Copper-catalyzed enantioselective conjugate addition of Grignard reagents to acyclic enones using monodentate phosphoramidite ligands

Article abstract of DOI:10.1016/j.tetlet.2008.01.019

Herein, we report efficient catalysts based on phosphoramidites for the asymmetric copper-catalyzed conjugate addition of Grignard reagents to acyclic α,β-unsaturated ketones. A variety of Grignard reagents can be added to aliphatic and aromatic acyclic e

Full text of DOI:10.1016/j.tetlet.2008.01.019

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Tetrahedron Letters 49 (2008) 1877–1880
Copper-catalyzed enantioselective conjugate addition
of Grignard reagents to acyclic enones using
monodentate phosphoramidite ligands
´
*
´
´
´
ˇ
ˇ ´
Beatriz Macia, M. Angeles Fernandez-Ibanez, Natasa Mrsic, Adriaan J. Minnaard ,
˜
Ben L. Feringa *
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands
Received 3 December 2007; revised 17 December 2007; accepted 3 January 2008
Available online 8 January 2008
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
Abstract
Herein, we report efficient catalysts based on phosphoramidites for the asymmetric copper-catalyzed conjugate addition of Grignard
reagents to acyclic a,b-unsaturated ketones. A variety of Grignard reagents can be added to aliphatic and aromatic acyclic enones with
good yields and moderate to good enantioselectivities.
Ó 2008 Published by Elsevier Ltd.
Keywords: Conjugate addition; Grignard reagents; Phosphoramidites; Asymmetric catalysis
The conjugate addition (CA) of organometallic reagents
to enones is one of the most widely used synthetic methods
for carbon–carbon bond formation.1 Enantioselective
metal-catalyzed versions of this key transformation2 have
been studied extensively with cyclic enones and chalcones
using dialkylzinc,3 organomagnesium,4 organoboron5 and
silicon reagents.6 However, for the more challenging acy-
clic enones, the progress has been limited. Only two notable
examples of highly enantioselective CA to acyclic enones
have been reported, despite the enormous synthetic poten-
tial of the resulting enantiopure b-substituted linear
ketones as building blocks for natural product synthesis.
The first example, reported by Hoveyda et al., comprises
the asymmetric Cu-catalyzed CA of dialkylzinc reagents
using peptidic phosphine ligands7 and the second one con-
sists of the Cu-catalyzed CA of Grignard reagents using
Josiphos ligand reported from our laboratories.8
Among all the ligands used so far in the field of Cu-cata-
lyzed 1,4-addition of organometallic reagents, phospho-
ramidites stand out for being readily accessible, cheap
and very easy to modify.9 The excellent enantioselectivities
that phosphoramidite ligands give in the CA of dialkylzinc
reagents to enones,10 encouraged us to use them as ligands
for the CA of Grignard reagents.
Phosphoramidites and Grignard reagents have been
combined before with success in the asymmetric Cu-cata-
lyzed allylic substitution11 and the Cu-catalyzed ring open-
ing of oxabicyclic alkenes.12 The fact that conjugate
additions and allylic substitutions are mechanistically
related,13 stimulated us to search for effective catalysts
based on phosphoramidites for the CA of Grignard
reagents.
In this Letter, recent advances in catalytic asymmetric
conjugate addition of Grignard reagents are discussed.
The first examples of the use of phosphoramidites in the
*
Corresponding authors. Tel.: +31 50 363 42 35; fax: +31 50 363 42 96
(B.L.F.).
E-mail address: B.L.Feringa@rug.nl (B. L. Feringa).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.01.019

