Copper-catalyzed enantioselective conjugate addition of Grignard reagents to acyclic enones

Article abstract of DOI:10.1021/ja046632t

A highly enantioselective Cu-catalyzed addition of Grignard reagents to acyclic aliphatic enones is described. In the presence of 5 mol % of CuBr·SMe₂ and 6 mol % of JosiPhos diphosphine aliphatic enones react with Grignard reagents to provide β-substituted linear ketones with high yields, regio-, and enantioselectivities. Copyright

Full text of DOI:10.1021/ja046632t

Published on Web 09/21/2004
Copper-Catalyzed Enantioselective Conjugate Addition of Grignard Reagents
to Acyclic Enones
Fernando L o´ pez, Syuzanna R. Harutyunyan, Adriaan J. Minnaard, and Ben L. Feringa*
Department of Organic Chemistry and Molecular Inorganic Chemistry, Stratingh Institute, UniVersity of Groningen,
Nijenborgh 4, 9747 AG, Groningen, The Netherlands
Received June 8, 2004; E-mail: B.L.Feringa@chem.rug.nl
The conjugate addition (CA) of organometallic reagents to enones
is one of the most widely used synthetic methods for carbon-carbon
1
bond formation. Enantioselective metal-catalyzed versions of this
key transformation have been studied extensively with cyclic enones
2
and chalcones using dialkylzinc, organoboron, and silicon re-
3
agents. However, despite the versatility and ready availability of
Grignard reagents for organic synthesis, enantioselectivities in
4
asymmetric CA reactions rarely reached the 90% ee level. Recently,
we showed that enantioselective Cu-catalyzed CA of Grignard
Figure 1. Chiral ferrocenyl-based diphosphines.
reagents to cyclic enones can be achieved using chiral ferrocenyl
diphosphines. Here we report the Cu-catalyzed addition of Grignard
Scheme 1
5
reagents to the challenging class of acyclic aliphatic enone substrates
with high regio- and enantioselectivity to provide optically active
â-substituted ketones.
Aliphatic â-substituted linear ketones are common subunits in
biologically active molecules and are important building blocks for
natural product synthesis. However, highly enantioselective catalytic
procedures for their preparation are rare, and enantioselectivities
Table 1. Enantioselective CA of EtMgBr to (E)-3-Nonen-2-one 7a
(R ) n-Pent, R ) Me, R ) Et)
1
2
3
a,b
8a:9ac
eec (R/S)
entry
ligand
CuX
solvent
temp (°C)
1
2
3
4
5
6
7
8
9
1
1
2
2
2
2
2
3
4
5
6
CuCl
CuCl
CuCl
CuI
CuBr‚SMe2
CuBr‚SMe2
CuBr‚SMe2
CuBr‚SMe2
CuBr‚SMe2
CuBr‚SMe2
CuBr‚SMe2
Et2O
Et2O
Et2O
0
-75
-75
-75
-75
-75
-75
-75
-75
-75
-75
84:16
1
6
are usually substrate- and ligand-dependent. Notable exceptions
70:30 48 (R)
86:14 80 (R)
83:17 72 (R)
91:9
99:1
77:23 74 (R)
86:14 44 (R)
95:5
80:20 21 (R)
71:29 27 (R)
are the Cu-catalyzed CA of dialkylzinc reagents using peptidic
7
Et O
phosphine ligands described by Hoveyda and a complementary
2
Et2O
86 (R)
90 (R)
approach by Lipshutz that relies on a CuH-catalyzed asymmetric
conjugate reduction of â,â-disubstituted enones.8 Nevertheless,
despite more than two decades of intensive research, a general
method based on asymmetric CA of organomagnesium reagents to
acyclic enones is still lacking.9
t
d
BuOMe
BuOMe
BuOMe
BuOMe
BuOMe
BuOMe
e
t
t
t
57 (R)
t
1
1
0
1
t
We started our investigation with the screening of TaniaPhos
ligand 1,10 recently found to be effective in the asymmetric addition
a
Conditions: EtMgBr (1.15 equiv) added to a solution of the enone
5
(0.1 M), 5 mol % CuX, and 6 mol % ligand unless otherwise noted. b All
of Grignard reagents to cyclic enones (Figure 1). In the present
c
conversions >98% (GC-MS) after 2 h. Regio- and ee’s determined by
study, the catalyst prepared in situ from 1 and CuCl provides good
regioselectivity in the Cu-catalyzed addition of EtMgBr to the model
substrate (E)-3-nonen-2-one (7a), although the product is obtained
with low enantioselectivity (Scheme 1, Table 1, entries 1 and 2).
