 5 h 94%; e) PTSA, MeOH 90%; f) i) MsCl, TEA, DCM; ii)
Na2S.7H2O, DMF, 80 oC, 12 h, 81% over two steps; g) KOH, EtOH, 24 h,
77%.
4.1. 6-(Benzyloxy)-2,3-dideoxy-L-threo-hexano-1,4-lactone (6)
To a solution of AD-mix-α (16.93 g) in t-BuOH-H2O (1:1, 120
mL) at 0 oC was added methane sulfonamide (1.15 g, 12.09 mmol)
and stirred at the same temperature. After stirring for 5 min, the
olefin 10 (3 g, 12.09 mmol) was added in one portion. The
Synthesis of (+)-α-lipoic acid 1a began with 4-carbon Wittig
reaction of hydroxy aldehyde 14 by which it was converted to
unsaturated hydroxy ester 13, in 87% yield,17 as an inseparable
mixture of cis and trans isomers (Scheme 5). Saturation of the
double bonds in 13 was carried out using catalytic Pd/C in
methanol under hydrogen atmosphere to afford 97% yield of
hydroxy ester 15.18 Once hydroxy ester 15 was in hand, it was
converted to iodo derivative 12 by treatment with I2, PPh3 and
o
reaction mixture was stirred at 0 C for 24 h and then quenched
with solid sodium sulfite (6 g). The stirring was continued for an
additional 45 min and then the solution was extracted with EtOAc
(3 x 30 mL). The combined organic fractions were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was chromatographed on

