A diethyltartrate-based synthesis of both (-)- and (+)-arundic acid

Article abstract of DOI:10.1016/j.tetlet.2009.08.004

A diethyltartrate-based synthesis of both enantiomers of the acute ischemic stroke therapeutic agent, arundic acid is presented. Separable diastereomers were obtained through the Johnson-Claisen rearrangement of the chiral vicinal diol based on the diethyltartrate skeleton and were converted separately into the two enantiomers of arundic acid.

Full text of DOI:10.1016/j.tetlet.2009.08.004

Tetrahedron Letters 50 (2009) 5903–5905
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A diethyltartrate-based synthesis of both (ꢀ)- and (+)-arundic acid
*
Rodney A. Fernandes , Abhinav Dhall, Arun B. Ingle
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A diethyltartrate-based synthesis of both enantiomers of the acute ischemic stroke therapeutic agent,
arundic acid is presented. Separable diastereomers were obtained through the Johnson–Claisen rear-
rangement of the chiral vicinal diol based on the diethyltartrate skeleton and were converted separately
into the two enantiomers of arundic acid.
Received 29 June 2009
Revised 30 July 2009
Accepted 5 August 2009
Available online 9 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diethyltartrate
Johnson–Claisen rearrangement
Acute ischemic stroke therapeutic agent
Arundic acid
Stroke is a major cause of death worldwide and is caused due to
oxygen deprivation leading to rapid nerve cell death and dysfunc-
tion of the body part controlled by the affected nerve cells. Stroke
is responsible for serious long-term disability, for example, paraly-
sis, cognitive deficits, dementia, dizziness, vertigo, impaired vision,
language deficits, emotional difficulties and pain. Research towards
synthesis of new therapeutic agents and analogues of inhibitors to
prevent and treat stroke is a priority. One novel agent that emerged
HO C
HO C
ent-1
2
1
2
(R)-(-)-arundic acid
(S)-(+)-arundic acid
Figure 1. Arundic acids.
1
is (R)-(ꢀ)-arundic acid 1 (Ono-2506, Fig. 1), which has shown effi-
dic acid. The Johnson–Claisen rearrangement of allyl alcohol 4 with
trimethylorthoacetate would give the diastereomer mixture 3 and
further chain elongation would result in 2. Compound 4 can easily
be derived from (R,R)-diethyltartrate 5.
cacy in preventing expansion of cerebral infarction by improving
astrocyte function. Arundic acid is undergoing phase II develop-
ment for the treatment of acute ischemic stroke, as well as clinical
development in other neurodegenerative diseases including Alz-
heimer’s disease and Parkinson’s disease.2
Arundic acid has been a synthetic target in recent years and a
3
–9
few enantioselective syntheses are reported in the literature.
The strategies employed so far are based on resolution of
3
,7
4
recemates, asymmetric alkylation of chiral enolates, chiral aux-
HO2C
HO2C
(S)-(+)-arundic acid
ent-1
1
5
,9
6
iliaries, diastereoselective photodeconjugation and metal-med-
(
R)-(-)-arundic acid
8
iated crotylation. In continuation of our research efforts in
10
asymmetric synthesis of natural products we have recently dem-
onstrated that chiral vicinal diols are good platforms for separable
diastereomers in the Johnson–Claisen rearrangement.1 We envi-
sioned a similar strategy to synthesize both the enantiomers of
arundic acid based on (R,R)-diethyltartrate as a chiral pool. Our ret-
rosynthetic plan is shown in Scheme 1. Separation of C-4 diastereo-
mers of 2, acetonide deprotection, cleavage of 1,2-diol to acid and
diene reduction was expected to give either enantiomers of arun-
CO Me
2
O
O
0e
BnO
4
BnO
O
3
O
2
O
OH
EtO C
2
OH
CO Et
BnO
HO
O
2
4
5
*
Corresponding author. Tel.: +91 22 25767174; fax: +91 22 25767152.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
Scheme 1. Retrosynthetic analysis of (ꢀ)- and (+)-arundic acid.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.004

5
904
R. A. Fernandes et al. / Tetrahedron Letters 50 (2009) 5903–5905
EtOH), lit.7
½
aꢁ
25
D
ꢀ6.1 (c 2, EtOH). A similar sequence of reactions
O
O
O
EtO C OH
2
a
with 2b gave the acid ent-10 which on hydrogenation led to (S)-
(+)-arundic acid ent-1,
b
BnO
BnO
1
5
25
D
OH
½
aꢁ
+6.6 (c 0.54, EtOH).