1878
B. Macia´ et al. / Tetrahedron Letters 49 (2008) 1877–1880
enantioselective Cu-catalyzed conjugate addition of Grig-
nard reagents to the challenging class of acyclic aliphatic
enone substrates are reported. Good levels of stereocontrol
(up to 80% ee) are achieved with Cu(I) halides, alkylmagne-
sium bromides and readily available phosphoramidites as
ligands.
L4 (entries 1 and 2). Different solvents were also evalu-
ated17 and t-BuOMe was found to give the same enantio-
selectivity in the reaction as toluene (entries 2 and 3).
Lower temperatures (ꢁ50 °C) led to a significant decrease
of regioselectivity (entry 4) while higher temperatures
(0 °C) produced a slight decrease in enantioselectivity
(entry 5).
Next, we examined the influence on the enantioselectiv-
ity of the ligand/copper ratio as well as the catalyst loading
in the addition of EtMgBr to the model substrate 1a (Table
2). From these results we concluded that with a copper to
ligand ratio ranging from 1:1 to 1:2, the addition was
equally effective, as long as the catalyst loading was
P6 mol % (entries 1, 4 and 6). Higher catalyst loadings
did not produce any increase in enantioselectivity (entries
2 and 5). Other ligand/copper ratios were investigated
without observing improvement in the enantioselectivity
(entries 3 and 6).
Having established the optimal protocol, the addition of
different Grignard reagents as well as a variety of aliphatic
and aromatic linear enones was examined. The results are
summarized in Table 3. Reactions were typically carried
out at ꢁ30 °C, with 6 mol % of (R)-L4 and 5 mol % of
CuBrꢀSMe2 in toluene, for aromatic substrates, and in
t-BuOMe, for the more volatile aliphatic substrates. A
solution of Grignard reagent in t-BuOMe18 was added
dropwise to the mixture of substrate and ligand-copper
complex at ꢁ30° C,19 and full conversion was achieved in
less than 1 h.
In a systematic search for the optimal ligand, copper
source and halide in the Grignard reagent, we initially
tested several types of phosporamidites, but the enantio-
selectivities were consistently poor. The first promising
results were achieved with ligands (R)-L114 and (R)-L214
and CuBrꢀSMe2, which gave 40% and 54% ee, respectively,
in the addition of EtMgBr to the model substrate (E)-3-
nonen-2-one (1a).15 The combination of structural
elements of these two ligands gave rise to the design of
3,30-dimethyl-octahydro-BINOL derivatives (S)-L3 and
(R)-L4 (Fig. 1).16 The addition of EtMgBr to 1a was stud-
ied at different temperatures and in different solvents with
these new ligands (Table 1). In toluene at ꢁ30 °C, both
ligands L3 and L4 gave the same enantioselectivity in the
model reaction, although the regioselectivity (1,4-addition
vs 1,2-addition product) was slightly better with ligand
O
O
O
O
P
P
N
N
The conjugate addition of different Grignard reagents to
linear aliphatic substrates (3-nonen-2-one and 4-hexen-3-
one) occurred smoothly within 1 h at ꢁ30 ° C with excel-
lent yields and good to moderate enantioselectivities (Table
3, entries 1-6). When linear alkyl Grignard reagents
(MeMgBr, EtMgBr) were used as nucleophiles, 2a, 2b and
2d were obtained with 52–80% ee (entries 1, 2 and 4). Grat-
ifyingly, for the challenging bulky Grignard reagents,
i-PrMgBr and i-BuMgBr, enantioselectivities were found
to be 56% and 80% ee, respectively (entries 3 and 5). Addi-
tion of the sp2 hybridized Grignard reagent PhMgBr
(R)-L1
(R)-L2
O
O
O
N
P
P
N
O
(S)-L3
(R)-L4
Fig. 1. Chiral phosphoramidites used in this study.
Table 1
Addition of EtMgBr to (E)-3-nonen-2-one (1a)a,b
Et
O
O
OH
Et
EtMgBr, CuBr.SMe2
Ligand
+
4
4
4
1a
2a
3a
Entry
Ligand
Solvent
Temp (°C)
2a:3a
eec (%)
1
2
3
4
5
a
(S)-L3
(R)-L4
(R)-L4
(R)-L4
(R)-L4
Toluene
Toluene
t-BuOMe
Toluene
Toluene
ꢁ30
ꢁ30
ꢁ30
ꢁ50
0
97/3
99/1
99/1
90/10
99/1
60
61
60
54
55
Reagents and conditions: 1a (1 equiv), EtMgBr (1.2 equiv), CuBrꢀSMe2 (5 mol %), ligand (6 mol %), 1 h.
All conversions >99% (GC–MS).
Determined by chiral GC (see Supplementary data).
b
c

