Enantioselective hydrogenation of α-aryloxy α,β- unsaturated acids. Asymmetric synthesis of α-aryloxycarboxylic acids

Article abstract of DOI:10.1021/ol0488035

(Chemical Equation Presented) A facile preparation of chiral α-aryloxy carboxylic acids via asymmetric hydrogenation of the corresponding unsaturated acids has been discovered. A number of catalysts have been identified that give high product enantioselectivity, and the scope of the reaction has been examined with respect to substitution on the aromatic ring and olefin.

Full text of DOI:10.1021/ol0488035

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3147-3150
Enantioselective Hydrogenation of
r-Aryloxy r,â-Unsaturated Acids.
Asymmetric Synthesis of
r-Aryloxycarboxylic Acids
Peter E. Maligres,* Shane W. Krska,* and Guy R. Humphrey
Department of Process Research, Merck & Co., Inc., Rahway, New Jersey 07065
peter_maligres@merck.com
Received June 23, 2004
ABSTRACT
A facile preparation of chiral r-aryloxy carboxylic acids via asymmetric hydrogenation of the corresponding unsaturated acids has been
discovered. A number of catalysts have been identified that give high product enantioselectivity, and the scope of the reaction has been
examined with respect to substitution on the aromatic ring and olefin.
The R-aryloxy acids and their derivatives have important
applications in the agrochemical field as herbicides,1 plant
hormone and growth regulators,2 pesticides,3 and fungicides.4
In addition, they exhibit important pharmacological proper-
ties, making them useful as nootropic and analgesic agents,5
hypocholesterolemic and hyperlipidemic agents,6 and imag-
ing agents.7 Furthermore, these compounds, especially when
optically active, are useful synthetic intermediates.8
number of methods exist for the enantioselective preparation
of structurally related 2-hydroxyacids, among them enzy-
matic,9 microbial,10 chiral auxiliary,11 chiral reagent,12 and
asymmetric hydrogenation,13 further elaboration of these
intermediates to the corresponding R-aryloxy acids without
racemization is expected to be a nontrivial process.14 The
direct preparation of R-aryloxy acids can be accomplished,
Until now, there have been few reported methods for
synthesis of optically active R-aryloxy acids. Although a
(8) (a) Perron, Y. J.; Minor, W. F.; Holdrege, C. T.; Gottstein, W. J.;
Godfrey, J. C.; Crast. L. B.; Babel, R. B.; Cheney. L. C. J. Am. Chem. Soc.
1960, 82, 3934-3938. (b) Mejorado, L. H.; Hoarau, C.; Pettus, T. R. R.
Org. Lett. 2004, 6, 1535-1538.
(9) (a) Kanomata, N.; Nakata, T. J. Chem. Soc. 2000, 122, 4563-4568.
(b) Ahmed, F.; Al-Mutairi, E. H.; Avery, K. L.; Cullis, P. M.; Primrose,
W. U.; Roberts, G. C. K.; Willis, C. L. J. Chem. Soc., Chem. Commun.
1999, 2046-2050. (c) Macritchie, J. A.; Silcock, A.; Willis, C. L.
Tetrahedron: Asymmetry 1997, 8, 3895-3902.
(10) (a) Chadha, A.; Manohar, M.; Soundararajan, T.; Lokeswari, T. S.
Tetrahedron: Asymmetry 1996, 7, 1571-1572. (b) Dao, D. C.; Okamura,
M.; Akasaka, T.; Kawai, Y.; Hida, K.; Ohno, A. Tetrahedron: Asymmetry
1998, 9, 2725-2737. (c) Jian-Xin, G.; Guo-Qiang, L. Tetrahedron 1993,
49, 5805-5816.
(11) (a) Devine, P. N.; Dolling, U.-H.; Heid, R. M.; Tschaen, D. M.
Tetrahedron Lett. 1996, 37, 2683-2686. (b) Solladie-Cavallo, A.; Ben-
choqroun, M. Tetrahedron: Asymmetry 1991, 2, 1165-1171. (c) Boireau,
G.; Deberly, A. Tetrahedron: Asymmetry 1991, 2, 771-774.
