New and concise approach to (R)-α-lipoic acid

Article abstract of DOI:10.1080/00397910802431073

A concise enantiospecific synthesis of (S)-6,8-bis(methylsulfonyloxy)- octanoic acid (2), a ready precursor of (R)-(+)-α-lipoic acid (1), is reported. The key step of the synthesis is the coupling of the tosylate derived from (R)-malic acid with phenylpro

Full text of DOI:10.1080/00397910802431073

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New and Concise Approach to
(R)-α-Lipoic Acid
Zhen Wei a , Hong-Qiao Lan a , Jian-Feng Zheng a &
Pei-Qiang Huang a
a Department of Chemistry and Key Laboratory
for Chemical Biology of Fujian Province , College
of Chemistry and Chemical Engineering, Xiamen
University , Xiamen, Fujian, China
Published online: 27 Jan 2009.
To cite this article: Zhen Wei , Hong-Qiao Lan , Jian-Feng Zheng & Pei-Qiang Huang
(2009) New and Concise Approach to (R)-α-Lipoic Acid, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:4,
691-701, DOI: 10.1080/00397910802431073
To link to this article: http://dx.doi.org/10.1080/00397910802431073
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Synthetic Communications1, 39: 691–701, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802431073
New and Concise Approach to (R)-a-Lipoic Acid
Zhen Wei, Hong-Qiao Lan, Jian-Feng Zheng, and Pei-Qiang Huang
Department of Chemistry and Key Laboratory for Chemical
Biology of Fujian Province, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian, China
Abstract: A concise enantiospecific synthesis of (S)-6,8-bis(methylsulfonyloxy)-
octanoic acid (2), a ready precursor of (R)-(þ)-a-lipoic acid (1), is reported.
The key step of the synthesis is the coupling of the tosylate derived from (R)-malic
acid with phenylpropyl magnesium bromide. A recently reported green procedure
was used for the oxidative unmasking of the phenyl group, used as a latent
carboxyl group.
Keywords: Asymmetric synthesis, lipoic acid, malic acid
(R)-(þ)-a-Lipoic acid (1) (thioctic acid; 6,8-dithiooctanoic acid) is an
important protein-bound coenzyme and growth factor first isolated in
1951 from processed insoluble liver residue.[1] Since then, lipoic acid
has been found to be widely distributed in animal and plant tissue,[2]
and displays an extremely high level of biological activity. Being a readily
bioavailable compound capable of scavenging a number of free radicals
and protecting cells from oxidative damage[3a] as well as from ionizing
radiation–induced damage,[3b] a-lipoic acid is termed the ideal antioxi-
dant.[4] Lipoic acid was also shown to possess protective and curative
effects in heavy-metal-poisoned animals.[5] It was also found to be a potent
growth-promoting factor, which stimulated reparative regeneration of soft
tissues.[6] Recently, it has also been reported that a-lipoic acid and its
derivatives are highly active as anti-HIV[7] and antitumor agents.[8] The
Received March 20, 2008.
Address correspondence to Jian-Feng Zheng or Pei-Qiang Huang College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian
361005, China. E-mail: zjf485@xmu.edu.cn or pqhuang@xmu.edu.cn
691

692
Z. Wei et al.
racemic a-lipoic acid can be used to treat various liver diseases including
metal poisoning[9] and alcoholic liver diseases.[10] Moreover, (R)-(þ)-a-
lipoic acid is effective to a great extent in the treatment of various diseases
such as mushroom poisoning,[11] diabetes, and neurodegenerative
disorders.[12]
It has been shown that the (R)-enantiomer is much more effective
than the (S)-enantiomer at enhancing insulin-stimulated glucose trans-
port and nonoxidative and oxidative glucose metabolism.[13]
The biological properties of (R)-(þ)-a-lipoic acid have created
significant interest in its synthesis.[14] In continuation of our effort in
developing malic acid–based synthetic methodologies,[15] we now report
a
new and concise synthesis of (S)-6,8-bis(methylsulfonyloxy)
octanoic acid (2), a ready precursor to (R)-(þ)-a-lipoic acid (1),[14j,14p]
starting from (R)-malic acid.
Although (R)-malic acid has been used as a chiron for the first
enantioselective synthesis of a-lipoic acid (S-1, and R-1),[14a,14b] the
reported approach to (S)-1 required a total of 15 synthetic steps starting
from (S)-malic acid. As depicted retrosynthetically in Scheme 1, our
approach is much shorter; only seven steps are required for the synthesis
of (S)-6,8-bis(methylsulfonyloxy)octanoic acid (2) and one more step for
(R)-lipoic acid. Our approach features the use of tosylate 4 as the key
intermediate and phenyl group as a latent carboxyl group.[16]
The synthesis started from the known (R)-1,2,4-butanetriol (6),[17–19]
easily available from (R)-malic acid either by lithium aluminum hydride
(LAH) reduction of malate, or by Hanessian’s one-pot method
[BH3.SMe2, B(OMe)3, THF, rt].[18] In the presence of trifluoroacetic acid
(TFA), treatment of triol 6 with benzaldehyde at refluxing dichloro-
methane afforded regio- and diastereoselectively a mixture of two
inseparable isomeric acetals in 73% yield, which contained 95% of
cis-1,3-dioxane 7 and 5% of 8[19] (Scheme 2). The two regioisomers,
although inseparable by column chromatography, can be easily separated
Scheme 1. Retrosynthetic analysis of (R)-(þ)-a-lipoic acid (1).

