Highly diastereo- and enantioselective copper-catalyzed domino reduction/aldol reaction of ketones with methyl acrylate

Article abstract of DOI:10.1002/anie.200503791

(Chemical Equation Presented) A good choice: A new catalytic method was found for the construction of stereogenic quaternary carbon centers through a copper-catalyzed domino conjugated reduction/aldol reaction of methyl acrylate with various alkyl aryl ke

Full text of DOI:10.1002/anie.200503791

Communications
Asymmetric Aldol Reactions
DOI: 10.1002/anie.200503791
Highly Diastereo- and Enantioselective Copper-
Catalyzed Domino Reduction/Aldol Reaction of
Ketones with Methyl Acrylate**
Julia Deschamp, Olivier Chuzel, JØrôme Hannedouche,
and Olivier Riant*
The development of efficient catalytic asymmetric method-
ologies for the construction of chiral, nonracemic tertiary
alcohols is currently a challenging research area of interest,[1]
and a few asymmetric catalytic methods dealing with this
demanding task have been described.[2–7] Despite excellent
progress in the field of metal-catalyzed enantioselective
nucleophilic addition to ketones, only limited success has
[*] J. Deschamp, O. Chuzel, Dr. J. Hannedouche, Prof. O. Riant
UnitØ de chimie organique et mØdicinale
UniversitØ catholique de Louvain
Place Louis Pasteur1, 1348 Louvain-la-Neuve (Belgium)
Fax: (+32)1047-4168
E-mail: riant@chim.ucl.ac.be
[**] This work was supported by the UniversitØ Catholique de Louvain.
Dr. B. Pugin (Solvias) and Dr. R. Schmid (Hoffmann–La Roche) are
gratefully acknowledged for generous gifts of chiral ligands. Mr. V.
Van Tran is also acknowledged for his assistance with the chiral
analysis of the new compounds.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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been achieved in catalytic enantioselective
aldol reaction to ketones.[7] The reported
systems suffer from either moderate enan-
tioselectivity and/or poor substrate scope and
practicality. Moreover, they involve silyl
enolate derivatives as nucleophilic partners
and thus require an additional and stoichiometric step for
their preparation. We are interested in developing an efficient
catalytic and enantioselective aldol reaction to simple ketones
that overcomes these limitations and does not involve
preactivation of the nucleophile in an independent step.[8]
For this purpose, we turned our intention to the domino
conjugate reduction/aldol reaction between a,b-unsaturated
carbonyl compounds and ketones with hydrosilane as the
reducing agent.[9] This three-component reaction,[10] which
allows the preactivation of the nucleophile in situ by gen-
eration of a silyl or metal enolate, was successfully employed
in the catalytic asymmetric reductive aldol reaction between
a,b-unsaturated esters and prochiral aldehydes in the pres-
ence of chiral rhodium and iridium complexes.[11,12] Never-
theless, to our knowledge, such a strategy for the develop-
ment of a catalytic asymmetric aldol process has not been
applied to ketones.[13] Herein we disclose our initial studies
towards this goal and report the first metal-catalyzed
diastereo- and enantioselective intermolecular domino con-
jugate reduction/aldol reaction between methyl acrylate and
simple ketones.[14]
Our initial experiment was conducted on acetophenone
(1; R = C6H5) and methyl acrylate (2) with a catalytic amount
of [CuF(PPh3)3]·2MeOH[25] (3) and Roche chiral ligand (S)-
L1 and a stoichiometric quantity of phenylsilane at 08C.[26] In
In 1997, pioneer work by Mori et al.[15] suggested that
[CuF(PPh3)3]·2EtOH was an efficient copper(i) source for the
generation of copper hydride species by transmetalation of an
hydrogen atom from hydrosilane without any additional
silane activator.[16,17] The copper hydride species generated
under theses conditions reduced a,b-unsaturated carbonyl
the presence of 3 and (S)-L1 (1.25 mol%) catalyst, the
reaction was almost complete in 2 h (95% conversion) to
afford solely a single product, which was identified as adduct
4.[27]
compounds
stoichiometrically[18]
in
a
1,4-selective
manner.[15,19] Later, various enantioselective copper hydride
catalyzed protocols for the 1,4-reduction of a variety of
prochiral conjugated compounds were successfully developed
by using other copper hydride precursors that were also
generated from a stoichiometric amount of silane reagent.[20]
These reactions are proposed to proceed by formation of a
copper enolate that subsequently undergoes metathesis with a
silane to form a silyl enolate. The latter can further participate
in an alkylation,[21a] arylation,[21b] or Mukaiyama aldol[21c]
reaction to give a one-pot sequential process overall. Trapping
Despite high chemoselectivity (99%), 4 was obtained in a
low diastereomeric ratio (d.r. = 41:59) but with an encourag-
ing 51% ee for the major threo isomer (Table 1, entry 1).[28] To
optimize these results, several parameters were changed.
