Formation of quaternary stereogenic centers by NHC-Cu-catalyzed asymmetric conjugate addition reactions with Grignard reagents on polyconjugated cyclic enones

Article abstract of DOI:10.1002/chem.201200502

The copper-catalyzed conjugate addition of various Grignard reagents to polyconjugated enones (dienone and enynone derivatives) is reported. The catalyst system, composed of copper triflate and an NHC ligand, led to the unusual selective formation of the 1,4-addition products. This reaction allows for the creation of all-carbon chiral quaternary centers with enantiomeric excesses up to 99 %. The remaining unsaturation on the 1,4 adducts give access to valuable synthetic transformations. Copyright

Full text of DOI:10.1002/chem.201200502

FULL PAPER
DOI: 10.1002/chem.201200502
Formation of Quaternary Stereogenic Centers by NHC–Cu-Catalyzed
Asymmetric Conjugate Addition Reactions with Grignard Reagents on
Polyconjugated Cyclic Enones
Matthieu Tissot,[a] Daniele Poggiali,[a] Hꢀlꢁne Hꢀnon,[a] Daniel Mꢂller,[a]
Laure Guꢀnꢀe,*[b] Marc Mauduit,*[c] and Alexandre Alexakis*[a]
Abstract: The copper-catalyzed conjugate addition of various Grignard reagents to
polyconjugated enones (dienone and enynone derivatives) is reported. The catalyst
system, composed of copper triflate and an NHC ligand, led to the unusual selec-
tive formation of the 1,4-addition products. This reaction allows for the creation of
all-carbon chiral quaternary centers with enantiomeric excesses up to 99%. The
remaining unsaturation on the 1,4 adducts give access to valuable synthetic trans-
formations.
Keywords: asymmetric synthesis ·
conjugate additions
·
copper
·
Grignard reagents · N-heterocyclic
carbenes
Introduction
of trialkylaluminum reagents to nonactivated trisubstituted
cyclic enones.[9–12]
The conjugate addition reaction has become a very powerful
Indeed, the Lewis acidic character of this organometallic
species led smoothly to the formation of quaternary centers
with high enantiocontrol by using SimplePhos and phos-
phoramidite ligands. Strategies to introduce the aryl[13,36] and
vinyl[14] moiety were also successfully developed through the
use of triorganoaluminum reagents, increasing the variety of
quaternary stereogenic centers that could be formed.
À
tool for C C bond formation. The asymmetric 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] With regard to copper catalysis,
one of the most important breakthroughs came through the
introduction of phosphorus ligands as very efficient chiral
inductors.[2] Following this discovery, many groups have con-
tributed to the further development of this reaction. The
ubiquity of all-carbon quaternary stereogenic centers in
Nature has inspired researchers to investigate the appropri-
ate conditions that would lead to this motif.[3] These were
successfully realized by the addition of diorganozinc re-
agents to very activated substrates, such as Meldrum acid
derivatives,[4–6] nitroolefins[7] and doubly activated cyclic
enones.[8] An improvement was achieved by the introduction
On the other hand, a very important contribution to the
asymmetric conjugate addition (A.C.A.) is the reaction de-
veloped by Woodward and Fraser[15] through the use of
a new class of ligand, the N-heterocyclic carbene (NHC),
that shows strong electron-donating and steric proprieties.
Since the first chiral example by the groups of Alexakis and
Mangeney[16] by using diethyl zinc on cyclohexenone with
NHC ligands, many reports have been published.[1] NHCs
have also been shown to be valuable ligands for the creation
of quaternary centers. Hoveyda et al. described the use of
very efficient Cu–NHC complexes for the addition of dio-
rganozinc reagents to not only methylcyclohexenone,[17] but
also to the more challenging methylcyclopentenone.[18] How-
ever, zinc and aluminum did not allow for the introduction
of many alkyl moieties. To circumvent this problem, our
group focused on the use of Grignard reagents as highly ver-
satile nucleophiles to create quaternary stereogenic centers.