B. Macia´ et al. / Tetrahedron Letters 49 (2008) 1877–1880
1879
Table 2
Addition of EtMgBr to (E)-3-nonen-2-one (1a)a,b
EtMgBr, CuBr.SMe2,
)-L4
Toluene, -30 oC, 1 h
Et
O
O
OH
Et
(R
+
4
4
4
1a
2a
3a
Entry
Ratio ligand/CuBrꢀSMe2 (mol %/mol %)
2a:3a
eec (%)
1
2
3
4
5
6
a
1/1 (6/5)
99/1
99/1
99/1
82/18
99/1
98/2
60
60
60
48
60
55
1/1 (11/10)
1.5/1 (8/5)
2/1 (6/2.5)
2/1 (11/5)
3/1 (13/4)
Reagents and conditions: 1a (1 equiv), EtMgBr (1.2 equiv), CuBrꢀSMe2 (x mol %), (R)-L4 (x mol %), toluene, ꢁ30 °C, 1 h.
All conversions >99% (GC–MS).
Determined by chiral GC (see Supplementary data).
b
c
Table 3
Addition of Grignard reagents to enonesa,b
R3MgBr, CuBr.SMe2
)-L4
OH
R3
R3
O
O
(R
+
R2
R1
R1
R2
R1
R2
Solvent, -30 oC, 1 h
1
3
2
Entry
1
R1
R2
R3
2/3
99/1
>99/1
>99/1
>99/1
>99/1
80/20
98/2
>99/1
98/2
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1d
1e
1e
1e
1f
n-Pent
n-Pent
n-Pent
Me
Me
Me
n-Pent
i-Pr
Ph
Ph
Ph
Me
Me
Me
Et
Et
Et
t-Bu
Me
Me
Me
Me
Me
Me
Me
Et
i-Pr
Et
i-Bu
Ph
Me
Et
81 (2a)
85 (2b)
88 (2c)
ndf (2d)
40f (2e)
72 (2f)
68 (2g)
92 (2h)
80 (2i)
79 (2j)
50 (2k)
56 (2l)
68 (2m)
52 (S)e
60 (S)e
56 (ꢁ)
80
80
54 (R)e
66 (ꢁ)
68 (+)
30 (S)e
22 (R)e
60 (+)
52 (+)
44 (+)
Et
10
11
12
13
a
i-Pr
i-Bu
Et
>99/1
>99/1
98/2
2-Furyl
2-Thienyl
1g
Et
99/1
Reagents and conditions: 1 (1 equiv), R3MgBr (1.2 equiv), CuBrꢀSMe2 (5 mol %), (R)-L4 (6 mol %), in t-BuOMe or toluene at ꢁ30 °C, 1 h.
b
c
d
e
f
All conversions >99% (GC–MS).
Isolated yield.
Determined by chiral GC or HPLC.
Absolute configuration determined by correlation with known compounds (see Supplementary data).
Volatile product.
proceeded in good yield and with moderate enantioselec-
tivity (entry 6).
Finally, we studied the addition of Grignard reagents to
aryl-substituted substrates (Table 3, entries 9–13). The reg-
ioselectivity of the addition was excellent in all cases, and
much higher than previously reported with Josiphos
ligand.8 Enantioselectivities varied from 30% to 52% for
the addition of EtMgBr to benzylideneacetone (1e) and
furyl and thienyl derivatives 1f and 1g (entries 9, 12 and
13). Addition of i-PrMgBr to 1e proceeded with low enanti-
oselectivity (entry 10), while the bulky Grignard reagent
i-BuMgBr gave 60% ee (entry 11).
We next studied the influence of the enone structure on
the efficiency of the asymmetric CA. Ethyl ketone 1b led to
an increase in enantioselectivity compared to the methyl
ketone 1a (Table 3, entries 2 and 4), while substrate 1c with
a t-butyl substituent, gave comparable results to the methyl
ketone 1a (entries 2 and 7). Bulky substituents, like i-Pr on
the b-position of the aliphatic enone, did not affect the
enantioselectivity of the process. Thus, ketone 2h was
obtained from enone 1d with 68% ee (entry 8); this selectiv-
ity is better than that already described for the same reac-
tion using Josiphos ligand.8
In conclusion, this study shows that CuBrꢀSMe2/L4 is
an active catalyst for the addition of Grignard reagents
to acyclic enones, providing optically active b-substituted