4
Tetrahedron
silica gel using ethyl acetate/ petroleum ether (1:2) as an eluent
x CH), 128.3 (2 x CH), 137.0 (C), 148.1 (CH), 166.1 (CO);
ACCEPTED MANUSCRIPT
to afford 6 (2.68 g, 94%) as a white solid.
Elemental Analysis: Analysis calcd. for C17H23O4I: C, 48.81; H,
o
5.54; I, 30.39. Found: C, 48.62; H, 5.74; I, 30.12.
Rf (EA: PE/2:3): 0.4; Yield: 94%; M. P.: 115-116 C (White
25
D
solid); [α] = + 40.59 (c = 1, CHCl3); IR (CHCl3, cm-1): 3434,
4.4. Ethyl (S)-6, 8-dihydroxy octanoate (3a)
1778, 1720, 1216, 758; 1H NMR (CDCl3, 200 MHz): δ 2.15 - 2.34
(m, 2 H), 2.43 - 2.74 (m, 3 H), 3.60 (d, J = 5.81 Hz, 2 H), 3.78 -
3.87 (m, 1 H), 4.54 - 4.62 (m, 3 H), 7.08 - 7.54 (m, 5 H); 13C NMR
(CDCl3, 125 MHz): δ 23.4 (CH2), 28.1 (CH2), 70.6 (CH), 71.6
(CH), 73.1 (CH2), 79.9 (CH2), 127.5 (2×CH), 128.1 (2×CH), 137.5
(CH), 177.7 (CO); MS (ESI, Solv.: MeOH + H2O + CH3COONH4
To a solution of 4 (0.92 g, 2.20 mmol) in absolute ethanol (15
mL) was added W2 Raney nickel (2.5 g) and the mixture was
flushed with H2 for 5 min. After stirring under an atmosphere of
hydrogen at room temperature for 24 h, the reaction mixture was
filtered through a pad of celite and the solvent was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography using ethyl acetate/ petroleum ether (2:1)
as an eluent to afford diol 3a (0.37 g, 84%) as colourless syrup.
+
): m/z = 254.05 (M+NH4 ); Elemental Analysis:Analysis calcd.
for C13H16O4: C, 66.13; H, 6.83. Found: C, 66.36; H, 6.92.
Rf (EA: PE/2:3): 0.2; Yield: 84%; IR (CHCl3, cm-1): 3378,
1
4.2. 5-Iodo-6-(benzyloxy)-2,3,5-trideoxy-D-erythro-hexano-1,4-
lactone (5)
2950, 2868; H NMR (CDCl3, 200 MHz): δ 1.22 (t, J = 8.01 Hz,
3H), 1.35-1.40 (m, 3H), 1.57-1.74 (m, 5H), 2.21-2.36 (m, 2H),
3.46 (t, J = 6.10 Hz, 2H), 3.79 (brs, 2H), 3.81-3.90 (m, 1H), 4.07
(q, J = 8.01 Hz, 2H); 13C NMR (CDCl3, 50 MHz): 14.2 (CH3),
24.8 (CH2), 25.2 (CH2), 29.1 (CH2), 32.9 (CH2), 34.2 (CH2), 60.1
(OCH2), 66.7 (OCH2), 72.1 (OCH), 173.7 (CO); Elemental
Analysis: Analysis calcd. for C10H20O4I: C, 58.79; H, 9.87. Found:
C, 58.53; H, 9.72.
A mixture of 6 (2.5 g, 10.59 mmol), PPh3 (5.55 g, 21.18 mmol),
imidazole (0.72 g, 10.59 mmol) and I2 (5.37 g, 21.18 mmol) was
stirred under nitrogen in anhydrous toluene (40 mL) at 70 oC for 3
h. After completion of the reaction (TLC) the reaction mixture was
diluted with EtOAc, washed with 20% aq. Na2S2O3 solution,
water, brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified on
silica gel by eluting with ethyl acetate/ petroleum ether (1:4) to
afford 5 (3.44 g, 94%) as a colourless syrup.
4.5. Ethyl (S)-6, 8-dimesyloxy octanoate (11)
To a solution of the diol 3a (0.35 g, 1.71 mmol) in anhydrous
CH2Cl2 (12 mL) were added Et3N (1.19 mL, 8.57 mmol) and MsCl
Rf (EA: PE/1:8): 0.5; Yield: 94%; IR (CHCl3, cm-1): 3020,
o
(0.30 mL, 3.94 mmol) at 0 C and stirred for 4 h at the same
25
2400, 1731, 757; [α] = - 19.77 (c = 1, CHCl3); 1H NMR (CDCl3,
temperature. The reaction mixture was poured into aqueous
sodium hydrogen carbonate and extracted with CH2Cl2 (2 x 15
mL). The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated under
D
200 MHz): δ 2.02 - 2.25 (m, 1 H), 2.42 - 2.92 (m, 3 H), 3.60 - 4.07
(m, 2 H), 4.20 - 4.45 (m, 1 H), 4.47 - 4.94 (m, 3 H), 6.94 - 7.40 (m,
5 H); 13C NMR (CDCl3, 50 MHz): δ 27.6 (CH2), 28.4 (CH2), 34.0 reduced pressure. The crude oily compound was purified by silica
gel column chromatography using ethyl acetate/ petroleum ether
(2:3) as an eluent to afford 6, 8 dimesylate 11 (0.57 g, 92%) as a
colourless syrup.
(CH), 71.4 (CH2), 72.9 (CH2), 78.8 (CH), 127.4 (3 x CH), 128.2 (2
x CH), 137.3 (C), 175.7 (CO); Elemental Analysis:Analysis calcd.
for C13H15O3I: C, 45.10; H, 4.37; I, 36.66. Found: C, 45.28; H,
4.40; I, 36.42.
Rf (EA: PE/2:3): 0.2; Yield: 92%; IR (CHCl3, cm-1): 3030,
25
D
1
4.3. ethyl (6S,7R,E)-8-(benzyloxy)-6-hydroxy-7-iodooct-2-enoate
(4)
1735, 1170; [α] = + 17.6 (c = 1, CHCl3); H NMR (200 MHz,
CDCl3): δ 1.26 (t, J = 6.96 Hz, 3 H), 1.36 - 1.51 (m, 4 H), 1.60 -
1.79 (m, 4 H), 2.30 (t, J = 7.33 Hz, 2 H), 3.08 (d, J = 2.93 Hz, 6
H), 4.12 (q, J = 7.08 Hz, 2 H), 4.21 - 4.30 (m, 1 H), 4.33 - 4.43 (m,
1 H), 4.80 - 4.93 (m, 1 H); 13C NMR (CDCl3+CCl4, 50MHz): δ
14.3 (CH3), 24.4 (CH2), 24.5 (CH2), 28.5 (CH2), 30.9 (CH2), 31.4
(CH2), 34.0 (CH2), 37.7 (SO2CH3), 38.7 (SO2CH3), 60.1 (OCH2),
69.4 (OCH2), 78.8 (OCH), 173.2 (CO); Elemental Analysis:
Analysis calcd. for C12H24O8S2: C, 39.98; H, 6.71; S, 17.79.
Found: C, 39.74; H, 6.82; S, 17.56.
To a solution of 5 (2.0 g, 5.78 mmol) in anhydrous CH2Cl2 (25
mL) was added 1.6 M DIBAL-H solution in toluene (4.3 mL, 8.09
o
o
mmol) at –78 C. After stirring for 1 h at –78 C absolute MeOH
(4.3 mL) was added to the reaction mixture and was allowed to
attain the room temperature. To the above reaction mixture was
added ethyl triphenyl phosphoranylidene acetate (4.02 g, 11.56
mmol) in anhydrous CH2Cl2 at room temperature and stirred for 16
h at the same temperature. The reaction mixture was diluted with
water, extracted with EtOAc (2 x 30 mL) and the combined
organic fractions were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography using
ethyl acetate/ petroleum ether (1:4) as an eluent to afford 4 (2.3 g,
96%) as colourless oil.
4.6. Ethyl R-(+)-lipoate or [Ethyl (5R)-5-(1,2-dithiolan-3yl)
Pentanoate] (2a)
A mixture of dimesylate 11 (0.56 g, 1.55 mmol), finely
powdered sodium sulfide nonahydrate (0.41 g, 1.78 mmol) and
sulfur (0.05 g , 1.78 mmol) in anhydrous DMF (5 mL) were heated
Rf (EA: PE/1:8): 0.7; Yield: 96%; IR (CHCl3, cm-1): 3406,
o
at 85-90 C for 24 h. The reaction mixture was diluted with cold
25
D
1
water, extracted with EtOAc (2 x 20 mL) and the combined
organic fractions were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography using
ethyl acetate/ petroleum ether (2:8) as an eluent to afford 2a (0.26
g, 72%) as light yellow oil.
1724, 1654; [α] = - 24.67 (c = 1, CHCl3); H NMR (CDCl3 +
CCl4, 200 MHz): δ 1.28 (t, J = 7.07 Hz, 3H), 1.55 - 1.90 (m, 3 H),
2.26 - 2.47 (m, 1 H), 2.79 - 3.06 (m, 1 H), 3.38 - 3.58 (m, 1 H),
3.63 - 3.81 (m, 1 H), 4.18 (q, J = 7.07 Hz, 2 H), 4.56 (d, J = 2.65
Hz, 1 H), 5.86 (d, J = 15.66 Hz, 1 H), 6.96 (d, J = 15.66 Hz, 1 H),
7.19 - 7.61 (m, 5 H); 13C NMR (CDCl3+CCl4, 50 MHz): δ 14.1
(CH3), 28.0 (CH2), 33.9 (CH2), 37.8 (ICH), 59.8 (CH2), 72.5
(CH2), 72.9 (CH2), 73.2 (OCH), 121.5 (CH), 127.5 (CH), 127.4 (2
Rf (EA: PE/1:4): 0.6; Yield: 72%; IR (CHCl3, cm-1): 3020,
25
D
1
2400, 1731, 757; [α] = + 64.7 (c = 0.5, CHCl3); H NMR (400

