Asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated esters catalyzed by dicationic palladium(II)-chiraphos complex for short-step synthesis of SmithKline Beecham's endothelin receptor antagonist

Article abstract of DOI:10.1055/s-2008-1078259

An asymmetric 1,4-addition of arylboronic acids to RCH=CHCO₂Ar (Ar = Ph or 4-acetylphenyl) was carried out at 50°C in aqueous acetone in the presence of [Pd(chiraphos)(Ph-CN)₂](SbF₆)₂. The reaction gave optically active β-aryl esters in up to 98% ee. The protocol provided a simple access to an endothelin receptor antagonist reported by SmithKline Beecham. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078259

LETTER
2487
Asymmetric 1,4-Addition of Arylboronic Acids to a,b-Unsaturated Esters
Catalyzed by Dicationic Palladium(II)–Chiraphos Complex for Short-Step
Synthesis of SmithKline Beecham’s Endothelin Receptor Antagonist
A
symmetric 1, 4
a
-Addition
o
f
A
rylboron
a
ic Acids shi Nishikata,a Shunsuke Kiyomura,b Yasunori Yamamoto,b Norio Miyaura*b
a
Innovation Plaza Hokkaido, Japan Science and Technology Agency, Sapporo 060-0819, Japan
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066561; E-mail: miyaura@eng.hokudai.ac.jp
b
Received 13 June 2008
Ar
Ar
O
Abstract: An asymmetric 1,4-addition of arylboronic acids to
RCH=CHCO2Ar (Ar = Ph or 4-acetylphenyl) was carried out at 50
°C in aqueous acetone in the presence of [Pd(chiraphos)(Ph-
CN)2](SbF6)2. The reaction gave optically active b-aryl esters in up
to 98% ee. The protocol provided a simple access to an endothelin
receptor antagonist reported by SmithKline Beecham.
R1
OR2
O
ArB(OH)2
2
4
R1
OR2
+
Pd2+ catalyst 3
50 °C, 20 h
1
O
Key words: arylboronic acids, palladium catalyst, asymmetric re-
action, conjugate addition, b-arylalkanoate, bioactive compound
R1
OR2
4'
Ph
Ph
Ph
(SbF6)2
P
P
NCPh
Pd
NCPh
Ph
Metal-catalyzed 1,4-additions of organometallic com-
pounds to a,b-unsaturated carbonyl compounds have at-
tracted much attention as methods for constructing chiral
centers via C–C bond-forming reactions. Although Rh-
based complexes have been used extensively as catalysts
for 1,4-additions of arylmetal compounds,1 palladium cat-
alysts have recently been found to be an excellent alterna-
tive.2 Palladium(II) catalysts have higher turnover
numbers than those of rhodium catalysts for cyclic and
acyclic unsaturated ketones, aldehydes and N-acylamides
with excellent enantioselectivities.3,4 However, they have
a strong tendency to undergo b-hydride elimination, giv-
ing Heck coupling products for unsaturated esters.2e,3e,5
Formation of such alkene by-products for unsaturated es-
ters has also been reported for rhodium,6 iridium,7 and ru-
thenium catalysts.8 Thus, we recently reported the
synthesis of chiral b-arylalkanoates, including total syn-
thesis of (+)-(R)-tolterodine, via stepwise palladium-cata-
lyzed 1,4-addition of arylboronic acids to enones and
regioselective Baeyer–Villiger oxidation.4f In this paper,
we report that aryl esters (1, R2 = Ph, 4-AcC6H4) selective-
ly afford 1,4-addition products 4 of arylboronic acids in
the presence of the dicationic palladium catalyst
[Pd((S,S)-chiraphos)(PhCN)2](SbF6)2 [(S,S)-3], whereas
the corresponding alkyl esters such as 1 (R2 = Me) result
in Heck coupling (4¢; Scheme 1). The protocol provides a
simple access to an optically active endothelin receptor
antagonist reported by SmithKline Beecham.
