Asymmetric dihydroxylation and hydrogenation approaches to the enantioselective synthesis of R-(+)-α-lipoic acid

Article abstract of DOI:10.1016/S0040-4039(01)00734-1

The asymmetric synthesis of methyl (S)-6,8-dihydroxyoctanoate (5) and (S)-6,8-dimethylsulfonyloxyoctane-1-carboxylic acid (13), key precursors to R-(+)-α-lipoic acid (6) is described using OsO₄-catalyzed asymmetric dihydroxylation and Ru-catalyzed asymmetric hydrogenation, respectively, as the key steps in the reaction sequence. These methods lead to an efficient formal synthesis of R-(+)-α-lipoic acid in 90% ee.

Full text of DOI:10.1016/S0040-4039(01)00734-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4891–4893
Asymmetric dihydroxylation and hydrogenation approaches to
the enantioselective synthesis of R-(+)-a-lipoic acid
T. T. Upadhya,† M. D. Nikalje and A. Sudalai*
Process Development Division, National Chemical Laboratory, Pune 411008, India
Received 2 February 2001; revised 12 April 2001; accepted 2 May 2001
Abstract—The asymmetric synthesis of methyl (S)-6,8-dihydroxyoctanoate (5) and (S)-6,8-dimethylsulfonyloxyoctane-1-car-
boxylic acid (13), key precursors to R-(+)-a-lipoic acid (6) is described using OsO4-catalyzed asymmetric dihydroxylation and
Ru-catalyzed asymmetric hydrogenation, respectively, as the key steps in the reaction sequence. These methods lead to an efficient
formal synthesis of R-(+)-a-lipoic acid in 90% ee. © 2001 Elsevier Science Ltd. All rights reserved.
R-(+)-a-Lipoic acid (6) plays an important role as a
protein-bound transacylating cofactor of several multi-
enzymatic keto acid dehydrogenase complexes and as a
asymmetric catalytic methods, i.e. asymmetric dihy-
droxylation (ADH)5 and asymmetric hydrogenation
(AH),6 as the key reactions to control the absolute
configuration at the C-3 position.
growth factor for
a
variety of microorganisms.1
Recently, it has also been reported that lipoic acids and
their derivatives are highly active as anti-HIV2 and
anti-tumor agents.3 Generally, it is reported that the
enantioselective synthesis of 6 has been achieved either
from ‘chiral pool’ starting materials or by asymmetric
synthesis4 including mostly bakers’ yeast reductions. In
this communication, we describe a short, efficient and
enantioselective synthesis of 6 starting from easily avail-
able starting materials and by employing two powerful
We envisaged that methyl (S)-6,8-dihydroxyoctanoate
(5) and (S)-6,8-dimethylsulfonyloxyoctane-1-carboxylic
acid (13) could serve as two key precursors for the
synthesis of 6 (Schemes 1 and 2). In order to obtain 5
the olefinic diester (1),7 obtained readily from o-capro-
lactone in three steps, was subjected to OsO4-catalyzed
asymmetric dihydroxylation6 using hydroquinidine 1,4-
phthalazinediyl diether [(DHQD)2–PHAL] as chiral lig-
Scheme 1. (i) OsO4, (DHQD)2–PHAL, K3Fe(CN)6, K2CO3, rt, 95%; (ii) SOCl2, Et3N, CH2Cl2, 0°C, 92%; (iii) RuCl3 (cat.),
NaIO4, 85%; (iv) NaBH4, DMAC, 20% H2SO4, 63%; (v) NaBH4, Et3N, MeOH:DMF (2:1), AcOH, 0°C, 5 h.
Keywords: asymmetric reactions; diols; disulfide; hydrogenation; hydroxylation.
* Corresponding author. E-mail: sudalai@dalton.ncl.res.in
†
Present address: Max-Planck Institute fur Molekulare Physiologie, Otto-Hahn Str. 11, 44227 Dortmund, Germany.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00734-1

