Enantioselective rhodium-catalyzed addition of arylboronic acids to α-ketoesters

Article abstract of DOI:10.1002/anie.200800423

(Chemical Figure Presented) Rhodium catalysis: The first example of a catalytic asymmetric addition of arylboronic acids to α-ketoesters was realized by using a chiral Rh^I-spirophosphite ligand complex in aqueous solvent to provide tertiary α-hydroxyesters in good yields with high enantioselectivities (see scheme; DCE = 1,2-dichloroethane).

Full text of DOI:10.1002/anie.200800423

Angewandte
Chemie
DOI: 10.1002/anie.200800423
Asymmetric Catalysis
Enantioselective Rhodium-Catalyzed Addition of Arylboronic Acids
to a-Ketoesters**
Hai-Feng Duan, Jian-Hua Xie, Xiang-Chen Qiao, Li-Xin Wang, and Qi-Lin Zhou*
The transition-metal-catalyzed asymmetric addition of or-
ganometallic reagents to carbonyl compounds to produce
enantiomer-enriched secondary or tertiary alcohols is a
powerful tool for the construction of carbon–carbon bonds.
Many organometallic reagents have been successfully used in
this addition reaction.[1] However,a drawback for most
organometallic reagents is their sensitivity to moisture and
air,both of which impede the practical applications of these
asymmetric carbon–carbon bond-forming reactions. As an
exception,arylboronic acids are very stable to air and
moisture. The catalytic enantioselective addition of arylbor-
onic acids to carbonyl compounds has became a current focus
for research,[1d] and a number of efficient chiral catalysts have
been developed for the catalytic asymmetric addition of
arylboronic acids to aldehydes[2] and aldimines.[3] However,
the catalytic asymmetric addition of arylboronic acids to
ketones,which are less active relative to aldehydes and
aldimines,is more difficult,and only limited progress has
been achieved. In 2006,Hayashi et al. reported the asym-
metric addition of arylboronic acids to isatins,cyclic a-
ketoamides,catalyzed by a rhodium/MeO-Mop (MeO-Mop =
2-methoxy-2’-diphenylphosphino-1,1’-binaphthyl) complex in
high enantioselectivities (72–91% ee).[4] By using a chiral
phosphoramidite ligand derived from H8-binol (binol = 2,2’-
dihydroxy-1,1’-binaphthyl),de Vries,Minnard,Feringa and
et al. obtained 55% ee in the same reaction.[5] The chiral
phosphoramidite ligand was also used in the asymmetric
addition of arylboronic acids to trifluoromethyl ketones with
good enantioselectivities (50–83% ee).[6] The intramolecular
asymmetric addition of arylboronic acids to ketones catalyzed
by a cationic palladium complex of binap (binap = 2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl) to give cyclic ter-
tiary alcohols in high enantioselectivities (53–96% ee) was
reported by Lu et al.[7] To the best of our knowledge,the
catalytic enantioselective addition of arylboronic acids to a-
ketoesters to provide tertiary a-hydroxyesters has not yet
been reported.[8]
In the search for highly efficient methods to construct
chiral 2-hydroxydiarylacetates,desirable chiral intermediates
for the synthesis of antagonists of muscarinic receptors,[9] we
became interested in the enantioselective addition of aryl-
boronic acids to the a-aryl- and a-alkenyl-a-ketoesters. The
RhI/ShiP (ShiP = aryl(1,1’-spirobiindane-7,7’-diyl)phosphite)
catalysts (1) recently developed by us[2c,3b] were found to be
highly efficient for this addition reaction to provide chiral
tertiary a-hydroxyesters[10] in good yields and high enantio-
meric excesses (up to 93% ee).
