Asymmetric synthesis of α-methoxyarylacetic acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2005.05.002

Stereoselective synthesis of a series of 2-aryl-2-methoxyethanols was achieved from inexpensive chiral pool tartaric acid employing a diastereoselective reduction of a symmetrical 1,4-diaryldiketone as the key step. 2-Aryl-2-methoxyethanols were enantioselectively prepared in 80-90% yield

Full text of DOI:10.1016/j.tetasy.2005.05.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1897–1900
Asymmetric synthesis of a-methoxyarylacetic acid derivatives
Kavirayani R. Prasad* and Appayee Chandrakumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 26 March 2005; accepted 2 May 2005
Abstract—Stereoselective synthesis of a series of 2-aryl-2-methoxyethanols was achieved from inexpensive chiral pool tartaric acid
employing a diastereoselective reduction of a symmetrical 1,4-diaryldiketone as the key step. 2-Aryl-2-methoxyethanols were enantio-
selectively prepared in 80–90% yield
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The synthesis of chiral ligands, bio-active compounds
and enantiomerically pure building blocks from inexpen-
sive chiral sources is of significant importance because of
the low cost and rich source of chirality associated with
these chiral pool compounds.1 With the advent of combi-
natorial and high-throughput techniques, there has been
a growing interest in small molecules as therapeutic
probes. Natural products such as 1 isolated from plant
Isodon excisus, have been reported to display potent
activity as apoptosis inhibitor.2 Furthermore it has been
demonstrated that 2 and 3, identified from a screening of
a combination of scaffolds based on core structure 1,
exhibited excellent selectivity in inducing apoptosis in
cancerous white blood cells but is non-toxic towards
non-cancerous white blood cells.3,4 Coupled with their
immense biological activity and potent pharmacological
properties, demand for the rapid access to enantiomeri-
cally pure compounds of this type has increased. Herein,
we report a general method for the synthesis of com-
pounds based on a-arylmethoxy acid core from easily
accessible chiral pool L-(+)-tartaric acid.
A methodology for the synthesis of the title compounds
is depicted in Scheme 1. We anticipated that the 1,2-diol
unit of tartaric acid could be used as a masked aldehyde/
acid synthon and as an appropriate chiral relay in mod-
ification of the existing carboxyl functionality. Thus, we
identified the C2-symmetric 1,4-diaryl-1,4-diols as the
potential starting compounds. Protection of the 1,4-diol
as its methyl ether followed by cleavage of the 2,3-diol
unit should lead to a-methoxyarylacetaldehyde, which
can either be oxidized or reduced to the acid or alcohol,
respectively.
With this postulate, at the outset, we began the synthesis
with bis-Weinreb amide 5, prepared according to the lit-
erature procedure5 from dimethyl-L-tartrate. The addi-
tion of aryl Grignard reagent to the bis-Weinreb
amide 5 efficiently furnished the corresponding 1,4-di-
ketones6 4a–d. Diketones 4a–d can also be obtained in
moderate to good yields by the addition of a Grignard
reagent to dimethylamide7 6, which is readily accessible
from tartaric acid on a large scale (Table 1).
OH
OMe
OH
OMe
H
H
N
H
N
N
R
R
OMe
O
MeO
HO
HO
2
3
R
1
*
Corresponding author. Fax: +91 80 23600529; e-mail: prasad@orgchem.iisc.ernet.in
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.002