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T. T. Upadhya et al. / Tetrahedron Letters 42 (2001) 4891–4893
Scheme 2. (i) (COCl)2, DMSO, CH2Cl2, TEA, 75%; (ii) N2CHCO2Et, CH2Cl2, SnCl2, 1 h, rt, 83%; (iii) Zn, BrCH2CO2Et,
benzene, 4 h, followed by PCC, NaOAc, CH2Cl2, 4 h, 65%; (iv) (S)-BINAP–Ru(II), H2 (400 psi), MeOH, 100°C, 6 h, 90%; (v)
NaBH4, CuSO4, EtOH, 7 h; (vi) MsCl, Et3N, CH2Cl2, 0°C, 6 h; (vii) pTSA, MeOH, 10 h; followed by oxidation with PCC,
CH2Cl2, 3 h and Ag2O, NaOH, EtOH, 1 h, 62%; (viii) KOH, H2O, Na2S·9H2O, DMF, HCl, 80°C, 28 h, 45%.
and affording the diol 2‡ in 95% yield and 96% ee (from
1H NMR analysis of its diacetate using Eu(III) chiral
shift reagent). The diol 2 was then converted to cyclic
sulfate 3 (85% yield) using standard conditions.8 Reduc-
tion of 3 at the a-position with NaBH4–N,N%-dimethyl-
acetamide (DMAC) resulted8 in selective formation of
the (3S)-alcohol 4 in 86% yield {gum, [h]2D5 +13.59 (c
1.2 in EtOH); 13C NMR (50.3 MHz, CDCI3): l 14.1,
24.7, 24.9, 33.8, 36.1, 41.3, 51.4, 60.6, 67.7, 172.8,
173.9}. Further selective reduction of one of the ester
groups in 4 is achieved by following the reported
method9 [NaBH4–Et3N, MeOH:DMF (2:1), 0°C] to
furnish 5 (85% yield), the spectroscopic data of which is
identical to the reported values.10 Conversion of (S)-5
diol into 6 has already been reported in the literature.10
Our strategy for the synthesis of 6,8-dimethylsulfonyl-
oxyoctane-1-carboxylic acid (13) starts from commer-
cially available 1,6-hexanediol. Monoprotection of 1,6-
hexanediol (1 mol of dihydropyran, pTSA, anhydrous
ether, 0°C) afforded 7 in 81% yield which underwent
Swern oxidation affording aldehyde 8 (75%). Two-car-
bon chain extension from aldehyde 8 to b-keto ester 9
was achieved by two routes: (i) CꢀH insertion of ethyl
diazoacetate11 with 8 in the presence of a catalytic
amount of anhydrous SnCl2 at 25°C afforded 9 in 83%
yield; (ii) Reformatsky reaction of 8 with ethyl bro-
moacetate in refluxing benzene gave the crude alcohol
followed by its oxidation with PCC produced 9 in 65%
yield. Although it is reported in the literature6 that
asymmetric hydrogenation of b-keto esters using (S)-(−) -
2,2% - bis(diphenylphosphino) - 1,1% - binaphthyl]dichloro-
ruthenium [(S)-(−)-BINAP–Ru(II) complex] proceeds
at 4 atmospheres of H2, we found that the reduction of
b-keto ester 9 under similar conditions did not proceed
at all and recovered only the starting materials.
‡ Spectroscopic data for selected compounds
Diol 2: Gum; [h]2D5 +9.39 (c 1.2, EtOH); IR (neat, cm−1): w 3600–3200,
2948, 2866, 1731, 1645–1633, 1440, 1369, 1269–1120, 1026, 864, 734;
1H NMR (200 MHz, CDCl3): l 1.2–1.4 (t, J=6.0 Hz, 3H), 1.4–1.73
(m, 7H), 2.1 (s, 1H), 2.27–2.34 (t, J=7.0 Hz, 2H), 3.64 (s, 3H),
3.79–3.87 (m, 1H), 4.00–4.01 (d, J=2.0 Hz, 1H), 4.20–4.30 (q,
J=7.0 Hz, 2H); 13C NMR (50.3 MHz, CDCl3): l 14.0, 24.6, 25.1,
33.1, 33.7, 51.2, 61.6, 72.2, 73.3, 173.3, 173.7; MS (m/z % rel.