Preliminary experiments were carried out in H2O with
catalyst generated in situ from 1.5 mol% [{RhCl-
(CH2CH2)2}2][11] and 6 mol% (S)-1a in the presence of two
equivalents of LiF.[12] The addition of phenylboronic acid to
ethyl 2-(4-chlorophenyl)-2-oxoacetate (2a) at room temper-
ature for 48 hours afforded tertiary a-hydroxyester 4a in 59%
yield with 70% ee (Table 1,entry 1). The low solubility of the
2-oxoacetate substrate in H2O was responsible for the long
Table 1: Optimization of the enantioselective addition of phenylboronic
acid to ethyl 2-(4-chlorophenyl)-2-oxoacetate.[a]
Entry
ShiP
Solvent[b]
t [h]
Yield [%][c]
ee [%][d]
[*] Dr. H.-F. Duan, Prof. J.-H. Xie, X.-C. Qiao, Prof. L.-X. Wang,
Prof. Q.-L. Zhou
1
2
3
4
5
6
7
8
9
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
H2O
H2O/Tol
48
15
15
15
10
12
12
24
12
59
92
71
75
99
87
96
25
94
70
69
72
71
72
32
77
61
68
State Key Laboratory and Institute of Elemento-organic Chemistry
Nankai University, Tianjin 300071 (China)
Fax: (+86)22-2350-6177
H2O/DME
H2O/EtOH
H2O/DCE
H2O/DCE
H2O/DCE
H2O/DCE
H2O/DCE
E-mail: qlzhou@nankai.edu.cn
[**] We thank the National Natural Science Foundation of China, the
Major Basic Research Development Program (Grant No.
2006CB806106), the “111” project (B06005) of the Ministry of
Education of China, and the Merck Research Laboratories for
financial support.
[a] 2a/3a/LiF/[{RhCl(CH2CH2)2}2]/(S)-1=1:2:2:0.015:0.06. [b] H2O/sol-
vent=4:1 v/v (2 mL). [c] Yield of the isolated product. [d] Determined by
chiral HPLC analysis by using a Daicel Chiralpak AD-H column.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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reaction time and low yield. When a small amount of organic
the aryl ring of arylboronic acid 3,the addition reaction
became very slow. Only a trace amount of the product was
observed at 408C after 48 hours (results not shown). The
absolute configuration of addition products can be changed
by simply exchanging the aryl groups of the a-oxoester and
the boronic acid,for instance,the additions of 4-methyl- and
4-methoxyphenylboronic acids to 2-phenyl-2-oxoacetate
afforded a-hydroxyesters 4h and 4i in 80 and 83% ee,
respectively,but with opposite configurations (Table 2,
entries 12 and 13).
Except for a-oxo(aryl)acetate,the less hindered ( E)-
benzyl 2-oxo-4-phenylbut-3-enoate (5) is also a suitable
substrate for the arylation reaction with arylboronic acids
catalyzed by RhI/(S)-1c. A variety of arylboronic acids can
undergo the enantioselective addition to compound 5 to
produce tertiary a-hydroxyacetates 6 (Table 3). All meta- and
solvent,such as toluene,dimethoxyethane (DME),EtOH,or
1,2-dichloroethane (DCE) was added (H2O/organic solvent =
4:1),the reaction proceeded much faster and produced 4a in
higher yields (Table 1,entries 2–5). The H O/DCE solvent
2
mixture is optimal as it gave the highest yield (99%) and good
enantioselectivity (72% ee; Table 1,entry 5). A comparison
of ligands showed that spirophosphite 1c,having a para-OMe
group on the phenyl ring,afforded product 4a with the
highest ee value (Table 1,entry 7). The LiF functions as a
Lewis base,promoting the transfer of the phenyl group of the
phenylboronic acid to rhodium by binding to the B atom and
accelerating the reaction rate.[13]
The scope of the reaction was investigated under the
optimal reaction conditions. From the results listed in Table 2,
we can see that the ester group in the substrate imposed a
Table 2: Asymmetric addition of arylboronic acids 3 to a-ketoesters 2
catalyzed by RhI/(S)-1c.[a]
Table 3: Asymmetric addition of arylboronic acids 4 to benzyl 2-phenyl-
vinyl-2-ketoester (3) catalyzed by RhI/(S)-1c.[a]
Entry
Ar
6
t [h]
Yield [%][b]
ee [%][c]
Entry R1
X
Ar
Prod. t [h] Yield [%][b] ee [%][c]
1[d]
2[d]
3[d]
4
C6H5
6a
6b
6c
6d
6e
6 f
6g
6h
6i
60
60
60
32
32
60
60
32
24
24
70
77
75
93
61
75
70
92
89
91
93
93
90
92
90
91
93
75
90
88
1
2
3
4
5
Et 4-Cl
iPr 4-Cl
tBu 4-Cl
Ph 4-Cl
Bn 4-Cl
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4a
4b
4c
4d
4e
4e
4 f
4g
4h
4i
12 96
12 93
12 51
12 90
12 95
48 81
48 84
48 93
36 96
36 93
60 78
36 85
36 80
77
80
70
72
84
90
88
91
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-CF3C6H4
3-MeC6H4
3-MeOC6H4
2-MeC6H4
2-naphthyl
2-thiophene
5
6[d]
7[d]
8
6[d] Bn 4-Cl
7[d] Bn 4-F
8[d] Bn 4-CF3
9
10
9
10
Bn 4-Me
Bn 4-MeO
84 (R)[e]
86
6j
11[d] Bn 3,4-(CH)4- C6H5
4j
4h
80
[a] 5/3/LiF/[{RhCl(CH2CH2)2}2]/ligand=1:2:2:0.015:0.06. [b] Yield of
isolated product. [c] Determined by chiral HPLC analysis (see the
Supporting Infomation). [d] 08C.