Noteworthy is that the use of JosiPhos ligand 211 dramatically
enhanced the selectivity of the addition, providing 8a in 80% ee
chiral GC. d 94% isolated yield (8a). e EtMgCl (1.15 equiv) was employed.
smoothly at -75 °C within 2 h to give the corresponding chiral
â-substituted ketones with excellent yields (62-91%), regio- (>94:
6), and enantioselectivities (90-98%). High enantioselectivities
were also observed in the formation of 8h,i despite the small â-Me
substituent in enone 7d (entries 8-10). In all cases, the 1,2-addition
products 9 were obtained as racemates. Particularly noteworthy is
the addition of MeMgBr (e.g., to octenone and heptenone, entries
3 and 7), which provides 8d and 8g with 97-98% ee. The influence
of the catalyst loading was examined for the addition of MeMgBr
to heptenone. With only 1 mol % of catalyst, ketone 8g was
obtained with good regioselectivity and in equal enantioselectivity
(97% ee) (entry 17). To the best of our knowledge, these values
constitute the highest enantioselectivities thus far reported in the
addition of alkylmetals to acyclic aliphatic enones. Furthermore,
the versatility of this procedure is illustrated by the fact that opposite
enantiomers for a particular ketone can be obtained just by judicious
selection of complementary enones and Grignard reagents, without
changing the configuration of the chiral diphosphine (entries 3, 9
and 4, 5).
(
entry 3). Optimization of solvent, Grignard halide, and copper
source (entries 4-7) resulted in a further improvement in the
selectivity of this process, providing 8a in 94% isolated yield and
2
9
0% ee (entry 6).1 Interestingly, ligand 2 proved to be clearly
superior to any of the structurally related ferrocenyl diphosphines
studied (3-6), with different alkyl and aryl residues at phosphorus
(entries 8-11).
Having established an optimal protocol, the addition of different
Grignard reagents as well as a variety of aliphatic linear enones
was examined. The results are summarized in Table 2. Gratifyingly,
the optimal conditions found for EtMgBr and the model substrate
7a resulted in high selectivities when Grignard reagents with
different linear alkyl chains were employed.
Thus, the CA of RMgBr reagents (R ) Me, Et, n-Pr, n-Bu) to
E)-nonenone, octenone, or heptenone (entries 1-7) occurred
(
12784
9
J. AM. CHEM. SOC. 2004, 126, 12784-12785
10.1021/ja046632t CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
3
Table 2. Enantioselective CA of Grignard Reagents (R MgBr) to
Aliphatic Methyl Linear Enones (R ) Me, Scheme 1)
Enone 7g reacted smoothly with n-PrMgBr reagent to give the
corresponding ketone (8s) with excellent yield and enantioselectivity
(entry 4). Not unexpected, with the sterically hindered t-Bu ketone
2
a,b
Grignard
(R3)
regio
(8: 9)c
yield (8)
ee (%);c
(R/S)e
entry
R1 (7)
(%)d
7
h a drastic decrease in enantioselectivity was observed (40% ee,
entry 5).