HO CO Et
O
2
O
In summary, we have developed an efficient strategy to both
enantiomers of arundic acid. The highlights of the synthesis are
(i) the use of (R,R)-diethyltartrate as a chiral pool to generate the
separable diastereomers in the Johnson–Claisen rearrangement,
ii) a stereodivergent approach targeting both enantiomers of
arundic acid in seven steps from the known compound 6 and in
1% overall yield and (iii) the versatility of the intermediates
e.g., 3) for the synthesis of analogues by changing the chain length
7
6
5
CO Me
2
O
OH
O
O
c
d
BnO
BnO
(
O
4
3
2
(
e
of the Wittig reagent to get different alkyl groups attached. Further
application of this strategy to the synthesis of other related natural
products is in progress.
O
O
4
4
BnO
BnO
BnO
Acknowledgements
O
2a
O
2b
f
The authors are indebted to IRCC, IIT-Bombay for financial sup-
port. A.B.I. is grateful to CSIR New Delhi for a research fellowship.
f
OH
OH
References and notes
BnO
1.
(R)-(ꢀ)-Arundic acid or (R)-(ꢀ)-2-propyloctanoic acid was discovered by
Minase Research Institute of Ono Pharmaceutical Co. Ltd., Osaka, Japan
during a screening process and was given the name Ono-2506. See: Tateishi,
N.; Mori, T.; Kagamiishi, Y.; Satoh, S.; Katsube, N.; Morikawa, E.; Morimoto, T.;
Matsui, T.; Asano, T. J. Cereb. Blood Flow Metab. 2002, 22, 723.
OH
OH
8
9
g
g
2
3
.
.
Sorbera, L. A.; Castaner, J.; Castaner, J. M. Drugs Future 2004, 441.
Kishimoto, K.; Nakai, H. Japan Patent 7-98328, 1995; Chem Abstr. 1997, 126,
7
4487.
Kishimoto, K.; Nakai, H. Japan Patent 7-102693, 1995; Chem Abstr. 1997, 126,
4488.
4
.
.
HO C
HO C
2
2
7
1
0
ent-10
5
(a) Hasegawa, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2000, 73, 423; (b)
Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E.; Iguchi, Y.; Yonekawa, Y.; Okamoto,
M.; Ohta, C.; Hashimoto, S.; Ohuchida, S. Org. Process. Res. Dev. 2003, 7, 168; (c)
Hasegawa, T.; Yamamoto, H. Synthesis 2003, 1181.
h
h
6
7
.
.
Pelotier, B.; Holmes, T.; Piva, O. Tetrahedron: Asymmetry 2005, 16, 1513.
Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E.; Ohta, C.; Nakabayashi, K.;
Okamoto, M.; Hamano, M.; Takahashi, K.; Ohuchida, S.; Hamada, Y. Org.
Process. Res. Dev. 2005, 9, 774.
HO C
HO2C
2
1
ent-1
(S)-(+)-arundic acid
(R)-(-)-arundic acid
8
9
.
.
Goswami, D.; Chattopadhyay, A. Lett. Org. Chem. 2006, 12, 922.
Garcia, J. M.; Odriozola, J. M.; Lecumberri, A.; Razkin, J.; Gonzalez, A.
Tetrahedron 2008, 64, 10664.
