Enantioselective total synthesis of (R)-α- Lipoic acid: An application of thermodynamically controlled deracemization of (±)-2-(2-Methoxyethyl)cyclohexanone

Article abstract of DOI:10.1055/s-0030-1258167

According to the concept of thermodynamically controlled deracemization, racemic 2-(2-methoxyethyl)cyclohexanone was converted into the R-isomer (99% ee) in 90% yield using (-)-(2R,3R)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4- dioxaspiro[5.4]decane as a host molecule under basic conditions. As an application, a short and enantioselective synthesis of (R) - lipoic acid was accomplished in 44% overall yield from (±)-2-(2-methoxyethyl) cyclohexanone.

Full text of DOI:10.1055/s-0030-1258167

PAPER
2931
Enantioselective Total Synthesis of (R)-a-Lipoic Acid: An Application of
Thermodynamically Controlled Deracemization of ( )-2-(2-Methoxyethyl)
cyclohexanone
Enantioselective
T
i
otal Sy
r
nthesis
o
o
f
(
R
)-
a
-Lipo
t
ic
A
cido Kaku,* Natsuko Okamoto, Takeshi Nishii, Mitsuyo Horikawa, Tetsuto Tsunoda*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
Fax +81(88)6553051; E-mail: kaku@ph.bunri-u.ac.jp; E-mail: tsunoda@ph.bunri-u.ac.jp
Received 18 March 2010; revised 6 May 2010
ro[5.4]decane (2a)13 (1.0–2.0 equiv) or (4R,5R)-a,a,a¢,a¢,2-
pentaphenyl-1,3-dioxolane-4,5-dimethanol (2b)13 as host
molecules with sodium hydroxide in aqueous methanol
converted racemic 2-allylcyclohexanone [( )-3] and 2-(2-
Abstract: According to the concept of thermodynamically con-
trolled deracemization, racemic 2-(2-methoxyethyl)cyclohexanone
was converted into the R-isomer (99% ee) in 90% yield using
(–)-(2R,3R)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspi-
ro[5.4]decane as a host molecule under basic conditions. As an ap- methoxyethyl)cyclohexanone [( )-4] into their R-isomers
plication, a short and enantioselective synthesis of (R)-a-lipoic acid
was accomplished in 44% overall yield from ( )-2-(2-methoxyeth-
yl)cyclohexanone.
with 74% ee and 94% ee, respectively, in quantitative
yields (Scheme 1).
Key words: (R)-a-lipoic acid, deracemization, molecular recogni-
tion, host–guest systems, asymmetric synthesis
O
OH
OH
O
Ph
Ph
Ph
R
R
R
2a or 2b
Ph
( )-
NaOH (4 equiv)
H2O–MeOH (1:1)
r.t., 2 d
O
O
(R)-a-Lipoic acid (1) (Figure 1), which was isolated as a
growth-promoting enzyme cofactor,1 plays an important
role as a protein-bound transacylating cofactor of several
multi-enzymatic a-keto acid dehydrogenase complexes.
Since its discovery, (R)-a-lipoic acid (1) has attracted
great attention because of its fascinating biological activ-
ity. For example, it shows effects in diabetes mellitus2 and
hepatic diseases.3 It has also been reported that 1 and its
derivatives are highly active as anti-HIV4 and antitumor
agents.5
R1
R2
(R)-3 98%, 74% ee
(R)-4 96%, 94% ee
( )-3 R = CH2CH=CH2
2a R1, R2 = -(CH2)5-
2b R1 = Ph, R2 = H
( )-4 R = CH2CH2OMe
Scheme 1 Thermodynamically controlled deracemization using
TADDOL-type host molecules
In the course of our detailed investigations on deracemiza-
tion, we found that the proportion of water in aqueous
methanol influenced the enantiomeric purity of the ketone
(R)-3.14 Based on this finding, we succeeded in obtaining
(R)-3 with 93% ee in 70% yield, when the recovery of 3
was sacrificed to some extent by filtration. We then syn-
thesized (–)-(R)-epilachnene, an antipode of the defensive
droplets from the Mexican bean beetle Epilachna varives-
tis, in a few steps using (R)-3 as the starting material.