1880
B. Macia´ et al. / Tetrahedron Letters 49 (2008) 1877–1880
(b) Martin, D.; Kehrli, S.; D’Augustin, M.; Clavier, H.; Mauduit, M.;
Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416–8417.
acyclic ketones in good yields and enantioselectivities up to
80%. Studies towards the elucidation of the mechanism of
this transformation are currently in progress.
5. See, for example: (a) Hayashi, T.; Takahashi, M.; Takaya, Y.;
Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052–5058; (b) Ma, Y.;
Song, C.; Ma, C.; Sun, Z.; Chai, Q.; Andrus, M. B. Angew. Chem.,
Int. Ed. 2003, 42, 5871–5874 and references cited therein.
6. (a) Yamasaki, K.; Hayashi, T. Chem. Rev. 2003, 103, 2829–2844; (b)
Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169–196; (c) Oi, S.;
Taira, A.; Honna, Y.; Inoue, Y. Org. Lett. 2003, 5, 97–99 and
references cited therein.
7. (a) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 779–781. For other examples of CA of dialkylzinc reagents
to acyclic enones, see: (b) Borner, C.; Dennis, M. R.; Sinn, E.;
Woodward, S. Eur. J. Org. Chem. 2001, 2435–2446 and references
cited therein.
Acknowledgements
Financial support from the Dutch Ministry of Econo-
mics Affairs (ETT scheme; Grant No’s.: EEKT-97107
and 99104). M.A.F.-I. thanks the Spanish Ministry of
Education and Science for a postdoctoral fellowship. We
thank T. D. Tiemersma-Wegman (GC and HPLC) and
A. Kiewiet (MS) for technical assistance. A generous gift
of (S)-BINOL and (R)-3,30-dimethyl-BINOL from DSM
is gratefully acknowledged.
´
8. (a) Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J.
Am. Chem. Soc. 2004, 126, 12784–12785. For asymmetric CA of
Grignard reagents to acyclic a,b-unsaturated esters and thioesters,
see: (b) Lo´pez, F.; Harutyunyan, S. R.; Meetsma, A.; Minnaard, A. J.;
Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 2752–2756; (c) Ruiz,
Supplementary data
´
´
B. M.; Geurts, K.; Fernandez-Ibanez, M. A.; ter Horst, B.; Minnaard,
˜
A. J.; Feringa, B. L. Org. Lett. 2007, 9, 5123–5126. For a review on
Experimental procedures, spectroscopic data of the
ligands and analytical data of the reaction products. Sup-
plementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2008.01.019.
´
enantioselective CA with Grignard reagents, see: (d) Lopez, F.;
Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179–
198.
9. Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353.
10. (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. 1996, 35, 2374–2376; (b) Feringa, B. L.; Pineschi, M.; Arnold,
L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. 1997, 36,
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References and notes
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15. Reaction conditions: (E)-3-nonen-2-one (0.25 mmol), ligand
(6 mol %), CuBrꢀSMe2 (5 mol %), toluene (2 mL), ꢁ30 °C, 1 h.
16. For the preparation of ligands L3 and L4, see Supplementary data.
17. The reaction of (E)-3-nonen-2-one (0.25 mmol) and EtMgBr using L4
(6 mol %), CuBrꢀSMe2 (5 mol %) at ꢁ30 °C in dichloromethane and
diethyl ether resulted in 10–20% ee.
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18. Grignard reagent solutions in diethyl ether caused a drastic drop in
enantioselectivity.
19. Addition of the substrate to the mixture of Grignard reagent and
phosphoramidite complex led to a decrease in enantioselectivity.
4. (a) Feringa, B. L.; Badorrey, R.; Pena, D.; Harutyunyan, S. R.;
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Minnaard, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834–5838;