Enantioselective synthesis of β-aryloxycarboxylic esters via asymmetric hydrogenation of β-aryloxy-α,β-unsaturated esters

Article abstract of DOI:10.1021/ol302518y

A novel synthesis of β-aryloxycarboxylic esters via asymmetric hydrogenation of the corresponding β-aryloxy-α,β-unsaturated esters has been demonstrated. Bis(norbornadiene)rhodium(I) tetrafluoroborate (1 mol %) and Walphos W008-1 were used to generate the

Full text of DOI:10.1021/ol302518y

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5440–5443
Enantioselective Synthesis of
β‑Aryloxycarboxylic Esters via
Asymmetric Hydrogenation of
β‑Aryloxy-r,β-Unsaturated Esters
Gavin W. Stewart,*,† Michael Shevlin,*,‡ Adam D. Gammack Yamagata,†
Andrew W. Gibson,† Stephen P. Keen,† and Jeremy P. Scott†
Global Process Chemistry, Merck Sharp and Dohme Research Laboratories,
Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, United Kingdom,
and Global Process Chemistry, Merck Sharp and Dohme Research Laboratories,
Rahway, New Jersey 07065, United States
gavin_stewart@merck.com; michael_shevlin@merck.com
Received September 12, 2012
ABSTRACT
A novel synthesis of β-aryloxycarboxylic esters via asymmetric hydrogenation of the corresponding β-aryloxy-r,β-unsaturated esters has
been demonstrated. Bis(norbornadiene)rhodium(I) tetrafluoroborate (1 mol %) and Walphos W008-1 were used to generate the saturated
products with high enantioselectivity and in high yield. The tolerability of the reaction to a diverse range of substituents on the aromatic ring
was also explored.
Enantioenriched β-aryloxycarboxylic acid derivatives
are pharmacologically active molecules with a wide range
of physiological activity, such as antithrombotic,1 anticancer,2
vasodilatory,3 and antimyotonic4 effects. In addition, this
structural motif is present in natural products,5 agricultural
chemicals,6 and synthetic intermediates.7
Enantioenriched β-aryloxycarboxylic acid derivatives
have been prepared by enzymatic resolution (with a max-
imum yield of 50%)8 while cyclic β-aryloxycarboxylic acid
derivatives have been synthesized using the asymmetric
Stetter reaction,9 asymmetric conjugate additions,10 and
enantioselective CÀH insertions.11
† Merck Sharp and Dohme Research Laboratories, Hertfordshire, U.K.
‡ Merck Sharp and Dohme Research Laboratories, New Jersey, U.S.
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R.; Susaki, H. World Patent WO2011024933, 2011. (b) Wang, S.; Beck,
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Chahwala, S.; Chander, C.; Holland, R.; Merette, S.; Zhao, L.; Blackney, M.;
Watts, A. J. Med. Chem. 2010, 53, 1465–1472.
(2) Vianello, P.; Bandiera, T. U.S. Patent 20030073688, 2003.
(3) Hashiyama, T.; Watanabe, A.; Inoue, H.; Konda, M.; Takeda,
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r
10.1021/ol302518y
Published on Web 10/16/2012
2012 American Chemical Society