1898
K. R. Prasad, A. Chandrakumar / Tetrahedron: Asymmetry 16 (2005) 1897–1900
Ar
OH
Ar
Ar
Ar
Ar
HO
HO
OMe
OMe
Stereoselective
reduction
HO
HO
O
O
HO
HO
O
O
O
O
OH
OH
or
Ar
OH
Tartaric acid
O
Scheme 1. Retrosynthesis for the preparation of a-methoxyarylacetic acid derivatives.
MeO
O
Me
Ar
NMe2
N
N
O
O
O
O
O
O
O
O
ArMgBr, THF
0°C
ArMgBr, THF
0°C
O
O
O
Ar
NMe2
MeO
Me
6
4
5
Table 1. Synthesis of 2,2-dimethyl-4,5-diaroyl-1,3-dioxalane 4 from 5 and 6
Ar
Phenyl 4a
4-Methoxyphenyl 4b
4-Methylphenyl 4c
3,4-Dimethylphenyl 4d
Yield from 5
Yield from 6
86
77
83
69
89
53
85
50
We then studied the reduction of 1,4-dione 4a as a
model and examined the effect of various reducing
agents on the formation of three possible diastereo-
meric diols (two C2-symmetric 7a and 8a and one C1-
symmetric 9a). The results are summarized in Table 2.
Salient features of the reduction as a function of the
reducing agent are as follows: (i) Use of NaBH4 exhi-
bited no preference in the formation of diastereomers,
while use of a combination of CeCl3Æ7H2O and NaBH4
produced a 2:1 mixture of 7a and 8a. (ii) LiAlH4
produced the alcohols with only 10% de, while use of
bulky reducing agents, such as LiAl(OtBu)2H2 and
LiAl(OtBu)3H, slightly improved the diastereomeric
ratio. (iii) A moderate ratio (ꢀ4:1) was observed with
K-Selectride as the reducing agent and 7a as the major
product, while a dramatic increment in the ratio 92:8
was observed using K-Selectride pre-complexed with
18-crown-6.
Ph
Ph
Ph
Ph
O
O
O
O
O
O
O
O
Reducing agent
OH
OH
OH
OH
OH
OH
O
O
+
+
Ph
Ph
Ph
Ph
4a
7a
8a
9a
Table 2. Reduction of 2,2-dimethyl-4,5-dibenzoyl-1,3-dioxalane 4a
S. no.
Reducing agent
Solvent
Temperature (°C)
Time (h)
Diastereomeric ratioa
Yieldb
7a
8a
9a
1
2
3
4
5
6
7
8
NaBH4
NaBH4/CeCl3Æ7H2O
LiAlH4
MeOH
MeOH
THF
THF
THF
THF
THF
THF
À20
À78
0
2
40c
66
55
68
63
67
71
92c
47
34
45
27
32
33
29
8
13
0
94
98
95
96
90
96
96
94
1
1
0
LiAlH2(Ot-Bu)2
LiAlH(Ot-Bu)3
L-Selectride
À78
À20
À78
À78
À78
1.5
1
5
5
1.5
0.5
4.5
0
K-Selectride
K-Selectride/18-C-6
0
0
a Determined by 1H NMR.
b Refers to combined yield of all diastereomers after chromatography.
c Determined by HPLC.