In 2006, through a collaboration with the Mauduit group, we
revealed the highly enantioselective conjugate addition of
Grignard reagents to trisubstituted cyclohexenone by using
the NHC L6 (see Figure 1).[19] Thanks to the contribution of
many researchers in the field of A.C.A. reactions catalyzed
by copper, new catalytic systems and also new Michael ac-
ceptors have emerged. Our expertise in the enantioselective
conjugate addition prompted us to investigate polyconjugat-
ed Michael acceptors. These substrates correspond to an ex-
[a] M. Tissot, D. Poggiali, Dr. H. Hꢀnon, D. Mꢁller, Prof. A. Alexakis
Departement of Organic Chemistry, Universitꢀ de Genꢂve
30 quai Ernest-Ansermet, 1211 Genꢂve-4 (Switzerland)
Fax : (+41)223796522
E-mail: alexandre.alexakis@unige.ch
[b] Dr. L. Guꢀnꢀe
Laboratory of crystallography
Ecole de Physique Universitꢀ de Genꢂve
30 quai Ernest-Ansermet, 1211 Genꢂve-4 (Switzerland)
Fax : (+41)223796522
E-mail: laure.guenee@unige.ch
[c] Dr. M. Mauduit
Ecole Nationale Supꢀrieure de Chimie de Rennes
Av. Gꢀnꢀral Leclerc, 35700 Rennes (France)
E-mail: marc.mauduit@ensc-remnnes.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200502.
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gioselective
addition
of
Grignard reagents to dien-
oates.[25] Excellent 1,6 selectivi-
ty and high stereocontrol were
reported thanks to ferrocene-
based phosphine ligands and
CuBr·Me2S as the catalyst com-
bination. An identical level of
regioselectivity was also report-
ed by Mauduit et al. and our
group for the addition of dio-
rganozinc reagents to cyclic di-
enones.[26] The Cu–diphenyl-
phosphinoazomethinylate salt
Figure 1. Selected ligands used in this study (2-Napht=2-naphthyl).
(DIPPAM) complex catalyzed
the formation of the 1,6 adduct
tension of the conjugated system of typical Michael accept-
ors with double or triple bonds. These types of substrate
posed a challenge in terms of regioselectivity due to the
presence of various electrophilic sites that, upon nucleophil-
ic attack, could lead to several regioisomers (Scheme 1).
with very high enantioselectivity of up to 99% (Scheme 2).
The general trend observed for copper catalysis led to a 1,6
addition. However, as demonstrated by Yamamoto et al., re-
finement of the copper reagents allows for the 1,4 addi-
tion.[22] Recently, we reported the copper-catalyzed A.C.A.
of trialkylaluminum reagents to
extended nitro-Michael accept-
ors, affording only the 1,4
adduct, with excellent stereo-
control.[27] Finally, two recent
contributions from our labora-
tory have disclosed the addition
of Grignard reagents to a,b,g,d-
unsaturated cyclic enones (dien-
ones and enynones), resulting
in 1,4 selectivity.[28] This reac-
tion has led to the formation of
all-carbon stereogenic centers
with very high enantioselectivi-
ty of up to 99%. Herein, we
report a full account of this
work, with several new dienone
and enynone derivatives, and
new synthetic applications of
the reaction are also disclosed
(Scheme 2).
Scheme 1. Regioselectivity with extended Michael acceptors (Nu=nucleophile, E=electrophile).
The Naef group were the pioneers in this field, describing
the first conjugate addition of cuprates to dienoates, with ex-
clusively 1,6 addition.[20] Furthermore, the conjugate addi-
tion to extended Michael acceptors has mainly been report-
ed by the Krause group[21] in the beginning of the 1990s.
They reported that copper reagents react preferentially in
a 1,6 manner with a,b,d,g-unsaturated Michael acceptors.
On the other hand, Yamamoto et al.[22] have shown that fine
tuning of the copper reagent allows regioselective 1,4 or 1,6
addition. The last ten years have seen the development of
an asymmetric version of this reaction.[23] Fillion et al. were
the first to report the copper-catalyzed 1,6 addition of di-
ACHTUNGTRENNUNG
Scheme 2. Summary of this study (Tf=triflyl).
