Highly enantioselective and regioselective copper-catalyzed 1,4 addition of grignard reagents to cyclic enynones

Article abstract of DOI:10.1021/ol200219m

In this letter we describe an unusual result in terms of regioselectivity with respect to copper-catalyzed conjugate additions of various Grignard reagents to cyclic enynones. The use of Cu(OTf)₂ and NHC ligand L1 as the catalyst combination in CH₂Cl₂ led to the unique formation of the 1,4 adduct. This selectivity does not follow the general trend previously observed in the literature using extended Michael acceptors. Moreover these reactions allowed for the creation of a quarternary stereogenic center with enantioselectivities up to 97% ee.

Full text of DOI:10.1021/ol200219m

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1524–1527
Highly Enantioselective and
Regioselective Copper-Catalyzed
1,4 Addition of Grignard Reagents to
Cyclic Enynones
†
†
†
,‡
ꢀ
ꢀ
€
Matthieu Tissot, Alexandra Perez Hernandez, Daniel Muller, Marc Mauduit,* and
Alexandre Alexakis*,†
ꢀ
ꢁ
ꢁ
ꢀ
Universite de Geneve, Departement de Chimie Organique, 30 Quai Ernest Ansermet,
1211 Geneve 4, Switzerland, and Ecole Nationale Superieure de Chimie de Rennes,
ꢀ
ꢀ ꢀ
CNRS, UMR 6226, Avenue General Leclerc, CS 50837, 35708 Rennes Cedex 7, France
marc.mauduit@ensc-rennes.fr; alexandre.alexakis@unige.ch
Received January 24, 2011
ABSTRACT
In this letter we describe an unusual result in terms of regioselectivity with respect to copper-catalyzed conjugate additions of
various Grignard reagents to cyclic enynones. The use of Cu(OTf)2 and NHC ligand L1 as the catalyst combination in CH2Cl2 led to the
unique formation of the 1,4 adduct. This selectivity does not follow the general trend previously observed in the literature using extended
Michael acceptors. Moreover these reactions allowed for the creation of a quarternary stereogenic center with enantioselectivities up to
97% ee.
The conjugate addition of carbon nucleophiles to electron-
deficient olefins has become one of the most important
methods for the formation of a C-C bond. The asym-
metric version of this reaction has been extensively studied
over the past few decades, highlighting Cu and Rh as the
catalysts of choice for this transformation.1 However, the
conjugate addition to the vinylogous electron-deficient
dienes has been much less developed due to the presence
of various electrophilic sites, which, upon nucleophilic
attack, can lead to several regioisomers.2
The use of copper reagents frequently result in 1,6
selectivity, as demonstrated extensively by Krause.3 Over
the past few years, copper-catalyzed 1,6 addition has
emerged as a new and interesting field of research. In
2008, Fillion was the first to describe the copper-catalyzed
enantioselective 1,6 addition employing diorganozinc re-
agentsand Meldrum’s acidasthe substrate.4 Highenantio-
selectivities up to 84% were obtained. Subsequently,
Feringa reported the addition of Grignard reagents to
dienic esters using a catalyst combination of ferrocene-
based phosphine ligands and CuBr Me2S exclusively
3
affording the 1,6 adduct with high stereoselectivities.5
Recently Mauduit and our group published the copper-
catalyzed asymmetric conjugate addition (ACA) of dior-
ganozinc reagents to cyclic dienones. 100% selectivities
in favor of the 1,6 adduct were obtained with excellent
†
ꢀ
ꢁ
Universite de Geneve.
‡
ꢀ
Ecole Nationale Superieure de Chimie de Rennes.
(1) Reviews on asymmetric conjugate additions, see: (a) Krause, N.;
€
Hoffmann-Roder, A. Synthesis 2001, 171. (b) Alexakis, A.; Benhaim, C.
Eur. J. Org. Chem. 2002, 3221. (c) Alexakis, A.; Backvall, J. E.; Krause,
N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796. (d) Harutyunyan,
S. R.;denHartog, T.;Geurts, K.;Minnard, A. J.;Feringa, B. L.Chem. Rev.
2008, 108, 2824. (e) Hayashi, T. Acc. Chem. Res. 2000, 33, 354. (f) Hayashi,
T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829. (G) Chrisyoffers, J.;
(3) Krause, N.; Thorand, S. Inorg. Chim. Acta 1999, 296, 1.
(4) Fillion, E.; Wilsily, A.; Liao, E. T. Tetrahedron: Asymmetry 2006,
17, 2957.
€
Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007, 1279.
ꢀ
ꢀ
(2) Csaky, A. G.; de la Herran, G.; Murcia, M. C. Chem. Soc. Rev.
(5) den Hartog, T.; Harutyunyan, S. R.; Font, D.; Minnaard, A. J.;
Feringa, B. L. Angew. Chem., Int. Ed. 2008, 47, 398.
2010, 39, 4080.
r
10.1021/ol200219m
Published on Web 02/23/2011
2011 American Chemical Society

