Copper-catalyzed enantioselective conjugate addition of Grignard reagents to α,β-unsaturated esters

Article abstract of DOI:10.1002/anie.200500317

(Chemical Equation Presented) Stable dinuclear Cu complexes have been used to catalyze the conjugate addition of inexpensive and readily available Grignard reagents to acyclic α,β-unsaturated esters. The method provides the correspending β-substituted optically active esters in high yields and with excellent enantioselectivities (see scheme). R³ = cyclohexyl, R ⁴ = Ph or R³ = Ph, R⁴ = cyclohexyl.

Full text of DOI:10.1002/anie.200500317

Communications
Asymmetric Catalysis
Copper-Catalyzed Enantioselective
Conjugate Addition of Grignard Reagents to
a,b-Unsaturated Esters**
Fernando Lꢀpez, Syuzanna R. Harutyunyan,
Auke Meetsma, Adriaan J. Minnaard, and
Ben L. Feringa*
The development of catalyst systems for the enantioselective
conjugate addition of organometallic reagents to a,b-unsatu-
rated compounds has been the subject of intensive research
over the past few decades.[1] Whereas extraordinary advances
have been made in asymmetric 1,4-additions to enones,
lactones, and nitroalkenes,[1–5] in the case of acyclic a,b-
unsaturated esters the progress has been limited,[6] despite the
enormous synthetic potential of the resulting enantiopure b-
substituted esters as building blocks for natural product
synthesis.[7,8]
The lower intrinsic reactivity of a,b-unsaturated esters
relative to that of enones,[9] and the challenge to control the
different conformers present in acyclic unsaturated systems,
may account for this paucity of versatile methodologies. To
address these issues, several alternatives based on the use of
different ester surrogates (i.e. oxazolidinones, pyrrolidinones,
pyrazolidinones, acyl phosphonates, and imides), were devel-
oped successfully, with highly enantioselective Michael addi-
tions of soft nucleophiles resulting.[10] However, for alkyl
metal compounds only an enantioselective conjugate addition
of dialkyl zinc reagents to unsaturated N-acyl oxazolidinones
has been reported to date.[11] Very recently, our research
group described an alternative strategy based on a conjugate
addition to alkylidene malonates that yields b-substituted
esters after a decarboxylation step, but the method is
restricted to the addition of dimethylzinc.[12,13] Therefore,
despite these important achievements, general and efficient
enantioselective conjugate additions of organometallic
reagents to a,b-unsaturated esters remain a major challenge.
[*] Dr. F. Lꢀpez, Dr. S. R. Harutyunyan, A. Meetsma, Dr. A. J. Minnaard,
Prof. Dr. B. L. Feringa
Department of Organic Chemistry and
Molecular Inorganic Chemistry
Stratingh Institute, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
Fax: (+31)50-363-4296
E-mail: b.l.feringa@rug.nl
[**] Financial support from the Dutch Ministry of Economic Affairs
under the EET Scheme (grant nos. EETK97107 and EETK99104) and
the Sixth Framework Programme of the European Community
(Marie Curie Intra-European Fellowship to F.L.; contract no: MEIF-
CT-2004-009767) is gratefully acknowledged. We thank T. D.
Tiemersma-Wegman for technical support (GC and HPLC) and Dr.
W. R. Browne for valuable discussions. We are grateful to Dr. H.-U.
Blaser (Solvias, Basel) for a generous gift of josiphos ligands.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Encouraged by the recent successful developments in the
asymmetric addition of Grignard reagents to enones,[14] we
decided to explore the conjugate addition to a,b-unsaturated
acid derivatives and report herein the first highly enantiose-
lective catalytic conjugate addition of organomagnesium
reagents to this class of substrates.[15] The reactions are easy
to execute, rigorously inert conditions are not required, and
an air-stable (pre)catalyst has been identified that can be
recycled and reused without any deterioration in yield or
enantioselectivity.
