Enantioselective 1,6-conjugate addition to cyclic dienones catalyzed by the Cu-DiPPAM complex

Article abstract of DOI:10.1021/ol1017382

Figure Presented. In the presence of a Cu/DiPPAM catalytic system, various diorganozinc reagents realize 1,6-asymmetric conjugate addition on various cyclic five- and six-membered cyclic dienones, with complete regioselectivity and high ees (93-99%).

Full text of DOI:10.1021/ol1017382

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4335-4337
Enantioselective 1,6-Conjugate Addition
to Cyclic Dienones Catalyzed by the
Cu-DiPPAM Complex
Joanna Wencel-Delord,†,‡ Alexandre Alexakis,*,§ Christophe Cre´visy,*,†,‡ and
Marc Mauduit*,†,‡
Ecole Nationale Supe´rieure de Chimie de Rennes, CNRS, UMR 6226, AVenue Ge´ne´ral
Leclerc, CS 50837, 35708 Rennes Cedex 7, France, UniVersite´ europe´enne de
Bretagne, 35000 Rennes, France, and UniVersite´ de Gene`Ve, De´partement de chimie
organique, 30 Quai Ernest Ansermet, 1211 Gene`Ve 4, Switzerland
alexandre.alexakis@unige.ch; christophe.creVisy@ensc-rennes.fr;
marc.mauduit@ensc-rennes.fr
Received July 26, 2010
ABSTRACT
In the presence of a Cu/DiPPAM catalytic system, various diorganozinc reagents realize 1,6-asymmetric conjugate addition on various cyclic
five- and six-membered cyclic dienones, with complete regioselectivity and high ee’s (93-99%).
Due to increasing economic and ecological pressure, the design
of readily available and efficient chiral ligands has become a
new challenge of modern asymmetric organometallic catalysis.
In this context, our group has recently developed original, “one-
step and quantitatively available” ligandssthe diphenylphos-
phinoazomethinylate salts (DiPPAMs).1 Structurally related to
“small peptide ligands”,2,3 the DiPPAMs have already proved
their efficiency for two C-C bond-forming reactions: copper-
catalyzed 1,4-asymmetric conjugate addition (ACA)1 and
palladium-catalyzed allylic alkylation.4 High enantioselec-
tivities combined with unusual behavior encouraged us to
focus on a much less explored reactionscopper-catalyzed
1,6-ACA. In fact, the challenge of this reaction is due to the
presence of an additional electrophilic site and the possibility
of forming regioisomers.5 The first example of the asym-
metric version of this reaction was disclosed in 2005 by
† Ecole Nationale Supe´rieure de Chimie de Rennes.
‡ Universite´ europe´enne de Bretagne.
§ Universite´ de Gene`ve.
(3) Soeta, T.; Selim, K.; Kuriyama, M.; Tomioka, K. AdV. Synth. Catal.
(1) (a) Wencel, J.; Rix, D.; Cre´visy, C.; Mauduit, M. PCT Int Appl WO
2009050284, 2009. (b) Wencel, J.; Rix, D.; Jennequin, T.; Labat, S.; Cre´visy,
C.; Mauduit, M. Tetrahedron: Asymmetry 2008, 19, 1804–1809.
(2) (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755–756. (b) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 13362–13363. (c) Brown, M. K.; Degrado, S. J.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2005, 44, 5306–5310. (d)
Kacprzynski, M. A.; Kazane, S. A.; May, T. L.; Hoveyda, A. H. Org. Lett.
2007, 349, 629–635.
(4) Wencel, J.; Laurent, I.; Toupet, L.; Cre´visy, C.; Mauduit, M.
Organometallics 2010, 29, 1530–1533.
(5) (a) Krause, N.; Thorand, S. Inorg. Chim. Acta 1999, 296, 1–11. (b)
Canisius, J.; Mobley, T. A.; Berger, S.; Krause, N. Chem.sEur. J. 2001,
7, 2671–2675. (c) Uerdingen, M.; Krause, N. Tetrahedron 2000, 56, 2799–
2804. (d) Yoshikai, N.; Yamashita, T.; Nakamura, E. Chem. Asian J. 2006,
1, 322–330. (e) Mori, S.; Uerdingen, M.; Krause, N.; Morokuma, K. Angew.
Chem., Int. Ed. 2005, 44, 4715–4719.
2007, 9, 3187–3190
.
10.1021/ol1017382  2010 American Chemical Society
Published on Web 09/01/2010

