Cu(I) Tol-BINAP-catalyzed enantioselective Michael reactions of Grignard reagents and unsaturated esters

Article abstract of DOI:10.1021/ja0666046

A highly efficient regio- and enantioselective catalytic asymmetric addition of Grignard regeants to α,β-unsaturated esters promoted by the CuI-Tol-BINAP system is described. Copyright

Full text of DOI:10.1021/ja0666046

Published on Web 12/21/2006
Cu(I) Tol-BINAP-Catalyzed Enantioselective Michael Reactions of Grignard
Reagents and Unsaturated Esters
Shun-Yi Wang,†,‡ Shun-Jun Ji,*,‡ and Teck-Peng Loh*,†
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
Technological UniVersity, Singapore 639798, and Key Laboratory of Organic Synthesis of Jiangsu ProVince,
College of Chemistry and Chemical Engineering, Suzhou (Soochow) UniVersity, Jiangsu 215123, China
Received September 13, 2006; E-mail: teckpeng@ntu.edu.sg
Scheme 1. Selected Diphosphine Ligands
The copper-catalyzed conjugate addition (CA) of organometallic
reagents to R,â-unsaturated compounds is one of the most versatile
synthetic methods for the construction of C-C bonds.1 The
application of Grignard reagents, which are among the most widely
used of organometallic compounds, in the asymmetric CA reactions
has received much less attention.2 Over the last 3 years, Feringa’s
group demonstrated that ferrocene-based diphosphine ligands such
as (R,S)-Josiphos and (R,S)-Taniaphos were useful for the highly
enantioselective conjugate addition of Grignard reagents onto
several classes of Michael acceptors (Scheme 1).3,4 Recently, they
had also proposed a mechanism to account for this high enantio-
selectivity. Copper N-heterocyclic carbene catalysts were also
applied in the asymmetric CA of Grignard reagents to trisubstituted
cyclic enones, which were reported in 2006 by Alexakis’s group.5
Whereas extraordinary advances have been made in the copper-
catalyzed conjugate addition with Grignard reagents, there are still
drawbacks in existing systems.3c,6 Some of these limitations include
the loss of enantioselectivity for sterically hindered alkyl, aryl
Grignard reagents or Grignard reagents bearing double bond.2
In our effort to develop an enantioselective method for the
synthesis of 8-deoxyanisatin,7 we are interested in the copper-
catalyzed asymmetric 1,4-addition of Grignard reagents to R,â-
unsaturated ester. In this Communication, we describe a new chiral
CuI Tol-BINAP catalyst for the asymmetric 1,4-addition of
Grignard regeants to R,â-unsaturated esters in high regio- and
enantioselectivities.
Initial study was conducted using 1 mol % CuI and 1.2 mol %
(R)-Tol-BINAP as the chiral catalyst for the reaction of EtMgBr
with (E)-methyl 5-phenylpent-2-enoate 2 in t-BuOMe. The desired
product was obtained with good enantioselectivity (82% ee).8 In
our efforts to have a further understanding of this reaction, we had
attempted to synthesize and isolate the chiral catalyst. The tetra-
hedral dinuclear Cu complex 1a was synthesized by mixing equi-
molar amounts of CuI and (R)-Tol-BINAP in t-BuOMe or CH2Cl2
at room temperature (Scheme 2). The resulting complex was isolated
as pure crystals, and the structure was elucidated through X-ray
crystallography.9 However, when the pure complex was used in syn-
thesis, lower enantioselectivity (57% ee) was observed (entry 2).
The above result encouraged us to evaluate the effect of the ratio
of the copper complex to the chiral ligand ratio on the enantio-
selectivity of the reaction (Table 1). It is important to note that a
0.5 equiv excess of the chiral Tol-BINAP to CuI is essential to
obtain the product with high enantioselectivities (entries 3 and 4).
The addition of other phosphine ligands to complex 1a also affects
the enantioselectivity of the reaction especially when tricyclophos-
phine was used as the additive (entry 8). The best result was
obtained using the catalytic system prepared from the CuI and (R)-
Tol-BINAP (1:1.5) in t-BuOMe.9
Scheme 2. Formation of Copper(I) (R)-Tol-BINAP Complex
Table 1. Additions of EtMgBr to 1a: Ligand Effecta
entry
catalyst
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
1 mol % CuI + 1.2 mol % L2
0.5 mol % 1a
85
85
88
87
85
83
85
88
86
82
57
93
93
85
48
53
83
65
1 mol % CuI + 1.5 mol % L2
0.5 mol % 1a + 0.5 mol % L2
1 mol % CuI + 1.5 mol % L1
1 mol % CuI + 1.5 mol % L3
0.5 mol % 1a + 1 mol % Ph3P
0.5 mol % 1a + 1 mol % Cy3P
0.5 mol % 1a + 0.5 mol % dppe
a All reactions were performed with 2 (0.5 mmol), EtMgBr (2.0 mmol,
3 M in ether) in t-BuOMe (1 mL) at -40 °C unless otherwise stated.
b Isolated yield. c Determined by HPLC analysis employing a Daicel
Chiracel ODH column.
With the reaction conditions optimized, we analyzed the scope
of this asymmetric conjugate addition to unsaturated ester 2 using
various Grignard reagents, and high enantioselectivities (86-98%
ee) were obtained (Table 2). Secondary Grignard regeant also works
well to afford the product in excellent enantioselectivity (entry 3).10
In contrast to the system reported by Feringa,3c the presence of a
double bond in the Grignard reagent did not lead to a decrease in
enantioselectivity (entries 4 and 7). However, the addition of
MeMgBr to 2 gave the desired product 3g in high ee but with poor
conversion (entry 9).
The reaction was extended to different R,â-unsaturated esters,