New and Concise Approach to (R)-a-Lipoic Acid
693
Scheme 2. Asymmetric synthesis of (R)-(þ)-a-lipoic acid (1).
by recrystallization of their tosylate derivatives 4[18c] and 9. In the
presence of a catalytic amount of CuI, the coupling of tosylate 4 with
phenylpropyl magnesium bromide proceeded smoothly, which afforded
the chain elongation product 10 in 88% yield.
For the cleavage of the acetal, compound 10 was treated with a
solution of 4:1 v/v mixture of AcOH=H2O, which gave the desired diol
11 in 67% yield. The yield was improved to 80% by using Szarek’s
method,[20] namely, by refluxing a methanolic solution of dioxane 10 in
the presence of a catalytic amount of iodine. Bismesylation of 11 under
standard conditions gave bismesylate 3 in 98% yield.
Next, we proceeded to investigate the oxidative cleavage of the
phenyl group into a carboxyl group using ruthenium tetraoxide as an
oxidant. Although subjection of 3 to the standard conditions established
by Sharpless[21] (2.2% RuCl3, 4.1 mol. equiv. NaIO4 in CCl4–MeCN–
H2O, 2=2=3, v/v) led to the desired product 2 in 68% yield, a recent report
about the replacement of environmentally harmful CCl4 by EtOAc[22]
attracted our attention. To our delight, the greener solvent system
(EtOAc–MeCN–H2O, 2=2=3, v=v)[22] worked similarly well (room
temperature, 5 days), affording bismesylate acid 2 in 67% yield. Because
bismesylate 2 has been converted previously into (R)-a-lipoic acid,[14j,14p]
our synthesis of 2 constitutes a formal enantioselective synthesis of (R)-a-
lipoic acid.

694
Z. Wei et al.
In summary, starting from (R)-malic acid, a concise enantioselective
synthesis of (S)-6,8-bis(methylsulfonyloxy)octanoic acid (2) was achieved
in seven steps with an overall yield of 26%. In combination with the
works of Page[14j] and Sudalai,[14p] our approach to (R)-(þ)-a-lipoic acid
(1) required only eight steps.
EXPERIMENTAL
General
Infrared spectra were measured with a Nicolet Avatar 360 FT-IR spec-
trometer using film KBr pellet techniques. 1H NMR and 13C NMR spectra
were recorded in CDCl3 on a Bruker Av400 spectrometer with tertra-
methylsilane (TMS) as an internal standard. Chemical shifts are
expressed in d (ppm) units downfield from TMS. Mass spectra were
recorded by Applied Biosystem 32000 Trap (ESI direct injection). Optical
rotations were measured with Rutoph-Autopol IV automatic polari-
meter. High resolution mass spectroscopy (HRMS) spectra were
recorded on a QSTAR Pulsar=LC=MS=MS System, ESI-QTOF instru-
ment (Applied Biosystem, Canada). Melting points were determined
on a Yanaco MP-500 melting-point apparatus and were corrected.
Tetrahydrofuran (THF) used in the reactions was dried by distillation
over metallic sodium and benzophenone; dichloromethane was distilled
over P2O5. Silica gel (Zhifu, 300–400 mesh) was used for column chroma-
tography, eluting (unless otherwise stated) with ethyl acetate=petroleum
ether (60–90 ꢀC) mixtures.
(2R,4R)-4-Hydroxymethyl-2-phenyl-l,3-dioxane (7)
Trifluoroacetic acid (0.2 mL) and benzaldehyde (5.5 mL, 53.9 mmol) were
added successively to a stirred CH2Cl2 solution (190 mL) of the known
triol 6 (4.08 g, 38.0 mmol), easily available from (R)-malic acid.[17–19]
After refluxing for 33 h, the reaction was quenched by addition of a satu-
rated aqueous solution of NaHCO3 at 0 ꢀC. The mixture was extracted
with CH2Cl2 (4 ꢁ 15 mL). The organic layers were washed with brine
(5 mL), dried over Na2SO4, filtered, and concentrated. Flash chromato-
graphic purification of the residue (ethyl acetate–petroleum ether, 1:3)
gave a colorless oil (5.45 g, 73%). According to the 1H NMR integration,
the resultant oil contained 95% of the regioisomer 7 and 5% of the
regioisomeric dioxolane, with the former being diastereomeric pure and
the latter being a ca. 1:1 mixture of the trans- and cis-diastereoisomers.
The two regioisomeric dioxolanes cannot be separated by flash

