Copper(I)-catalyzed enantio- and diastereoselective tandem reductive aldol reaction

Article abstract of DOI:10.1021/ol062398v

(Chemical Equation Presented) An efficient method for the enantioselective tandem reductive aldol reaction of methyl acrylate with aldehydes is reported. By using a copper-(I) precursor and a proper diphosphane ligand, high reactivities can be reached, with TOF up to 40 000 h^-1. Taniaphos-based ligands lead to enantioselectivities of up to 97% in the case of the major syn diastereoisomer.

Full text of DOI:10.1021/ol062398v

ORGANIC
LETTERS
2006
Vol. 8, No. 26
5943-5946
Copper(I)-Catalyzed Enantio- and
Diastereoselective Tandem Reductive
Aldol Reaction
Olivier Chuzel, Julia Deschamp, Christophe Chausteur, and Olivier Riant*
Unite´ de chimie organique et me´dicinale, UniVersite´ catholique de LouVain,
Place Louis Pasteur, 1, 1348 LouVain-la-NeuVe, Belgium
riant@chim.ucl.ac.be
Received September 29, 2006
ABSTRACT
An efficient method for the enantioselective tandem reductive aldol reaction of methyl acrylate with aldehydes is reported. By using a copper-
-
(I) precursor and a proper diphosphane ligand, high reactivities can be reached, with TOF up to 40 000 h 1. Taniaphos-based ligands lead to
enantioselectivities of up to 97% in the case of the major syn diastereoisomer.
The aldol reaction is a classical method for the creation of
carbon-carbon bonds in organic synthesis.1 Reductive aldol
reaction of R,â-unsatured esters with aldehydes promoted
by catalytic amounts of various transition-metal complexes
and a silane source is a powerful tool for stereocontrolled
C-C bond formation.2 By using this method, the preacti-
vation of the nucleophile in an independent step is not
required as the enolate (the activated form of the nucleophile)
is generated in situ through the conjugated addition of a metal
hydride onto a Michael acceptor. Previous works in this area
has been described, including the obtention of good levels
of diastereo- and enantioselectivity variants with rhodium
or iridium metal complexes.3 We were interested in develop-
ing a more economic process and selected copper as the
transition metal. To our knowledge, copper was only
employed in intramolecular reductive aldol cyclization as the
Stryker’s reagent or as Cu(OAc)2‚H2O.4-6 In a preliminary
communication, we have recently reported a new catalytic
method for the construction of stereogenic quaternary carbon
(3) For reductive aldol reactions catalyzed by rhodium and iridium
complexes, see: (a) Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc. 1999,
121, 12202. (b) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem.
Soc. 2000, 122, 4528. (c) Zhao, C. X.; Duffey, M. O.; Taylor, S. J.; Morken,
J. P. Org. Lett. 2001, 3, 1829. (d) Townes, J. A.; Evans, M. A.; Queffelec,
J.; Taylor, S. J.; Morken, J. P. Org. Lett. 2002, 4, 2537. (e) Russell, A. E.;
Fuller, N. O.; Taylor, S. J.; Aurriset, P.; Morken, J. P. Org. Lett. 2004, 6,
2309. (f) Fuller, N. O.; Morken, J. P. Synlett 2005, 1459. (g) Fuller, N. O.;
Morken, J. P. Org. Lett. 2005, 7, 4867. (h) Nishiyama, H.; Shiomi, T.;
Tsuchiya, Y.; Matsuda, I. J. Am. Chem. Soc. 2005, 127, 6972. For an indium-
catalyzed reductive aldol reaction, see: (i) Shibata, I.; Kato, H.; Ishida, T.;
Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 711.
(4) For intramolecular reductive aldol reactions with a stoichiometric
amount of Stryker reagent, see: (a) Chiu, P.; Chen, B.; Cheng, K. F.
