Copper-catalyzed asymmetric 1,4-conjugate addition of Grignard reagents to linear α,β,γ,δ-unsaturated ketones

Article abstract of DOI:10.1039/c3cc42088d

A highly regioselective and enantioselective copper-catalyzed 1,4-conjugate addition of Grignard reagents to linear α,β,γ,δ- unsaturated ketones was developed. The 1,4-addition products were obtained regioselectively in high yields with up to 98% ee. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc42088d

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Copper-catalyzed asymmetric 1,4-conjugate addition
of Grignard reagents to linear a,b,c,d-unsaturated
ketones†
Cite this: Chem. Commun., 2013,
49, 5292
Received 22nd March 2013,
Accepted 21st April 2013
Zhenni Ma, Fang Xie,* Han Yu, Yiren Zhang, Xiaoting Wu and Wanbin Zhang*
DOI: 10.1039/c3cc42088d
www.rsc.org/chemcomm
A
highly regioselective and enantioselective copper-catalyzed
1,4-conjugate addition of Grignard reagents to linear a,b,c,d-unsaturated
ketones was developed. The 1,4-addition products were obtained
regioselectively in high yields with up to 98% ee.
Conjugate addition (CA) as a practical and efficient strategy to
construct carbon–carbon bonds is of great interest.1 Controlling the
regio- and stereo-selectivity of a reaction is a significant challenge in
organic synthesis, especially in asymmetric conjugate additions
(ACA). Excellent regio- and stereo-selectivity have been achieved in
reactions involving transition metal-catalyzed a,b-unsaturated
Michael acceptors.2 However, due to an additional electrophilic
site, the use of a,b,g,d-unsaturated Michael acceptors in asymmetric
reactions remains a challenge and investigations are currently
Fig. 1 Chiral ligands used in this work.
ongoing to control the formation of specific regioisomers promising results are derived from the specific structural features of
(1,2-, 1,4-, as well as 1,6-products) with high enantioselectivity.3–8
the substrates. Highly regioselective and enantioselective 1,4-ACA
Over the past few years, Hayashi et al. have developed several reactions of linear a,b,g,d-unsaturated ketones, the products of
successful examples of rhodium- and iridium-catalyzed 1,6-ACAs which can be readily transformed into important intermediates of
to both cyclic and linear a,b,g,d-unsaturated compounds, utilizing peptide isosteres,10–12 are yet to be reported. Herein we report the
arylnucleophiles.4 More recently, the same group also reported the first copper-catalyzed ACA of simple alkyl Grignard reagents to
cobalt-catalyzed 1,6-ACA of (triisopropylsilyl)-acetylene to a,b,g,d- linear a,b,g,d-unsaturated ketones, exclusively providing the single
unsaturated carbonyl compounds.5 The copper-catalyzed ACA of 1,4-product.5
alkyl Grignard and organozinc reagents to a,b,g,d-unsaturated
A series of phosphoramidite ligands bearing a D2-symmetric
compounds has found use in a wide variety of applications. Fillion biphenyl backbone (Fig. 1, L1–L4) were first employed because
et al.,6 Feringa et al.7 and Alexakis et al.8 have reported successful of their excellent performance in previous 1,4-ACA reactions
reactions involving this type of 1,6-ACA. However, only two reported by our group.13 After preliminary studies optimizing the
examples of copper-catalyzed 1,4-ACA reactions involving reaction conditions, it was found that the conjugate addition of
a,b,g,d-unsaturated compounds have been reported by Alexakis. 1.5 equiv. EtMgBr to (2E,4E)-1,5-diphenyl-2,4-pentadien-1-one (1a)
One method concerns the copper-catalyzed ACA of trialkylaluminum was successful in DCM at À70 1C using a 3 mol% Cu–L1–4 catalyst
reagents to linear nitrodienes and nitroenynes producing 1,4- or system (Table 1, entries 1–5). Remarkably, a completely 1,4-selective
1,6-products (with up to 95% ee and 91% ee respectively).8b product was obtained, albeit with low enantioselectivities and
Another methodology concerns a copper-catalyzed 1,4-ACA of moderate yields. No 1,2- or 1,6-products were formed.