5
reaction mixture was diluted with EtOAc, washed with saturated
MHz, CDCl ): δ 1.25 (t, J = 7.34 Hz, 3H), 1.46-1.53 (m, 2H),
1.66-1.71 (m, 4H), 1.89-1.93 (m, 1H), 2.37 (t, J = 7.86 Hz, 2H),
ACCEPTED MANUSCRIPT
3
NaHCO3 solution, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified on
silica gel by eluting with light ethyl acetate/ petroleum ether (1:9)
to afford iodo ester compound 12 (2.16 g, 73%) as a colourless
syrup.
2.41-2.49 (m, 1H), 3.11-3.19 (m, 2H), 3.54-3.61 (m, 1H), 4.13 (q,
J = 7.34 Hz, 2H); 13C NMR (CDCl3+CCl4, 50 MHz): δ 14.3
(CH3), 24.6 (CH2), 28.7 (CH2), 34.0 (CH2), 34.6 (CH2), 38.4
(CH2), 40.1 (SCH2), 56.2 (SCH), 60.1 (OCH2), 173.1 (CO);
Elemental Analysis: Analysis calcd. for C10H18O2S2: C, 51.24; H,
7.74; S, 27.36. Found: C, 51.43; H, 7.52; S, 27.14.
Rf (EA: PE/1:4): 0.7; Yield: 73%; IR (CHCl3) νmax: 2955, 1735,
763 cm-1; [α] : +51.6 (c 1.1, chloroform); H NMR (200 MHz,
25
1
D
4.7. Methyl (2E,4E)-5-((2R,4S,5R)-5-hydroxy-2-methyl-1,3-
dioxan-4-yl)penta-2,4-dienoate (13)
CDCl3): δ 1.09 - 1.89 (m, 9 H), 2.33 (t, J = 1.0 Hz, 2 H), 2.53 -
2.82 (m, 1 H), 3.67 (s, 3 H), 3.89 - 4.40 (m, 3 H), 4.75 (q, J = 5.1
Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 20.87 (CH3), 23.66
In a single necked, round-bottomed flask, fitted with a nitrogen
inlet, aldehyde 14 (8.03 gm, 55 mmol) was taken in DCM (80 (CH2), 24.55 (CH2), 33.48 (CH2), 33.79 (CH2), 37.64 (CH2), 51.51
mL). To this solution, Wittig ylide (Ph3P=CH-CH=CHCOOMe) (18
gm, 60.5 mmol) was added. The reaction mixture was stirred for 5
h at room temperature. After completion of reaction (monitored by
TLC), solvent was removed under reduced pressure. The crude
product was purified by column chromatography over silica with
ethyl acetate/ petroleum ether (1:4) as eluent to yield 10.9 g
inseparable mixture of cis, trans isomers of unsaturated ester 13 as
a colourless liquid in 87% yield.
(OCH3), 74.01 (CH2), 78.07 (CH), 100.01 (CH), 173.93 (CO);
HRMS calculated for C11H19IO4: 365.0226, found 365.0220
[M+Na]+.
4.10. Methyl 5-((2R,4S)-2-methyl-1,3-dioxan-4-yl)pentanoate (16)
To a solution of iodo compound 12 (1 g, 29.2 mmol) and
triethylamine (590 mg, 58.4 mmol) in dry methanol was added
freshly prepared Raney nickel (0.05 g) and the reaction mixture
was stirred under an atmosphere of H2 (60 psi) for 5 h at 25oC.
After the completion of the reaction (monitored by TLC), the
reaction mixture was filtered over celite and the filtrate was
concentrated under reduced pressure to provide the reduced
compound, which was purified by column chromatography using
ethyl acetate/ petroleum ether (1:9) to obtain 0.6 g pure
dehalogenated compound 16 in 94% yield as colourless liquid.
Rf (EA: PE/2:3): 0.3; yield: 87%; IR (CHCl3) νmax: 3431, 3019,
1732, 757 cm-1; (for cis-trans mixture) 1H NMR (200 MHz,
CDCl3+ CCl4): δ 1.18 - 1.52 (m, 3 H), 2.11 - 2.40 (m, 1 H), 3.32 -
3.60 (m, 2 H), 3.76 (s, 3 H), 3.87 - 4.47 (m, 2 H), 4.03 - 4.51 (m, 2
H), 4.63 - 4.85 (m, 1 H), 5.64 - 6.04 (m, 2 H), 6.13 - 6.64 (m, 1 H),
7.09 - 7.77 (m, 2 H); (for cis-trans mixture) 13C NMR (50 MHz,
CDCl3+CCl4): δ 20.34 (CH3), 51.48 (OCH3), 51.61 (OCH3), 64.94
(CH), 65.25 (CH), 70.40 (CH2), 70.61 (CH2), 77.97 (CH), 80.74
(CH), 98.55 (CH), 98.63 (CH), 121.34 (CH), 122.85 (CH), 128.68
(CH), 129.18 (CH), 130.05 (CH), 131.82 (CH), 132.02 (CH),
135.87 (CH), 138.65 (CH), 139.75 (CH), 144.03 (CH), 167.33
(CO), 167.38 (CO).
25
Rf (EA: PE/1:4): 0.5; Yield: 94%; [α] : -19.7 (c 1.02,
D
1
chloroform); IR (CHCl3) νmax
:
3009, 1734, 754 cm-1; H NMR
(200 MHz, CDCl3): δ 1.31 (d, J = 5.1 Hz, 3 H), 1.34 - 1.76 (m, 8
H), 2.22 - 2.40 (m, 2 H), 3.51 - 3.64 (m, 1 H, OCHaH), 3.67 (s, 3
H), 3.76 (dd, 1 H, OCHHb), 3.98 - 4.17 (m, 1 H), 4.67 (q, J = 5.1
Hz, 1 H); 13C NMR (50 MHz, CDCl3): δ 21.21 (CH3), 24.53
(CH2), 24.83 (CH2), 31.09 (CH2), 33.95 (CH2), 35.60 (CH2), 51.45
(OCH3), 66.50 (OCH2), 76.36 (CH), 98.92 (CH), 174.09 (CO);
HRMS calculated for C11H20O4: 239.1259; found: 239.1254
(M+Na)+.
4.8. Methyl 5-((2R,4S,5R)-5-hydroxy-2-methyl-1,3-dioxan-4-
yl)pentanoate (15)
To a solution of 13 (4 g, 17.5 mmol) in dry methanol ( 40 mL)
was added Pd/C (0.05 g) and the reaction mixture was stirred
o
under hydrogen atmosphere (60 psi) for 2 h at 25 C. After the
completion of the reaction (monitored by TLC), the reaction
mixture was filtered over celite and the filtrate was concentrated
under reduced pressure to provide the reduced compound, which
was purified by column chromatography using ethyl acetate/
petroleum ether (1:4) to obtain 3.95 g pure compound 15 as a
colourless liquid.
4.11. Methyl (S)-6,8-dihydroxyoctanoate (3b)
To a cold stirring solution of acetal ester 7 (500 mg, 2.31
mmol) in methanol (10 mL) was added PTSA (44 mg, 0.23 mmol)
and stirred at room temperature for 2 h. After completion of
reaction (monitored by TLC), reaction was quenched with
saturated NaHCO3 and extracted with CH2Cl2 (4 x 20 mL). The
combined organic layer was washed with water and brine, dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. Purification of crude material by flash column
chromatography using ethyl acetate/ petroleum ether (2:3)
afforded 0.4 g of diol 3b as colorless viscous liquid.
25
Rf (EA: PE/2:3): 0.3; Yield: 97%; [α] : -27.6 (c 1.02,
D
1
Chloroform); IR (CHCl3) νmax: 3469, 3010, 1733, 754 cm-1; H
NMR (400 MHz, CDCl3): δ 1.31 (d, J = 5.0 Hz, 3 H), 1.37 - 1.73
(m, 5 H), 1.77 - 1.94 (m, 2 H), 2.34 (t, J = 7.3 Hz, 2 H), 3.24 - 3.37
(m, 2 H), 3.39 - 3.50 (m, 1 H), 3.67 (s, 3 H), 4.07 (dd, J = 10.5, 5.0
Hz, 1 H), 4.63 (q, J = 5 Hz, 1 H); 13C NMR (100 MHz CDCl3) δ
20.50 (CH3), 24.49 (CH2), 24.82 (CH2), 31.19 (CH2), 33.88 (CH2),
51.49 (OCH3), 65.47 (CH), 70.82 (CH2), 81.15 (CH), 98.82 (CH),
174.34 (CO); ESIMS (m/z): 254.88 (M+Na)+; HRMS calculated
for: C11H20O5 255.1208; found 255.1204 (M+Na)+.
25
D
Rf (EA: PE/2:3): 0.2; Yield: (90%); [α] = -4.2 (c = 1, CHCl3)
25
{Lit.20 [α] : -3.8 (c 1.0, CHCl3)}; IR (CHCl3) νmax 3020, 2400,
D
1
1731, 757 cm-1; H NMR (200 MHz, CDCl3): δ 1.24 - 1.82 (m, 8
4.9. Methyl 5-((2R,4S,5S)-5-iodo-2-methyl-1,3-dioxan-4-
yl)pentanoate (12)
H), 2.32 (t, J = 1.0 Hz, 2 H), 2.99 (br. s., 2 H), 3.64 (s, 3 H), 3.70 -
3.99 (m, 3 H); 13C NMR (50 MHz, CDCl3): δ 24.69 (CH2), 24.95
(CH2), 33.89 (CH2), 37.20 (CH2), 38.24 (CH2), 51.48 (OCH3),
61.45 (OCH2), 71.50 (OCH), 174.28 (CO); HRMS calculated for
C9H18O4: 213.1103, found: 213.1097 (M+Na)+.
A mixture of alcohol 15 (2 g, 8.61 mmol), PPh3 (3.40 g, 12.9
mmol), imidazole (1.2 g, 17.23 mmol) and I2 (2.63 g, 10.35 mmol)
was stirred under nitrogen in anhydrous xylene (40 mL) at 70 C
o
for 6 h. After completion of the reaction (monitored by TLC), the