Tetrahedron Lett. 1998, 39, 9229. (b) Chiu, P.; Szeto, C.-P.; Geng, Z.;
Cheng, K.-F. Org. Lett. 2001, 3, 1901. (c) Chiu, P.; Szeto, C. P.; Geng, Z.;
Cheng, K. F. Tetrahedron Lett. 2001, 42, 4091. For intramolecular reductive
aldol reactions with a catalytic amount of Stryker reagent, see: (d) Chiu,
P.; Leung, S. K. Chem. Commun. 2004, 2308. (e) Chiu, P. Synthesis 2004,
2210. For intramolecular reductive aldol reactions catalyzed by Cu(OAc)2‚
H2O, see: (f) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225. (g)
Lam, H. W.; Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743.
(1) For reviews on asymmetric aldol reactions, see: (a) Nelson, S. G.
Tetrahedron: Asymmetry 1998, 9, 357. (b) Carreira, E. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Plaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, Germany, 1999; Vol. III, Chapter 29.1, pp 997-
1065. Mahrwald, R., Ed. Modern Aldol Reactions; Wiley-VCH: Weinheim,
Germany, 2004. (c) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc.
ReV. 2004, 33, 65.
(2) For original reports of catalytic reductive aldol reactions, see: (a)
Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809. (b) Isayama, S.;
Mukaiyama, T. Chem. Lett. 1989, 2005. (c) Matsuda, I.; Takahashi, K.;
Sato, S. Tetrahedron Lett. 1990, 37, 5331. (d) Kiyooka, S.; Shimizu, A.;
Torii, S. Tetrahedron Lett. 1998, 39, 237.
10.1021/ol062398v CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/23/2006

centers through a copper-catalyzed domino conjugated
reduction/aldol reaction of methyl acrylate with various alkyl
aryl ketones that gave high chemo-, diastereo-, and enanti-
oselectivity.7 These results prompted us to investigate the
use of this system for the construction of small propionate-
type compounds.
In our initial experiment we used benzaldehyde 1a (R )
Ph) and methyl acrylate 2 (2.0 equiv), with a catalytic amount
of [CuF(PPh3)3]‚2MeOH (3),8 (S)-BINAP (L1), and a sto-
ichiometric quantity of phenylsilane, at room temperature.
In the presence of 3 and (S)-L1 (0.01 mol %), a smooth
reaction was almost complete within 15 min (94% conver-
sion) affording the aldol adduct 4a (syn:anti, 60:40) (eesyn
) 45%) and the benzyl alcohol 5a in a ratio of 86:14. This
catalytic system displays a very high activity and the TON
was estimated to be 10.000 and the TOF to be 40 000 h-1.
Cyclohexanecarboxaldehyde (1b, R ) Cy) and 2 were also
tested in the presence of 3 and (S)-L1 (0.1 mol %) catalyst.
The reaction was completed in 1 h at room temperature
leading to 4b (R ) Cy) and 5b (R ) Cy) in a ratio of 89:11,
a syn:anti diastereomeric ratio of 58:42, and an enantiomeric
excess for the syn adduct of 30% (Table 1, entry 1).9
Table 1. Copper-Catalyzed Asymmetric Reductive Aldol
Reaction with Various Ligandsa
Figure 1. Chiral diphosphane ligands evaluated in asymmetric
reductive aldol reaction.
families of chiral diphosphane ligands L2-L10 (Figure 1)
were employed and some of the most pertinent results are
summarized in Table 1 (entries 2-11), with cyclohexan-
ecarboxaldehyde (4b) as the substrate.10 The reactions were
almost complete in less than 2 h, regardless of the ligand’s
structure (except entries 6, 10, and 11). However, the ratio
between 4b and 5b fluctuates and depends upon the structure
conversion
(%)b
eesyn (eeanti
)
entry ligand
4b:5b syn:anti
(%)c
1c-e
2f
3
L1
L2
L3
L4
L5
L6
L7
L7
L8
L9
L10
99
99
99
99
99
75
99
99
99
39
51
89:11
88:12
30:70
67:33
34:67
2:98
58:42
70:30
65:35
64:36
76:24
52:48
77:23
77:23
31:69
63:37
62:38
30
60 (12)
44
57 (30)
83
38
95 (74)
94 (74)
40 (30)
61
(5) For intramolecular reductive aldol cyclizations catalyzed by Wilkin-
son’s complex, see: (a) Emiabata-Smith, D.; McKillop, A.; Mills, C.;
Motherwell, W. B.; Whitehead, A. J. Synlett 2001, 8, 1302. (b) Freiria, M.;
Whitehead, A. J.; Tocher, D. A.; Motherwell, W. B. Tetrahedron 2004,
60, 2673.