B(OH)2
FG
(S,S)-3
2
Scheme 1 Asymmetric 1,4-addition of ArB(OH)2 to a,b-unsatura-
ted esters
which undergoes Heck coupling (4¢) is in equilibrium with
O-enolate susceptible to hydrolysis by water to produce
1,4-addition products 4.9 For smooth formation of such O-
enolates in aqueous solvents, cationic palladium(II) com-
plexes are better catalysts than neutral complexes, and un-
saturated ketones and aldehydes are better substrates than
esters and amides.
We recently succeeded in using palladium catalysts for
1,4-addition to electron-deficient amides such as
RCH=CHCON(Ph)COPh.4h Although simple extension
of this protocol for acid anhydrides PhCH=CHCO2COR3
(R3 = Ph, t-Bu, NMe2, Ot-Bu) failed due to rapid hydroly-
sis of these substrates with water, aryl esters (1, R2 = Ph,
4-AcC6H4) selectively provided 1,4-addition products.
The effects of ester groups and stoichiometry of arylbo-
Ar
[Pd]+
OR2
O
Ar-[Pd]+
Ar
O
R1
H
OR2
1
R1
O-enolate
[Pd]+
This 1,4-addition and the Heck reaction may involve a
common C-enolate intermediate generated by insertion of
an alkene into the C–Pd bond (Scheme 2). The C-enolate
C-enolate
β-elimination
H2O
4
4'
Heck coupling
SYNLETT 2008, No. 16, pp 2487–2490
Advanced online publication: 21.08.2008
x
x
.x
x
.2
0
0
8
1,4-addition
DOI: 10.1055/s-2008-1078259; Art ID: U06208ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 1,4-Addition vs. Heck coupling

2488
T. Nishikata et al.
LETTER
Table 1 Reaction Conditionsa
ronic acids at 50 °C in aqueous acetone (10:1) are shown
in Table 1. The Heck product was the major product for
methyl ester (entry 1), but the reaction provided the 1,4-
addition product with 92% selectivity for phenyl ester (en-
try 2) and with more than 98% selectivity for 4-acetylphe-
nyl ester (entry 3). Other ester derivatives such as C6F5, 4-
MeOC6H4, 4-CF3C6H4, 4-PhCOC6H4, and 4-CNC6H4 es-
ters (R2 of 1) were less effective. The yields were very low
when 1.5 equivalents of boronic acid were used (entry 3),
but they were increased to practical levels (70–80%) in
the presence of 3–4 equivalents of boronic acid (entries 4
and 5).
Entry
R2 of 1
4-MeC6H4B(OH)2 Yield
(equiv)
4:4¢
(R1 = Ph)
(%)b
1
2
3
4
5
Me
1.5
7
20:80
92:8
Ph
1.5
48
51
71
80
4-AcC6H4
4-AcC6H4
4-AcC6H4
1.5
98:<2
98:<2
98:<2
3.0
4.0
a A mixture of unsaturated ester (0.5 mmol), 4-MeC6H4B(OH)2 and
Pd catalyst 3 (1 mol%) in acetone–H2O (2 mL/0.2 mL) was stirred at
50 °C for 20 h.
Results of enantioselective 1,4-additions of arylboronic
acids (3 equiv) to the representative a,b-unsaturated esters
are shown in Table 2. All reactions selectively gave 1,4-
addition products with concomitant formation of less than
2% of Heck product. Although rhodium-catalyzed reac-
tions of electron-deficient arylboronic acids resulted in
b NMR yields.
Table 2 Synthesis of Chiral b-Aryl Estersa,13
Entry
1
R1
R2
Ar of ArB(OH)2
4-MeC6H4
3-MeC6H4
3-MeOC6H4
3-MeO2CC6H4
4-ClC6H4
Product
4a
4b
4c
Yield (%)b
(71)
(81)
(90)
89
ee (%)
97 (S)
95
Ph
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
4-AcC6H4
Ph
2
Ph
3
Ph
97
4
Ph
4d
4e
95
5
Ph
(88)
(99)
99
97
6
Ph
3-MeCOC6H4
4-MeOC6H4
Ph
4f
96
7
Ph
4g
4h
4i
96c
97
8
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2,3-(MeO)2C6H3
Me
(80)
(80)
(71)
87
9
Ph
97
10
11
12
13
14d,e
15
16d
17
18d,f
19
20d,f
Ph
4j
95
3-MeCOC6H4
Ph
4k
4l
95
(86)
80
97
3-MeCOC6H4
3-MeOC6H4
3-MeCOC6H4
3-MeCOC6H4
3-MeCOC6H4
3-MeCOC6H4
3-MeCOC6H4
3-MeCOC6H4
4m
4n
4o
4p
4q
4r
90
Me
78
92
n-Pr
69
84
n-Pr
80
90
Me(CH2)3CH2
Me(CH2)3CH2
i-Pr
4-AcC6H4
Ph
88
88
80
91
4-AcC6H4
Ph
4s
60
88
i-Pr
4t
90
90
a A mixture of unsaturated ester (0.5 mmol), ArB(OH)2 (1.5 mmol) and Pd catalyst (1 mol%) in acetone–H2O (2 mL/0.2 mL) was stirred at 50
°C for 20 h.