The asymmetric hydrogenation of R-aryloxy-R,β-
unsaturated acids has been reported.12 To the best of our
knowledge, however, there have been no reports of asym-
metric hydrogenations of β-aryloxy-R,β-unsaturated car-
boxylic acid derivatives. The enantioselective reduction
of structurally similar β-alkoxy-R,β-unsaturated esters
has been reported; however, these reactions require high
pressures and employ a catalyst that is not commercially
available.13
conditions for further manipulation at this position.
The enantioselective hydrogenation of 3a was exam-
ined with a wide range of rhodium and ruthenium cata-
lysts prepared in situ from chiral ligands (Figure 1) and
bis(norbornadiene)rhodium(I) tetrafluoroborate17 or(cyclo-
octadiene)bis(methallyl)ruthenium(II) and tetrafluoroboric
acid.18
In the course of our research to synthesize key inter-
mediates for a clinical program, we requiredrapid access to
enantioenriched β-aryloxybutanoic acid esters. Given
that asymmetric hydrogenation of prochiral olefins is a
powerful method for synthesizing compounds with high
optical purity,14 and enantioselective reduction of R,β-
unsaturated esters can generate a wide variety of chiral
esters,14 we envisioned that asymmetric hydrogenation of
β-aryloxy-R,β-unsaturated esters could provide access to
chiral β-aryloxyesters in high optical purity. Encouraged
by a report of racemic hydrogenation of β-aryloxy-R,β-
unsaturated esters by homogeneous rhodium catalysis,15
we began our search for an enantioselective reaction.
Figure 1. Ligands used in screening.
We were encouraged to find that the Ru/J212-1 catalyst
system, previously reported for the asymmetric hydroge-
nation of a β-aryl-R,β-unsaturated ester,19 gave good
conversion to the desired product with good enantioselec-
tivity (Table 1, entry 1). Further screening revealed that
higher enantioselectivity could be obtained with Josiphos
ligands20 containing a bis(tert-butyl)phosphino substitu-
ent on the ferrocene ring (entries 2 and 3). However, the
highly respectable enantiomeric excesses achieved (91.2
and 96.6%) still fell short of the requirements of our
clinical program. We next turned our attention to rhodium
catalysts. While Rh/J212-1 and Rh/J506-1 provided ex-
cellent reactivity, they suffered from poor enantioselectiv-
ity (entries 4 and 5). Josiphos ligands J009-1, J001-1, and
J031-1 provided increasing levels of enantioselectivity, but
they also caused significant cleavage of the sensitive aryl
enol ether moiety to form phenol 1a (entries 6À8). Switch-
ing to the structurally related Walphos ligands21 also gave
goodreactivity and selectivity (entries 9À11). Inparticular,
the Rh/W008-1 catalyst system gave high conversion and
very good selectivity for this reaction (entry 11). In all
cases, formation of byproduct 5 via reduction of the aryl
halide was minimal.
Scheme 1
We began by focusing on the reduction of substrate 3a
which was prepared by conjugate addition of phenol 1a
to alkyne 2 (Scheme 1).16 The (E)-olefin was separated
from a 97:3 mixture of E/Z isomers (1H NMR ratio) using
chromatography. 2-Bromophenol 1a was selected to as-
sess the tolerance of an ArÀBr bond to hydrogenation
Having identified the optimal catalyst, we turned our
efforts toward optimizing the reaction parameters. Given
that the solvent can have a marked influence on the
(13) Zhu, Y.; Burgess, K. Adv. Synth. Catal. 2008, 350, 979–983.
(14) Ohkuma, T.; Kitamura, M.; Noyori, R. Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, NY, 2000;
Chapter 1, pp 1À110.
(15) Mohrig, J. R.; Rosenberg, R. E.; Apostol, J. W.; Bastienaansen,
M.; Evans, J. W.; Franklin, S. J.; Frisbie, C. D.; Fu, S. S.; Hamm, M. L.;
Hirose, C. B.; Hunstad, D. A.; James, T. L.; King, R. W.; Larson, C. J.;
Latham, H. A.; Owen, D. A.; Stein, K. A.; Warnet, R. J. Am. Chem. Soc
1997, 119, 479–486.
(18) Dobbs, D. A.; Vanhessche, K. P. M.; Brazi, E.; Rauchenstrauch,
^
V.; Lenoir, J.-Y.; Genet, J.-P.; Wiles, J.; Bergens, S. H. Angew. Chem.,
Int. Ed. 2000, 39, 1992–1995.
(19) Molinaro, C.; Shultz, S.; Roy, A.; Lau, S.; Trinh, T.; Angelaud,
R.; O’Shea, P. D.; Abele, S.; Cameron, M.; Corley, E.; Funel, J.-A.;
Steinhuebel, D.; Weisel, M.; Krska, S. J. Org. Chem. 2010, 76, 1062–
1071.
(16) DABCO-mediated addition of substituted phenols to alkyl but-
2-ynoates has been reported previously: (a) Fan, M.-J.; Li, G.-Q.; Li,
L.-H.; Yang, S.-D.; Liang, Y.-M. Synthesis 2006, 14, 2286–2292. (b) Li,
C.; Zhang, Y.; Li, P. J. Org. Chem. 2011, 76, 4692–4696.
(20) Blaser, H.-U.; Brieden, W.; Pugin, B.; Spindler, F.; Studer, M.;
Togni, A. Top. Catal. 2002, 19, 3–16.
(21) Sturm, T.; Weissensteiner, W.; Spindler, F. Adv. Synth. Catal.
2003, 345, 160–164.
(22) Heller, D.; Drexler, H.-J.; Spannenberg, A.; Heller, B.; You, J.;
Baumann, W. Angew. Chem., Int. Ed. 2002, 41, 777–780.
(17) At the high catalyst loadings we employ for screening, the NBD
precursor can be much more effective than the corresponding COD
precursor. See: (a) Cobley, C. J.; Lennon, I. C.; McCague, R.; Ramsden,
J. A.; Zanotti-Gerosa, A. Tetrahedron Lett. 2001, 42, 7481–7483.
(b) Drexler, H.-J.; Baumann, W.; Spannenberg, A.; Fischer, C.; Heller, D.
J. Organomet. Chem. 2001, 621, 89–102.
Org. Lett., Vol. 14, No. 21, 2012
5441