Copper(i) salts were first surveyed to assess the effect of the
copper hydride precursor on the reaction. No significant
changes in chemo-, diastereo-, and enantioselectivity of the
domino reaction between 1 (R = C6H5) and 2 were observed
when using either PPh3-free CuF–L1,[29] CuOtBu–L1[30] or
CuCl/NaOtBu–L1 systems under the same conditions.[31] The
media effect was then examined by using the easy to handle
and air-stable precatalyst 3 and ligand (S)-L1.
The selectivity of the domino process did not improve by
replacing THF with toluene. However, a more polar solvent
such as DMF led to poorer conversion and a lower ee value of
the threo isomer. We next investigated the temperature
dependence of the reaction. Varying the temperature from 0
to ꢀ508C raised the ee value of erythro-4 from 2 to 25%
(Table 1, entry 1 versus 2), but had hardly any influence on
the chemo- and diastereoselectivity of the reaction or on the
ee value of the threo isomer. However, when the reaction was
run at ꢀ788C, chemoselectivity dropped significantly from 99
to 52% (Table 1, entry 1 versus 3). Diverse chiral ligands were
subsequently screened under the optimized conditions (3,
ꢀ
the copper enolate by the formation of a C C bond with an
electrophilic ketone partner at a rate faster than the metath-
esis step could be an opportunity for the development of a
copper-catalyzed stereoselective domino reaction between
a,b-unsaturated carbonyl compounds and ketones. Shibasaki
et al. recently reported a general method for the catalytic
aldol reaction between ketene trimethylsilyl acetates and
ketones by using catalytic [CuF(PPh3)3]·2EtOH in the
presence of a stoichiometric amount of (EtO)3SiF additive.[22]
Mechanistic studies showed that the copper enolate inter-
mediate was the reactive nucleophile in this process.[23,24]
These observations prompted us to investigate the use of
chiral diphosphane-modified copper fluoride as a catalyst for
the stereoselective reductive aldol reaction between methyl
acrylate and aromatic ketones with hydrosilanes [Eq. (1)].
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Table 1: Asymmetric copper-catalyzed reductive aldol reaction between methyl acrylate (2) and acetophenone (1; R=C6H5) under various reaction
conditions with different chiral ligands L1–L11.[a]
Entry
Ligand
t [h]
Conversion [%][b]
Chemoselectivity [%][b, c]
d.r.[b] erythro
ee[b] [%]
ee[b] [%]
threo
(erythro-4)
(threo-4)
[e,f]
1
2
3
4
5
6
7
8
9
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L9
L10
L11
2
2
2
1
1
1
1
2
2
1
1
4
2
2
95
80
77
99
98
99
98
96
99
99
99
92
99
99
99
98
52
98
98
>99
>99
98
>99
99
>99
>99
99
41:59
41:59
45:55
78:22
54:46
54:46
56:44
74:26
77:23
76:24
92:8
2
25
16
0
29
51
55
38
2
52
[e]
[e][g]
ꢀ73
ꢀ63
40
45
16
13
ꢀ85
95[d]
87
ꢀ1
35
10
11
12[h]
13
14
ꢀ94
72
89:11
88:12
64:36
55
37
46
ꢀ22
>99
4
[a] Reactions were carried out in solution (0.25m) in toluene at ꢀ508C under an oxygen-free argon atmosphere containing 1 (R=C6H5) (1.0 equiv), 2
(1.2 equiv), 3 (1 mol%), ligand (1 mol%), PhSiH3 (1.4 equiv) unless otherwise stated. [b] Determined by chiral GC analysis. [c] Chemoselectivity=(4/
(4+phenylethanol)”100). [d] Absolute configuration: 2R,3S (see Supporting Information). [e] 1 (0.8 equiv), 2 (1.0 equiv), 3 (1 25 mol%), ligand
(1.25 mol%), PhSiH3 (1.2 equiv). [f] At 08C. [g] At ꢀ788C. [h] 3 (0.1 mol%), L9 (0.1 mol%).