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Asymmetric Conjugate Addition Reactions
FULL PAPER
Results and Discussion
the best result was obtained by using ligand L1, affording
a 68% ee (Table 1, entry 3). We also decided to test the
Grignard reagents, with our first attempt using ligand L1,
which led to the unique formation of the 1,6 adduct, but no
enantioselectivity was detected (Table 1, entry 4). The ferro-
cene-based phosphine ligand L5 was also tried and 1,6 selec-
tivity was obtained with moderate enantiocontol (36% ee;
Table 1, entry 5). NHC ligand L6, recently discovered to be
a very efficient ligand in the A.C.A. of Grignard reagents to
trisubstituted cyclic enones,[19] was also tested (Table 1,
entry 6). Surprisingly, the 1,4 adduct was found to be the
major regioisomer, corresponding to conjugate addition at
the most hindered position. We were delighted to see that
this transformation generates all-carbon quaternary centers
with high enantioselectivity (95.5% ee). After opti-
mization of the reaction conditions, the use of di-
chloromethane as the solvent allowed for almost
perfect regioselectivity in favor of the 1,4 adduct
with the same level of enantioselectivity. However,
a decrease in reactivity was observed (Table 1,
entry 7). We circumvented this problem by using
two equivalents of the Grignard reagent (Table 1,
entry 8). Furthermore, if the reaction temperature
was decreased to À108C, the reaction afforded
Dienones: Cyclohexenone derivatives have been extensively
studied in the field of A.C.A. However, their polyconjugat-
ed analogues, the dienones, have received less attention.
Hayashi et al. were the first to use this substrate type to de-
velop the 1,6 conjugate addition of aryl zinc reagents to 3-al-
kenyl cyclohexen-2-ones, such as S1, by using Rh/2,2-bis(di-
phenylphosphino)-1,1’-binaphthyl (BINAP) catalysis with
enantioselectivities up to 98% ee.[29] Our investigation into
this substrate, by using copper catalysis, commenced with an
initial study of the different organometallic reagents, such as
Et2Zn, Et3Al, and EtMgBr, under different reaction condi-
tions (Table 1).
Table 1. Optimization of the reaction with dienone S1.
a
higher enantioselectivity of 97% ee (Table 1,
entry 9). Altering the order of addition appeared to
be detrimental to this reaction since the addition of
the Grignard reagent to a mixture of the catalytic
system and the substrate afforded a mixture of the
regioisomers and a decrease in the enantioselectivi-
ty for the 1,4 adduct (Table 1, entry 10).
RM
([equiv])
L* Solvent
T
[8C]
2/3[a]
Conv. Yield ee (2/3)
[%][a] [%] [%][b]
G
1[c] Et2Zn (1.2)
2[d] Et2Zn (1.2)
3[c] Et3Al (1.2)
4[c] EtMgBr (1.2)
5[d] EtMgBr (2)
L2 Et2O
L4 MeTHF
L1 Et2O
L1 Et2O
L5 CH2Cl2
L6 Et2O
L6 CH2Cl2
L6 CH2Cl2
L6 CH2Cl2
À30
RT
À30
À30
À10
0
0:100 100
0:100 100
0:100 100
0:100 100
0:100 100
66
–/89
75
53
–/97
–/68
n.d.
n.d.
n.d.
n.d.
n.d.
62
–/0
–/36
95.5/20
95/n.d.
95/n.d.
97/–
Next, a screening of different NHC ligands was
carried out to determine whether this nontypical re-
gioselectivity was specific to this family of ligands
(Table 2). First, the achiral NHC L8 was tested
under the optimized reaction conditions (Table 2,
entry 2). Only the formation of the 1,6 adduct was
detected, highlighting the importance of the hy-
droxyl appendage on NHC L6 for the 1,4 selectivity
(Table 2, entry 1). Furthermore, L9 and L10 were
employed to examine the effect of the substituent
tethered at the b-position to the hydroxy group.