With optimized conditions in hand,24 we turned our
attention to investigating the scope and limitations of this
chemistry. Unsaturated esters 3aÀ3k were prepared pre-
dominantly as the (E)-olefin isomers25 in good yield by
conjugate addition of phenols 1aÀ1k to alkyne 2 in the
presence of DABCO in acetonitrile (Scheme 2, Table 2).
These conditions were established through screen-
ing and were optimized to minimize formation of the
minor (Z)-isomer (removed by chromatography) which
was demonstrated to favor the undesired enantiomer
of the saturated ester in the subsequent asymmetric
hydrogenation (vide infra). Variables screened included
type of base, concentration, and temperature, but the
choice of acetonitrile as solvent and the stoichiometry
of DABCO were found to be particularly important
factors.
Table 1. Catalyst Screeninga
entry
M
ligandb
4ac
% eed
5c
1ac
1
Ru
Ru
Ru
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
J212-1
J502-1
J506-1
J212-1
J506-1
J009-1
J001-1
J031-1
W006-1
W002-1
W008-1
93.5
71.1
95.6
98.1
98.0
97.7
78.8
65.4
81.3
86.5
94.0
90.2 (R)
91.2 (R)
96.6 (R)
41.5 (R)
7.8 (S)
3.4
1.1
3.3
0.7
0
3.1
2
1.7
3
0.3
4
1.2
5
2.0
6
76.1 (S)
89.7 (R)
92.2 (R)
87.9 (R)
92.5 (R)
98.0 (R)
0.9
2.6
0
1.4
7
18.5
34.6
18.1
13.5
5.3
8
9
0.7
0
10
11
0.7
a Reaction conditions: 25 mol % (COD)Ru(Methallyl)2/HBF4 OEt2
in 2-Me-THF or 25 mol % (NBD)2RhBF4 in EtOH, 500 psi H2, 0.016 M
substrate, 50 °C, 18 h. b See Figure 1 for ligand structures. c HPLC Area
Percentage. d Optical purity determined by chiral HPLC analysis.
3
Scheme 2
reactivity of asymmetric hydrogenations,22 we conducted
catalyst loading studies in a number of different solvents.23
Common solvents for hydrogenation such as MeOH,
iPrOAc, and 2-MeTHF gave lower reactivity and
slightly diminished enantioselectivity (94À97%), but 1,2-
dichloroethane (DCE) gave complete conversion and
98.2% ee even at 0.2% catalyst loading (Figure 2). Still
better performance was observed in halogenated aro-
matics, with good conversion using as little as 0.1 mol %
catalyst and high enantioselectivities in PhCF3 and chloro-
benzene (97.6 and 98.2% ee, respectively). We postulate
that the halogenated solvents offer superior performance
(over MeOH, iPrOAc, and 2-MeTHF) due to their rela-
tively weak coordination with the catalyst. We chose
chlorobenzene as the solvent for further studies, as it
facilitated higher reactivity in the hydrogenations and is
commercially available on a large scale.
Table 2. Preparation of β-Aryloxybuten-2,3-oatesa
entry
phenol
R
unsat. esterb
yieldc
1
1a
1b
1c
1d
1e
1f
2-Br
H
3a
3b
3c
3d
3e
3f
77
74
81
79
69
81
83
78
74
81
56
2
3
2-Me
4-Me
2-OMe
2-F
4
5
6
7
1g
1h
1i
4-F
3g
3h
3i
8
2-Cl
3-Br
2-I
9
10
11
1j
3j
1k
4-NO2
3k
a Reaction conditions: 1.2 equiv of 1, 0.98 equiv of DABCO, MeCN,
1
70 °C, 2 h. b Ratio of E/Z formed was at least 96:4 in each case by H
NMR. c Isolated yield obtained by chromatographic purification of
stereoisomerically pure (E)-isomer.
(23) Catalyst loading studies were performed at 120 psi H2, 0.3 M
substrate, 50 °C, 18 h. See Supporting Information for tabular results.
(24) We also examined the effect of other parameters on the outcome
of the reaction. Decreasing the pressure of H2 led to reduced reac-
tivity (with no observable impact on enantioselectivity), but a lower
pressure was used due to autoclave constraints. To compensate, increas-
ing the temperature increased reactivity (with a slight decrease in
enantioselectivity) and increasing the concentration also led to in-
creased reactivity (with minimal impact on enantioselectivity). See
Supporting Information for details.
(25) Olefin geometry determined by NMR (see Supporting
Information).
(26) The absolute configuration of 4a was established by chemical
correlation with a sample independently synthesized from commercially
available (S)-4-penten-2-ol (see Supporting Information). The absolute
configuration of 4bÀ4j were assigned by analogy.
Figure 2. Catalyst loading studies in various solvents.
5442
Org. Lett., Vol. 14, No. 21, 2012