(6) Alternatively, molecular hydrogen may be used as the reducing agent
for the reductive aldol cyclization catalyzed by rhodium and cobalt
complexes, see: (a) Baik, T.-G.; Luis, A. L.; Wang, L.-C.; Krische, M. J.
J. Am. Chem. Soc. 2001, 123, 5112. (b) Huddleston, R. R.; Krische, M. J.
Org. Lett. 2003, 5, 1143. (c) Jang, H. Y.; Krische, M. J. Acc. Chem. Res.
2004, 37, 653. (d) Jang, H. Y.; Krische, M. J. Eur. J. Org. Chem. 2004,
3953.
(7) (a) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew.
Chem., Int. Ed. 2006, 45, 1292. After our submission, Shibasaki reported
a similar catalytic system for the reductive aldol reaction: (b) Zhao, D. B.;
Oisaki, K.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403.
(8) The complex was prepared according to a literature procedure, see:
Gulliver, D. J.; Levason, W.; Webster, M. Inorg. Chim. Acta 1981, 52,
153. The amount of methanol molecules was determined by single-crystal
X-ray crystallographic analysis of the complex (unpublished results).
(9) Syn and anti diastereoisomers were identified by comparison of
chemical shifts obtained by 1H NMR with those reported by Morken et
al.3a-e and Nishiyama et al.3h Conversion, chemo-, diastereo-, and enanti-
oselectivities were determined by chiral GC. Analytical gas chromatography
was performed on a ThermoFinningan Trace GC, using a CHIRALSIL-
DEX CB (25 m, 0.25 mm, 25 µm). The ratios are based upon crude
integrations which correspond to the corrected integrations by calibration.
(10) For example, monodentate Feringa phosphonite, bidentate Reetz
phosphites, and tetradentate Trost ligands gave also good activities but low
diastero- and enantioselectivities.
4
5
6
7c
8g
9f
99:1
97:3
15:85
6:94
10
11
5:95
41
a All reactions were carried out in solution (0.25 M) in THF at -78 °C
under an oxygen-free argon atmosphere containing 1b (1.0 equiv), 2 (1.2
equiv), 3 (1 mol %), ligand (1 mol %), and PhSiH3 (1.4 equiv) unless
otherwise stated. b Determined by chiral GC analysis CHIRALSIL-DEX
CB (25 m, 0.25 mm, 25 µm). c 3 (0.1 mol %), ligand (0.1 mol %). d 1b
(0.8 equiv), 2 (1.0 equiv), 3 (1.25 mol %), ligand (1.25 mol %), PhSiH3
(1.2 equiv). e At room temperature. f At 0 °C. g In toluene.