Surprisingly, both ligands produced only the formation of
the 1,6 isomer (Table 2, entries 3 and 4). These observations
argue that the regioselectivity issue is highly dependent on
chelation between the deprotonated alcohol and the transi-
tion metal during catalysis. Moreover, we presume that the
selectivity issue is highly dependent on the byte angle
formed between the carbene center, the transition metal
and the hydroxyl group. Next, we studied NHC L11 with
the same features as L6 on the hydroxyl arm, but with
a homo mesityl moiety instead of a mesityl moiety on the
other arm (Table 2, entry 5). Again, this structural change
influenced the regioselectivity, forming the 1,4 adduct as the
minor isomer. Finally, we observed an unexpected change in
6
EtMgBr (1.2)
78:22
>99:1
>99:1
100
28
100
100
100
7[e] EtMgBr (1.2)
8[e] EtMgBr (2)
9[e] EtMgBr (2)
0
0
À10 >99:1
10[e] reverse addition L6 CH2Cl2
À10 51:49
n.d.
88/0
[a] Determined by GC-MS methods. [b] Determined by chiral GC methods using
chiral stationary phase. [c] Reaction performed with Cu(OTf)2/L*=2:4 mol%.
[d] Reaction performed with Cu(OTf)2/L*=5:10 mol%. [e] Reaction performed with
Cu(OTf)2/L*=6:9 mol%. n.d.=not determined.
a
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
We first examined the copper-catalyzed A.C.A. of diethyl-
zinc to S1. With respect to the general trend observed with
copper reagents, we noted that only the 1,6 adduct was
formed as the deconjugated isomer 3a’. To prevent the for-
mation of oxidative byproducts,[30] hydrochloric acid, which
had previously been degassed with argon, was used to
quench the reaction. The isomerization of 3a’ by using 1,8-
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU, 1 equiv) under argon
led to totally reconjugated adduct 3. By using phosphorami-
dite ligand L2 we obtained good enantioselectivity (89%;
Table 1, entry 1). Recently, Mauduit et al. and our group
have discovered that diphenylphosphinoazomethinylate salts
(DIPPAMs; L4) afford excellent enantioselectivity (97% ee)
in MeTHF at room temperature (Table 1, entry 2).[26] Next,
the evaluation of triethylaluminum reagents was performed;
À
regioselectivity when L7, a homologue of L6 with PF6 as
the counteranion instead of ClÀ, was used. Whereas L6 dis-
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A. Alexakis, L. Guꢀnꢀe, M. Mauduit et al.
Table 2. Screening of the NHC ligand.
this selectivity problem. Unfortunately, the general trend to-
wards a 1,6 addition,[21] as well as the preference for the
least substituted position,[1a] appeared to be difficult to over-
come. Selectivity problems were also observed with
iBuMgBr and the secondary Grignard reagents, for which
the established conditions provided a mixture of regioisom-
ers (Table 3, entries 5 and 6).[28a] However, after optimiza-
tion of the reaction conditions, we discovered that the pres-
ence of Et2O was detrimental to the regiocontrol of these
reactions. Indeed, by replacing Et2O within the Grignard re-
agent with CH2Cl2, the 1,4 adducts were obtained as the
major isomers (Table 3, entries 7, 8, and 9). The phenyl
Grignard reagent was also tested, giving an inseparable mix-
ture of compounds, and involving the formation of side
products from the 1,2 addition and subsequent dehydration
of the tertiary alcohol, among others (Table 1, entry 10).
Subsequently, various dienones were tested to extend the
scope of this reaction. We started by synthesizing different
dienone derivatives (Scheme 3, Figure 2). The six-membered
L*
2/3[a]
Conv.
[%][a]
ee (2/3)
[%][b]
1
2
3
4
5
6
L6
L8
L9
L10
L11
L7
>99:1
100
100
100
100
100
100
97/–
–/–
–/–
–/–
78/0
95.5/0
0:100
0:100
0:100
16:84
32:68
[a] Determined by GC-MS methods. [b] Determined by chiral GC meth-
ods using a chiral stationary phase.
played high regioselectivity in favor of the 1,4 adduct, L7
furnished mainly the 1,6 adduct (Table 2, entry 6).