Scheme 2. Preparation of the copper catalyst 4a.
complex 4a’. The X-ray crystal structure obtained for this
complex is shown in Figure 1.[19,20]
Preliminary screening involved the crotonic acid deriva-
tives 1a–d (Scheme 1). The data obtained indicated that the
catalyst complexes prepared from the ligands josiphos (2a) or
Figure 1. X-ray structure of 4a’. Hydrogen atoms have been omitted
for clarity.
Scheme 1. Initial screening of catalysts and crotonic acid derivatives.
Cy =cyclohexyl.
Next, we analyzed the scope of the asymmetric conjugate
addition to methyl crotonate 1a with respect to the Grignard
reagent. Reactions were typically carried out with 0.5 mol%
of the copper catalyst 4a, and conversion was complete within
2 h at À758C. As shown in Table 1, the method is suitable for
the addition of several different Grignard reagents and
provides exclusively the product of 1,4-addition (regioselec-
tivity > 99:1) with high to excellent enantioselectivity.[21]
To determine the scope of the reaction with respect to the
b substituent on the electrophile, a series of a,b-unsaturated
esters were prepared in a single step by a Horner–Emmons
2b,[14,16] CuBr·SMe2, and EtMgBr were the most efficient.
These complexes led to higher stereoselectivities than the
other combinations of diphosphines, Cu sources, and ethyl-
magnesium halides tested. Remarkably, the use of sterically
hindered esters (e.g. 1c) to avoid the undesired 1,2-addition,
or more reactive ester surrogates, such as the oxazolidinone
1d, is not required. Indeed, the highest conversions and
stereoselectivities were observed with methyl crotonate (1a).
The influence of the catalyst loading was investigated for
the addition of EtMgBr to 1a. The addition was equally
effective with 1 mol% of the catalyst 2a/CuBr·SMe2, and
even with 0.2 mol% (substrate-to-catalyst ratio (S/C) of
500:1); the same conversion and enantioselectivity were
observed (99% conversion, 95% ee).[17] No less significantly,
the reaction proved to be very robust; reagent grade solvents
were tolerated without the need for the rigorous exclusion of
moisture and oxygen. This robustness led us to believe that a
relatively air-stable catalyst could be participating in the
process. After completion of the reaction, the addition of
pentane to the crude residue led to the recovery, following
filtration, of the dinuclear Cu complex 4a.[18] The participa-
tion of this complex in the catalytic cycle is evident, as the
reaction of 1a with recovered 4a (0.5 mol%) and EtMgBr
afforded 3a with the same yield and enantioselectivity.
Furthermore, 4a could be prepared independently as shown
in Scheme 2 and proved to be air-stable, which significantly
increased the simplicity of the procedure. Interestingly, the
slow evaporation of a solution of 4a in acetonitrile provided
single crystals of the related mononuclear trigonal-planar Cu
Table 1: Enantioselective conjugate addition of Grignard reagents
RMgBr to methyl crotonate (1a).[a]
Entry RMgBr
Product
Yield [%][b,c] ee [%][d,e]
1
2
nPrMgBr
nBuMgBr
86
92
95 (S)
95 (S)
3
90
96
4
5
84
67
87
85 (S)
[a] Conditions: 1a was added dropwise over 1 h to a solution of RMgBr
(1.15–1.25 equiv) and 4a (0.5 mol%) in tBuOMe. [b] Conversion >98%
(GC-MS) after 2 h in all cases. [c] Yield of isolated product. [d] Deter-
mined by GC on a chiral phase (G-TA for entries 1, 2, and 5; dex-CB for
entry 3) or HPLC (chiralcel OD-H for entry 4).[22] [e] Absolute config-
urations were established by comparison with known compounds.
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Table 2: Scope of the enantioselective conjugate addition of Grignard reagents to a,b-unsaturated
reaction or through olefin cross-
esters.[a]
metathesis.[23] The results, sum-
marized in Table 2, indicate that
a broad range of unsaturated
esters with different groups at
the b position participate suc-
cessfully in the enantioselective
conjugate addition. As a general
trend, less hindered a,b-unsatu-
rated esters, without branching
at the g position (Table 2,
entries 1–8), afforded better
results with the complex 4a,
derived from josiphos (2a); the
corresponding products were
formed with complete regiose-
lectivity and enantioselectivities
in the range 86–95% ee. How-
ever, for substrates with bulky
groups at the double bond (e.g.