toluene, ꢀ508C). Among them, diphosphane-based ligands
were the most promising ligands in terms of activity and
selectivity.[32] Various families of chiral diphosphane ligands
L2–L11 were tested, and some results are summarized in
Table 1, entries 4–14. To our delight, the reactions were highly
chemoselective (> 98%) and almost complete (95–98%
conversion) in less than 2 h (unoptimized reaction time),
regardless of the ligand structure. The erythro-4 isomer was
favored in all cases. We first investigated axially chiral biaryl
ligands L2 and L3. The substitution of (S)-L1 for (S)-L2 led to
a remarkable improvement in the diastereoselectivity (d.r.
41:59!78:22) in favor of the erythro isomer (Table 1, entry 2
versus 4). Unfortunately, both isomers were obtained as a
racemic mixture. The employ of commonly used (S)-L3
restored some enantioselectivity to the reaction with 29 and
52% ee for the major and minor isomers, respectively, despite
a decrease in the diastereoselectivity (Table 1, entry 4 versus
5).
We then assessed chiral ferrocenyl-based diphosphane
ligands available from the Solvias kit. Among the different
ligand families tested, the josiphos[33a] and taniaphos[33b] ligand
families were the most efficient in terms of diastereo- and/or
enantioselectivities. For example, the combination of C1-
symmetric (R,S)-L4 and precatalyst 3 in the presence of 1, 2,
and phenylsilane afforded almost quantitatively the adduct 4
with a moderate ꢀ73%ee for the erythro isomer, despite a
low 54:46 d.r. (Table 1, entry 6). The use of L5, which bears a
more acidic phosphane group on the side chain, did not
improve the diastereomeric ratio but led to a significantly
lower enantioselectivity (Table 1, entry 7). Improved diaste-
reocontrol of the reaction was observed with mandyphos
diphosphane ligands (R,S)-L6 and (R,S)-L7, which have a C2-
symmetric backbone (Table 1, entries 8 and 9). Unfortu-
nately, both ligands afforded 4 with low enantioselectivities.
We subsequently tested taniaphos ligand (R,S)-L8, which
contains a 1,5-diphosphane unit and hence is capable of
forming an eight-membered chelate ring with a metal.
Taniaphos ligand (R,S)-L8 provided a diastereoselectivity
(d.r. 76:24) similar to that obtained with mandyphos ligands
(R,S)-L6 and (R,S)-L7. However, the enantiodifferentiation
was drastically enhanced for both isomers of 4. Under the
optimal conditions, the reaction with (R,S)-L8 furnished
adduct 4 with ꢀ85 ee and ꢀ94% ee for the erythro and threo
isomers, respectively (Table 1, entry 10). The substitution of
phenyl groups attached to phosphorus atoms of L8 by
cyclohexyl substituents further improved the diastereo- and
enantioselectivity of the reaction.[34] Indeed, the addition of 1,
2, and phenylsilane to 3 (1 mol%) and (R,S)-L9 (1 mol%)in
toluene gave 4 with 92:8 d.r. in favor of the erythro isomer and
95% ee for the major isomer (Table 1, entry 11). The catalyst
loading can be decreased to 0.1 mol% without significant
variation of chemo- and diastereocontrol (Table 1, entry 12).