b Isolated yields of 4. NMR yields are in parentheses.
c The product was converted into ethyl ester for analysis of enantioselectivity.
d The reaction was carried out at 35 °C for 20 h.
e The reaction was carried out in THF–H2O (10:1).
f A higher amount of Pd catalyst (5 mol%) was used.
Synlett 2008, No. 16, 2487–2490 © Thieme Stuttgart · New York

LETTER
Asymmetric 1,4-Addition of Arylboronic Acids
2489
low yields due to their slow insertion into Ar–Rh bond, Selective antagonists of endothelin receptors are currently
both boronic acids possessing an electron-withdrawing being evaluated as potential therapeutic agents for the
group and those possessing an electron-donating group af- treatment of hypertension, congestive heart failure and re-
forded good yields of products with excellent enantio- nal diseases. 1,3-Diarylindan-2-caraboxylic acid deriva-
selectivities in a range of 95–97% ee (entries 1–7). tives are highly potent antagonists selective for endothelin
Substrates having alkoxy substituents in the b-aryl ring receptors. We recently reported the synthesis of two an-
also resulted in high selectivities (95–97% ee, entries 8– tagonists reported by SmithKline Beecham (Scheme 3)11
12). It was interesting to note that aliphatic substrates hav- and Merck–Banyu12 by the rhodium-catalyzed 1,4-addi-
ing an alkyl substituent at the b-carbon gave selectivities tion to build the first stereogenic center in a five-mem-
higher than 90% ee (entries 13–20), which are clearly bered ring of 10. Although a rhodium–chiraphos catalyst
higher than those in the case of analogous reactions with achieved 89% ee,4j this selectivity can be improved by us-
aliphatic ketones, which resulted in 78–89% ee for n-pen- ing the corresponding palladium–chiraphos catalyst. Pal-
tyl, isopropyl and cyclohexyl b-substituents at –15 °C.4c ladium catalysts are also advantageous for accessing an
For these reactions of aliphatic substrates, phenyl esters indene intermediate (9) in one step from 8 by a tandem
(entries 16, 18 and 20) resulted in yields and selectivities 1,4-addition–aldol cyclization protocol recently devel-
comparable to those of 4-acetylphenyl ester (entries 13, oped by our group.4i b-(2-Benzoylphenyl) a,b-unsaturat-
14, 15, 17 and 19). Addition of 4-methylphenylboronic ed ester 5 produced optically active indenes 6 via
acid to 4-acetylphenyl cinnamate afforded S product (en- sequential 1,4-addition–aldol condensation (Table 3).
try 1). The absolute configuration was determined by re- Representative boronic acids afforded good yields of aryl-
ported specific rotation of the corresponding methyl ester indenes with excellent enantioselectivities in the range of
{[a]D –2.7°, (CHCl3)} after conversion of 4a into methyl 88–98% ee. Indeed, the palladium–(R,R)-chiraphos cata-
ester {[a]D +2.4° (CHCl3)}.10
lyst (R,R)-3 directly provided 9 in the absence of an acid
OMe
HO
CHO
Br
OMOM
O
4 steps
n-PrO
O
OPh
7
O
8 (58%)
OMe
B(OH)2
O
O
n-PrO
OMOM
O
H2
CO2Ph
(3 equiv)
Pd/C
R,R-3 (3 mol%)
AgSbF6 (10 mol%)
DMF–i-PrOH (1:0.06)
45 °C, 12 h
O
O
9 (70%)
OMe
O
OMe
O
n-PrO
OMOM
n-PrO
OH
CO2Ph
CO2H
known method
O
10 (88%, 95% ee)
O
O
O
Scheme 3 SmithKline Beecham’s endothelin receptor antagonists
Synlett 2008, No. 16, 2487–2490 © Thieme Stuttgart · New York

2490
T. Nishikata et al.
LETTER
study, see: Nishikata, T.; Yamamoto, Y.; Miyaura, N.