(12) (a) Chauvin, R. Tetrahedron: Asymmetry 1990, 1, 737-742. (b)
Brown, H. C.; Ramachandran, P. V.; Weissman, S. A.; Swaminathan, S. J.
Org. Chem. 1990, 55, 6328-6333. (c) Wang, Z.; La, B.; Fortunak, J. M.;
Meng, X.-J.; Kabalka, G. W. Tetrahedron Lett. 1998, 39, 5501-5504. (d)
Ramachandran, P. V.; Brown, H. C.; Pitre, S. Org. Lett. 2001, 3, 17-18.
(1) (a) Secor, J.; Cseke, C.; Owen, W. J. In Biocatalysis in Agricultural
Biotechnology; Whitaker, J. R., Sonnet, P. E., Eds.; ACS Symposium Series
389: American Chemical Society: Washington, DC, 1989; pp 265-276.
(b) Kikuo, A.; Kiyotaka, Y. Japanese Patent 4202168, 1992.
(2) Haskelberg, L. J. Org. Chem. 1947, 12, 423-433.
(3) Mathew, N.; Subramanian, S.; Kalyanasundaram, M. Ind. J. Chem.
1996, 35, 40-44.
(4) Joshi, K. C.; Bahel, S. C. J. Ind. Chem. Soc. 1960, 37, 365-366.
(5) Gualtieri, F.; Bottalico, C.; Calandrella, A.; Dei, S.; Giovannoni, M.
P.; Maelli, S.; Romanelli, M. N.; Scapecchi, S.; Teodori, E.; Galeotti, N.;
Ghelardini, C.; Giotti, A.; Bartolini, A. J. Med. Chem. 1994, 37, 1712-
1719.
(6) (a) Amoroso, R.; Bettoni, G.; Tricca, M. L.; Loiodice, F.; Ferorelli,
S. Il Farmaco 1998, 53, 73-79. (b) Feller, D. R.; Kamanna, V. S.; Newman
H. A. I.; Romstedt, K. J.; Witiak, D. T.; Bettoni, G.; Bryant, S. H.; Conte-
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10.1021/ol0488035 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/06/2004

albeit in 50% maximum theoretical yield, by microbial or
enzymatic resolution of the racemic acids or esters15 or the
well-known resolution of carboxylic acid salts via crystal-
lization with optically active amines. The microbial derace-
mization of the racemic R-aryloxy acids with the potential
of a quantitative yield is known.16 Unfortunately, this
microbial deracemization is sensitive to the nature of the
aryloxy substituent where steric bulk would not allow the
reaction to proceed, and ortho or meta substituents resulted
in unselective reactions.
Scheme 1
As part of an ongoing effort to synthesize key intermedi-
ates for a clinical program, we required rapid access to chiral
R-aryloxy acid derivatives. Homogeneous enantioselective
hydrogenation of prochiral olefins is a powerful technique
for synthesizing a variety of chiral compounds with excellent
enantioselectivity.17 Given the general utility of asymmetric
hydrogenation of unsaturated acids,17 we envisioned the
R-aryloxy R,â-unsaturated acids could potentially provide
directly a broad variety of R-aryloxy acids in high optical
purity. Despite isolated reports on the enantioselective
hydrogenation of benzofuran,18 furan,19 and benzopyran20
carboxylic acids, to the best of our knowledge R-aryloxy
R,â-unsaturated acids represent a new substrate class for
asymmetric hydrogenation.21 Herein we report that asym-
metric hydrogenation of R-aryloxy R,â-unsaturated acids
provides saturated R-aryloxy acids in high optical purity.