6
Tetrahedron
ACCEPTED MANUSCRIPT
4.12. (5R)-Methyl 5-(1,2-dithiolan-3-yl)pentanoate or (R)-
6. Acknowledgements
methyl lipoate (2b)
KPP and NBP thank CSIR, New Delhi, India, for financial
support. The authors thank Dr. H. B. Borate and Dr. U. R. Kalkote
for helpful discussions and CSIR, New Delhi, India, for financial
support as part of XII Five Year plan programme under title ACT
(CSC-0301).
To a solution of methyl 6,8-dihydroxyoctanoate 3b (100 mg,
0.49 mmol) in anhydous CH2Cl2 (5 mL) was added Et3N (319 mg,
0.98 mmol) at 0 °C followed by MeSO2Cl (463 mg, 0.98 mmol)
dropwise. After completion of reaction (monitored by TLC),
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 anhydrous Na2SO4, filtered and concentrated under
vacuum. The crude compound was used directly in the next
reaction. The solution of crude mesylate, finely ground Na2S·H2O
(410 mg, 0.6 mmol) and sulfur (54 mg, 0.6 mmol) in anhyd DMF
(5 mL) was heated at 80 °C for 24 h and then stirred at room
temperature for 1h. 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 anhydrous Na2SO4,
filtered, and evaporated under reduced pressure to furnish 94 mg
(81%) of 2b as yellow oil.
7. References
1. Reed, L. J.; Gunsalus, I. C.; De Busk, B. G.; Hornberger, C. S. Jr.
Science 1951, 114, 93–94.
2. Walton, E.; Wagner, A. F.; Peterson, L. H.; Holly, F. W.; Folker, K.
J. Am. Chem. Soc. 1954, 76, 4748-7367.
3. Brookes, M. H.; Golding, B. T.; Howes, D. A.; Hudson, A. T. J.
Chem. Soc., Chem. Commun. 1983, 1051–1053.
4. Baur, A.; Harrer, T.; Peakert, M.; Jahn, G.; Kalden, J. R.;
Fleckenstein, B.; Klin. Wochenschr. 1991, 69, 722-724; Chem.
Abstr. 1992, 116, 207360.
5. Wang. Y.; El-Boubbou, K.; Kouyoumdjian, H.; Sun, B.; Huang, X.;
Langmuir 2010, 26, 4119-4125.
6. Bast, L. J.; Haenen, G. R. M. M. Biochem. Biophys. Acta 1988, 963,
558-561.
25
Rf (EA: PE/1:4): 0.6; Yield: 94 mg (81%); yellow oil; [α]
:
D
25
7. Bingfham, P. M.; Zarchar, Z. PCT. Int. Appl. WO 0024, 734, 2000;
Chem. Abstr. 2000, 132, 3081921.
8. Yadav, J. S.; Mysorekar, S. V.; Garyali, K. J. Sci. Ind. Res. 1990,
49, 400-409 and references cited therein.
+63 (c = 0.22, CHCl3) {Lit.21 [α] = +64 (c 0.23, CHCl3)}; IR
D
1
(CHCl3) νmax: 2960, 1735, 757 cm-1; H NMR (400 MHz, CDCl3):
δ 1.38 - 1.57 (m, 2 H), 1.58 - 1.78 (m, 4 H), 1.85 - 1.98 (m, 1 H),
2.33 (t, J = 7.3 Hz, 2 H), 2.42 - 2.53 (m, 1 H), 3.06 - 3.25 (m, 2 H),
3.53 - 3.62 (m, 1 H), 3.68 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ
24.64 (CH2), 28.73 (CH2), 33.82 (CH2), 34.57 (CH2), 38.46 (CH2),
40.19 (CH2), 51.51 (OCH3), 56.30 (CH), 173.92 (CO).
9. Zhang, S.; Chen, X.; Zhang, J.; Wang, W.; Duan, W.; Synthesis
2008, 383-386.
10 . Marshell, A. W.; Graul, R. S.; Morgan, M. Y.; Sherlock, S. Gut
1982, 23, 1088-1093.
11. Plotzker, R.; Jensen, D.; Payne, J. A. Am. J. Med. Sci. 1979, 283,
79-82.
12 . Muller, L.; Menzel, H. Biochim. Biophys. Acta 1990, 1052, 386-
391.
4.13. (R)-5-(1,2-Dithiolan-3-yl)pentanoic acid or (R)-α-Lipoic
acid (1a)2
13. Alterkrich, H.; Stoltenburg-Didinger, G.; Wagner, H. M.;
Herrmann, J.; Walter, G. Neurotoxicol. Teratol. 1990, 12, 619-622.
14. (a) Elliott, J. D.; Steele, J.; Johnson, W. S. Tetrahedron Lett. 1985,
26, 2535-2538; (b) Rama Rao, A. V.; Garyali, K.; Gurjar, M. K.;
Ravindranathan, T. Carbohydr. Res. 1986, 148, 51-55; (c) Rama
Rao, A. V.; Mysorekar, S. V.; Gurjar, M. K.; Yadav, J. S.
Tetrahedron Lett. 1987, 28, 2183-2186; (d) Menon, R. B.; Kumar,
M. A.; Ravindranathan, T. Tetrahedron Lett. 1987, 28, 5313-5314;
(e) Brookes, M. H.; Golding, B. T.; Hudson, A. T. J. Chem. Soc.
Perkin Trans.1 1988, 9-12; (f) Wei, Z.; Lan, H.-Q.; Zheng, J.-F.;
Huang, P.-Q. Synth. Commun. 2009, 39, 691-701; (g) Gopalan, A.
S.; Jacobs, H. K. Tetrahedron Lett. 1989, 30, 5705-5708; (h)
Gopalan, A. S.; Jacobs, H. K. J. Chem. Soc., Perkin Trans. 1 1990,
1897-1900; (i) Dasaradhi, L.; Fadnavis, N. W.; Bhalerao, U. T. J.
Chem. Soc., Chem. Commun. 1990, 729-730; (j) Bezbarua, M.;
Saikia, A. K.; Barua, N. C.; Kalita, D. Synthesis 1996, 1289-1290;
(k) Adger, B.; Bes, M. T.; Grogan, G.; McCague, R.; Pedragosa-
Moreau, S.; Roberts, S. M.; Villa, R.; Wan, P. W. H.; Willetts, A. J.
J. Chem. Soc., Chem. Commun. 1995, 1563-1564; (l) Bes, M. T.;
Villa, R.; Roberts, S. M.; Wan, P. W. H.; Willetts, A. J. Mol. Catal.
B: Enzym. 1996, 1, 127-134; (m) Santosh Laxmi, Y. R.; Iyenger, D.
S. Synthesis 1996, 594-596; (n) Adger, B.; Bes, M. T.; Grogan, G.;
McCague, R.; Pedragosa-Moreau, S.; Roberts, S. M.; Villa, R.;
Wan, P. W. H.; Willetts, A. J. Bioorg. Med. Chem. 1997, 5, 253-
261; (o) Fadnavis, N. W.; Babu, R. L.; VadiVel, S. K.; Deshpande,
A. A.; Bhalerao, U. T. Tetrahedron: Asymmetry 1998, 9, 4109-
4112; (p) Schwarz-Linek, U.; Krödel, A.; Ludwig, F.-A.; Schuleze,
A.; Rissom, S.; Kragl, U.; Tishkov, V. I.; Vogel, M. Synthesis 2001,
947-951; (q) Bulman Page, P. C.; Rayner, C. M.; Sutherland, I. O.
J. Chem. Soc., Chem. Commun. 1986, 1408-1409; (r) Bulman Page,
P. C.; Rayner, C. M.; Sutherland, I. O. J. Chem. Soc. Perkin Trans.
1, 1990, 1615-1618; (s) Zimmer, R.; Hain, U.; Berndt, M.; Gewald,
R.; Reissig, H.-U. Tetrahedron: Asymmetry 2000, 11, 879-887; (t)
Upadhya, T. T.; Nikalje, M. D.; Sudalai, A. Tetrahedron Lett. 2001,
42, 4891-4893; (u) Zimmer, R.; Peritz, A.; Czerwonka, R.;
Schefzig, L.; Reissig, H.-U. Eur. J. Org. Chem. 2002, 3419-3428;
(v) Chavan, S. P.; Praveen, C.; Ramakrishna, G.; Kalkote, U. R.
Tetrahedron Lett. 2004, 45, 6027-6028; (w) Bose, D. S.; Fatima,
L.; Rajender, S. Synthesis 2006, 1863-1867; (x) Panchagalle, S. P.;
Jogdand, G. F.; Chavan S. P.; Kalkote, U. R. Tetrahedron Lett.
2010, 51, 3587–3589; (y) Chavan, S. P.; Shivsankar, K.; Pasupathy,
To a solution of 2b (80 mg, 0.341 mmol) in MeOH (5 mL) was
added aqueous KOH (0.1 M, 4 mL) and stirred at room
temperature for 24 h. MeOH was evaporated under reduced
pressure and the reaction mixture was washed with Et2O (2 x 10
mL) and the aqueous layer was acidified carefully with 6N HCl to
pH 2. The product was extracted with Et2O (2 x 10 mL) and the
combined organic phases were dried over anhydrous Na2SO4,
filtered and concentrated on a rotary evaporator under reduced
pressure to afford crude lipoic acid. The resulting residue was
purified by flash column chromatography (silica gel) using ethyl
acetate/petroleum ether (15:85) as an eluent, to afford 1a as yellow
solid.
Rf (EA: PE/1:2): 0.3; Yield: 54 mg (77%); yellow solid; mp 48
25
D
25
D
°C; 1a: [α] : +103.18 (c 0.9, Benzene); 1b: [α] : - 102 (c = 0.9,
25
benzene); {Lit.2 [α] = +106 (c 1, Benzene)}; IR (CHCl3): νmax
D
1
3021, 2928, 1709, 1409, 1216, 758 cm-1; H NMR (400 MHz,
CDCl3) δ 1.39 - 1.59 (m, 2 H), 1.62 - 1.79 (m, 4 H), 1.86 - 1.99
(m, 1 H), 2.38 (t, J = 7.4 Hz, 2 H), 2.43 - 2.53 (m, 1 H), 3.06 - 3.27
(m, 2 H), 3.51 - 3.67 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ
24.34 (CH2), 28.64 (CH2), 33.74 (CH2), 34.55 (CH2), 38.47 (CH2),
40.19 (CH2), 56.25 (CH), 179.50 (CO); ESIMS (m/z): 204.95 (m-
1)+.
5. Supplymentary information
Supplementary data (supplementary material includes
1
Experimental details H, 13C NMR spectra and HRMS for new
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/xxxx.