Despite the high activity of this catalytic system and the
rather good chemoselectivity attained, 4a,b (R ) Ph or Cy)
was obtained only with moderate diastereomeric and enan-
tiomeric excesses. To optimize these results, several param-
eters were modified. Some chiral ligands were initially
screened in THF at lower temperature (-78 °C). Various
5944
Org. Lett., Vol. 8, No. 26, 2006

of the ligands. In some cases, the chemoselectivity could
almost be completely shifted in favor of the reduction product
5b (Table 1, entries 6, 9, 10, and 11). Promising results were
observed in the case of ligands JOSIPHOS L2, WALPHOS
L4 ,and L5. Good enantioselectivities were reached in the
case of the syn isomer (Table 1, entries 2, 4, and 5). We
subsequently tested TANIAPHOS ligands L7-L9, which
contain a 1,5-diphosphane unit and hence are capable of
forming an eight-membered chelate ring with the metal. To
our delight, L7 provided a remarkable improvement in the
chemoselectivity in favor of 4b (99:1), with a diastereose-
lectivity (dr 77:23) (Table 1, entries 7 and 8) similar to that
obtained with the L2 or L4 ligands, in favor of the syn adduct
(Table 1, entries 2 and 4). However, the enantiodifferentiation
was drastically enhanced for both isomers of 4b. Under these
conditions, the reaction with L7 furnished adduct 4b with
95% ee and 74% ee for the syn and anti isomers, respectively
(Table 1, entry 7). The catalyst loading can be decreased to
0.1 mol % without any variation in chemo-, diastereo-, and
enantioselectivities (Table 1, entries 1 and 7). Interestingly,
TANIAPHOS L8 and L9 showed poor results in the
reductive aldol reaction compared to L7 (Table 1, entries 9
and 10).
Next, we studied the scope of the copper-catalyzed
asymmetric reductive aldol reaction with respect to the
aldehyde substrates and the TANIAPHOS chiral ligand L7,
under optimal conditions. A variety of aliphatic, aromatic,
or heteroaromatic aldehydes were tested at -78 °C in THF.
However, the low solubility of aromatic substrates at low
temperature in THF or toluene forced us to select a
compromise in which in toluene, at -50 °C, provided the
best results.11 Remarkably, the selectivity of the domino
process did not change when THF was replaced by toluene,
and we observed that all substrates participate successfully
in the reaction (conversion >99%). The chemoselectivity
remains excellent (generally >95:5) with good enantiose-
lectivities but moderate diastereoselectivities (Table 2). The
isolated yields for the corresponding adducts after chromato-
graphic purification were all in the range of 74-99%. For
acyclic aliphatic aldehydes, good chemoselectivities and
moderate diastereoselectivities were observed (entries 1 and
2) and some enantioselectivity was detected in the case of
isobutyraldehyde (eesyn ) 73%) (entry 1).
Table 2. Asymmetric Copper-Catalyzed Reductive Aldol
Reaction between 2 and Various Aldehydes 1 in the Presence of
(R,S)-L7 under the Optimal Conditionsa
conversion
(%)b
eesyn (eeanti
)
entry
R
4:5
syn:anti
(%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
i-Pr
t-Bu
Cy
99
99
99
99
99
99
99
99
99
99
99
99
99
94
100:0
77:23
100:0
99:1
100:0
95:5
97:3
74:26
95:5
95:5
95:5
95:5
99:1
64:36
76:24
57:43
77:23
88:12
41:58
44:56
47:53
44:56
60:40
41:59
67:33
51:49
67:33
73 (26)
0 (0)
86 (70)
96 (74)
97 (30)
nd (72)
86 (76)
84 (65)
85 (69)
68 (72)
58 (78)
83 (nd)
86 (76)
34 (44)
Cyd
Cye
C6H5
p-FC6H4
p-CF3C6H4
p-ClC6H4
p-MeOC6H4
o-MeOC6H4
2-thienyld-f
3-thienyl
2-pyridyld
82:18
a All reactions were carried out in toluene (0.25 M) at -50 °C under an
oxygen-free argon atmosphere containing 1 (1.0 equiv), 2 (1.2 equiv), 3
(1 mol %), L7 (1 mol %), and PhSiH3 (1.4 equiv) unless otherwise stated.
b Determined by chiral GC analysis CHIRALSIL-DEX CB (25 m, 0.25 mm,
25 µm). c Configuration determined by comparison with known products.
d At -78 °C. e Ph2SiH2 (1.4 equiv) instead of PhSiH3. f In THF.