5g and 5h), superior efficiency
was observed when the ligand
2b, in which the positions of the
alkyl and aryl phosphine groups
have been interchanged, was
used instead of 2a (Table 2,
entries 9, 10).[24] Thus, the addi-
tion of EtMgBr to 5g and 5h
(Table 2, entries 10, 12) pro-
ceeded smoothly at À758C to
afford the desired products with
nearly complete stereoselectivity
(98–99% ee) and in excellent
yields. To further demonstrate
the potential of this method, the
conjugate addition to 5g was
Entry
5
RMgBr
Product (6)
Catalyst Yield [%][b] ee [%][c]
(mol%)
1
2
3
4
a
b
c
c
EtMgBr
EtMgBr
EtMgBr
nBuMgBr
4a (0.5) 99[d]
4a (0.5) 89
4a (0.5) 91
4a (0.5) 94
93
88
91
92
5
6
d
e
EtMgBr
EtMgBr
4a (0.5) 75
4a (2.5) 85
95
86
7
8
4a (0.5) 87
88
92
f
nBuMgBr
4a (2.5) 99[d]
9
10
11
4a (2.5) 93[d,e]
4b (2.5) 99[d,e]
4b (0.5) 88[e]
87 (S)
99 (S)
98 (S)
g
EtMgBr
12
h
a
EtMgBr
4b (2.5) 86[e]
98 (S)
13
14
4a (2.5) 19[d]
4a (2.5) 37[d,g]
93
90
MeMgBr
15
16
4a (2.5) 62[d,e]
4b (0.5) 90[e]
86
95
i
j
EtMgBr
EtMgBr
17
18
4a (2.5) 42[d–f]
4b (1.5) 94[e,f]
75 (S)
98 (S)
carried out on
a 1-g scale
(0.5 mol% catalyst); 6g was
afforded in 88% yield and with
an excellent 98% ee (Table 2,
entry 11). Interestingly, the
study of the addition of
MeMgBr to 5a led us to find a
practical limitation of the
method: Although the product
was formed with high enantiose-
lectivity (93% ee), the reaction
rate was prohibitively slow (19%
conversion after 24 h; 37% con-
version in the presence of
TMSCl; Table 2, entries 13, 14).
Finally, we studied the addi-
19
20
k
l
EtMgBr
EtMgBr
4b (1.5) 99[e,f]
96
88
4b (5)
80[e,f]
21
22
m
n
EtMgBr
EtMgBr
4b (1.5) 92[e,f]
97
97
4b (1.5) 91[e,f]
tion to aryl-substituted a,b-unsa-
[a] Conditions: 4 (see table), RMgBr (1.15 equiv), 0.35m in tBuOMe, À758C, unless otherwise noted.
[b] Yield of isolated product unless otherwise noted. [c] Determined by GC on a chiral phase (G-TA or
dex-CB) or HPLC (chiralcel OD-H).[22] [d] Conversion (GC).[22] [e] RMgBr: 2.5 equivalents. [f] Reaction
carried out in CH2Cl2, 0.25m. [g] TMSCl (5.0 equiv) used. Bn=benzyl, TMS=trimethylsilyl.
turated
esters
(Table 2,
entries 15–22). As in the case of
b-substituted hindered sub-
strates, higher enantioselectivi-
ties were observed in these reactions when the Cu complex
18). The poor solubility at low temperature in aliphatic ethers
4b was used as the catalyst (e.g. Table 2, entries 15, 16 and 17,
of most of these substrates (5j–n) required the use of CH2Cl2
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[7] For approaches to b-substituted esters based on chiral-auxiliary
as the solvent to achieve complete conversions and to avoid
undesired 1,2-addition products. Although slightly longer
reaction times (3–5 h) were needed than for aliphatic
substrates, the method proved to be highly effective and
afforded exclusively the desired 1,4-addition products with
enantioselectivities ranging from 88–98% ee. Finally, prelimi-
nary results indicate that aryl moieties that bear donor and
acceptor substituents are tolerated, even those with poten-
tially competitive groups, such as nitrile groups.