7
ACCEPTED MANUSCRIPT
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Pasupathy, K. Synlett 2005, 1129-1132; aa) Purude, A. N.; Pawar,
K. P., Patil, N. B.; Kalkote, U. R.; Chavan, S. P. Tetrahedron
Asymmetry 2015, 26, 281-287; ab) Kaku, H.; Okamoto, N.; Nishii,
T.; Horikawa, M.; Tsunoda, T. Synthesis 2010, 2931.
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16. Fengler-Veith, M.; Schwardt, O.; Kautz, U.; Krämer, B.; Jäger, V.
Org. Synth. 2002, 78, 123-128.
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Young, W. B.; Gangloff, A. R.; Kuo, E. Y.-L.; Cregar, L. Putnam
D.; Wong, M. Bioorg. Med. Chem. Lett. 2001, 11, 1629–1633; (b)
Shu, Z. C.; Zhu, J. B.; Liao, S.; Sun, X. L.; Tang, Y, Tetrahedron
2013, 69, 284-292; (c) Mathieson, J. E.; Crawford, J. J.;
Schmidtmann M.; Marquez. R. Org. Biomol. Chem. 2009, 7, 2170–
2175.
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54, 4851–4853.
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Synthesis 2010, 4307–4311.
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2008, 383–386.
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Khimiya 1990, 16, 1670-1674.