Hayashi using the Rh-BINAP complex.6 The same group
reported in 2010 an Ir-tbf catalytic system for the 1,6-
addition of arylboroxines to linear dienones.7 Moreover,
several reports have appeared on copper-catalyzed 1,6-ACA
to both cyclic and linear substrates.8 Those publications, as
well as previous studies on an achiral version of copper-
catalyzed 1,6-CA,5 suggest that nucleophilic attack usually
leads to the 1,6-adducts. However, recent results reported
by Alexakis seem to contradict this observation.9 Alexakis
observed that the regioselectivity of the ACA to R,ꢀ,γ,δ-
unsaturated six-membered cyclic dienone 1a depends on the
nature of the nucleophile and the chiral ligand; 1,6 regiose-
lectivity was observed if Et2Zn or Et3Al was used in the
presence of a Cu-phosphoramidite complex, whereas the
1,4-adduct was isolated when Grignard reagents were
employed in the presence of a Cu-NHC catalyst. Hoveyda
reported, as well, one example of the 1,4-selectivity for the
additionofMe2Zntodienonecatalyzedbyaniminopeptide-Cu
complex.10 Those studies show that copper-catalyzed 1,6-
ACA to cyclic substrates, and in particular five-membered
cyclic dienones, never reported in the literature, is still
underdeveloped. Moreover, the resulting products, original
Michael acceptors, could have great potential in synthesis.
Thus, we explored the potential of DiPPAM in 1,6-ACA,
and we report herein the regio- and enantioselective addition
of diorganozinc to five- and six-membered functionalized
cyclic dienones.
particularly efficient in 1,6-ACA to linear dienoates,8c for
this selected reaction were totally regioselective but seemed
to be less enantioselective (L3, 67% ee; L4:, 75% ee; Scheme
1). Thus, L1 could be considered as a highly promising
ligand for this transformation.
Indeed, the optimization of the experimental conditions
enabled us to increase the enantiocontrol of this reaction.
The choice of the cosolvent (33% of the solvent is hexanes
from the commercial Et2Zn solution) was crucial for an
efficient enantiocontrol. The reactions, carried out in both
Et2O and t-BuOMe, afforded 2a with moderate ee’s (Table
1, entries 2 and 3), whereas the use of toluene or AcOEt
Table 1. Optimization of Experimental Conditions
entry
x %
y %
solvent
convn (%)a
ee (%)b
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
6
7.5
10
10
10
10
5
5
5
5
5
5
10
5
5
5
THF
Et2O
t-BuOMe
toluene
AcOEt
MeTHF
MeTHF
MeTHF
MeTHF
MeTHF
MeTHF
MeTHF
MeTHF
>99
98
83
83
63
56
80
84
87
56
91
93
94
-
98
>99
>99
>99
>99
>99
>99
-
The first test reaction with Cu-L1 led to the formation
of the desired product 2a (after reconjugation in the presence
of DBU) with total regioselectivity, as expected, and 83%
ee (Scheme 1). This nonoptimized result was slightly worse
9
10
11
12c
-
5
5
>99
>99
96
97
13c d e
,
,
Scheme 1. Cu-Catalyzed 1,6-ACA on Cyclic Dienone 1
a Determined by GC-MS analysis. b Determined by GC analysis.
c Reaction performed at 0 °C. d Addition of a Et2Zn solution in MeTHF.11
e Reaction treatment: NH4Cls, argon.
gave 2a with ee > 80% (Table 1, entries 4 and 5). The best
result, 87% ee, was obtained in MeTHF (Table 1, entry 6).
The Cu/DiPPAM ratio also has a very important influence
on the enantioselectivity of the reaction. The excess of Cu
toward the ligand led to a drastic decrease of the ee (Table
1, entry 7). On the contrary, when the Cu/DiPPAM ratio
was inferior to 1, an improvement of the enantioselectivity
was observed (Table 1, entries 8-10). Nevertheless, the
reaction performed in the absence of Cu(OTf)2 did not afford
any product, thus the necessity of the presence of the metal
was demonstrated (Table 1, entry 11).
than the unique reported example, -89% ee, obtained with
the Cu-L2 catalyst.9 The Josiphos-type ligands (L3 and L4),
(6) Hayashi, T.; Yamamoto, S.; Tokunaga, N. Angew. Chem., Int. Ed.
2005, 44, 4224–4227.
The additional improvement of the enantioselectivity was
reached through a decrease of the reaction temperature to 0
°C and the use of a Et2Zn solution in MeTHF (Table 1,
entries 12 and 13).11 Unsurprisingly, the desired reaction was
accompanied by the formation of a small amount of the
oxidative byproduct.9,12 To prevent this, a slight modification
(7) Nishimura, T.; Yasuhara, Y.; Sawano, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 7872–7873.
(8) (a) Fillion, E.; Wilsily, A.; Liao, E.-T. Tetrahedron: Asymmetry 2006,
17, 2957–2959. (b) den Hartog, T.; Harutyunyan, S. R.; Font, D.; Minnaard,
A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2008, 47, 398–401. (c) Lee,
K.-s.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 2898–2900. (d) Tissot,
M.; Mu¨ller, D.; Belot, S.; Alexakis, A. Org. Lett. 2010, 12, 2770–2773.
(9) He´non, H.; Mauduit, M.; Alexakis, A. Angew. Chem., Int. Ed. 2008,
47, 9122–9124.
(10) Cesati, R. R.; de Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc.
2004, 126, 96–101.
(11) For experimental procedure, see Supporting Information.
(12) Jin, Z.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 5995–5996
.
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Org. Lett., Vol. 12, No. 19, 2010