Grignard reagents to a,b,g,d-unsaturated cyclic enones.9 These two
In order to develop a more effective catalytic system, chiral
metallocene-based phosphinooxazoline ligands14 were employed in
the reaction. To our delight, using chiral P,N-metallocene catalysts,
1,4-products were obtained exclusively with improved yield and
enantioselectivity. Using monophosphinooxazoline ligands
(entries 8–10) improved catalytic behavior compared to the bis-
(phosphinooxazoline) ligands (entries 6 and 7). The substituent
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, P. R. China. E-mail: wanbin@sjtu.edu.cn;
Fax: +86-21-5474-3265; Tel: +86-21-5474-3265
† Electronic supplementary information (ESI) available. CCDC 930399. For ESI
and crystalllographic data in CIF or other electronic format see DOI: 10.1039/
c3cc42088d
c
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Table 1 Optimizing reaction conditions
Table 2 Substrate scope
Entry Substrate R1
R2
Yielda (%) eeb (%)
Entry L
R
Cu salt
Temp. (1C) Yielda (%) eeb (%)
1
2
3
4
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
Ph
Ph
Ph
Ph
Ph
86 (2a)
84 (2b)
82 (2c)
90 (2d)
85 (2e)
83 (2f)
86 (2g)
73 (2h)
84 (2i)
87 (2j)
80 (2k)
88 (2l)
92 (2m)
94
94
87
76
83
96
97
36
92
82
96
97
95
83
98
62
89
1
2
3
4
5
6
7
8
cis-L1
Et Cu(I)(MeCN)4ClO4 À70
trans-L1 Et Cu(I)(MeCN)4ClO4 À70
trans-L2 Et Cu(I)(MeCN)4ClO4 À70
trans-L3 Et Cu(I)(MeCN)4ClO4 À70
trans-L4 Et Cu(I)(MeCN)4ClO4 À70
72 (3a)
73 (3a)
76 (3a)
71 (3a)
31 (3a)
76 (3a)
56 (3a)
81 (3a)
86 (3a)
77 (3a)
86 (2a)
40 (4a)
78 (2a)
84 (2a)
75 (2a)
88 (2a)
84 (2a)
83 (2a)
79 (2a)
67 (2a)
17
À8
28
5
0
12
4
54
53
66
94
4
92
93
91
90
89
80
78
97
o-MeC6H4
m-MeC6H4
p-MeC6H4
5
p-MeOC6H4 Ph
6
o-ClC6H4
p-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7c
8
L5
L6
L7a
L7b
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
Et Cu(I)(MeCN)4ClO4 À70
Et Cu(I)(MeCN)4ClO4 À70
Et Cu(I)(MeCN)4ClO4 À70
Et Cu(I)(MeCN)4ClO4 À70
Et Cu(I)(MeCN)4ClO4 À70
Me Cu(I)(MeCN)4ClO4 À70
Bn Cu(I)(MeCN)4ClO4 À70
o-MeC6H4
m-MeC6H4
p-MeC6H4
m-ClC6H4
p-ClC6H4
p-CF3C6H4
9
9
10
11
12c
13c
14
15
16
17
10
11
12
13
14
15
16
17
18
19
20c
Me Cu(I)TC
Me Cu(I)(C6H6)OTf
À70
À70
2-Naphthyl 70 (2n)
p-ClC6H4
Ph
Ph
p-ClC6H4
2-Thienyl
2-Furyl
92 (2o)
69 (2p)
86 (2q)
Me Cu(II)(OAc)2ÁH2O À70
Me Cu(II)(Me3CCO2)2 À70
Me Cu(II)(acac)2
Me Cu(II)(OTf)2
À70
À70
a
b
Yield of the isolated product. Determined by HPLC, Chiralcel AD-H
c
Me Cu(I)(MeCN)4ClO4 À60
column. The reaction was stirred at À60 1C for 24 h.
Me Cu(I)(MeCN)4ClO4 À80
a
b
substituents displayed excellent enantioselectivity, irrespective
of their position being ortho, meta or para (entries 6–7 and
11–13). Replacing the phenyl ring R2 with a 2-naphthyl group
gave the desired product with 83% ee (entry 14). A para-chloro
group on the phenyl ring R1 and R2 provided the best results,
with products being obtained with 98% ee (entry 15). To expand
the range of the substrates, compounds containing hetero-
cycles such as thienyl and furyl rings were also employed in
this reaction, which proceeded with moderate to excellent
enantioselectivities (up to 89% ee, entries 16 and 17). When
R2 was replaced by a methyl group, the reaction occurred via a
1,2-addition, affording a racemic product in 81% yield with no
formation of the 1,4-addition product.