which were prepared through a Horner-Emmons reaction or a
Wittig-Horner reaction. More reactive EtMgBr was used as the
nucleophile. The results, summarized in Table 3, indicated that most
of them gave the products in high to excellent enantioselectivities
and high chemical yields. A maximum of 95% ee was obtained in
the case of 4c as the acceptor (entry 3).
† Nanyang Technological University.
‡ Suzhou (Soochow) University.
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C O M M U N I C A T I O N S
Table 2. Additions of Grignards to 2a
entry
RMgBr
product
yield (%)b
ee (%)c
1
2
3
4
5
6
7
EtMgBr
n-PrMgBr
i-PrMgBr
n-BuMgBr
n-PentMgBr
n-HeptMgBr
3a
3b
3c
3d
3e
3f
3g
3h
3i
88
90
89
90
86
89
90
93
92
91
92
90
92
94
Figure 1. The configuration relationship.
enantiomer using (R)-Tol-BINAP (Figure 1). To demonstrate, cis-
enoate 2 was subjected to the same reaction conditions using CuI/
(R)-Tol-BINAP. The (+)-3a was obtained in 94%ee (Table 3, entry
6). We had also obtained (-)-3a from the reaction of phenethyl-
magnesium bromide with trans-enoate 4h catalyzed by CuI with
(R)-Tol-BINAP (90% ee) (Figure 1). Interestingly, higher enantio-
selectivities was observed when the cis-enoates was used in the
CA reactions (entries 6 and 9).
To summarize, we have developed a highly regio- and enantio-
selective addition of Grignard regeants to R,â-unsaturated esters
using simple reaction procedures, employing commercially available
chiral Tol-BINAP. Further work in our laboratory will be directed
toward exploiting the reaction mechanism, the use of CuI-Tol-
BINAP in the catalytic addition of MeMgBr to other Michael
acceptors and other organic transformations.
8
9
i-BuMgBr
91
20
86
MeMgBr
>98
a All reactions were performed with 2 (0.5 mmol), RMgBr (2.5 mmol,
3 M in ether), CuI (1 mol %), (R)-Tol-BINAP (1.5 mol %) in t-BuOMe (1
mL) at -40 °C. b Isolated yield. c Determined by HPLC analysis employing
a Daicel Chiracel ODH or OJ column.
Table 3. Variation of R, â-Unsaturated Estersa
Acknowledgment. We gratefully acknowledge the Nanyang
Technological University for the funding of this research and we
thank Dr. Y.-X. Li and Dr. K. F. Mok for X-ray support.
Supporting Information Available: Additional experimental pro-
cedures, all chromatograms, cif file of crystallographic data for 1a,
and spectral data for reactions products. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3236. (b)
Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry, Series 9; Pergamon: Oxford, 1992. (c)
Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771-806.
(2) Review see: Woodward, S. Angew. Chem., Int. Ed. 2005, 44, 5560-
5562.
(3) (a) Feringa, B. L.; Badorrey, R.; Pen˜a, D.; Harutyunyan, S. R.; Minnaard,
A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834-5838. (b) Lo´pez, F.;
Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
2004, 126, 12784-12785. (c) Lo´pez, F.; Harutyunyan, S. R.; Minnaard,
A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 2752-2756. (d)
Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.; Minnaard,
A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966-9967.
(4) Harutyunyan, S. R.; Lo´pez, F.; Browne, W. R.; Correa, A.; Pen˜a, D.;
Badorrey, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2006, 128, 9103-9118.
(5) Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis,
A. J. Am. Chem. Soc. 2006, 128, 8416-8417.
(6) Besides Feringa group’s work (ref 3c), only a Rh-catalyzed asymmetric
conjugate addition of aryl boron reagents to R,â-unsaturated esters has
been reported. (a) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org.
Chem. 2000, 65, 5951-5955. (b) Takaya, Y.; Senda, T.; Kurushima, H.;
Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10, 4047-
4056. (c) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-2844.
(7) Loh, T.-P.; Hu, Q.-Y. Org. Lett. 2001, 3, 279-281.
a All reactions were performed with 2 or 4 (0.5 mmol), EtMgBr (2.5
mmol, 3 M in ether), CuI (1 mol %), (R)-Tol-BINAP (1.5 mol %) in
t-BuOMe (1 mL) at -40 °C unless otherwise described. b Isolated yield.
cDetermined by Chiral HPLC or GC analysis. d (S)-Tol-BINAP was used.
(8) Reactions carried out in other solvents such as Et2O, CH2Cl2, and THF
gave the product in lower ee (< 80% ee).
f
e (-)-3a was obtained. CuI (5 mol%), (R)-Tol-BINAP (7.5 mol%). g 4f in
0.2 mL CH2Cl2 was added to the catalyst system in 1 mL of t-BuOMe.
(9) See Supporting Information.
h The reaction was performed in CH2Cl2.
(10) The CA reaction of sterically hindered Grignard reagents, such as i-PrMgBr
and PhMgBr also provided the desired products under the the same
reaction conditions (eq 2). In contrast to reported results of CuBr‚Me2S/
Josiphos catalyst system,3c the desired products were obtained with
improved yields and enantioselectivities.
In principle, the absolute stereochemistry of the product can be
reversed by using the enantiomer of the ligand or by using the
geometrical isomer of the starting material. This was demonstrated
by the CA of EtMgBr to trans-enoates 2 carried out using (S)-Tol-
BINAP under the general conditions, and the desired product (-)-
3a with opposite configuration was obtained with similar enantio-
selectivity (Table 3, entry 5). Another strategy involves the use of
the cis-enoate instead of the trans-enoate to obtain the opposite
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