enantioselectivities up to 99% using a Cu-DiPPAM (L2)
complex (Scheme 1).6
Table 1. Result of Initial Organometallic Screening for the
Conjugate Addition to Enynone 1
However, few examples have highlighted that this gen-
eral trend, leading to a preferential 1,6 attack, could be
unfavored depending on the substrate and/or the reaction
conditions. The first example was described by Yamamoto
who showed that a fine-tuning of the copper reagent allows
regioselective 1,4 addition.7 Recently, we developed the
copper-catalyzed ACA of trialkyl aluminum reagents
to extended nitro-Michael acceptors affording the 1,4
adducts only, with excellent stereocontrol.8 In addition,
our group disclosed that the selectivity can be altered in
favor of the 1,4 addition by changing the nucleophile and
the catalytic reaction conditions. Indeed by using a
Grignard reagent in combination with N-heterocyclic
carbene (NHC) L1 we observed mainly 1,4 addition to
the cylic dienone, resulting in the highly enantioselective
formation of the 1,4 adduct on the most substituted
position (Scheme 1).9
organometallic
source
conv
[%]c
eed
1,4
entry
t [°C]
L*
2/3/4c
1a
EtMgBr
EtMgBr
EtMgBr
EtMgBr
Et2Zn
-10
-10
-10
-10
-10
-10
-10
-30
-30
L1
L1
L3
L3
L1
L1
L3
L1
L3
100
100
100
100
10
91.5:0:8.5
28:nd:ndf
0:100:0
ndf
85
93
-
-
-
2a,e,f
3a
4a,e
5a
ndf
6a,e
7b
Et2Zn
100
60
75:25:0
0:100:0
5:95:0
99
Et2Zn
-
-
-
8a,e
9b
Et3Al
100
100
Et3Al
0:100:0
a Reaction performed with Cu(OTf)2/L* = 6/9 mol % in CH2Cl2.
b Reaction performed with Cu(OTf)2/L* = 2/4 mol % in Et2O. c De-
termined by GC-MS. d Determined by GC on a chiral phase. e Et2O was
used as solvent. f Messy reaction.
Scheme 1. Regiodivergent 1,4 versus 1,6 ACA
First, we performed the addition of EtMgBr using the
reaction conditions previously published9 for the 1,4 addi-
tion on cyclic dienone using the NHC ligand L1 and
Cu(OTf)2 as the catalyst in CH2Cl2 (and a small amount
of Et2O from the Grignard solution) (Table 1, entry 1). We
were delighted to observe that the 1,4 adduct was mainly
formed with the enantioselectivity reaching 85%. This
impressive selectivity, resulting in the formation of a
stereogenic quaternary center, demonstrates that cyclic
enynones react in a similar way as the corresponding
dienones under the same reaction conditions. When pure
Et2O was used in place of CH2Cl2 (Table 1, entry 2), the 1,4
addition was observed in a minor amount, despite a messy
reaction due to the large quantities of 1,2 and 1,6 addition
products. This result highlights the detrimental effect of
this solvent in terms of regioselectivity. The use of the
phosphoramidite ligand L3 in CH2Cl2 led to the formation
of the 1,6 adduct exclusively and to a messy reaction in
Et2O (Table 1, entries 3 and 4).
Then, the use of diethylzinc was investigated under the
initial reaction conditions (with NHC L1), which showed a
very low conversion (Table 1, entry 5). However, when Et2O
was used, an enantioselectivity of 99% was detected in a
ratio of 3:1 in favor of the 1,4 adduct 2a (Table 1, entry 6).
Under the same reaction conditions, L3 afforded only the
1,6 adduct (Table 1, entry 7). Finally Et3Al was also tested
affording mainly the 1,6 adduct (Table 1, entries 8 and 9).
As a consequence of the high regioselectivity displayed
with Grignard reagents, as shown in the previous table,
and the various possibilities offered by this organometallic
reagent, we investigated the scope of these nucleophiles on
the reaction with enynone 1a (Table 2, entries 1-5). After
a slight modification in terms of dilution and addition
time of the EtMgBr (see Supporting Information), the 1,4
In this report, we detail an extension of this previous
methodology using cyclic enynones. These types of ex-
tended Michael acceptors were first studied by Hulce10
who observedonly the 1,6additionviaaddition of acopper
reagent. Hayashi reported the rhodium-catalyzed 1,6 addi-
tion of aryltitanates to this family of substrates to afford
chiral allenes.11 We found two reports by Hoveyda in
recent literature, including two isolated examples of copper-
catalyzed 1,4 additions on this type of substrate using
diethylzinc12 and trimethylaluminium.13
We initially evaluated the addition of three different
types of organometallic reagents to the enynone 1 using
NHC ligand L1 and phosphoramidite ligand L3 under
various reaction conditions (Table 1).
ꢀ
(6) Wencel-Delord, J.; Alexakis, A.; Crevisy, C.; Mauduit, M. Org.
Lett. 2010, 12, 4335.
(7) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.; Maruyama,
K. J. Org. Chem. 1982, 47, 119.
€
(8) Tissot, M.; Muller, D.; Belot, S.; Alexakis, A. Org. Lett. 2010, 12,
2770.
(9) Henon, H.; Mauduit, M.; Alexakis, A. Angew. Chem., Int. Ed.
2008, 47, 9122.
(10) Hulce, M. Tetrahedron Lett. 1988, 29, 5851.
(11) Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305–7.
(12) Lee, K.-L.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am.
Chem. Soc. 2006, 128, 7182.
(13) May, T. L.; Brown, M. K.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2008, 47, 7358.
Org. Lett., Vol. 13, No. 6, 2011
1525