A single crystal X-ray structure of 2a (Fig. 2) was obtained, which
indicated that 2a was the 1,4-product with R absolute configu-
ration.15 The catalytic cycle for the 1,4-ACA reaction can thus be
proposed (Scheme 1). The Cu–ligand complex A forms a p complex
B with MeMgBr and substrate 1a. The Cu(III) s complex C is formed
via oxidative addition, which is stabilized by the diconjugated
system. This accounts for the preference of the 1,4-selectivity over
1,6-selectivity.7a Reductive elimination of C occurs to give complex A
and the 1,4-product D. The enantioselectivity can be explained using
the mechanism reported by Feringa’s group involving the 1,4-ACA of
Grignard reagents.16
Yield of the isolated product. Determined by HPLC, Chiralcel AD-H
c
column. The reaction was stirred for 72 h.
attached to the oxazoline ring of the ruthenocene-based ligands
had little effect on enantioselectivity. The use of ferrocene-
based ligand L8 possessing an i-Pr group gave the desired
product with an ee of 66% (entry 10). L8 was thus chosen as
the chiral ligand for subsequent reactions.
Using the chosen ligand L8, three general Grignard reagents
were screened (entries 10–12). It was found that the Grignard
reagent had a great effect on enantioselectivity as well as on yield.
As the steric hindrance of the Grignard reagent was increased,
enantioselectivity and yield decreased. When methyl Grignard was
used, the reaction proceeded with 86% yield and 94% ee (entry 11).
The effects of copper salts on the reaction were next examined
(entries 11 and 13–18). Cu(I)(MeCN)4ClO4 provided the most satis-
factory result (entry 11). Different temperatures were then screened
in this asymmetric 1,4-conjugate addition to optimize the reaction
conditions (entries 11, 19 and 20). Increasing the temperature of
the reaction to À60 1C gave moderate enantioselectivity (entry 19).
The highest enantioselectivity was observed at À80 1C, but the
product was only obtained in 67% yield after 72 h (entry 20).
With the optimized reaction conditions in hand, substrate
scope was investigated using Cu(I)(MeCN)4ClO4–L8 as a catalytic
system in DCM at À70 1C. The results are shown in Table 2.
To test the effect of steric hindrance on the reaction outcome, we
introduced a methyl group at the ortho-, meta- and para-positions
(R1 and R2) of the phenyl groups of substrate 1 (entries 1–4 and
8–10). 1b (R1 = o-MeC6H4) and 1i (R2 = m-MeC6H4) gave their
corresponding products with 94% ee and 92% ee respectively
(entries 2 and 9). When an electron-donating methoxy group
was introduced at the para-position of the phenyl ring R1,
enantioselectivity decreased (entry 5). However, addition of an
electron-withdrawing substituent was beneficial to this reaction.
Electron-withdrawing groups such as chloro or trifluoromethyl
Fig. 2 X-ray structure of 2a.
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The (R)-1,4-product, g,d-unsaturated ketone 2a, provides
access to a simple synthesis of important chiral 2-substituted-
g-keto acid intermediates.11 These intermediates are useful for
the preparation of peptide mimetics (peptide isosteres) in drug
discovery. For example, they can be used for the synthesis of human
neutrophile elastase inhibitors12 and angiotensin converting
enzyme inhibitors.13 2-Substituted-g-keto acids 5a can be prepared
as shown in Scheme 2 in 89% yield with 94% ee.
In summary, we have developed a new method for highly
regio- and enantio-selective copper-catalyzed asymmetric
1,4-conjugate addition reactions of Grignard reagents to
a,b,g,d-unsaturated ketones, using 1,2-disubstituted planar
chiral ferrocene-based phosphinooxazoline ligands. A series of
g,d-unsaturated ketones 2 were obtained in high yields and with
high enantioselectivity (up to 98% ee and 92% yield). The
products could be readily converted to important intermediates
such as chiral 2-substituted-g-keto acids.
This work was partially supported by the National Natural
Science Foundation of China (No. 21172143, 21172144 and
21232004), Science and Technology Commission of Shanghai
Municipality (No. 09JC1407800), Nippon Chemical Industrial
Co., Ltd and the Instrumental Analysis Center of Shanghai
Jiao Tong University. We thank Prof. Tsuneo Imamoto and
Dr Masashi Sugiya for helpful discussion.
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5294 Chem. Commun., 2013, 49, 5292--5294
This journal is The Royal Society of Chemistry 2013