CO2H
S
S
1
Figure 1 (R)-a-Lipoic acid (1)
Lipoic acid is often used in its racemic form for therapy
purposes because the S-enantiomer shows no significant
biological side effects. However, the enantioselective
synthesis of the R-enantiomer 1 has attracted a great deal
of interest among organic and medicinal chemists. For ex-
ample, the synthesis has been achieved by using of ‘chiral
pool’ starting materials,6 baker’s yeast reductions,7 asym-
metric allylation,8 asymmetric dihydroxylation/hydroge-
nation,9 Sharpless asymmetric epoxidation,10 and so on.11
As another application of the deracemization, we have
successfully accomplished an enantioselective total syn-
thesis of (R)-a-lipoic acid (1) starting from ( )-4 in five
steps (Scheme 2). Here, we report the results in detail.
OMe
OMe
O
O
deracemization
(R)-1
Recently, we developed thermodynamically controlled
deracemization of racemic a-monosubstituted cycloal-
kanones utilizing a chiral host molecule under basic sus-
pension media.12 For example, the use of (–)-(2R,3R)-
trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspi-
( )-4
(R)-4
Scheme 2 Deracemization of ( )-4
We reported previously that 250 mg of ( )-4 was convert-
ed into the R-isomer (94% ee) in 96% yield using 2a (2
equiv) with sodium hydroxide (4 equiv) in a mixture of
water–methanol (2:1) (vide supra) after stirring for two
days.12c However, a prolonged reaction time (7 d) was re-
SYNTHESIS 2010, No. 17, pp 2931–2934
x
x.
x
x
.
2
0
1
0
Advanced online publication: 12.07.2010
DOI: 10.1055/s-0030-1258167; Art ID: F04710SS
© Georg Thieme Verlag Stuttgart · New York

2932
H. Kaku et al.
PAPER
2a (2 equiv)
H2O–MeOH (2:1)
r.t., 24 h
1)
O
O
O
OMe
OMe
OMe
R
R
2a (2 equiv), NaOH (4 equiv)
H2O–MeOH (2:1), r.t., 7 d
2) filtration
( )-4
99%, 92% ee
90% (from racemic 4)
99% ee
500 mg
Scheme 3 A 500-mg scale of deracemization of 4
O
O
MCPBA (1.2 equiv)
NaH2PO4 (3.0 equiv)
I
SiH2I2 (6 equiv)
OMe
O
CH2Cl2
93%
CH2Cl2
reflux, 24 h
OMe
HO2C
OH
(R)-4
5
6
99% ee
Na2S⋅9H2O (1.15 equiv)
MsCl (5 equiv)
Et3N (5.5 equiv)
CH2Cl2
–30 °C, 10 min
67% (2 steps)
I
sulfur (1.16 equiv)
R-(+)-α-lipoic acid (1)
DMF, 80 °C
79%
HO2C
OMs
total 44% (5 steps from racemic 4)
7
Scheme 4 Total synthesis of (R)-a-lipoic acid
quired for a 500-mg scale deracemization. To reproduce which was employed as a starting material for the total
the 250-mg scale result, the period of reaction had to be synthesis of (R)-a-lipoic acid (1).
extended up to one week. Then, optical resolution by in-
This illustrates that thermodynamically controlled derace-
clusion complexation was carried out to remove the unfa-
mization could provide a convenient and excellent meth-
vorable enantiomer (S-isomer) of 4. This was
od for the preparation of optically active a-mono-
substituted cyclohexanones. Further studies to disclose
accomplished by mixing the obtained (R)-4 again with 2a
(2 equiv) in a fresh mixture of water–methanol (2:1) with-
the principle of the molecular recognition process and the
out base for one day. After filtration, a solid residue was
applicability of the present method are now in progress.
recovered and subjected to silica gel column chromatog-
raphy to afford (R)-4 with 99% ee in 90% yield from ( )-
4 (Scheme 3), and host molecule 2a (>99%) that was re-
usable after recrystallization. In contrast, (R)-4 with 5.9%
ee was recovered in 9.0% yield from the filtrate.