However, under these conditions, a slight decrease in the
enantioselectivity was observed for the preponderant isomer.
Notably, for both privileged[35] josiphos and taniaphos ligand
families, the opposite absolute configuration of the major
compound was observed when the groups on the phosphorus
atoms were changed from alkyl to aryl substituents (Table 1,
entry 6 versus 7and entry 10 versus 11). Moreover, a change
from josiphos ligands (R,S)-L4 and (R,S)-L5 to taniaphos
ligand (R,S)-L9 and (R,S)-L8, respectively, which exhibit the
same planar chirality, afforded erythro-4 with the opposite
configuration (Table 1, entry 6 versus 11 and entry 7versus
10).[36] The use of other chiral ligands bearing a 1,5-diphos-
phane unit such as walphos ligands (R,R)-L10 and (R,R)-L11
afforded adduct 4 with lower diastereo- and enantioselectivity
(Table 1, entries 13 and 14).
Next, we analyzed the scope of the copper-catalyzed
asymmetric reductive aldol reaction with respect to the
ketone substrate by using taniaphos chiral ligand (R,S)-L9
under the optimal conditions. A variety of aromatic and
heteroaromatic ketones participate successfully in the reac-
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Table 2: Asymmetric copper-catalyzed reductive aldol reaction between 2 and various aromatic ketones 1 with (R,S)-L9 underthe optimal conditions. [a]
Entry
R
t [h]
Yield [%][h]
Chemoselectivity [%][b][c]
d.r.[b] erythro/
ee[b] [%]
ee[b] [%]
threo
(erythro-4)
(threo-4)
1
2
3
4
5
6
C6H5
1
1
1
1
1
1
2
2
98
88
87
31[f]
95
70
94
95
>99
94
89
97
95
89
>99
>99
92:8
91:9
95[d]
92
83
90
90
82
90
95
72
73
72
56
p-FC6H5
p-CF3C6H5
pMeOC6H5
p-ClC6H5
m-ClC6H5
2-thienyl
3-thienyl
80:20
92:8
86:14
88:12
96:4
95:5
77
n.d.[e]
15
7[g]
8
65
[a] Reactions were carried out in solution (0.25m) in toluene at ꢀ508C under an oxygen-free argon atmosphere containing 1 (1.0 equiv), 2 (1.2 equiv),
3 (1 mol%), (R,S)-L9 (1 mol%), PhSiH3 (1.4 equiv) unless otherwise stated. [b] Determined by chiral GC analysis. [c] Chemoselectivity=(4/
(4+phenylethanol)”100). [d] Absolute configuration: 2R,3S. [e] Not determined. [f] Conversion determined by GC analysis and not optimized. [g] 3
(3 mol%), (R,S)-L9 (3 mol%). [h] Yield of isolated product.
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tion (Table 2). For the range of substrates studied, the
diastereo- and enantioselectivity of the reaction were mod-
erate to high (erythro-4: d.r. 80:20–96:4 and 82–95% ee). As a
general trend, the introduction of a halogen substituent at the
para or meta position of acetophenone slightly decreased the
diastereoselectivity of the reaction and the enantioselectivity
of the major isomer (Table 2, entry 1 versus entries 2, 5, and
6). The substitution of an electron-withdrawing group at the
para position of acetophenone by an electron-donating group
increased both the diastereomeric ratio and the ee of the
erythro compound (Table 2, entry 3 versus 4). Heteroaro-
matic ketones such as 2- and 3-thiophene-substituted ketones
also took part efficiently in the domino sequence to give the
corresponding erythro-4 compound with very high chemo-,
diastereo-, and enantioselectivity (Table 2, entries 7and 8).