12
13
Bn
Bn
H
H
4-MeC6H4
4-MeOC6H4 4i
80 (S)[e]
83 (À)
[a] 2/3/LiF/[{RhCl(CH2CH2)2}2]/ligand=1:2:2:0.015:0.06. [b] Yield of
isolated product. [c] Determined by chiral HPLC analysis (see the
Supporting Infomation). [d] 08C. [e] Determined by comparing the
measured optical rotation with the reported data.[14]
para-substituted arylboronic acids,with electron-donating or
electron-withdrawing substituents gave good yields and high
enantioselectivities (90–93% ee),showing that the electronic
properties of the arylboronic acids has a negligible effect on
the enantioselectvity of the addition reaction (Table 3,
entries 2–7). However,the fact that the ortho-methylphenyl-
boronic acid afforded a lower enantioselectivity (75% ee)
indicated that the steric hindrance has a negative influence on
the enantioselectivity of the reaction (Table 3,entry 8). The 2-
naphthyl- and 2-thiopheneboronic acids can also be used in
the addition reaction with a-ketoester 5 to produce corre-
sponding tertiary a-hydroxyesters 6i and 6j,respectively
(Table 3,entries 9 and 10).
The ester group of the addition products can be converted
into other functional groups by simple operations. For
example,the benzyl 2-hydroxy-2-phenyl-4-phenylbut-3-
enoate (6a) was hydrolyzed by aqueous NaOH to afford
tertiary a-hydroxy acid 7 in 94% yield with complete
retention of the optical purity. Furthermore,the chiral 12,-
dihydroxy compound 8 was easily obtained in 83% yield by
notable effect on both the yield and the enantioselectivity.
The best result was obtained with the benzyl ester (Table 2,
entry 5). Lowering the reaction temperature to 08C improved
the enantioselectivity to 90% ee,but diminished the yield of
reaction to 81%. The electronic properties of the substituents
on the a-oxo(aryl)acetates had a limited influence on the
enantiomeric excess of the products,but it markedly affected
the reaction rate. For example,the reactions of benzyl a-
oxo(aryl)acetates with an electron-withdrawing group,such
as Cl,F,or CF 3,at the para-position can be performed at 08C
(Table 2,entries 6–8). However,room temperature (20–
258C) is necessary for the reaction of a-oxo(aryl)acetates
with an electron-donating group such as Me and MeO at the
para-position (Table 2,entries 9 and 10). The addition reac-
tion is sensitive to the steric effect of the substrates and the
reagents; for example,when an ortho or meta substituent was
introduced onto the aryl ring of a-oxo(aryl)acetate 2 or onto
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Rudolph,C. Bolm, Synthesis 2005,429; c) H.-F. Duan,J.-H. Xie,
W.-J. Shi,Q. Zhang,Q.-L. Zhou, Org. Lett. 2006, 8,1479;
reducing compound 6a with LiAlH4 in Et2O. Both com-
pounds 7[15] and 8[16] are important intermediates in the
synthesis of biologically active molecules (Scheme 1).
d) R. B. C. Jagt,P. Y. Toullec,J. G. de Vries,B. L. Feringa,A. J.