The scope of the Cu-catalyzed asymmetric CA includes both
â-substituted aliphatic and aromatic enones. Benzylideneacetone
7i) and thienyl and furyl derivatives 7j and 7k react smoothly in
1
2
3
4
5
6
7
8
9
n-pent (7a)
n-Bu (7b)
n-Bu (7b)
n-Bu (7b)
n-Pr (7c)
n-Pr (7c)
n-Pr (7c)
Me (7d)
Me (7d)
Me (7d)
n-Pr (7c)
Me (7d)
n-Bu (7b)
Me (7d)
n-PrMgBr
EtMgBr
MeMgBr
n-PrMgBr
n-BuMgBr
EtMgBr
98:2
96:4
99:1
94:6
95:5
95:5
99:1
95:5
95:5
95:5
95:5
96:4
97:3
98:2
96:4
81:19
83:17
84 (8b)
91 (8c)
86 (8d)
88 (8e)
91 (8e)
66 (8f)
62 (8g)
54 (8h)
78 (8d)
63 (8i)
90 (8j)
64 (8k)
89 (8l)
58 (8m)
83 (8n)
75 (8o)
8g
90
90
98 (R)
91
95
91 (R)
97
93 (S)
93 (S)
94
93
93
84
86 (S)
48
(
t
BuOMe at -75 °C with RMgBr reagents to give the corresponding
enones in good yields and high regioselectivities and enantiose-
lectivities of 90-97% (entries 6-9). It is noteworthy that the scope
of the Cu-catalyzed CA reactions presented here is not limited to
MeMgBr
EtMgBr
n-BuMgBr
Cl-BuMgBr
i-Pr(CH2)2MgBr
i-Pr(CH2)2MgBr
i-BuMgBr
i-BuMgBr
i-PrMgBr
PhMgBr
10
11
12
13
14
15
16
17
(
E)-enones. The versatility of the present method is illustrated in
the reactions of (Z)-4-furyl-3-en-2-one 7k, providing chiral ketones
w and 8x in 80-89% yield and with excellent enantioselectivities
f
f
8
(90-96% ee) (entries 8 and 9).
n-pent (7a)
n-Pr (7c)
n-Pr (7c)
In summary, we have developed a general and efficient catalytic
76
97
f,g
MeMgBr
CA of Grignard reagents to achiral acyclic enones to provide
optically active â-substituted acyclic ketones with high yields and
enantioselectivities. Studies toward the elucidation of the mechanism
of this transformation are currently in progress.
a
3
Conditions: 5 mol % CuBr‚SMe2, 6 mol % 2, 1.15 equiv of R MgBr,
t
b
c
0
.1 M in BuOMe, -75 °C, 2 h. All conversions >98% (GC-MS).
13 d
Regio- and enantioselectivities determined by chiral GC.
Isolated yields
e
of 8. Absolute configuration was established by comparison with known
A solution of the enone was added to the mixture of
catalyst and R MgBr over 1 h. 1 mol % CuBr‚SMe2, 1.12 mol % 2.
Acknowledgment. We thank T. D. Tiemersma-Wegman for
technical support (GC). F.L. thanks the Spanish Ministry of
Education and Culture (M.E.C.D.) for a postdoctoral fellowship.
6
c,13
3
f
compounds.
g
The effect of the steric hindrance in the organometallic reagent
was examined in γ [i-Pr(CH ) ], â (i-Bu), and R (i-Pr) alkyl-
2 2
substituted Grignard reagents. Branching at the γ position is
Supporting Information Available: Experimental procedures and
spectroscopic data of the reaction products (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
tolerated, providing the ketones with excellent regioselectivities and
References
93% ee (entries 11 and 12). Substitution at the â position required,
(
1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
however, a small modification of the experimental conditions to
achieve high enantioselectivities: enones were slowly added to the
mixture of catalyst and RMgBr reagent over 1 h. Thus, ketones 8l
and 8m can be obtained with excellent regio- and enantioselec-
tivities (84-86%, entries 13 and 14).14 With R-branched reagents
Tetrahedron Organic Chemistry Series 9; Pergamon: Oxford, 1992.
(2) (a) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
Germany, 2002, pp 224-258. (b) Krause, N.; Hoffmann-R o¨ der, A.
Synthesis 2001, 171-196. (c) Tomioka, K.; Nagaoka, Y. In Comprehen-
siVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer-Verlag: New York, 1999; Vol. 3, pp 1105-1120.
as iPrMgBr the reaction occurred with only 48% ee (entry 15).
Finally, the use of PhMgBr was also examined, providing the ketone
(
3) (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
therein.
8o in 75% yield and 76% ee (entry 16).