adduct 2a was obtained as a single regioisomer with an
enantioselectivity of 82% (Table 2, entry 1). On the other
hand, but-3-enylmagnesium bromide afforded perfect se-
lectivity and an excellent enantioselectivity of 95% under
the initial reaction conditions (Table 2, entry 2). Isopropyl
and -butyl Grignard reagents required slight modifications
of reaction conditions, but also with the maximum of Et2O
contained within the Grignard reagent being replaced by
CH2Cl2 to obtain the 1,4 adduct as the major isomer with
high ee’s (Table 2, entries 3 and 4).
reaction conditions, but low conversion and a mixture of
products were observed.
This regioselective 1,4 ACA was also extended to differ-
ent ring sizes. The seven-membered ring displayed our best
results in terms of enantioselectivity (97%) with perfect
regioselectivity (Scheme 2), whereas the five-membered
ring gavea verymessy reaction, indicating very low control
of the regioselectivity.
Scheme 2. Conjugate Addition of Grignard Reagent to Seven-
Membered Ring
Table 2. Conjugate Addition of Grignard Reagent to Enynones
4a-fa
To determine the limitation of this methodology, we
synthesizedenynone1fpossessing a terminal alkyne. Slight
modifications of the methodology gave a very interesting
result since we observed the formation of the 1,4 and 1,6
adducts in equal quantities. An enantioselectivity of 91%
was detected for adduct 2p (Scheme 3). This result high-
lighted the power of this catalytic system since even with
the 1,6 position completely naked the 1,4 attack occurred.
entry
1
R0
conv [%]b
yield [%]
ee[%]c 1,4
1d
2
3d,e
4d,e,f
5d,e
6g
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1d
1d
1e
Et
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
72 (2a)
90 (2b)
60 (2c)
88 (2d)
nd (2e)
29 (2f)
82 (2g)
57 (2h)
87 (2i)
98 (2j)
72 (2k)
74 (2l)
81 (2m)
87 (2n)
79 (2o)
82
95
92
95
nd
83
79
87
93
95
91
96
94
93
96
But-3-enyl
iPr
iBu
Me
Me
7
Et
8
iPr
9
iBu
10
11
12h
13
14
15
iBu
Scheme 3
But-3-enyl
Cy
iBu
But-3-enyl
But-3-enyl
a All reactions performed with 1 (0.25 mmol), R0MgBr (2 equiv),
Cu(OTf)2/L* = 6/9 mol % in CH2Cl2 at -10 °C. b Determined by
GC-MS. c Determined by GC on a chiral phase. d Solution was twice as
diluted as under standards reaction conditions, substrate addition times
of 30 min instead of 15 min. e Et2O of the Grignard is replaced by
CH2Cl2. f The product is isolated from a mixture 1,2/1,4/1,6 = 11:17:71.
g The product is isolated from a mixture 1,2/1,4/1,6 = 4:93:3. h The
product is isolated from a mixture 1,4/1,6 = 95:5.
Scheme 4. Sequence Ene-Yne Methathesis/Diels-Alder/Aro-
matization Reaction
Despite many attempts, the addition of MeMgBr re-
mained problematic as with cyclic dienones since the 1,6
adduct was the major isomer (Table 2, entry 5). In order to
drive the selectivity in favor of the 1,4 adduct we used
substrate 1b possessing a bulky tert-butyl group at the 1,6
position, and as expected, the selectivity went in favor of the
1,4 adduct with good enantioselectivity (Table 2, entry 6).
We also applied different Grignard reagents to substrate
1b, always affording perfect regioselectivities with enan-
tioselectivities up to 95% (entries 7-9). TMS- and phenyl-
substituted substrates (1c and 1d) also gave excellent
results in terms of regio- and enantioselectivities (entries
10-14). We also tried to apply our methodology to
enynone 1e, affording an enantioselectivity of 96%. The
correponding unprotected alcohol was also tried under our
In order to illustrate the synthetic potential of the 1,4
adducts, possessing an acetylenic appendage, a sequence
ene-yne methathesis/Diels-Alder/aromatization was
1526
Org. Lett., Vol. 13, No. 6, 2011