strategies, see: a) W. Oppolzer, H. J. Lꢀher, Helv. Chim. Acta
1981, 64, 2808 – 2811; b) W. Oppolzer, T. Stevenson, Tetrahedron
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chiral additives, see: e) F. Xu, R. D. Tillyer, D. M. Tschaen,
E. J. J. Grabowski, P. J. Reider, Tetrahedron: Asymmetry 1998, 9,
1651 – 1655.
[8] For a catalytic approach based on an asymmetric 1,4-hydro-
silylation of a,b-unsaturated esters, see: a) B. H. Lipshutz, J. M.
Servesko, B. R. Taft, J. Am. Chem. Soc. 2004, 126, 8352 – 8353;
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Buchwald, J. Am. Chem. Soc. 1999, 121, 9473 – 9474.
[9] For an explanation of the reactivity of a,b-unsaturated carbox-
ylic acid derivatives relative to that of enones on the basis of
their respective LUMO energies, see: S. Matsunaga, T. Kino-
shita, S. Okuda, S. Harada, M. Shibasaki, J. Am. Chem. Soc.
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In conclusion, we have demonstrated that inexpensive and
readily available Grignard reagents and stable dinuclear Cu
complexes can be used for the first time in catalytic
enantioselective conjugate addition reations to simple acyclic
a,b-unsaturated methyl esters. These reactions provide access
to highly valuable b-substituted chiral esters in good yields
and with excellent enantioselectivities (up to 99% ee).
Studies are underway to establish the full scope of this
methodology, as well as to elucidate the reaction mechanism.
[10] For selected recent examples, see: a) M. S. Taylor, E. N. Jacob-
sen, J. Am. Chem. Soc. 2003, 125, 11204 – 11205, and references
therein; b) D. A. Evans, K. A. Scheidt, J. N. Johnston, M. C.
Willis, J. Am. Chem. Soc. 2001, 123, 4480 – 4491; for examples
with heteroatom-based nucleophiles, see: c) C. D. Vanderwall,
E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 14724 – 14725;
d) M. P. Sibi, N. Prabagaran, S. G. Ghorpade, C. P. Jasperse, J.
Am. Chem. Soc. 2003, 125, 11796 – 11797, and references
therein; e) see also references [1a] and [1e].
Received: January 27, 2005
Published online: April 11, 2005
Keywords: asymmetric catalysis · conjugate addition · copper ·
.
enantioselectivity · Grignard reaction
[11] A. W. Hird, A. H. Hoveyda, Angew. Chem. 2003, 115, 1314 –
1317; Angew. Chem. Int. Ed. 2003, 42, 1276 – 1279.
[1] For reviews, see: a) N. Krause, A. Hoffmann-Rꢀder, Synthesis
2001, 171 – 196; b) B. L. Feringa, R. Naasz, R. Imbos, L. A.
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Chem. Res. 2000, 33, 346 – 353; d) A. Alexakis, C. Benhaim,
Eur. J. Org. Chem. 2002, 3221 – 3236; e) K. Tomioka, Y. Nagaoka
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[3] For recent advances with acyclic enones, see: a) A. P. Duncan,
J. L. Leighton, Org. Lett. 2004, 6, 4117 – 4119; b) A. Alexakis, D.
Polet, S. Rosset, S. March, J. Org. Chem. 2004, 69, 5660 – 5667;
c) P. K. Fraser, S. Woodward, Chem. Eur. J. 2003, 9, 776 – 783;
d) H. Mizutani, S. J. Degrado, A. H. Hoveyda, J. Am. Chem. Soc.
2002, 124, 779 – 781.