ACCEPTED MANUSCRIPT
Chirality induction and chiron approaches to enantioselective
total synthesis of α-lipoic acid
Subhash P. Chavan,* Kailash P. Pawar, Ch. Praveen and Niteen B. Patil
a Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune -411008, India.
Email: sp.chavan@ncl.res.in
Contents:
SI-2
General information
SI-3-7
SI-8-36
Experimental section
Copies of 1H and 13C NMR
1

ACCEPTED MANUSCRIPT
General information:
All reagents and solvents were used as received from the manufacturers. Melting
points are recorded using Buchi B-540 melting point apparatus in capillary tubes and
are uncorrected and the temperatures are in centigrade scale. IR spectra were recorded
on a Perkin-Elmer Infrared Spectrophotometer Model 68B or on a Perkin-Elmer 1615
1
13
FT Infrared spectrophotometer. H (200 and 400 MHz) and C (50 and 100 MHz)
NMR spectra were recorded on Bruker and Bruker Advance 400 spectrometers, using
a 2:1 mixture of CDCl3 and CCl4 as solvent. The chemical shifts (δ ppm) and
coupling constants (Hz) are reported in the standard fashion with reference to
1
13
chloroform, δ 7.26 (for H) or the central line (77.0 ppm) of CDCl3 (for C). In the
13C NMR spectra, the natures of the carbons (C, CH, CH2, or CH3) were determined
by recording the DEPT-135 spectra. The following abbreviations were used to explain
the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. The
reaction progress was monitored by the TLC analysis using thin layer plates precoated
with silica gel 60 F254 (Merck) and visualized by fluorescence quenching or iodine or
by charring after treatment with p-anisaldehyde and also 2,4-DNP. Merck’s flash
silica gel (230-400 mesh) was used for column chromatography.
2

ACCEPTED MANUSCRIPT
Experimental section:
3

ACCEPTED MANUSCRIPT
i) (±)-3-Butene-1, 2-diol (8)
OH
HO
Procedure: A mixture of 2-butene-1, 4-diol 7 (80 g, 90.9 mmol), water (35 mL),
catalytic amount of concentrated sulphuric acid (0.5 mL) and mercuric sulphate (0.36
o
g) was heated under reflux. After 1.5 h the reaction mixture was cooled to 0 C and
neutralized with 10 % sodium hydroxide to pH 7. The contents of the flask were
distilled by using a 12’ vigreaux fractionating column. The first fraction boiled
o
between 38-43 C/15 mm contained water, second fraction collected between 78-90
oC/15 mm contained 3-butene-1, 2-diol 8 (49 g, 61 %) as a colourless syrup and
subsequently, third fraction obtained had traces of unreacted starting material at 110-
115 oC/15mm.
o
1
Yield: 61 %; B.P: 85 C /15 mm; IR (CHCl3, cm-1): 3456, 1621; H NMR (CDCl3 +
CCl4, 200MHz): δ 3.45 (dd, J = 10.56, 7.71 Hz, 1H), 3.63 (dd, J = 11.49, 3.28 Hz,
1H), 3.94 (s, 2H, OH), 4.22 (m, 1H), 5.18 (dt, J = 10.56, 1.52 Hz, 1H), 5.32 (dt, J =
17.31, 1.52 Hz, 1H), 5.81 (ddd, J = 17.31, 10.56, 5.56 Hz, 1H); 13C NMR
(CDCl3+CCl4, 50MHz): δ 66.0, 73.2, 116.3, 136.6; Elemental analysis: Analysis
calcd. for C4H8O2: C, 54.52; H, 9.15. Found: C, 54.14; H, 9.46.
OH
BnO
ii) (±)-1-Benzyloxy-3-butene-2-diol (9)
To a solution of 8 (6 g, 68.18 mmol) in anhydrous THF (100 mL) was added sodium
hydride (3.27 g, 68.18 mmol, 50 % dispersion in oil) under nitrogen atmosphere. The
o
reaction mixture was cooled to –20 C and then benzyl bromide (11.68 g, 68.18 mol)
4