Our initial studies focused on R-phenoxybutenoic acid (Z)-
3a,22 which was prepared from the reaction of 2-bro-
mobutenoate 2a23 with phenol 1a followed by hydrolysis of
the methyl ester (Scheme 1). The enantioselective hydroge-
nation of 3a to 4a2,5,8a was examined using a library of
(bisphosphine)ruthenium precatalysts prepared in situ from
[(p-cymene)RuCl2]2 and the commercially available bispho-
sphine ligands.24 The hydrogenation was conducted in the
presence of triethylamine in MeOH. The results of the
catalyst screen are shown in Table 1. We were pleased to
Table 1. Catalyst Screen for Hydrogenationa of 3a to 4a
ligandb
% conversion % eec area % phenol
(S)-Synphos
(S)-P-Phos
(+)-TMBTP
(R)-Cl-MeO-BIPHEP
(S)-BINAPd
100.0
95.4
100.0
100.0
100.0
92.1
97(S)
91(S)
99(R)
92(R)
93(S)
55(S)
48(R)
1(S)
78(R)
89(S)
21(S)
86(R)
0
0.4
2.6
0.0
2.1
0.0
4.4
1.8
0.0
0.7
0.9
0.0
0.0
0.0
(S)-BINAM
(R,S)-PPF-PtBu
(S,S,S,S)-Me-f-KetalPhos
(S)-Binapine
(R,R)-iPr-DUPHOS
(R)-PHANEPHOS
(R,R)-Et-FerroTANE
(S)-Me-BoPhoz
98.6
100.0
100.0
100.0
100.0
100.0
100.0
(13) (a) Zuo, X.; Liu, H.; Guo, G.; Yang, X. Tetrahedron: Asymmetry
1999, 55, 7787-7804. (b) Wandeler, R.; Kunzle, N,; Schneider, M. S.;
Mallat, T.; Baiker, A. J. Chem. Soc., Chem. Commun. 2001, 673-674. (c)
Benincori, T.; Cesarotti, E.; Piccolo, O.; Sannicolo, F. J. Org. Chem. 2000,
65, 2043-2047.
a Solution containing 4 mg/mL of 3a, 1.05 equiv of Et3N, 11.5 mol %
ligand, and 5.75 mol % [(p-cymene)RuCl2]2 in a mixture of 80:13:7 by
volume MeOH/EtOH/CH2Cl2 was hydrogenated at 20-25 °C under 90 psig
hydrogen for 20 h. The reaction mixtures were directly assayed by HPLC
for % conversion and % ee. b See Supporting Information for ligand
structures. c Absolute configuration25 in parentheses. d Performed with 20
mol % [(S)-BINAP]RuCl2.
(14) For a recent example employing a Mitsunobu coupling of a phenol
with a chiral 2-hydroxyamide see ref 8b.
(15) (a) Massolini, G.; Calleri, E.; Lavecchia, A.; Loiodice, F.; Lubda,
D.; Temporini, C.; Fracchiolla, G.; Tortorella, P.; Novellino, E.; Caccialanza,
G. Anal. Chem. 2003, 75, 535-542. (b) Colton, I. J.; Ahmed, S. N.;
Kazlauskas, R. J. J. Org. Chem. 1995, 60, 212-217.
(16) Kato, D.-I.; Mitsuda, S.; Ohta, H. J. Org. Chem. 2003, 68, 7234-
7242.
(17) (a) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric
Synyhesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994.
(18) (a) Maris, M.; Huck, W.-R.; Mallat, T.; Baiker, A. J. Catal. 2003,
52-58.
find high conversions and >90% ee for a number of ligands.
In most cases, the chemical selectivity was high with the
only by-product being low levels of phenol. It is noteworthy
that the sense of enantioinduction observed in the hydroge-
nation of 3a ((S)-4a25 with (S)-BINAP) was the same as that
observed with simple 2-alkyl and 2-arylacrylates.17
Among all the ligands tested, the atropisomeric bisphos-
phines, BINAP, Synphos, P-Phos, Cl-MeO-BIPHEP, and
TMBTP, provided the highest enantioselectivities, consistent
with literature precedent.17 Of this series BINAP is by far
(19) Studer, M.; Wedemeyer-Exl, C.; Spindler, F.; Blaser, H.-U. Monatsh.
Chem. 2000, 131, 1335-1343.
(20) Kurano, M.; Kondo, Y.; Miura, K.; Usui, T.; Unno, R.; Kakigami,
T.; Sawai, K. U.S. Patent 5171865, 1992.