(4) (a) Villacorta, G. M.; Rao, C. P.; Lippard, S. J. J. Am. Chem. Soc. 1988,
1
10, 3175-3182. (b) van Klaveren, M.; Lambert, F.; Eijkelkamp, D. J.;
Table 3. Acyclic Enones in the Cu-Catalyzed Asymmetric CA of
a
Grove, D. M.; van Koten, G. Tetrahedron Lett. 1994, 35, 6135-6138.
c) Zhou, Q.-L.; Pfaltz, A. Tetrahedron 1994, 50, 4467-4478. (d)
Stangeland, E. L.; Sammakia, T. Tetrahedron 1997, 53, 16503-16510.
e) Kanai, M.; Nakagawa, Y.; Tomioka, K. Tetrahedron 1999, 55, 3843-
Grignard Reagents (Scheme 1)
(
Grignard
(R3)
regio
yield 8
(%)b
ee (%)
(R/S)
(
1
2
entry
enone (R , R ), (7)
(8:9)
3
854. (f) Pichota, A.; Pregosin, P. S.; Valentini, M.; W o¨ rle, M.; Seebach,
D. Angew. Chem., Int. Ed. 2000, 39, 153-156.
1
2
3
i-Pr, Me (7e)
MeMgBr
MeMgBr
n-BuMgBr
n-PrMgBr
MeMgBr
MeMgBr
MeMgBr
EtMgBr
90:10
90:10
90:10
98:2
77:23
85:15
83:17
93:7
52 (8p)
81 (8q)
86 (8r)
83 (8s)
56 (8t)
73 (8u)
72 (8v)
89 (8w)
80 (8x)
94
97 (R)
93
95
40
97 (S)
97
90
(
5) Feringa, B. L.; Badorrey, R.; Pe n˜ a, D.; Harutyunyan, S. R.; Minnaard, A.
J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834-5838.
(t-Bu)CH2, Me (7f)
(t-Bu)CH2, Me (7f)
Me, n-Bu (7g)
n-pent, t-Bu (7h)
Ph, Me (7i)
2-thienyl, Me (7j)
2-furyl, Me (7k)
2-furyl, Me (7k)
(
6) (a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3236 and
references therein. (b) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida,
K. J. Am. Chem. Soc. 2003, 125, 11508-11509. (c) For an addition of
c
4
5
6
7
8
9
3
AlMe to linear aliphatic enones (ee’s ) 76-93%, 20 mol % catalyst),
d
see: Frase, P. K.; Woodward, S. Chem.-Eur. J. 2003, 9, 776-783.
7) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
(
d,e
f
124, 779-781.
d
f
MeMgBr
87:13
96
(8) (a) Lipshutz, B. H.; Servesko, J. M. Angew. Chem., Int. Ed. 2003, 42,
4789-4792. (b) For a related approach for the reduction of linear
a
Conditions: see Table 2. All conversions >98% (GC-MS). b Isolated
unsaturated esters, see: Apella, D. H.; Moritani, Y.; Shintani, R.; Ferreira,
E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473-9474.
9) Promising results (ee < 82%) limited to benzylideneacetone were reported
in refs 4b and 4d.
c
yields of 8. A solution of the enone was added to the mixture of catalyst
(
d
e
and Grignard reagent over 1 h. Reaction time: 12 h. EtMgBr (1.0 M in
Et2O) was added dropwise over 3 h. f (Z) geometry.
(
10) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P. Angew.
Chem., Int. Ed. 1999, 38, 3212-3215.
(
11) Blaser, H.-U.; Brieden, W.; Pugin, B.; Spindler, F.; Studer, M.; Togni,
A. Top. Catal. 2002, 19, 3-16 and references therein.
We next studied the influence of the enone structure on the
efficiency of the asymmetric CA. The results are summarized in
Table 3. Bulky substituents (i-Pr or t-Bu) at the â or γ positions of
the enone did not affect the enantioselectivity of the process. Thus,
ketones 8p-8r were obtained from enones 7e and 7f with
enantioselectivities ranging from 93 to 97% (Table 3, entries 1-3).
n
i
(12) Other solvents (THF, Bu
CuTC, Cu(OTf) , CuCl
13) See Supporting Information for more details.
(14) Standard conditions gave 8l in 62% ee (90:10 regio). The use of BuOMe
2 2
O, Pr O, DME, toluene) and Cu sources (CuBr,
2
2
) evaluated provided lower selectivities.
(
t
was crucial (the reaction in Et
2
O provided 8l with 42% ee, 78:22 regio).
JA046632T
J. AM. CHEM. SOC.
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VOL. 126, NO. 40, 2004 12785