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
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