good to excellent but the diastereoselectivity remained
moderate, favoring either the syn or the anti isomers (Table
2, entries 6 to 14). In all cases, good to excellent enantiomeric
excesses were obtained (up to 86% for the syn isomer) at
-50 °C. As a general trend, the introduction of a halogen
substituent at the para position (entries 7 to 9) did not change
the selectivity, whereas the replacement of an electron-
withdrawing group, at the para position of benzaldehyde,
by an electron-donating group increased the diastereoselec-
tivity in favor of the syn isomer. Unfortunately, the enan-
tiomeric excess on the syn isomer was slightly decreased
(Table 2, entry 10).
Nevertheless, the domino process was more efficient when
aromatic and heteroaromatic aldehydes were employed. For
the range of substrates studied, the chemoselectivity was
Heteroaromatic aldehydes, such as 2- and 3-thiophene-
substituted aldehydes, also took part efficiently in the domino
sequence to give the syn-4 adducts with rather good
enantioselectivities (Table 2, entries 12 and 13).
(11) General procedure for catalytic reductive aldol reaction: A 10 mL
flame-dried round-bottomed flask, equipped with a magnetic stirrer, was
charged with CuF(PPh3)3‚2MeOH (9.0 mg, 0.01 mmol), ligand (0.01 mmol),
and toluene (4.8 mL). The catalyst solution was stirred for 30 min at room
temperature and phenylsilane (180 µL, 1.40 mmol) was added at the same
temperature. After the solution was cooled at -50 °C, methyl acrylate
(110 µL, 1.20 mmol) and the corresponding aldehyde (1.00 mmol) were
simultaneously added to the solution. The mixture was stirred for 1 h at
-50 °C under argon. Conversion, dr and ee were followed by gas
chromatography (aliquots were hydrolyzed by 1 mL of aqueous NH4F
solution and filtered through a plug of silica). The reaction mixture was
quenched by adding aqueous NH4F solution (5 mL). The aqueous layer
was extracted by diethyl ether (3 × 5 mL). Then, the combined organic
layers were washed with brine (20 mL), dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The crude product was
purified by flash chromatography to yield the corresponding adduct.
We have also investigated the dependence of the structure
of the silane on the domino process. Various silanes were
tested, such as (Me3SiO)2MeSiH, Me2EtOSiH, (Me2SiH)2O,
or PMHS, in the reductive asymmetric aldol reaction process,
with carboxylaldehyde as the electrophile. Unfortunately,
only Ph2SiH2 gave excellent results as the diastereomeric
ratio and the enantiomeric excesses were both improved at
-50 °C in toluene (syn:anti 88:12, eesyn ) 97%) (Table 2,
entries 3 and 4 versus 5). Alas, Ph2SiH2 did not lead to
significantly improved selectivities with the other aldehydes
used.
Org. Lett., Vol. 8, No. 26, 2006
5945

In summary, we have developed a new catalytic asymmet-
ric system for the reductive/aldol reaction sequence between
methyl acrylate and various aldehydes. The process, catalyzed
by a chiral diphosphane modified copper(I) fluoride complex,
in the presence of phenylsilane or diphenylsilane, is highly
chemoselective but gives moderate diastereoselectivity. How-
ever, good to excellent enantioselectivities were obtained for
a wide range of cyclic aliphatic, aromatic, and heteroaromatic
aldehydes when the TANIAPHOS ligand L7 was employed.
This observation clearly reveals that the key parameter in
this reaction strongly depends on the choice of the ligand.12
Acknowledgment. This work was supported by the
Universite´ catholique de Louvain. Dr. B. Pugin (Solvias) and
Dr. R. Schmid (Hoffmann-La Roche) are gratefully acknowl-
edged for generous gifts of chiral ligands. SHIMADZU
Benelux is gratefully acknowledged for financial support for
the acquisition of a FTIR-8400S spectrometer.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2006, 128, 7164.
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Org. Lett., Vol. 8, No. 26, 2006