Melting points were determined on a Yanaco MP-3 apparatus and
are uncorrected. IR spectra were recorded from either neat liquid
films or solids in KBr pellets on a Jasco Model FT/IR-410 spectro-
1
photometer. H NMR spectra were recorded on a Varian Gemini
200 (200 MHz), Varian Unity 200 (200 MHz), Varian Mercury 300
The R-isomer (R)-4 was subjected to Baeyer–Villiger ox-
idation using 3-chloroperoxybenzoic acid with anhydrous
(300 MHz), or Varian 400 MR (400 MHz) spectrometer in CDCl3
relative to internal TMS. 13C NMR spectra were taken on a Varian
sodium dihydrogen phosphate to afford lactone 5 in 93%
400 MR (100 MHz) and chemical shifts were referenced to the re-
yield (Scheme 4). Treatment of 5 with diiodosilane15
sidual solvent signal (CDCl3: d = 76.9). Mass spectra including
HRMS were recorded on a Jeol AX-500 spectrometer.
cleaved the methyl ether linkage with concomitant ring-
opening iodination of the lactone via a SN2-type mecha-
nism at C6. Without further purification, the resulting pri-
mary alcohol 6 was subsequently converted into mesylate
7. The final step was achieved by treating 7 with a mixture
of sodium sulfide and sulfur in N,N-dimethylformamide at
80 °C without protection of the carboxylic acid. Silica gel
column chromatography of the resulting mixture gave 1 in
Optional rotations were measured on a Jasco DIP-1000 polarimeter
using a 10-cm microcell. Capillary gas chromatographic analyses
were performed on a Shimadzu GC-14A gas chromatograph
equipped with 30 m × 0.25 mm fused-silica a-DEX120 and b-
DEX325 SUPELCO columns. Helium was used as the carrier gas
and peak area integrations were uncorrected for flame ionization de-
tector response. Analytical HPLC was performed on a Jasco system
consisting of a pump (PU-980) and a photodiode array detector
(UV-970, set at 330 nm) and equipped with a Daicel Chiracel OJ or
OD column. Peak areas were measured by electronic integration on
a Shimadzu C-R7Aplus chromatopac.
19
79% yield [mp 43–45 °C (pentane), [a]D +112 (c 0.24,
benzene)], whose physical properties compared well with
those in the literature16 [mp 46–48 °C, [a]D25 +104 (c 0.88,
benzene)]. Thus, (R)-a-lipoic acid (1) was synthesized
quite satisfactorily in five steps (44% overall yield) start-
ing from ( )-2-(2-methoxyethyl)cyclohexanone [( )-4].
In general, reagent grade solvents were used. DMF was distilled
from CaH2 under reduced pressure. CH2Cl2 and Et3N were distilled
from CaH2 under an argon atmosphere. Analytical TLC was per-
formed on precoated silica gel 60 F-254 plates (0.2-mm layers) on
glass with fluorescent indicator, supplied by E. Merck. For column
chromatography, Fuji silysia BW-127ZH (53–150 mm) or BW-300
(32–53 mm) was used.
The deracemization of ( )-2-(2-methoxyethyl)cyclohex-
anone [( )-4] was accomplished utilizing (–)-(2R,3R)-
trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspi-
ro[5.4]decane (2a) as a host molecule to afford (R)-4,
Synthesis 2010, No. 17, 2931–2934 © Thieme Stuttgart · New York

PAPER
Enantioselective Total Synthesis of (R)-a-Lipoic Acid
2933
Deracemization of ( )-2-(2-Methoxyethyl)cyclohexanone (4);
Preparation of (R)-4
To a soln of crude 6 in anhyd CH2Cl2 (5 mL) was added Et3N (405
mL, 2.91 mmol) and MsCl (200 mL, 2.58 mmol) at –30 °C and the
mixture was stirred for 10 min. 2 M HCl (15 mL) was added fol-
lowed by extraction with CH2Cl2 (3 × 20 mL). The combined or-
ganic layers were dried (MgSO4), filtered, and concentrated.
Purification of the residue by column chromatography (silica gel, 6
g, hexane–EtOAc, 5:1 to 3:1, 2:1, and 1:1) yielded 7 (134 mg, 67%)
as a colorless oil; Rf = 0.38 (hexane–EtOAc, 1:3).
[a]D22 +12.2 (c 1.00, CHCl3).