(21) R-Acyloxyacrylates, which contain a chelating acyl group, have been
enantioselectively hydrogenated using rhodium catalysts. (a) Lotz, M.;
Polborn, K.; Knochel, P. Angew. Chem. 2002, 114, 4902-4905. (b) Lotz,
M.; Ireland, T.; Perea, J. J. A.; Knochel, P. Tetrahedron: Asymmetry 1999,
10, 1839-1842. (c) Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem.
Soc. 1998, 120, 4345-4353. (d) Schmidt, U.; Langner, J.; Kirschbaum,
B.; Braun, C. Synthesis 1994, 1138-1140. The enantioselective hydrogena-
tion of aryl enol ethers is known. (e) Ohta, T.; Miyake, T.; Seido, N.;
Kumobayashi, H.; Takaya, H. J. Org. Chem. 1995, 60, 357-363.
(22) (a) Rosnati, V.; Saba, A.; Salimbeni, A. Tetrahedron Lett. 1981,
22, 167-168. (b) Padmanathan, T.; Sultanbawa, M. U. S. J. Chem. Soc.
1963, 4210-4218. X-ray crystallographic data for unsaturated acids 3e and
3f show the stereochemistry of the olefin to be the (Z)-configuration.
(23) Prostenik, M.; Salzman, N. P.; Carter, H. E. J. Am. Chem. Soc.
1955, 77, 1856.
(24) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.;
Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya,
H. J. Org. Chem. 1994, 59, 3064-3076.
(25) (a) Smeets, J. W. H.; Kieboom, A. P. C. Recl. Trac Chim. Pays-
Bas 1992, 111, 490-495. (b) Tsuda, Y.; Kawai, K.-I.; Nakajima, S. Chem.
Pharm. Bull. 1985, 33, 1955-1960. (c) Piekarski, S. Bull. Soc. Chim. Fr.
1959, 441-445. (d) Matell, M. Ark. Kemi. 1953, 6, 251-255.
3148
Org. Lett., Vol. 6, No. 18, 2004

the least expensive and most widely available and was
therefore chosen for further studies to examine the scope of
the hydrogenation reaction with respect to substrate. To
with >99% conversion and moderate to high yields (Table
3). Substrates 3a-l with a trisubstituted olefin gave the
Table 3. Asymmetric Hydrogenation of R-Aryloxy
Unsaturated Acidsa
Scheme 2
unsaturated
acid
mol %
R-aryloxy
phenol
(area %)c
catalyst acid (% yield)b
% eed
3a
3b
3c
3d
3e
3f
3g
3h
3i
20, 1
20
20, 1
20, 1
20
20, 1
20
20, 1
20
4a (99, 93)
4b (79)
4c (96, 98)
4d (79, 89)
4e (74)
4f (94, 94)
4g (84)
4h (84, 97)
4i (80)
1a (<1, <1) 93, 94
1b (3.8) 93
1c (<1, 0.9) 92, 95
1d (<1, <1) 94, 93
1e (1.5)
1f (<1, <1) 95, 95
1g (2.8) 77
1h (2.5, 1.6) 92, 95
1i (6.4) 86
1j (2.0, 2.0) 91, 93
88
3j
3k
3l
20, 2
20
20
4j (90, 91)
4k (79)
4l (65)
1k (9.7)
1a (<1)
1l (<1)
61
90
32
3m
20
4m (90)
explore the scope of the asymmetric hydrogenation, R-aryl-
oxy unsaturated acids 3b-k were prepared in excellent yields
as the (Z)-isomers22 by reaction of phenols 1b-k with
bromobutenoate 2a in a manner like that used for 3a (Table
2). The unsaturated acids were readily isolated in high yields
a Unsaturated acids 3a-m (0.5 mmol) were hydrogenated in the presence
of [(S)-BINAP]RuCl2 and Et3N (0.54 mmol) in MeOH (1 mL) at 25 °C
under 90 psig hydrogen for 20 h. b Assay yield determined by quantitative
HPLC; all reactions reached >99% conversion. c Area % phenol byproduct
by HPLC. d Optical purity determined by chiral HPLC. Optical rotation in
all cases was negative.