co-catalyst, which was previously used for accelerating
1,4-addition and final dehydration.4i After hydrogenation
of the double bond in 9 to yield 10, the enantiomeric ex-
cess was determined by HPLC {88%, 95% ee; [a]D –94°
(CHCl3)}. The total yield of 10 starting from 7 was 38%
(Scheme 3). Compound 10 was led to the desired antago-
nist by epimerization and hydrolysis of the ester group by
a known method.4j,11
Organometallics 2004, 23, 4317.
(3) (a) Zhang, T.; Shi, M. Chem. Eur. J. 2008, 14, 3759.
(b) Song, J.; Shen, Q.; Xu, F.; Lu, X. Org. Lett. 2007, 9,
2947. (c) Sieber, J. D.; Liu, S.; Morken, J. P. J. Am. Chem.
Soc. 2007, 129, 2214. (d) Suzuma, Y.; Yamamoto, T.; Ohta,
T.; Ito, Y. Chem. Lett. 2007, 36, 470. (e) Gini, F.; Hessen,
B.; Minnaard, A. J. Org. Lett. 2005, 7, 5309.
(4) (a) Yamamoto, Y.; Nishikata, T.; Miyaura, N. Pure Appl.
Chem. 2008, 80, 807. (b) Nishikata, T.; Yamamoto, Y.;
Miyaura, N. Adv. Synth. Catal. 2007, 349, 1759.
(c) Nishikata, T.; Yamamoto, Y.; Gridnev, I. D.; Miyaura, N.
Organometallics 2005, 24, 5025. (d) Nishikata, T.;
Yamamoto, Y.; Miyaura, N. Chem. Lett. 2005, 34, 720.
(e) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem.
Commun. 2004, 1822. For application of Pd-catalyzed 1,4-
addition reaction, see: (f) Kobayashi, K.; Nishikata, T.;
Yamamoto, Y.; Miyaura, N. Bull. Chem. Soc. Jpn. 2008, in
press. (g) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Tetrahedron Lett. 2007, 48, 4007. (h) Nishikata, T.;
Yamamoto, Y.; Miyaura, N. Chem. Lett. 2007, 36, 1442.
(i) Nishikata, T.; Kobayashi, Y.; Kobayashi, K.; Yamamoto,
Y.; Miyaura, N. Synlett 2007, 3055. (j) Itoh, T.; Mase, T.;
Nishikata, T.; Iyama, T.; Tachikawa, H.; Kobayashi, Y.;
Yamamoto, Y.; Miyaura, N. Tetrahedron 2006, 62, 9610.
(5) (a) Du, X.; Suguro, M.; Hirabayashi, K.; Mori, A.;
Nishikata, T.; Hagiwara, N.; Kawata, K.; Okeda, T.; Wang,
H.-F.; Fugami, K.; Kosugi, M. Org. Lett. 2001, 3, 3313.
(b) Cho, C. S.; Motofusa, S.; Uemura, S. Tetrahedron Lett.
1994, 35, 1739.
Table 3 Synthesis of Chiral Arylindenesa
O
Ph
ArB(OH)2 (3 equiv)
Ph
CO2Ph
OPh
(S,S)-3 (1 mol%),
AgSbF6 (10 mol%)
acetone–H2O (2:0.04)
60 °C, 12 h
Ar
O
6
5
Entry
Ar of ArB(OH)2
Ph
Yield (%)b
ee (%)
1
2
3
4
5
6
7
8
9
78
80
87
73
81
68
88
61
66
93
91
92
95
97
98
88
96
98
3-FC6H4
3-MeC6H4
3-MeOC6H4
3-HOC6H4
3,5-Me2C6H3
4-ClC6H4
4-MeC6H4
4-PhC6H4
(6) Mori, A.; Danda, Y.; Fujii, T.; Hirabayashi, K.; Osakada, K.