With these optimized conditions in hand we turned our
attention to the scope of the reaction with respect to the
Grignard reagent (Table 3). Firstly, the addition of linear or-
Table 3. Enantioselective 1,4 conjugate addition of several Grignard re-
agents to dienone S1.
R
Prod.
2/3[a]
Conv.
[%][a]
Yield
[%]
ee 2
[%][b]
1
2
3
4
5
6
Et
Bu
But-3-enyl
Me
iBu
iPr
iPr
iBu
Cy
2a
2b
2c
2d
2e
2 f
2 f
2e
2g
2h
>99:1
96:4
95:5
0:100
56:44
65:35
>99:1
>99:1
>99:1
n.d.
100
100
100
100
100
100
100
100
100
93
62
67
65
n.d.
39
25
53
58
62
–
97
97
99
–
99
95
94
89
86
n.d.
Scheme 3. Synthesis of substrates.
7[c,d]
8[c,d]
9[c,d]
10
Ph
[a] Determined by GC-MS methods. [b] Determined by chiral GC meth-
ods using a chiral stationary phase. [c] Et2O in the Grignard reagent was
replaced with CH2Cl2. [d] The solution was twice as diluted as under the
standard reaction conditions, and substrate addition times were 30 min
instead of 15 min.
Figure 2. Substrate scope (Cy=cyclohexyl).
ganomagnesium reagents, such as ethyl, butyl, and but-3-
enyl Grignard reagents, provided the 1,4 adducts in a high
level of regioselectivity (greater than 95%) and excellent
enantioselectivities of up to 99% (Table 3, entries 1–3).
However, the addition of the methyl Grignard reagent re-
sulted in a total shift in regioselectivity towards exclusive
formation of the 1,6 adduct (Table 3, entry 4). This result
can be attributed to the particular behavior of this Grignard
reagent in conjugate addition reactions. Many modifications
of the conditions have been tried in attempts to circumvent
rings were obtained through 1,2 addition of organometallic
nucleophiles to the cyclic ketoenol ether S2. Substrates S3
and S4 were synthesized by using triorganoaluminum re-
agents generated in situ through hydroalumination of the
corresponding alkynes. S6 was obtained by addition of the
commercially available Grignard reagents to S2. Finally, the
addition of lithium reagents, prepared in situ by lithium–
bromine exchange with the corresponding vinyl bromides,
afforded S5, S7, S8 and S9. The bicyclic dienone S10 was
prepared according to a literature procedure.[31]
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Asymmetric Conjugate Addition Reactions
FULL PAPER
First, we applied our optimized conditions to these differ-
ent substrates (Figure 2). The addition of ethyl Grignard re-
agents to substrates S3–S6 displayed a high level of regiose-
lectivity, affording the 1,4 adducts (2i–2l) in high enantiose-
lectivities (Table 4, entries 1–4). The addition of the prob-
selectivity issue observed previously with the methyl
Grignard reagent and dienone S1. We hypothesized that the
extension of the conjugation would prevent the 1,6 addition
and favor the 1,4 addition, whereas the 1,8 addition would
be disfavored by the hindrance induced by the gem-dimethyl
groups. Our standard reaction conditions were applied to
this system; a mixture of regioisomers were detected, com-
prising mainly the 1,6 adduct. However, a very encouraging
31% conversion into the 1,4 adduct was observed with an
enantioselectivity of 80%. The 1,2 adduct was also observed
to a lesser extent (Table 5, entry 1).
Table 4. Enantioselective 1,4 conjugate addition of Grignard reagents to
various dienones S3–S9.
2/3[a]
Conv.
[%][a]
Yield
[%]
ee 2
Table 5. Conjugate addition of the methyl Grignard reagent to trienone
S9.
Substrate
R
Prod.