the same catalyst/ligand combination and found that they
gave good yields of the product with high but opposite
absolute stereochemistry (entries 12À14). Webelieve thisis
an unusual instance where a given enantiomer of a hydro-
genation catalyst can enantioselectively hydrogenate either
the (E)- and (Z)-isomers of a prochiral substrate with
opposite but equally high selectivity. This observation
highlights the importance of controlling E/Z selectivity in
the conjugate addition step.27
In summary, we have demonstrated an efficient method
of preparing highly enantioenriched β-aryloxycarboxylic
esters via a two-step conjugate addition/aymmetric
hydrogenation sequence, starting from commercially
available materials. Specifically, a highly (E)-selective
conjugate addition of substituted phenols to ethyl but-
2-ynoate was developed. The resulting (E)-olefins were
then asymmetrically hydrogenated in the presence of
just 1 mol % bis(norbornadiene)rhodium(I) tetrafluoro-
borate and Walphos W008-1 to afford the saturated
products in high enantiopurity and yield. The compat-
ibility of the reaction with a range of aromatic sub-
stituents was also demonstrated.
Table 3. Asymmetric Hydrogenation of β-Aryloxy Ene-Estersa
entry
unsat. ester
product
yieldb
%eec
1
3a
4a
83
88
88
83
95
85
87
90
81
77d
97.7 (R)
95.7 (R)
96.0 (R)
95.7 (R)
91.3 (R)
94.5 (R)
96.7 (R)
95.1 (R)
96.8 (R)
71.9 (R)
À
2
3b
4b
3
3c
4c
4
3d
4d
5
3e
4e
6
3f
4f
7
3g
4g
8
3h
4h
9
3i
4i
10
11
12
13
14
3j
4j
e
3k
4k
À
(Z)-3a
(Z)-3b
(Z)-3f
(S)-4a
(S)-4b
(S)-4f
81
93
93
96.0 (S)
93.9 (S)
94.5 (S)
a Reaction conditions:1% (NBD)2RhBF4, 1.05% SL-W008-1, PhCl,
80 °C, 125 psi H2, 20 h. b Isolated yield. c Optical purity determined by
chiral HPLC analysis. d 3 mol % catalyst used. e Nitro functional group
reduced to aniline.
Unsaturated substrates 3aÀ3i were reduced to the ana-
logous saturated products 4aÀ4i in good yield and high
optical purity (Table 3, entries 1À9).26 Hydrogenation of
ortho-iodo substrate 3j proceeded in lower yield and
selectivity (entry 10), presumably due to steric effects.
The nitro functionality in substrate 3k was not tolerated
and was reduced to the corresponding aniline (entry 11).
We also examined several of the (Z)-olefin isomers using
Acknowledgment. We acknowledge our fellow Merck
Sharp & Dohme colleagues: Tanja Brkovic and Andy
Kirtley for assistance with chiral HPLC assays, Shane
W. Krska and Steven Miller for helpful discussions, David
Murray for mass spectrometry characterization, and
Robert A. Reamer for running 2D NMR experiments.
Supporting Information Available. General experimen-
tal methods for the preparation of 3aÀ3k and 4aÀ4j with
isolated yields; characterization data for 3aÀ3k, (Z)-3a,
(Z)-3b, (Z)-3f, and 4aÀ4j; chiral HPLC methods and
traces for racemates and saturated products 4aÀ4j,
(S)-4a, (S)-4b, and (S)-4f; NMR evidence for (E)-olefin
geometry; details of independent synthesis of 4a from
(S)-4-penten-2-ol to establish absolute configuration.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(27) For examples of asymmetric hydrogenation of (E)- and
(Z)-diastereomers of β-substituted ene-esters where one diastereomer
gives diminished selectivity compared to the other, see: (a) Lu, W.-J.;
Chen, Y.-W.; Hou, X.-L. Adv. Synth. Catal. 2010, 352, 103–107. (b)
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Kallstrom, K.; Andersson, P. G. Tetrahedron Lett. 2006, 47, 7477–7480.
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(c) Hedberg, C.; Kallstrom, K.; Brandt, P.; Hansen, L. K.; Andersson,
€
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P. G. J. Am. Chem. Soc. 2006, 128, 2995–3001. (d) Kallstrom, K.;
Hedberg, C.; Brandt, P.; Bayer, A.; Andersson, P. G. J. Am. Chem.
Soc 2004, 126, 14308–14309. (e) Tang, W.; Wang, W.; Zhang, X. Angew.
Chem., Int. Ed. 2003, 42, 943–946. (f) Murakami, M.; Kobayashi, K.;
Hirai, K. Chem. Pharm. Bull. 2000, 48, 1567–1569. (g) Marchetti, M.;
Alberico, E.; Bertucci, C.; Botteghi, C.; Del Ponte, G. J. Mol. Catal. A:
Chem 1997, 125, 109–117.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
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