In summary, we have developed a new strategy for the
catalytic asymmetric aldol reaction of ketones that relies on a
domino reduction/aldol reaction sequence between methyl
acrylate and aromatic ketones. The process, catalyzed by a
diphosphane-modified copper(i) fluoride complex in the
presence of phenylsilane, is highly selective (chemo-, dia-
stereo-, and enantioselectivity) for a range of aromatic
ketones. This strategy circumvents the need to preactivate
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ꢀ
the nucleophile prior to the C C bond-forming step and
affords highly functionalized products with two contiguous
stereogenic centers, one of which is a chiral tertiary alcohol.
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Received: October 26, 2005
Published online: January 20, 2006
Keywords: aldol reaction · copper · enantioselectivity · enolates ·
.
hydrosilylation
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Chem. Int. Ed. 2005, 44, 1602.
[11] a) S. J. Taylor, M. O. Duffey, J. P. Morken, J. Am. Chem. Soc.
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d) N. O. Fuller, J. P. Morken, Synlett 2005, 1459; e) H. Nish-
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[12] a) S. Isayama, T. Mukaiyama, Chem. Lett. 1989, 2005; b)
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1998, 39, 5237; d) S. J. Taylor, J. P. Morken, J. Am. Chem. Soc.
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2001, 3, 2839; f) I. Shibata, H. Kato, T. Ishida, M. Yasuda, A.
Baba, Angew. Chem. 2004, 116, 729; Angew. Chem. Int. Ed. 2004,
43, 711; g) M. Freiría, A. J. Whitehead, D. A. Tocher, W. B.
Motherwell, Tetrahedron 2004, 60, 2673.
[13] For the intramolecular reductive aldol reaction of alkenediones
with a stoichiometric amount of the Stryker reagent, see: a) P.
Chiu, C. P. Szeto, Z. Geng, K. F. Cheng, Org. Lett. 2001, 3, 1901;
b) P. Chiu, B. Chen, K. F. Cheng, Tetrahedron Lett. 1998, 39,
9229; c) P. Chiu, C. P. Szeto, Z. Geng, K. F. Cheng, Tetrahedron
Lett. 2001, 42, 4091; for intramolecular reductive aldol reaction
of alkynediones with stoichiometric or catalytic amounts of the
Stryker reagent, see: d) P. Chiu, S. K. Leung, Chem. Commun.
2004, 2308; for an intramolecular reductive Henry reaction with
stoichiometric amounts of the Stryker reagent, see: e) W. K.
Chung, P. Chiu, Synlett 2005, 55.
[14] During the preparation of this manuscript, a diastereo- and
enantioselective copper-catalyzed intramolecular reductive
aldol reaction of a,b-unsaturated esters and ketones was
reported: H. W. Lam, P. M. Joensuu, Org. Lett. 2005, 7, 4225.
[15] a) A. Mori, A. Fujita, Chem. Commun. 1997, 2159; b) H. Ito, T.
Ishizuka, K. Arimoto, K. Miura, A. Hosomi, Tetrahedron Lett.
1997, 38, 8887; c) A. Mori, A. Fujita, H. Kajiro, Y. Nishihara, T.
Hiyama, Tetrahedron 1999, 55, 4573.
[16] We have reported the use of copper fluoride–phosphine com-
plexes for the catalytic enantioselective hydrosilylation of
aromatic ketones with excellent yields and enantioselectivities:
a) S. Sirol, J. Courmarcel, N. Mostefai, O. Riant, Org. Lett. 2001,
3, 4111; b) J. Courmarcel, N. Mostefai, S. Sirol, S. Choppin, O.
Riant, Isr. J. Chem. 2002, 42, 231; for a review on catalytic
asymmetric hydrosilylation to ketones and imines, see: c) O.
Riant, N. Mostefai, J. Courmarcel, Synthesis 2004, 2943.
[17] For a special topic on copper-mediated conjugate reductions and
reductive aldol reactions with organosilanes as the hydride
source, see: P. Chiu, Synthesis 2004, 2943.
[21] a) B. H. Lipshutz, W. Chrisman, K. Noson, P. Papa, J. A. Sclafani,
R. W. Vivian, J. M. Keith, Tetrahedron 2000, 56, 2779; b) J. Yun,
S. L. Buchwald, Org. Lett. 2001, 3, 1129; c) J. Chae, J. Yun, S. L.
Buchwald, Org. Lett. 2004, 6, 4809.