New and Concise Approach to (R)-a-Lipoic Acid
695
chromatography. IR (film) nmax: 3418 (br), 3065, 3035, 2923, 2859, 1635,
1
1454, 1363, 1103 cmꢀ1. The data for 7[19b]: H NMR (400 MHz, CDCl3)
d: 1.40–1.44 (m, 1H, H-5), 1.84–1.94 (m, 1H, H-5), 2.35 (br s, 1H, –OH),
3.60–3.67 (m, 2H, H-4, H-6), 3.93–3.99 (m, 2H, CH2OH), 4.26–4.30 (m,
1H, H-6), 5.53 (s, 1H, H-2), 7.39–7.54 (m, 5H, Ph-H); 13C NMR
(100 MHz, CDCl3) d: 26.7, 65.5, 66.5. 77.5, 101.2, 126.1, 126.1, 128.2,
128.2, 128.9, 138.3; MS (ESI) m=z 217 (M þ Naþ, 100).
(2R,4R)-4-Tosyloxymethyl-2-phenyl-l,3-dioxane (4)
Pyridine (4 mL) and a CH2Cl2 solution (10 mL) of p-TsCl (2.82 g,
15.0 mmol) were added successively to a stirred solution of dioxolane 7
(2.35 g, 12.0 mmol) and a catalytic amount of 4-N,N-dimethylamino-
pyridine (DMAP) in anhydrous CH2Cl2 (6 mL) at 0 ꢁC. After stirring for
48h at room temperature, the reaction was quenched with 5 mL of water
and extracted with CH2Cl2 (4 ꢂ 15 mL). The organic layers were washed
successively with saturated aqueous CuSO4 and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Flash-chromatographic
purification of the residue (ethyl acetate–petroleum ether, 1:3) gave a white
solid (3.81 g, 91%). Recrystallization of the crude solid from pentane–
ether–CH2Cl2 (2=1=1) gave isomerically pure dioxolane 4[19e] (3.27 g,
86%) as white crystals. Mp 69–70ꢁC (pentane–ether–CH2Cl2, 2=1=1)
[lit.[19e] mp 65 ꢁC (ether–pentane, 1=2)]; [a]D þ 2.1 (c 1.4, CHCl3) [lit.[19e]
20
25
25
[a]D þ 3.0 (c 1.1, CHCl3), [a]D ꢀ 2.1 (c 0.89, CHCl3) for the (S,S)-enan-
tiomer]; IR (film) nmax: 3065, 3030, 2964, 2851, 1594, 1454, 1361, 1177,
1120 cmꢀ1 1H NMR (400 MHz, CDCl3) d: 1.52–1.54 (m, 1H, H-5),
;
1.76–1.83 (m, 1H, H-5), 2.42 (s, 3H, PhCH3), 3.91–3.98 (m, 1H, H-6),
4.04–4.10 (m, 1H, H-4), 4.11–4.15 (m, 2H, CH2OTs), 4.25–4.30 (m, 1H,
H-6), 5.45 (s, 1H, H-2), 7.26–7.78 (m, 9H, Ph-H); 13C NMR (100 MHz,
CDCl3) d: 21.6, 27.2, 66.3, 71.5, 74.1, 101.0, 126.0, 126.0, 127.9, 127.9,
128.2, 128.2, 128.9, 129.8, 129.8, 132.7, 137.9, 144.9. MS (ESI) m=z 371
(M þ Naþ, 100).
(2R,4S)-2-Phenyl-4-(4-phenylbutyl)-1,3-dioxane (10)
A solution of bis-tosylate 4 (576 mg, 1.70 mmol) in THF (3 mL) and CuI
(250 mg) were added successively to a cooled (ꢀ78 ꢁC) THF solution of
3-phenylpropyl magnesium bromide, freshly prepared from 1-bromo-3-
phenylpropane (1.2 mL, 8.27 mmol) and magnesium (298 mg, 12.0 mmol)
in anhydrous Et2O (6 mL) followed by diluting with anhydrous THF
(8 mL). After stirred for 48 h at room temperature, the reaction was
quenched with aqueous NH4Cl (11 mL) and extracted with CH2Cl2