Scheme 2. Reagents and conditions: (a) Ref. 10a; (b) (i) (COCl)
1.5 equiv), ꢀ78 °C, 20 min, 6, 1 h, Et
Ph P@CHCOCH (1.2 equiv), THF, rt, 12 h, 82% (two steps); (c) DIBAL-H (1.5 equiv),
°C, CH Cl , 2 h, 95%; (d) MeC(OMe) (10.0 equiv), EtCO H (cat), toluene, reflux,
2 h, 85%; (e) (i) DIBAL-H (1.1 equiv), ꢀ80 °C, CH Cl , 2 h; (ii) Ph
2
(1.2 equiv), DMSO
N (4.0 equiv), ꢀ60 °C, 30 min, to rt, 1 h; (ii)
1
0. (a) Fernandes, R. A. Eur. J. Org. Chem. 2007, 5064; (b) Fernandes, R. A.
Tetrahedron: Asymmetry 2008, 19, 15; (c) Fernandes, R. A.; Chavan, V. P.
Tetrahedron Lett. 2008, 49, 3899; (d) Fernandes, R. A.; Chavan, V. P.; Ingle, A. B.
Tetrahedron Lett. 2008, 49, 6341; (e) Fernandes, R. A.; Ingle, A. B. Tetrahedron
Lett. 2009, 50, 1122.
1. For Johnson–Claisen rearrangement see: (a) Johnson, W. S.; Werthemann, L.;
Bartlett, W. R.; Brocksom, T. J.; Li, T.-T.; Faulkner, D. J.; Peterson, M. R. J. Am.
Chem. Soc. 1970, 92, 741; (b) Hiyama, T.; Kobayashi, K.; Fujita, M. Tetrahedron
Lett. 1984, 25, 4959; (c) Ziegler, F. Chem. Rev. 1988, 88, 1423; (d) Agami, C.;
Couty, F.; Evano, G. Tetrahedron Lett. 2000, 41, 8301; (e) Brenna, E.; Fuganti, C.;
Gatti, F. G.; Passoni, M.; Serra, S. Tetrahedron: Asymmetry 2003, 14, 2401; (f)
Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem.
(
3
3
3
0
1
CH
2
2
3
2
+
2
2
3
P CH
2
CH
2 2
CH -
3
Brꢀ (1.3 equiv), n-BuLi (1.4 equiv), THF, ꢀ80 °C, 15 min, aldehyde from 3,
1
warmed to rt, 8 h, 2a (41%), 2b (40%); (f) 3 N HCl, MeOH, rt, 6 h, 90%; (g) (i) NaIO
4
(
(
(
2.0 equiv), NaHCO
3
,
CH
2
Cl
2
,
rt, 6 h; (ii) NaClO
2
(10 equiv), NaH
2
PO
4
ꢂH
2
O
7.0 equiv), cyclohexene (5.0 equiv), t-BuOH, rt, 12 h, 66% (two steps); (h) H
4 atm), Pd–C, MeOH, 2 h, 96%.
2
1
976, 41, 3497.
The synthesis of both enantiomers of arundic acid by a common
2. Diastereomeric ratio was determined by 1H NMR.
1
strategy is depicted in Scheme 2. (R,R)-Diethyl tartrate 5 was con-
13. The relative configuration for the C-4 centre in 2a and 2b was assigned after
converting them separately into the known enantiomers of arundic acid and
working backward. In flash column chromatography the compound 2b was
eluted first followed by 2a (petroleum ether/EtOAc, 95:5).