of the treatment procedure was incorporated.9 The reaction
was quenched by the addition of solid NH4Cl followed by
the direct addition of the solution of DBU in CH2Cl2 to the
reaction mixture.
With the optimized conditions in hand, we turned our
attention to the scope of this reaction. Thereby, a panel of
five- and six-membered cyclic substrates was prepared by
modifying the hindrance at the δ position, introducing
substitution on the ring or introducing a supplementary
functional group. Additionally, different organozinc reagents
were used, including the noncommercial functionalized
Zn((CH2)3OAc)2.13 The results are summarized in Table 2.
structure of the dienone nor the type of diorganozinc reagent
had an important influence on the ee’s. Furthermore,
unprecedented results were observed for the five-membered
ring substrates (Table 2, entries 6-12). Seven products were
isolated with 93% < ee e 99%. Cu-DiPPAM catalyst
tolerated the silyl ether protecting group of the substrate and
the acetoxy group of the diorganozinc reagent (Table 2,
entries 9 and 12). The hindrance at the δ position made the
reaction more sluggish; nonetheless, a longer reaction time
enabled total conversions of starting materials to products
(Table 2, entries 4 and 10-12). To explore the tolerance of
Cu-DiPPAM catalyst for challenging bicyclic compounds,
substrate 3 was prepared.14 Unfortunately, the results were
quite disappointing. Although the regioselectivity of the
reaction was complete, the enantiocontrol was moderate for
the addition of both Et2Zn (ee ) 40%) and i-Pr2Zn (ee )
30%) (Scheme 2).
Table 2. Cu/DiPPAM-Catalyzed 1,6-ACA on Various Dienones
Scheme 2
.
Cu/DiPPAM-Catalyzed 1,6-ACA on Bicyclic
Dienone 3
These results are similar to those reported by Alexakis
with L2 and confirm that bicyclic compounds are very
demanding substrates for 1,6-ACA.9 In summary, we have
developed a very efficient catalytic system for copper-
catalyzed 1,6-ACA to R,ꢀ,γ,δ-unsaturated five- and six-
membered cyclic dienones. Due to the strong tolerance of
the Cu/DiPPAM catalyst to numerous, even functionalized,
substrates and mild experimental conditions, this method
should prove to be of use in the total synthesis of complex
molecules. Nevertheless, the design of new ligands should
be carried out to develop more efficient catalysts for copper-
catalyzed 1,6-ACA on bicyclic compounds.
a Reaction performed at 0 °C. b Reaction time ) 40 h. c Reaction time
) 60 h. d ee determined by GC. e ee determined by HPLC. f Formation of
byproduct 2a was observed, due to the presence of Et2Zn in the crude
Zn((CH2)3OAc)2. g Two treatments with DBU were required.
Acknowledgment. This work was supported by the
Ministe`re de la Recherche et de la Technologie and by the
Universite´ europe´enne de Bretagne (grant to J.W.-D.).
As expected, the regiocontrol of the reaction was complete
in all cases. The isolated yields were moderate to good, which
could be explained by the partial volatility of the products
and the moderate stability of the substrates. High enantio-
control was observed with all six-membered cyclic substrates
(95% < ee e 97%) (Table 2, entries 1-5). Neither the
Supporting Information Available: Experimental pro-
cedures and spectral data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL1017382
(13) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.;
Knochel, P. J. Org. Chem. 1996, 61, 8229–8243.
(14) For the synthesis of 3, see Supporting Information.
Org. Lett., Vol. 12, No. 19, 2010
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