696
Z. Wei et al.
(4 ꢁ 10 mL). The organic layers were washed with successively with
aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Flash-chromatographic purification of the residue
(ethyl acetate–petroleum ether, 1:20) gave 10 (430 mg, 88%) as a colorless
20
oil. [a]D ꢂ29 (c 1.1, CHCl3). IR (film) nmax: 3062, 3026, 2933, 2843,
1
1598, 1495, 1453, 1363, 1242, 1104 cmꢂ1; H NMR (400 MHz, CDCl3) d:
1.43–1.81 (m, 8H, H-5, (CH2)3CH2Ph), 2.62 (t, J ¼ 7.6 Hz, 2H, CH2Ph),
3.79–3.82 (m, 1H, H-4), 3.94 (td, J ¼ 12.2, 2.4 Hz, 1 H, H-4), 4.04–4.10
(m, 1H, H-3), 5.49 (s, 1H, H-2), 7.16–7.49 (m, 9H, Ph-H); 13C NMR
(100 MHz, CDCl3) d: 24.6, 31.4, 31.3, 35.8, 67.1, 77.1, 101.1, 125.6,
126.0, 126.0, 128.1, 128.1, 128.2, 128.2, 128.4, 128.4, 128.6, 138.9, 142.6;
HRMS calcd. for [C20H24O2 þ NH4]þ: 314.2115; found: 314.2117. Anal.
calcd. for C20H24O2: C, 81.04; H, 8.16. Found: C, 81.19; H, 8.57.
(S)-7-Phenylheptane-1,3-diol (11)
A methanolic (130 mL) solution of 10 (1.30 g, 4.39 mmol) and I2 [1.270 g,
1% (w=v)] was refluxed for 12 h. The resulting mixture was quenched by
addition of saturated aqueous Na2S2O3 until the iodine’s characteristic
brown color disappeared. After concentration under reduced pressure,
the residue was extracted with CH2Cl2 (4 ꢁ 10 mL), and the combined
organic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Flash-chromatographic purification
of the residue (ethyl acetate–petroleum ether, 1:1) gave 11 (0.729 g, 80%) as
20
a colorless oil, and 16% of the starting material was recovered. [a]D ꢂ 2.8
(c 1.2, CHCl3); IR (film) nmax: 3353 (br), 3077, 3054, 3025, 2933, 2857,
1602, 1489, 1059cmꢂ1 1H NMR (400 MHz, CDCl3) d: 1.35–1.74 (m,
;
8H, H-2, (CH2)3CH2Ph), 2.54 (br s, 2H, 2OH), 2.62 (t, J ¼ 7.7 Hz, 2H,
CH2Ph), 3.79–3.89 (m, 3H, H-1, H-3), 7.16–7.20 (m, 3H, Ph-H), 7.25–
7.29 (m, 2H, Ph-H); 13C NMR (100 MHz, CDCl3) d: 25.1, 31.4, 35.9,
37.6, 38.2, 61.8, 72.2, 125.7, 128.3, 128.3, 128.4, 128.4, 142.5; HRMS calcd.
for [C13H20O2 þ NH4]þ: 226.1802; found: 226.1804. Anal. calcd. for
C13H20O2: C, 74.96; H, 9.68; Found: C, 74.39; H, 9.92.
(S)-7-Phenylheptan-1,3-diol Dimesylate (3)
Methanesulfonyl chloride (0.8 mL, 10.2 mmol) was added to a CH2Cl2
solution (23 mL) of diol 11 (0.961 g, 4.62 mmol) and triethylamine
(4.5 mL, 32.3 mmol) at 0 ꢀC. After stirring for 5 h, the reaction was
quenched with 5 mL of saturated aqueous NaHCO3. The aqueous phase
was extracted with CH2Cl2 (4 ꢁ 10 mL). The combined organic layers