[4] For conjugate additions to lactones, see: a) M. T. Reetz, A.
Gosberg, D. Moulin, Tetrahedron Lett. 2002, 43, 1189 – 1191;
b) M. Yan, L.-W. Yang, K.-Y. Wong, A. C. S. Chan, Chem.
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Tomioka, Tetrahedron 1999, 55, 3843 – 3854.
[5] For recent advances with nitroalkenes, see: a) A. Duursma, A. J.
Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2003, 125, 3700 –
3701; b) C. A. Luchaco-Cullis, A. H. Hoveyda, J. Am. Chem.
Soc. 2002, 124, 8192 – 8193, and references therein.
[6] To date, only a Rh-catalyzed asymmetric conjugate addition of
aryl boron reagents to a,b-unsaturated esters has been reported,
but the method is intrinsically unsuitable for the direct addition
of alkyl groups: a) S. Sakuma, M. Sakai, R. Itooka, N. Miyaura, J.
Org. Chem. 2000, 65, 5951 – 5955; b) Y. Takaya, T. Senda, H.
Kurushima, M. Ogasawara, T. Hayashi, Tetrahedron: Asymmetry
1999, 10, 4047 – 4056.
[12] J. Schuppan, A. J. Minnaard, B. L. Feringa, Chem. Commun.
2004, 792 – 793.
[13] With other alkyl zinc reagents only modest selectivities were
observed; see also: A. Alexakis, C. Benhaim, Tetrahedron:
Asymmetry 2001, 12, 1151 – 1157.
[14] a) B. L. Feringa, R. Badorrey, D. Peꢁa, S. R. Harutyunyan, A. J.
Minnaard, Proc. Natl. Acad. Sci. USA 2004, 101, 5834 – 5838;
b) F. Lꢂpez, S. R. Harutyunyan, A. J. Minnaard, B. L. Feringa, J.
Am. Chem. Soc. 2004, 126, 12784 – 12785.
[15] a) For enantioselective additions of Grignard reagents to
lactones, see references [14a] (5 mol% catalyst: 47–82% ee)
and [4c] (32 mol% catalyst: 76–90% ee).
[16] H.-U. Blaser, W. Brieden, B. Pugin, F. Spindler, M. Studer, A.
Togni, Top. Catal. 2002, 19, 3 – 16, and references therein.
[17] A further decrease in the catalyst loading to 0.05 mol% (S/C =
2000:1) still led to 3a with a remarkable 86% ee and 70%
conversion (GC-MS).
[18] Compound 4a was recovered in 82% yield. For related achiral
halogen-bridged dinuclear Cu species, see: a) E. D. Blue, A.
Davis, D. Conner, T. B. Gunnoe, P. D. Boyle, P. S. White, J. Am.
Chem. Soc. 2003, 125, 9435 – 9441; b) S. P. Neo, Z-Y. Zhou,
T. C. W. Mak, T. S. A. Hor, J. Chem. Soc. Dalton Trans. 1994,
3451 – 3458, and references therein.
[19] Alternatively, 4a’ can be prepared by mixing 2a and CuBr·SMe2
in acetonitrile and converted into the dimeric complex 4a by
treatment with halogenated solvents. See Supporting Informa-
tion for the characterization of 4a and 4a’ and further
information.
[20] CCDC 261573 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[21] Sterically hindered Grignard reagents, such as iPrMgBr, and aryl
Grignard reagents, such as PhMgBr, have provided poor results
so far. (iPrMgBr: 26% conversion, 12% ee; PhMgBr: 55%
conversion, 1% ee.)
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[22] See Supporting Information for details.
[23] For a Review on olefin cross-metathesis, see: a) S. J. Connon, S.
Blechert, Angew. Chem. 2003, 115, 1944 – 1968; Angew. Chem.
Int. Ed. 2003, 42, 1900 – 1923.
[24] A Cu complex 4b obtained from 2b and CuBr·SMe2 was
prepared by the method shown in Scheme 2 and used in these
reactions. The same results were obtained when 4b was prepared
in situ.
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