K. R. Prasad, A. Chandrakumar / Tetrahedron: Asymmetry 16 (2005) 1897–1900
1899
After optimizing the conditions for reduction, we ap-
plied the protocol for the reduction of representative
aryl substituted diketones 4b–d. As indicated in Table
3, in all cases, 1,4-diols were obtained with good diaste-
reomeric ratio. Major diastereomer 7 was separated by
column chromatography from the minor isomer 8. Min-
or isomer 8 was oxidized quantitatively to the corre-
sponding starting dione 4 with IBX,8 thus enabling the
process almost 100% for the formation of the major dia-
stereomer. However, for ease of purification and estima-
formed stereogenic centre was further confirmed by
comparing the specific rotation with the already
known10 methoxy alcohol 12a and acid 13a.11
3. Conclusion
In summary, a high yielding enantioselective approach
to a-methoxyarylacetic acid derivatives was described
from L-(+)-tartaric acid. Application of this strategy
for the synthesis of other functionalized and non-func-
1
tion of dr by H NMR, crude reaction mixtures of the
Ar
Ar
Ar
O
O
O
O
OH
OH
O
OH
OH
K-Selectride, THF
+
18-C-6, -78oC
O
O
O
Ar
8
Ar
4
Ar
7
Table 3. Reduction of 2,2-dimethyl-4,5-diaroyl-1,3-dioxalane 4a–d with K-Selectride
Ar
4a
4b
4c
4d
dra 7:8
Yieldb
91:9
92
86:14
87
89:11
93
91:9
89
a Determined by 1H NMR spectra of the crude reaction mixture of the diol or the corresponding dimethyl ether.
b Isolated yield of the mixture of diastereoisomers after chromatography as its methyl ether 10.
alcohols were transformed in to their corresponding
methyl ethers 10a–d.
tionalized hydroxy acids en route to a library of amino
alcohols and diol moieties is underway. The evaluation
of diols 10a–d, which are analogues to TADDOL
ligands12 in asymmetric catalysis, is also under
investigation.
Facile deprotection of the acetonide of methyl ethers
10a–d was effected with FeCl3 in DCM9 in 72–95% yield.
Treatment of 1,4-dimethoxy-2,3-diols 11a–d with
Pb(OAc)4 produced 2 mol of the corresponding alde-
hyde, which was either reduced with NaBH4 to yield
the alcohol or oxidized with NaClO2 to furnish the cor-
responding acid. Stereochemical integrity was preserved
in all these transformations and 2-aryl-2-methoxyetha-
nols 12a–d with a (1R)-configuration were produced
with complete selectivity. The configuration at the newly
Acknowledgements
We thank the Department of Science and Technology,
New Delhi, for funding of this project. A.C. thanks
CSIR, New Delhi, for a research fellowship.
Ar
Ar
Ar
O
O
O
O
HO
OH
OH
OMe
OMe
FeCl3.6H2O
DCM, rt
72-95%
OMe
OMe
NaH, MeI
DMF, rt
87-92%
HO
Ar
7a-d
Ar
Ar
11a-d
10a-d
Ar
NaBH4
HO
HO
MeOH, 0oC
(80-91%)
OMe
Ar
O
12a-d
Pb(OAc)4
C6H6, rt
OR
Ar
H
NaClO2
OMe
NaH2PO4
tBuOH, water
O
13a Ar= Ph 95%

1900
K. R. Prasad, A. Chandrakumar / Tetrahedron: Asymmetry 16 (2005) 1897–1900
7. Toda, F.; Tanaka, K. J. Org. Chem. 1988, 53, 3607.
References
8. De Munari, S.; Frigerio, M.; Santagostino, M. J. Org.
Chem. 1996, 61, 9272; Frigerio, M.; Santagostino, M.;
Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60,
7272.
1. Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler,
M.; Sturmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004,
¨
43, 788.
9. Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.;
Magrath, J. J. Org. Chem. 1997, 62, 6684.
2. Lee, C.; Kim, J.; Lee, H.; Lee, S.; Kho, Y. J. Nat. Prod.
2001, 64, 659.
3. Nesterenko, V.; Putt, K. S.; Hergenrother, P. J. J. Am.
Chem. Soc. 2003, 125, 14672.
4. Xing, X.; Ho, P.; Bourquin, G.; Yeh, L.-A.; Cuny, G. D.
Tetrahedron 2003, 59, 9961.
5. Nugiel, D. A.; Jakobs, K.; Worley, T.; Patel, M.; Kalten-
bach, R. F., III; Meyer, D. T.; Jadhav, P. K.; De Lucca, G.
V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner,
M. M.; Seitz, S. P. J. Med. Chem. 1996, 39, 2156–2169.
6. McNulty, J.; Veronika Grunner, V.; Mao, J. Tetrahedron
Lett. 2001, 42, 5609.
10. For 12a [a]D = À146 (c 0.13, CHCl3) for (R)-isomer. Lit.11
[a]D = À99.0 (c 0.13, CHCl3).
For 13a [a]D = À141.8 (c 0.13, CHCl3) for (R)-isomer.
Lit.11 [a]D = À144 (c 1.03, CHCl3).
11. Moreno-Dorado, F. J.; Guerra, F. M.; Ortega, M. J.;
`
Zubıa, E.; Massanet, G. M. Tetrahedron: Asymmetry
2003, 14, 503.
12. Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int.
Ed. 2001, 40, 92.