IR (neat): 2938 (OH), 1708 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 10.9 (br s, 1 H, COOH), 4.45 (dt,
J = 10.2, 5.1 Hz, 1 H, H8a), 4.40–4.32 (m, 1 H, H8b), 4.21–4.13 (m,
1 H, H6), 3.06 (s, 3 H, CH3), 2.40 (t, J = 7.3 Hz, 2 H, H2), 2.20–2.13
(m, 2 H, H7), 1.98–1.87 (m, 1 H, H5a), 1.84–1.73 (m, 1 H, H5b),
1.73–1.56 (m, 3 H, H3, H4a), 1.56–1.43 (m, 1 H, H4b).
To a soln of ( )-4 (500 mg, 3.20 mmol)17 in MeOH (16.7 mL) was
added host compound 2a (3.25 g, 6.41 mmol, 2 equiv), then distilled
H2O (20.5 mL) and aq 1 M NaOH (12.8 mL, 4 equiv) were added.
The resulting mixture was stirred vigorously at r.t. for 7 d and then
it was poured into sat. aq NH4Cl soln (100 mL) and extracted with
Et2O (3 × 100 mL). After evaporation of the ethereal solns in vacuo,
the residue was chromatographed (silica gel, 200 g, toluene–Et2O to
hexane–Et2O) to afford ketone (R)-4 (503 mg, >99%, 92% ee) as a
colorless oil and 2a (3.31 g, >99%). The obtained (R)-4 was mixed
again with fresh host 2a (3.25 g, 2 equiv) in 33% aq MeOH (50 mL)
without base. After vigorous stirring at r.t. for 1 d, the resulting mix-
ture was filtered and the residue was washed with H2O–MeOH (2:1,
3 × 5 mL). The residue was subjected to column chromatography
(silica gel, 200 g, toluene–Et2O to hexane–Et2O) to afford (R)-4;
yield: 90% [from ( )-4]; 99% ee [GLC (chiral column, SUPELCO,
a-DEX120, 110 °C): tR = 24.6 min]; Rf = 0.36 (hexane–EtOAc,
3:1).
13C NMR (100 MHz, CDCl3): d = 178.6, 69.6, 40.0, 39.3, 37.3, 33.4,
32.0, 28.7, 23.6.
MS (CI): m/z = 365 [M + H]+, 347 (base peak), 269, 237, 219, 123.
HRMS (CI): m/z [M + H]+ calcd for C9H18IO5S: 364.9920; found:
[a]D21 +0.82 (c 1.00, CHCl3) [Lit.18 [a]D +0.38 (c 9, CHCl3)].
1H NMR (400 MHz, CDCl3): d = 3.43 (ddd, J = 9.4, 6.5, 5.9 Hz, 1
H, H2¢a), 3.39 (ddd, J = 9.4, 6.9, 5.9 Hz, 1 H, H2¢b), 3.31 (s, 3 H,
CH3), 2.53–2.45 (m, 1 H), 2.44–2.36 (m, 1 H), 2.36–2.27 (m, 1 H),
2.18–2.10 (m, 2 H), 2.10–2.02 (m, 1 H), 1.90–1.81 (m, 1 H), 1.75–
1.60 (m, 2 H), 1.45–1.33 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 213.0, 70.3, 58.4, 47.1, 42.1, 34.2,
29.3, 28.0, 25.0.
364.9918.
(R)-a-Lipoic Acid (1)
Na2S·9 H2O (76.8 mg, 0.320 mmol) and sulfur (10.4 mg, 0.325
mmol) were stirred in anhyd DMF (8 mL) at 80 °C for 1 h under an
argon atmosphere in the dark and then a soln of 7 (102 mg, 0.279
mmol) in anhyd DMF (4 mL) was added to the mixture. The mix-
ture was stirred at 80 °C for 2 h, distilled H2O (20 mL) and 2 M HCl
(2 mL) were added, and the resulting mixture was extracted with
Et2O (3 × 40 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated. Purification of the residue by
column chromatography (silica gel, 10 g, hexane–Et2O, 5:1 to 3:1)
yielded 1 (46 mg, 79%, 93% ee) as a yellow solid. Recrystallization
(pentane) gave 1; 99% ee [HPLC (chiral column, Daicel, Chiralcel
OD; hexane–i-PrOH–TFA, 99:1:0.05; UV 330 nm), tR = 29.9 min];
mp 43–45 °C (pentane) (Lit.16 46–48 °C); Rf = 0.37 (hexane–
EtOAc, 1:1).