verted into the known alcohol 6.10a Oxidation of the alcohol 6 and
subsequent Wittig olefination provided the
a,b-unsaturated
2
5
methyl ketone 7 in good yields of 82%. DIBAL-H reduction of the
14. Data for 2a: Colourless oil. ½
a
ꢁ
ꢀ20.2 (c 1.1, CHCl
3
). IR (CHCl
3
): m = 3012, 2983,
D
2
7
1
932, 2863, 1600, 1495, 1455, 1379, 1251, 1215, 1169, 1087, 971, 905, 856,
ketone led to the allyl alcohol 4 (95%) which on Johnson–Claisen
ꢀ
1
1
58, 697 cm
3
. H NMR (400 MHz, CDCl /TMS): d = 0.89 (t, J = 7.3 Hz, 3H),
1
1
rearrangement (with trimethylorthoacetate and catalytic propi-
.21–1.35 (m, 2H), 1.39 (s, 6H), 1.67 (d, J = 5.2 Hz, 3H), 1.96–2.06 (m, 2H), 2.07–
onic acid) provided calcd12 1:1, C-3 diastereomeric mixture 3 in
2.12 (m, 2H), 2.13–2.28 (m, 1H), 3.53 (d, J = 4.9 Hz, 2H), 3.88 (dd, J = 8.4, 2.3 Hz,
1
3
2
H), 3.97–4.01 (m, 1H), 4.59 (d, J = 7.0 Hz, 2H), 5.22–5.3 (m, 1H), 5.31–5.42 (m,
H), 7.27–7.36 (m, 5H). 13C NMR (100 MHz, CDCl
): d = 13.8, 22.7, 26.8, 26.9,
7.0, 27.1, 29.3, 44.3, 70.5, 70.7, 73.3, 79.9, 108.7, 126.8, 127.1, 127.4, 127.5,
8
5% yield. The reduction of methyl ester with DIBAL-H and subse-
3
quent Wittig olefination of the corresponding aldehyde at ꢀ80 °C
provided the C-4 diastereomers 2a and 2b which were efficiently
separated by flash column chromatography in 41% and 40% yields,
+
127.6, 128.2, 128.3, 129.0, 130.8, 138.0. HRMS (ESI-TOF) (m/z) [M ] calcd for
: 358.2509, found 358.2514.
23 34 3
C H O
2
5
1
3,14
Data for 2b: Colourless oil. ½
aꢁ
D
ꢀ17.2 (c 3.2, CHCl
3
). IR (CHCl
3
):
m
= 3019, 2868,
respectively.
and 2b led to the diols 8 and 9, respectively (90% for each). The
NaIO -mediated cleavage of the diol 8 followed by further oxida-
Deprotection of the acetonide functionality in 2a
ꢀ1
1
602, 1451, 1380, 1372, 1216, 1163, 1084, 1040, 971, 916, 858, 757, 667 cm
.
1
H NMR (400 MHz, CDCl /TMS): d = 0.88 (t, J = 7.3 Hz, 3H), 1.31–1.38 (m, 2H),
3
1.41 (s, 3H), 1.42 (s, 3H), 1.55 (dd, J = 6.4, 1.5 Hz, 3H), 1.95–2.0 (m, 2H), 2.0–2.1
4
(
m, 1H), 2.15–2.2 (m, 1H), 2.38–2.41 (m, 1H), 3.41–3.43 (m, 1H), 3.57 (dd,
tion of the corresponding aldehyde furnished the acid 10 in 66%
J = 10.5, 2.6 Hz, 1H), 3.65 (t, J = 8.1 Hz, 1H), 3.94–3.98 (m, 1H), 4.58 (d,
yield. Reduction of the diene functionality by hydrogenation pro-
13
J = 6.4 Hz, 2H), 4.99–5.04 (m, 1H), 5.25–5.5 (m, 3H), 7.31–7.35 (m, 5H).
C
15
25
D
vided the (R)-(ꢀ)-arundic acid 1, in 96% yield, ½
aꢁ
ꢀ6.8 (c 0.82,
NMR (100 MHz, CDCl ): d = 13.9, 22.7, 27.0, 27.1, 27.2, 27.9, 29.8, 48.2, 70.8,
3

R. A. Fernandes et al. / Tetrahedron Letters 50 (2009) 5903–5905
5905
7
1
3
3.2, 79.3, 79.7, 108.8, 127.5, 127.6, 127.7, 128.1, 128.2, 128.3, 129.1, 129.8,
15. The spectroscopic and analytical data including optical rotation of 1 and 2 were
+
7,9
30.6, 138.1. HRMS (ESI-TOF) (m/z) [M ] calcd for C23
H
34
O
3
: 358.2509, found
in full agreement with those reported. The sign of optical rotation values
reported in Ref. 9 is just reverse for each enantiomer.
58.2511.