investigated (Scheme 4). After deprotection of 2k under
classical reactionconditions, 2pwas submittedtoa Grubbs
I catalyst in the presence of an ethylene atmosphere.14 The
spiro-bicyclic compound 7 was formed in 65% yield. This
intermediate was applied to the Diels-Alder reaction
using DMAD as a dienophile. Unfortunately, a 1:1 dia-
stereomeric mixture was observed for compound 8. There-
fore this system has been easily rearomatized affording
compound 9 in a quantitative yield.
quaternary stereocenter. Development of the 1,6 addition
on this type of substrate is being pursued in our labora-
tories and will be published in the future.
Acknowledgment. The authors thank the Swiss Na-
tional Research Foundation (Grant No. 200020-126663)
and COST action D40 (SER Contract No. C07.0097) for
financial support. Special thanks to Dr. Beth Ashbridge,
from the Rockefeller University (US), for support and
correction of the manuscript.
In summary, we have developed a highly stereoselective
and regioselective 1,4 addition of Grignard reagents to
cyclic enynones with excellent ee values for an all-carbon
Supporting Information Available. Experimental pro-
cedures and spectral analyses of all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Furstner, A.; Davies, P. W. Chem. Commun. 2005, 2307.
Org. Lett., Vol. 13, No. 6, 2011
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