(R)-7-(2-Methoxyethyl)oxepan-2-one (5)
To a mixture of (R)-4 (660 mg, 4.22 mmol) and NaH2PO4 (1.53 g,
12.7 mmol) in CH2Cl2 (40 mL) was added MCPBA (1.56 g, 6.33
mmol, 1.5 equiv). The mixture was stirred at r.t. for 6 h and then fil-
tered through Celite. The filtrate was diluted with CH2Cl2 (50 mL)
and washed with sat. aq Na2S2O3 (150 mL), sat. aq NaHCO3 (150
mL), and sat. aq NaCl (100 mL). The organic layer was dried
(MgSO4), filtered, and concentrated. Purification of the residue by
column chromatography (silica gel, 27 g, hexane–Et2O, 3:1) yielded
5 (683 mg, 93%) as a colorless oil; Rf = 0.35 (hexane–EtOAc, 3:1).
19
25
[a]D +112.2 (c 0.24, benzene) [Lit.16 [a]D +104 (c 0.88, ben-
[a]D25 –63.3 (c 1.00, CHCl3).
IR (neat): 1729 cm–1 (C=O).
zene)].
IR (KBr): 3040 (OH), 1705 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 4.45 (td, J = 8.8, 4.3 Hz, 1 H, H7),
3.56 (ddd, J = 9.4, 8.8, 4.5 Hz, 1 H, H9a), 3.45 (dt, J = 9.6, 5.1 Hz,
1 H, H9b), 3.34 (s, 3 H, CH3), 2.72–2.59 (m, 2 H, H3), 1.99–1.88
(m, 4 H), 1.80 (dddd, J = 14.3, 8.8, 5.3, 3.9 Hz, 1 H), 1.70–1.56 (m,
3 H).
13C NMR (100 MHz, CDCl3): d = 175.7, 76.9, 68.2, 58.7, 36.4, 34.8,
34.6, 28.1, 22.9.
1H NMR (400 MHz, CDCl3): d = 10.6 (br s, 1 H, COOH), 3.58 (dtd,
J = 8.3, 6.4, 6.3 Hz, 1 H, H6), 3.19 (dddd, J = 11.0, 7.0, 5.3, 0.3 Hz,
1 H, H8a), 3.12 (dt, J = 11.0, 6.9 Hz, 1 H, H8b), 2.47 (dtd, J = 11.9,
6.6, 5.4 Hz, 1 H, H7a), 2.38 (t, J = 7.3 Hz, 2 H, H2), 1.92 (dtd,
J = 12.8, 7.0, 6.9 Hz, 1 H, H7b), 1.78–1.61 (m, 4 H, 2 CH2), 1.59–
1.41 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 178.3, 56.2, 40.1, 38.4, 34.5, 33.4,
28.6, 24.3.
MS (EI): m/z = 206 (M+, base peak), 173, 149, 105, 123, 95.
HRMS (EI): m/z [M]+ calcd for C8H14O2S2: 206.0435; found:
MS (CI): m/z = 173 ([M + H]+, base peak), 155, 141, 123, 81.
HRMS (CI): m/z [M + H]+ calcd for C9H17O3: 173.1178; found:
173.1174.
206.0433.
(S)-6-Iodo-8-(methylsulfonyloxy)octanoic Acid (7)
A soln of SiH2I2 (300 mL, 2.99 mmol) in anhyd CH2Cl2 (4 mL) was
added to a soln of lactone 5 (101 mg, 0.585 mmol) in anhyd CH2Cl2 Acknowledgment
(3 mL) under an argon atmosphere and the mixture was stirred at 50
This work was supported in part by a Grant-in-Aid for Scientific
°C for 1 d. The resulting mixture was quenched with sat. aq
NaHCO3 soln (20 mL) and sat. aq Na2CO3 (40 mL) and washed with
CH2Cl2 (3 × 50 mL). After acidification of the aqueous layer with 6
M HCl soln (pH 1) followed by addition of NaCl, the mixture was
extracted with CH2Cl2 (5 × 100 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated to afford unpurified
(S)-8-hydroxy-6-iodooctanoic acid (6) (153 mg).
Research (C, 19590028) from MEXT (the Ministry of Education,
Culture, Sports, Science and Technology of Japan). We are also
thankful to MEXT.HAITEKU, 2003-2007.
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H. Kaku et al.
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