ACCEPTED MANUSCRIPT
in anhydrous THF (50 mL) was added dropwise for 30 min at the same temperature.
After stirring at room temperature for 5 h, the reaction mixture was concentrated,
diluted with CH2Cl2, washed with water, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue thus obtained was purified by silica
gel column chromatography with EtOAc-light petroleum (1:2) as an eluent to afford 9
(8.4 g, 69 %) as colourless syrup.
(or)
To a solution of 8 (5 g, 56.8 mmol) in anhydrous benzene (100 mL) were added KOH
(3.5 g, 62.5 mmol) and benzyl chloride (6.5 mL, 56.8 mmol) and the reaction mixture
was heated under reflux for 6 h. After completion of the reaction, the reaction mixture
was diluted with water, extracted with EtOAc (2 x 60 mL) and the combined organic
fractions were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was chromatographed on silicagel
using EtOAc-light petroleum (1: 2) as an eluent to afford 9 (6.47 g, 64 %) as
colourless syrup.
1
Yield: 69 %; IR (CHCl3, cm-1): 3450, 2400, 1731, 757; H NMR (CDCl3 + CCl4,
200MHz): δ 2.55 (broad, 1H, OH), 3.37 (dd, J = 9.86, 7.71 Hz, 1H), 3.55 (dd, J =
9.86, 3.42 Hz, 1H), 4.35 (m, 1H), 4.58 (s, 2H), 5.20 (dt, J = 10.26, 1.47 Hz, 1H), 5.37
13
(dt, J = 17.09, 1.47 Hz, 1H), 5.84 (ddd, J = 17.09, 10.26, 5.86 Hz, 1H); C NMR
(CDCl3+CCl4, 50MHz): δ 71.0, 72.9, 73.9, 115.6, 127.4, 128.1, 136.8, 137.6;
Elemental analysis: Analysis calcd. for C11H14O2: C, 74.12; H, 7.92. Found: C, 74.36;
H, 7.73.
iii) (4E)-Ethyl-6-Benzyloxy hexanoate (10)
O
BnO
OC2H5
5

ACCEPTED MANUSCRIPT
Procedure: A mixture of compound 9 (3.5 g, 19.66 mmol), Propionic acid (cat) and
triethyl orthoacetate (6.37 g, 39.32 mmol) was heated at 140 oC for 2 h with distillate
removal of ethanol. After completion of the reaction the reaction mixture was
quenched with water and extracted with CH2Cl2 (2 x 50 mL) and the combined
organic fractions were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was chromatographed on silica gel
using EtOAc-light petroleum (1:10) as an eluent to afford 10 (4.57 g, 94 %) as
colourless syrup.
1
Yield: 94 %; IR (CHCl3, cm-1): 2995, 1740, 1180, 965; H NMR (CDCl3 + CCl4,
500MHz): 1.25 (t, J = 7.18, 3H), 2.40 (s, 4H), 3.97 (d, J = 5.66, 2H), 4.13 (q, J = 7.18,
2H), 4.49 (s, 2H), 5.66-5.71 (m, 2H), 7.32-7.35 (m, 5H); 13C NMR (CDCl3+CCl4,
50MHz): δ 14.3, 27.6, 33.7, 60.1, 70.5, 71.8, 127.5, 127.3, 128.3, 131.9, 138.4,
+
172.5; MS (ESI, Solv.: MeOH + H2O + CH3COONH4 ): m/z = 266.04 (M+NH4 ).
Elemental Analysis:Analysis calcd. for C15H20O3: C, 72.54; H, 8.12. Found: C, 72.38;
H, 8.24.
iv) 6-(Benzyloxy)-2,3-dideoxy-L-threo-hexano-1,4-lactone (6)
O
O
HO
BnO
To a mixture of K3Fe(CN)6 (11.94 g, 36.29 mmol), K2CO3 (5.01 g, 36.29 mmol) and
o
(DHQ)2PHAL (0.094 g, 0.12 mmol) in t-BuOH-H2O (1:1, 120 mL) cooled at 0 C
was added osmium tetroxide (0.81 mL, 0.1 M solution in toluene, 0.4 mol %)
followed by methane sulfonamide (1.15 g, 12.09 mmol). After stirring for 5 min at 0
oC, the olefin 10 (3 g, 12.09 mmol) was added in one portion. The reaction mixture
o
was stirred at 0 C for 24 h and then quenched with solid sodium sulfite (6 g). The
stirring was continued for an additional 45 min and then the solution was extracted
with EtOAc (3 x 30 mL). The combined organic fractions were washed with brine,
6

ACCEPTED MANUSCRIPT
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
residue was chromatographed on silica gel using EtOAc-light petroleum (1:2) as an
eluent to afford 6 (2.68 g, 94 %) as a white solid.
(or)
To a solution of AD-mix α (16.93 g) in t-BuOH-H2O (1:1, 120 mL) at 0 oC was added
methane sulfonamide (1.15 g, 12.09 mmol) and stirred at the same temperature. After
stirring for 5 min, the olefin 10 (3 g, 12.09 mmol) was added in one portion. The
o
reaction mixture was stirred at 0 C for 24 h and then quenched with solid sodium
sulfite (6 g). The stirring was continued for an additional 45 min and then the solution
was extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The residue was chromatographed on silica gel using EtOAc-light petroleum
(1:2) as an eluent to afford 6 (2.68 g, 94 %) as a white solid.
o
Yield: 94 %; M. P.: 115-116 C (White solid); + 40.59 (c = 1, CHCl3); IR (CHCl3,
1
cm-1): 3434, 1778, 1720, 1216, 758; H NMR (CDCl3 + CCl4, 200MHz): δ 2.25 (m,
2H), 2.48 (m, 2H), 2.69 (m, 1H), 3.59 (m, 2H), 3.84 (m, 1H), 4.57 (m, 3H), 7.33-7.43
(m, 5H); 13C NMR (CDCl3+CCl4, 125MHz): δ 23.4, 28.1, 70.6, 71.6, 73.1, 79.9,
127.5, 128.1, 137.5, 177.7; MS (ESI, Solv.: MeOH + H2O + CH3COONH4 ): m/z =
+
254.05 (M+NH4 ); Elemental Analysis: Analysis calcd. for C13H16O4: C, 66.13; H,
6.83. Found: C, 66.36; H, 6.92.
7