New and Concise Approach to (R)-a-Lipoic Acid
697
were washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Flash-chromatographic purification of the
residue (CH2Cl2–petroleum ether, 3:1) gave 3 as a colorless oil (1.65 g,
20
98%). [a]D þ 19 (c 1.4, CHCl3); IR (film) nmax: 3027, 2937, 2863, 1602,
1
1495, 1453, 1352, 1171 cmꢂ1; H NMR (400 MHz, CDCl3) d: 1.41–1.47
(m, 2H, H-4), 1.64–1.82 (m, 4H, H-5, H-6), 2.01–2.11 (m, 2H, H-2),
3.04 (t, J ¼ 7.6 Hz, 2H, CH2Ph), 2.99–3.04 (m, 6H, Ms-H), 4.32–4.35
(m, 2H, H-1), 4.85–4.88 (m, 1H, H-3), 7.16–7.20 (m, 3H, Ph-H), 7.26–
7.29 (m, 2H, Ph-H); 13C NMR (100 MHz, CDCl3) d: 24.3, 30.9, 34.0,
34.7, 35.5, 37.4, 38.6, 65.6, 78.8, 125.8, 128.3, 128.3, 128.4, 128.4, 141.9.
HRMS calcd. for [C15H24O6S2 þ NH4]þ: 382.1353; found: 382.1351.
Anal. calcd. for C15H24O6S2: C, 49.43; H, 6.64. Found: C, 49.78; H, 6.77.
(S)-6,8-Bis(methylsulfonyloxy)octanoic Acid (2)
NaIO4 (11.19 g, 52.3 mmol) in one portion and a 0.05 M aqueous solution
of RuCl3.xH2O (1.6 mL, 2.2%) were added successively to a solution of
compound 3 (1.27 g, 3.49 mmol) in a mixed solvent system containing
EtOAc–CH3CN–H2O [15 mL=15 mL=22 mL, 2=2=3 (v=v)] at 0 ꢀC. The
mixture was stirred at room temperature for 5 days. After addition of
brine, the resulting mixture was filtered, and the aqueous phase was
extracted with CH2Cl2 (4 ꢁ 15 mL). The combined organic layers were
washed successively with NaHSO3 and brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure at 40 ꢀC. After purification of
the residue by flash chromatography and eluting with ethyl acetate, the
known bismesylate 2[14j,14p] was obtained as a colorless oil (0.793 g,
68%), which solidified upon standing at 0 ꢀC. White crystals were
obtained after recrystallization from ether. Mp 56–57 ꢀC (ether) [lit.[14j]
mp 54–55 ꢀC (ether)]; [a]D þ 20 (c 1.0, CHCl3) [lit.[14p] [a]D þ 22 (c
20
25
1.0, CHCl3)]; IR (film) nmax: 3568 (br), 3029, 2941, 2872, 1712, 1349,
1172 cmꢂ1 1H NMR (400 MHz, CDCl3) d: 1.44–1.53 (m, 2H, H-5),
;
1.65–1.83 (m, 4H, H-3, H-4), 2.05–2.16 (m, 2H, H-7), 2.40 (t, J ¼ 7.2 Hz,
2H, H-2), 3.06–3.07 (m, 6H, Ms-H), 4.32–4.93 (m, 2H, H-6), 4.87–4.93
(m, 1H, H-6); 13C NMR (100 MHz, CDCl3) d: 24.1, 24.2, 33.5, 34.0,
34.6, 37.4, 38.7, 65.6, 78.4, 178.8; HRMS calcd. for [C8H14O2S2 þ NH4]þ:
: 350.0938; Found: 350.0939.
ACKNOWLEDGMENTS
The authors are grateful to the Natural Science Foundation of China
(20572088 and 20602028), the Natural Science Foundation of Fujian

698
Z. Wei et al.
Province of China (No. U0650024), Xiamen Science Foundation (No.
3502Z20055019), and the program for Innovative Research Team in
Science and Technology (University) in Fujian province for financial sup-
port. We thank Professor Y. F. Zhao for the use of her Bruker Dalton
Esquire 3000 Plus LC-MS apparatus.
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