J. Am. Chem. Soc. 2001, 123, 10774.
(7) Koike, T.; Du, X.; Sanada, T.; Danda, Y.; Mori, A. Angew.
Chem. Int. Ed. 2003, 42, 89.
(8) Farrington, E. J.; Brown, J. M.; Barnard, C. F. J.; Rowsell,
E. Angew. Chem. Int. Ed. 2002, 41, 169.
(9) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009.
(10) Arai, Y.; Ueda, K.; Xie, J.; Masaki, Y. Chem. Pharm. Bull.
2001, 49, 1609.
a A mixture of 5 (0.5 mmol), ArB(OH)2 (1.5 mmol), Pd catalyst (1
mol%) and AgSbF6 (10 mol%) in acetone–H2O (2 mL/0.04 mL) was
stirred at 60 °C for 12 h.
b Isolated yields of 6.
(11) (a) Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.;
Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine,
N. H. J. Am. Chem. Soc. 1998, 120, 4550. (b) Elliott, J. D.;
Amparo, M.; Cousins, R. D.; Gao, A.; Leber, J. D.; Erhard,
K. F.; Nambi, P.; Elshourbagy, N. A.; Kumar, C.; Lee, J. A.;
Bean, J. W.; Brooks, C. P.; Feuerstein, G.; Ruffolo, R. R.,
Jr.; Weinstock, J.; Gleason, J. G.; Peishoff, C. E.; Ohlstein,
E. H. J. Med. Chem. 1994, 37, 1553.
(12) (a) Kato, Y.; Niiyama, K.; Nemoto, T.; Jona, H.; Akao, A.;
Okada, S.; Song, Z. J.; Zhao, M.; Tsuchiya, Y.; Tomimoto,
K.; Mase, T. Tetrahedron 2002, 58, 3409. (b) Song, Z. J.;
Zhao, M.; Frey, J.; Li, L.; Tan, C. Y.; Chen, D. M.; Tschaen,
R.; Tillyer, E. J. J.; Grabowski, L.; Volante, R.; Reider, P. J.;
Kato, Y.; Okada, S.; Nemoto, T.; Sato, H.; Akao, A.; Mase,
T. Org. Lett. 2001, 3, 3357.
(13) General Procedure: A flask charged with [Pd((S,S)-
chiraphos)(PhCN)2](SbF6)2 [(S,S)-3; 1 mol%], ArB(OH)2
(1.5 mmol) and 1 (0.5 mmol) was flushed with nitrogen.
Acetone (2 mL) and H2O (0.2 mL) were then added. After
stirring for 20 h at 50 °C, the product was isolated by
chromatography on silica gel. The enantiomer excess was
determined by Chiral HPLC using Daicel Chiralpak IA, IB
or IC.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
in Priority Areas (No. 18064001, Synergy of Elements) and the
Global COE Program (No. B01, Catalysis as the Basis for Innova-
tion in Materials Science) from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
References and Notes
(1) (a) Kurihara, K.; Sugishita, N.; Oshita, K.; Piao, D.;
Yamamoto, Y.; Miyaura, N. J. Organomet. Chem. 2007,
692, 428. (b) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003,
103, 2829. (c) Takaya, Y.; Ogasawara, M.; Hayashi, T.;
Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579.
(2) (a) He, P.; Lu, Y.; Dong, C.-G.; Hu, Q.-S. Org. Lett. 2007, 9,
343. (b) Lin, S.; Lu, X. Tetrahedron Lett. 2006, 47, 7167.
(c) Denmark, S. E.; Amishiro, N. J. Org. Chem. 2003, 68,
6997. (d) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew.
Chem. Int. Ed. 2003, 42, 2768. (e) Ohe, K.; Uemura, S. Bull.
Chem. Soc. Jpn. 2003, 76, 1423. (f) For a mechanistic
Synlett 2008, No. 16, 2487–2490 © Thieme Stuttgart · New York