Minnaard, Org. Biomol. Chem. 2006, 4,773; e) D. Tomita,M.
Kanai,M. Shibasaki, Chem. Asian J. 2006, 1,161; f) K. Suzuki,
K,KondoT, . Aoyama, Synthesis 2006, 8,1360; g) R. B. C. Jagt,
P. Y. Toullec,E. P. Schudde,J. G. De Vries,B. L. Feringa,A. J.
Minnaard, J. Comb. Chem. 2007, 9,407.
[3] a) D. J. Weix,Y. Shi,J. A. Ellman, J. Am. Chem. Soc. 2005, 127,
1092; b) H.-F. Duan,J.-H. Xie,L.-X. Wang,Q.-L. Zhou,
Org.
Lett. 2006, 8,2567; c) R. B. C. Jagt,P. Y. Toullec,D. Geerdink,
J. G. de Vries,B. L. Feringa,A. J. Minnaard, Angew. Chem. 2006,
118,2855; Angew. Chem. Int. Ed. 2006, 45,2789; d) M. A.
Beenen,D. J. Weix,J. A. Ellman, J. Am. Chem. Soc. 2006, 128,
6304; e) H. Nakagawa,J. C. Rech,R. W. Sindelar,J. A. Ellman,
Org. Lett. 2007, 9,5155; f) Z.-Q. Wang,C.-G. Feng,M.-H. Xu,
G.-Q. Lin, J. Am. Chem. Soc. 2007, 129,5336.
Scheme 1. Conversion of ester 6a to the acid and the diol.
[4] R. Shintani,M. Inoue,T. Hayashi, Angew. Chem. 2006, 118,
3431; Angew. Chem. Int. Ed. 2006, 45,3353.
[5] P. Y. Toullec,R. B. C. Jagt,J. G. de Vries,B. L. Feringa,A. J.
Minnaard, Org. Lett. 2006, 8,2715.
[6] S. L. X. Martina,R. B. C. Jagt,J. G. de Vries,B. L. Feringa,A. J.
Minnaard, Chem. Commun. 2006,4093.
[7] G. Liu,X. Lu, J. Am. Chem. Soc. 2006, 128,16504.
[8] For catalytic asymmetric addition of organozinc reagents to a-
In summary,the first asymmetric addition of arylboronic
acids to a-ketoesters was developed by using rhodium
catalysts bearing spirophosphite ligands. This protocol pro-
vides a new enantioselective approach to the synthesis of 2-
hydroxydiarylacetates and alkenylarylacetates,as well as
related a-hydroxy acids and vicinal diols that have a tertiary
chiral center. This method was performed in aqueous media,
which is benign to the environment.
ketoesters,see: a) E. F. DiMauro,M. C. Kozlowski,
J. Am.
Chem. Soc. 2002, 124,12668; b) K. Funabashi,M. Jachmann,M.
Kanai,M. Shibasaki, Angew. Chem. 2003, 115,5647; Angew.
Chem. Int. Ed. 2003, 42,5489; c) L. C. Wieland,H. Deng,M. L.
Snapper,A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127,15453;
d) G. Blay,I. Fernandez,A. Marco-Aleixandre,J. R. Pedro, Org.
Lett. 2006, 8,1287. For nonasymmetric addition of arylboronic
acids to a-ketoesters,see: e) P. He,Y. Lu,C.-G. Dong,Q.-S. Hu,
Org. Lett. 2007, 9,343; f) S. Miyamura,T. Satoh,M. Miura, J.
Org. Chem. 2007, 72,2255; g) G. R. Ganci,J. D. Chisholm,
Tetrahedron Lett. 2007, 48,8266.
Experimental Section
Typical procedure: A Schlenk tube was charged with [{RhCl-
(CH2CH2)2}2] (1.2 mg,0.006 mmol) and ( S)-1c (4.8 mg,0.012 mmol)
under a nitrogen atmosphere. DCE (0.4 mL) and water (1.6 mL) were
then added,and the mixture was stirred at room temperature for
10 min. PhB(OH)2 (49 mg,0.4 mmol),LiF (13 mg,0.4 mmol),and
benzyl 2-(4-chlorophenyl)-2-oxoacetate (42 mg,0.2 mmol) were
added sequentially to the reaction mixture,which was then stirred
at 08C for 48 h. The mixture was extracted with CH2Cl2,dried over
MgSO4,and purified by chromatography on silica gel with petroleum
ether/ethyl acetate (8:1) to give product 4e in 81% yield as a white
solid,mp 61–62 8C. The Enantiomeric excess (90% ee) was deter-
mined by chiral HPLC analysis using a Daicel Chiralpak AS column.