[22] K. Oisaki, Y. Suto, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2003, 125, 5644; for complementary work, see reference [7d].
[23] The copper enolate intermediate was proposed to be generated
by dynamic ligand exchange between silicon and copper;[22] for
pioneering work on a CuF–(S)-tolbinap-catalyzed enantioselec-
tive aldol reaction between silyl dienolate and aldehyde that
involved a metalloenolate intermediate, see: a) J. Krꢂger, E. M.
Carreira, J. Am. Chem. Soc. 1998, 120, 837; b) B. L. Pagenkopf, J.
Krꢂger, A. Stojanovic, E. M. Carreira, Angew. Chem. 1998, 110,
3312; Angew. Chem. Int. Ed. 1998, 37, 3124.
[24] For
a CuF–tolbinap-catalyzed enantioselective vinylogous
Mukaiyama reaction on aliphatic ketones, see reference [7e].
[25] The complex was prepared according to a literature procedure:
D. J. Gulliver, W. Levason, M. Webster, Inorg. Chim. Acta 1981,
52, 153; the amount of methanol molecules contained in the
complex was determined by single-crystal X-ray crystallographic
analysis of the complex (unpublished results).
[26] PhSiH3 was chosen as hydride source for its tendency not to form
stable silyl enol ethers upon transmetalation with copper
enolate.[19c]
[27] A minor trace of phenylethanol (< 1%), the product of
reduction of acetophenone, was observed by GC analysis.
[28] Under the same conditions, without any additional ligand, 3
(1.25 mol%) gave only 20% conversion after a 2-hour reaction.
[29] For the preparation, see: D. Tomita, R. Wada, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2005, 127, 4138.
[30] For the preparation of CuOtBu, see: T. Tsuda, T. Hashimoto, T.
Saegusa, J. Am. Chem. Soc. 1972, 94, 658.
[31] Notably, no effect on the reaction rate was observed when using
either preprepared CuOtBu or CuOtBu prepared in situ (from
CuCl/NaOtBu); for a report on the salt effect on the rate of the
enantioselective 1,4-reduction of b,b-disubstituted nitroalkenes
when using both methods of CuOtBu preparation, see refer-
ence [20 h].
[32] For example, monodentate Feringa phosphonite, tridentate tBu-
pybox, and tetradentate Trost ligand gave very low activity and/
or no enantioselectivity.
[33] For original work, see: a) A. Togni, C. Breutel, A. Schnyder, F.
Spindler, H. Landert, A. Tijani, J. Am. Chem. Soc. 1994, 116,
4062; b) T. Ireland, G. Grossheimann, C. Wieser-Jeunesse, P.
Knochel, Angew. Chem. 1999, 111, 1560; Angew. Chem. Int. Ed.
1999, 38, 3212.
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Angewandte
Chemie
[34] These observations are in contrast to those usually made in other
processes using taniaphos-derived ligands containing either alkyl
or aromatic substituents on phosphorus atoms. Generally, a
change from electron-rich aromatic groups to cyclohexyl groups
has a negative effect on the enantioselectivity of the process. For
some examples, see: a) B. L. Feringa, R. Badorrey, D. Peꢃa, S. R.
Harutyunyan, A. J. Minnaard, Proc. Natl. Acad. Sci. USA 2004,
101, 5834; b) F. Spindler, C. Malan, M. Lotz, M. Kesselgruber, U.
Pittelkow, A. Rivas-Nass, O. Briel, H.-U. Blaser, Tetrahedron:
Asymmetry 2004, 15, 2299.
[35] T. P. Yoon, E. N. Jacobsen, Science 2003, 299, 1691.
[36] A similar observation was previously made in the copper-
catalyzed asymmetric conjugate addition of Grignard reagents
to cyclic enones.[34a]
Angew. Chem. Int. Ed. 2006, 45, 1292 –1297
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