intensity): 248 (M+, 2), 199 (2), 143 (3), 125 (20), 113 (68), 104 (92),
95 (22), 85 (21), 76 (100), 67 (40).
However, increasing the pressure of H2 (400 psi) and
temperature (100°C) brought about the hydrogenation
of 9 smoothly in an enantioselective manner to give the
optically active alcohol 10‡ in 90% yield. The optical
purity of the alcohol 10 was found to be 96% from 19F
NMR analysis of the ester formed by reaction with
(S)-(−)-a-methoxy-a-trifluromethylphenylacetyl chlo-
ride. Reduction of the ester function in 10 using
NaBH4–CuSO4 in EtOH yielded the diol 11, which was
subsequently mesylated under standard conditions to
yield 12. The transformation of 12 into 13‡ was
achieved sequentially in three steps of deprotection
(pTSA, MeOH) and oxidations (PCC and Ag2O); the
overall yield being 62%.
Cyclic sulfate 3: Gum; [h]D25 +54.25 (c 1.2, EtOH), IR (neat, cm−1): w
2985, 2954, 2873, 1768, 1737, 1438, 1394, 1302, 1209, 1163, 1041–
1029, 948, 885, 842, 651; 1H NMR (200 MHz, CDCl3): l 1.31–1.38
(t, J=7.5 Hz, 3H), 1.54–1.74 (m, 4H), 1.95–2.06 (m, 2H), 2.32–2.38
(t, J=6.0 Hz, 2H), 3.67 (s, 3H), 4.28–4.39 (q, J=7.5 Hz, 2H),
4.85–4.96 (m, 2H); 13C NMR (50.3 MHz, CDCl3): l 13.6, 23.77,
23.99, 32.30, 32.2, 51.1, 63.0, 79.8, 83.8, 164.5, 173.2.
Alcohol 10: Viscous liquid; IR (neat, cm−1): w 3500–3300, 1723, 1670,
1635, 1532, 1448, 1442, 1366, 1335, 1296, 1190, 1099, 998, 926, 888,
813, 767, 631, 576, 420; 1H NMR (200 MHz, CDCl3): l 1.2–1.35 (t,
J=8.0 Hz, 3H), 1.35–1.7 (m, 14H), 2.4–2.55 (m, 2H), 3.4–3.6 (m,
4H), 3.95–4.1 (m, 1H), 4.1–4.25 (q, J=7.2 Hz, 2H), 4.55 (brs, 1H);
13C NMR (50.3 MHz, CDCl3): l 14.1, 19.5, 25.3, 25.5, 26.1, 29.6,
30.7, 36.6, 41.6, 60.3, 61.9, 67.3, 67.9, 98.6, 172.5; elemental analysis:
C15H28O5 requires C, 62.50; H, 9.70%. Found: C, 62.51; H, 9.90%.
Mesylate 13: Mp 48°C, [h]D25 +22 (c 1.0, CHCl3); IR (neat, cm−1): w
3550–3300, 1728, 1697, 1460, 1405, 1380, 1350, 1198, 1178, 1090,
970, 822, 535, 420; 1H NMR (200 MHz, CDCl3): l 1.2–1.75 (m, 6H),
2.05–2.15 (m, 2H), 2.45 (t, J=6.4 Hz, 2H), 3.05 (s, 6H), 4.25 (t,
J=5.0 Hz, 2H), 4.75–4.9 (m, 1H), 10.30 (brs, 1H); 13C NMR (50.3
MHz, CDCl3): l 24.0, 33.2, 34.0, 34.5, 37.5, 38.6, 64.9, 78.0, 180.0
one signal is missing due to overlap; elemental analysis: C10H20O8S2
requires C, 36.15; H, 6.02; S, 19.28%. Found: C, 36.22; H, 6.08; S,
19.30%.
The absolute configuration of natural (+)-a-lipoic acid
is R. This was achieved by a step that involves a single
inversion of configuration, i.e. the displacement of O-
methanesulfonate by a thiolate nucleophile. Accord-
ingly, disulfide displacement12 of the methanesulfonate
groups of the potassium salt of the 3(S)-acid (13)
proceeded with inversion of configuration at C-3 to give
R-(+)-a-lipoic acid in 45%. {[h]2D5 −93.2 (c 0.9 in ben-
zene) [lit.13 −104 (c 0.88 in benzene) agreeing well with
the published spectroscopic data13}.

T. T. Upadhya et al. / Tetrahedron Letters 42 (2001) 4891–4893
4893
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