corresponding saturated products 4a-l in moderate to high
optical purities, while tetrasubstituted olefin 3m exhibited
markedly lower enantioselectivity in the hydrogenation. The
enantioselective hydrogenation accepted a variety of substi-
tution on the aryl group, including ortho and meta substit-
uents, which were not tolerated in the microbial deracem-
ization protocol mentioned previously.16 Furthermore, the
reaction was demonstrated to proceed using only 1 mol %
catalyst for a number of substrates (3a,c,d,f,g in Table 3)
without appreciable effect on the yield or optical purity.28
Interestingly, it appears that the levels of the phenol impurity
are increased in the presence of greater steric bulk in the
ortho-substituted cases and in the more electron-deficient aryl
ethers. It is also noteworthy that functionalities sensitive to
reduction (cf. 3i, 3j, and 3k) are unaffected by the enantio-
selective hydrogenation.
Table 2. Preparation of R-Aryloxy Unsaturated Acids
unsaturated % assay
R
ArOH bromoenoate
acid
yielda
% yieldb
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
3a
3b
3c
3d
3e
3f
3g
3h
3i
99
99
99
99
96
94
99
98
99
95
99
98
97
94
92
93
94
92
93
95
98
94
94
98
97c
95
2-Me
4-Me
2-OMe
2-F
4-F
2-Cl
3-Br
2-I
3-I
4-NO2
H
1j
3j
3k
3l
1k
1a
1l
4-OMe
3m
a Assay yield determined by quantitative HPLC at the end of the reaction.
b Isolated yield of crystallized product 3. c Isolated by extraction of the
acidified reaction mixture with t-BuOMe followed by crystallization as the
dicyclohexylamine salt.
In summary, we have shown that asymmetric hydrogena-
tion of R-aryloxy unsaturated acids provides an efficient
means to synthesize optically active R-aryloxy acids. This
method tolerates a variety of substitution patterns on the
aromatic ring as well as limited variation in substitution on
the olefin.
as crystalline solids by simple acidification of the aqueous
reaction mixture after basic hydrolysis. The unsaturated acids
3l and 3m were prepared from 2b26 and 2c,27 respectively,
to observe the effects of further substitution on the olefin.
Substrates 3a-m were screened using 20 mol % [(S)-
BINAP]RuCl2 as precatalyst giving R-aryloxy acids 4a-m
Acknowledgment. We acknowledge Dr. Chris Welch and
Ms. Mirlinda Biba for their assistance with the chiral HPLC
assays, Ms. Jennifer Chilenski for her work on the X-ray
crystal structures, Ms. Audrey Wong for obtaining elemental
analysis, Dr. Tom Novak for high-resolution mass spectra,
and Ms. Lisa DiMichele and Mr. Bob Reamer for their NMR
support.
(26) (a) Stacy, G. W.; Wagner, G. D. J. Am. Chem. Soc. 1952, 74, 909-
911. (b) Bachman, G. B. J. Am. Chem. Soc. 1933, 55, 4279-4284.
(27) (a) Lloveras, M.; Ramos, I.; Molins, E.; Messeguer, A. Tetrahedron
2000, 56, 3391-3397. (b) Yoshida, M.; Mori, K. Eur. J. Org. Chem. 2000,
1313-1317. (c) Korhonen, I. O. O.; Pitkanen, M.; Korvola, J. N. J.
Tetrahedron 1982, 38, 2837-2841.
(28) Hydrogenation of 3a was demonstrated to proceed to complete
conversion in 72 h using only 0.24 mol % [(S)-BINAP]RuCl2.
Org. Lett., Vol. 6, No. 18, 2004
3149

Supporting Information Available: General experimen-
tal methods for preparation of 3a-m, racemic acids 4a-m
and for the enantioselective hydrogenations with isolated
yields; characterization data for 2b, 3b-m, and 4h; HPLC
data and methods for all compounds; HPLC traces of
racemates and isolated products 4a-m from the hydrogena-
tions; X-ray crystal data for 3e and (S)-4h; literature
references for 4b-g and 4i-m; and structures and sources
of ligands in Table 1. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0488035
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Org. Lett., Vol. 6, No. 18, 2004