[9] a) D. O. Kiesewetter,J. V. Silverton,W. C. Eckelman, J. Med.
Chem. 1995, 38,1711; b) D. O. Kiesewetter,R. E. Carson,E. M.
Jagoda,C. J. Endres,M. G. Der,P. Herscovitch,W. C. Eckelman,
Bioorg. Med. Chem. 1997, 5,1555; c) M. B. Skaddan,M. R.
Kilbourn,S. E. Snyder,P. S. Sherman,T. J. Desmond,K. A. Frey,
J. Med. Chem. 2000, 43,4552; d) J. Selent,W. Brandt,D.
Pamperin,B. Goeber, Bioorg. Med. Chem. 2006, 14,1729.
[10] For reviews: see a) H. Grꢀger, Adv. Synth. Catal. 2001, 343,547;
b) D. J. Ramꢁn,M. Yus, Angew. Chem. 2004, 116,286; Angew.
Chem. Int. Ed. 2004, 43,284. For recent example,see c) Y.-T.
Received: January 27,2008
Published online: April 29,2008
Hong,C.-W. Cho,E. Skucas,M. J. Krische,
3745.
Org. Lett. 2007, 9,
Keywords: a-ketoester · alcohols · asymmetric catalysis ·
.
[11] [{RhCl(CH2CH2)2}2] was the best choice for the precatalyst
becasue it led to high yields.
[12] The reaction was incomplete and the yield was very low in the
absence of LiF.
[13] a) S. W. Wright,D. L. Hageman,L. D. McClure, J. Org. Chem.
1994, 59,6095; b) A. Suzuki, J. Organomet. Chem. 1999, 576,147;
c) A. F. Littke,C. Dai,G. C. Fu, J. Am. Chem. Soc. 2000, 122,
4020.
[14] A. I. Meyers,J. Slade, J. Org. Chem. 1980, 45,2912.
[15] a) C. Bugno,S. M. Colombani,P. Dapporto,G. Garelli,P. Giorgi,
boronic acids · rhodium
[1] For reviews,see: a) Comprehensive AsymmetricCatalysis (Eds.:
st
E. N. Jacobsen,A. Pfaltz,H. Yamamoto),1
ed.,Springer,
Berlin, 1999; b) L. Pu,H.-B. Yu, Chem. Rev. 2001, 101,757; c) K.
Fagnou,M. Lautens, Chem. Rev. 2003, 103,169; d) S. E. Den-
mark,J. Fu, Chem. Rev. 2003, 103,2763; e) C. Garcia,V. S.
Martin, Curr. Org. Chem. 2006, 10,1849; f) O. Riant,J.
Hannedouche, Org. Biomol. Chem. 2007, 5,873. For recent
A. Subissi,L,Turbanti,
Chirality 1997, 9,713; b) E. R.
examples,see g) F. Schmidt,J. Rudolph,C. Bolm,
Adv. Synth.
Atkinson,D. D. McRitchi,L. F. Schoer, J. Med. Chem. 1977,
20,1612.
Catal. 2007, 349,703; h) J. Siewert,R. Sandmann,P. von Zezsch-
with, Angew. Chem. 2007, 119,7252; Angew. Chem. Int. Ed.
2007, 46,7122.
[16] a) M. Scholl,R. H. Grubbs, Tetrahedron Lett. 1999, 40,1425;
b) M. E. Vargas-Dꢂaz,L. C. Garcꢂa,P. Velꢃzquez,J. Tamariz,P. J.
Nathan,L. G. Zepeda, Tetrahedron: Asymmetry 2003, 14,3225.
[2] a) M. Sakai,M. Ueda,N. Miyaura, Angew. Chem. 1998, 110,
3475; Angew. Chem. Int. Ed. 1998, 37,3279; b) T. Fuchen,J.
Angew. Chem. Int. Ed. 2008, 47, 4351 –4353
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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