ACCEPTED MANUSCRIPT
Chirality induction 1H, 13C NMR Copies
8

ACCEPTED MANUSCRIPT
Chlorof orm-d
OH
HO
0.95
2.00
1.08 2.29 1.06
4.0 3.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
3.0
2.5
2.0
1.5
1H NMR Spectrum of compound 8 in CDCl3
Chlorof orm-d
OH
HO
170 160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
13C NMR Spectrum of compound 8 in CDCl3
9

ACCEPTED MANUSCRIPT
OH
HO
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
1H NMR Spectrum of compound 8 in CDCl3
Chlorof orm-d
OH
BnO
5.45
7.5
0.89
6.0
2.00
1.94 0.93
4.5
0.97
3.5
1.05
2.5
7.0
6.5
5.5
5.0
4.0
3.0
2.0
1H NMR Spectrum of compound 9 in CDCl3 + CCl4
10

ACCEPTED MANUSCRIPT
Chloroform-d
OH
BnO
150
140
130
120
110
100
90
80
70
60
50
13C NMR Spectrum of compound 9 in CDCl3 + CCl4
OH
BnO
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
DEPT NMR Spectrum of compound 9 in CDCl3 + CCl4
11

ACCEPTED MANUSCRIPT
O
BnO
OR
5.39
1.92
2.00 2.33
4.02
3.38
8
7
6
5
4
3
2
1
0
1H NMR Spectrum of compound 10 in CDCl3 + CCl4
Chlorof orm-d
O
BnO
OR
150
100
50
0
13C NMR Spectrum of compound 10 in CDCl3 + CCl4
12

ACCEPTED MANUSCRIPT
O
BnO
OR
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
DEPT NMR Spectrum of compound 10 in CDCl3 + CCl4
Chloroform
1.0
O
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
O
HO
BnO
5.00
2.96
2.05
3.09 2.10
10
9
8
7
6
5
4
3
2
1
0
1H NMR Spectrum of compound 6 in CDCl3
13

ACCEPTED MANUSCRIPT
Chloroform-d
O
O
HO
BnO
150
100
50
0
13C NMR Spectrum of compound 6 in CDCl3
O
O
HO
BnO
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
DEPT NMR Spectrum of compound 6 in CDCl3
14

ACCEPTED MANUSCRIPT
HPLC of Compound 6
0.020
0.015
0.010
0.005
0.000
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
26.00
28.00
30.00
Minutes
Name
Retention Time
Area
% Area
Height
Int Type
Amount
Units
Peak Type
Code
s
1
2
10.153
11.424
38328
1009240
3.26
96.74
1981 bB
22129 Bb
Unknown
Unknown
Column
CC054
: Chiracel OD (4.6mm ID x 25cm L), 10um Column no.-OD00CE-
Mobile Phase : Pet.Ether : Isopropanol (80:20)
Flow : 0.5 ml/min
Spectrochem
Wavelength : 254nm
HPLC of Compound 6
0.025
0.020
0.015
0.010
0.005
0.000
0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
45.00
50.00
Minutes
Name
Retention Time
Area
% Area
Height
Int Type
Amount
Units
Peak Type
Cod
es
1
2
17.647
20.490
1005420
35314
96.61
3.39
26968 bb
986 bb
Unknown
Unknown
Column
CC054
: Chiracel OD (4.6mm ID x 25cm L), 10um Column no.-OD00CE-
Mobile Phase : Pet.Ether : Isopropanol (80:20)
Flow : 1.0 ml/min
Wavelength : 254nm
Spectrochem
15

ACCEPTED MANUSCRIPT
Chloroform
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
O
O
I
BnO
5.00
7.5
2.97 1.07
4.5
2.03
4.0
3.15
2.5
0.79
2.0
8.0
7.0
6.5
6.0
5.5
5.0
3.5
3.0
1.5
1.0
0.5
1H NMR Spectrum of compound 5 in CDCl3 + CCl4
Chloroform-d
O
O
I
BnO
150
100
50
0
13C NMR Spectrum of compound 5 in CDCl3 + CCl4
16

ACCEPTED MANUSCRIPT
O
O
I
BnO
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
DEPT NMR Spectrum of compound 5 in CDCl3 + CCl4
1.0
I
0.9
COOC2H5
0.8
OH OH
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
5.00 0.76
7
0.79
1.81 1.63
0.90 1.39 1.47
3
3.03 4.47
10
9
8
6
5
4
2
1
0
1HNMR Spectrum of compound 4 in CDCl3 + CCl4
17

ACCEPTED MANUSCRIPT
I
COOC2H5
OH OH
13C NMR Spectrum of compound 4 in CDCl3 + CCl4
I
COOC2H5
OH OH
DEPT NMR Spectrum of compound 4 in CDCl3 + CCl4
18

ACCEPTED MANUSCRIPT
TMS
COOC2H5
OH OH
4.20
7.0
2.01 2.00 3.25 2.02
4.5 4.0 3.5
2.00
5.01
1.5
3.08
9.88
1.0
8.0
7.5
6.5
6.0
5.5
5.0
3.0
2.5
2.0
0.5
0.0
1H NMR Spectrum of compound 3a in CDCl3 + CCl4
COOC2H5
OH OH
13C NMR Spectrum of compound 3a in CDCl3 + CCl4
19

ACCEPTED MANUSCRIPT
COOC2H5
OH OH
DEPT NMR Spectrum of compound 3a in CDCl3 + CCl4
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
COOC2H5
OMs OMs
1.00
5.0
1.39 1.77
4.5 4.0
6.35
3.0
2.37
4.29 4.53
1.5
7.5
7.0
6.5
6.0
5.5
3.5
2.5
2.0
1.0
0.5
1H NMR Spectrum of compound 11 in CDCl3 + CCl4
20

ACCEPTED MANUSCRIPT
Chlorof orm-d
COOC2H5
OMs OMs
150
100
50
0
13C NMR Spectrum of compound 11 in CDCl3 + CCl4
COOC2H5
OMs OMs
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
DEPT NMR Spectrum of compound 11 in CDCl3 + CCl4
21