[%][b]
1
2
3
4
5
6
7
8
S3
S4
S5
S6
S6
S7
S8
S9
Et
Et
Et
Et
Me
Et
Et
Et
2i
2j
>99:1
>99:1
>99:1
100:0
100:0
90:10
100:0
100:0
100
100
100
100
100
100
100
100
60
44
63
69
60
62
71
70
93
92
94
90
92
88
95
91
2k
2l
2m
2n
2o
2p
[a] Determined by GC-MS methods. [b] Determined by chiral GC meth-
ods using a chiral stationary phase.
Conv.
[%][a]
2q/3q/4q[a]
ee 2q
[%][b]
1
95
96
29
90
0
31:54:10
26:70:0
8:2:19
37:24:29
–
80
2[c]
3[c,d]
4[e]
5[f]
6[g]
n.d.
n.d.
85
–
n.d.
lematic methyl Grignard reagent was also tested with the
substrate S6. The increase in the bulk of the 6 position al-
lowed the exclusive formation of the 1,4 adduct 2m
(Table 4, entry 5). To explore the limitations of our highly
regioselective catalytic system, we investigated the dienone
S7 without a substituent at the 1,6 position. To our delight
the 1,4 adduct was detected as the major isomer with good
enantiocontrol (Table 4, entry 6). The more challenging tri-
enones S8 and S9 were also used under our reaction condi-
tions. We were pleased to find that even with an additional
electrophilic site (the 1,8 position), the 1,4 adduct was
formed as a single regioisomer with excellent enantioselec-
tivity (Table 4, entries 7 and 8).
These results encouraged us to investigate the addition of
the methyl Grignard to trienone S9. Indeed, this transforma-
tion could allow for the formation of the chiral synthon 2q,
a key intermediate in the total synthesis of ent-Riccardiphe-
nol B (Scheme 4), a natural product that was isolated from
the liverwort Riccardia Crassa by Toyota and Asakawa[32]
Two syntheses of this compound have so far been devel-
oped, by Tori et al.[33] and more recently by Hoveyda
et al.[14c] We speculated that the presence of the additional
conjugated double bond in the system could overcome the
43
21:8:14
[a] Determined by GC-MS methods. [b] Determined by chiral GC meth-
ods using a chiral stationary phase. [c] The solution was twice as diluted
as under the standard reaction conditions. [d] The substrate addition time
was 30 min instead of 15 min. [e] Et2O in the Grignard reagent was re-
placed with CH2Cl2. [f] 1 equivalent of BF3·Et2O was used as an additive.
[g] MeMgI was used instead MeMgBr.
Following this promising result we started to investigate
some modifications of the reaction conditions to direct the
selectivity in favor of the 1,4 adduct (Table 5). Dilution of
the reaction mixture afforded a cleaner reaction with no 1,2
addition being detected, although the 1,6 addition still oc-
curred preferentially (Table 5, entry 2). Slowing down the
addition time of the substrate to the catalytic system led to
a drop in conversion, with a large amount of 1,2 addition
product (Table 5, entry 3). Knowing the detrimental effect
Et2O had on the regioselectivity, we were encouraged to re-
place the Et2O contained within the Grignard reagent with
CH2Cl2. In this case, the 1,4 addition was favored, although
the 1,2 and 1,6 addition products were still detected in sub-
stantial amounts (Table 5, entry 4). Inspired by the results
reported by Yamamotoꢄs group,[22] we used BF3 as an addi-
tive. However, no conversion was detected under these con-
ditions (Table 5, entry 5). Finally, MeMgI was tested as the
nucleophile, generating mainly the 1,4 adduct, however,
with low conversion and formation of the 1,2 product
(Table 5, entry 6). After many different attempts, we were
Scheme 4. Application to the synthesis of ent-Riccardiphenol B.
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A. Alexakis, L. Guꢀnꢀe, M. Mauduit et al.
Table 7. Optimization on enynone S11.
unable to achieve good regioselectivity with reasonable con-
version with the trienone S9.
To complete the study into the scope of the reaction with
respect to substrates, the optimized reaction conditions for
the 1,4 and 1,6 addition reactions were tested with bicyclic
dienone S10 (Table 6). Diethylzinc and triethylaluminum
Table 6. Enantioselective conjugate addition of organometallic reagents
to bicyclic dienone S10.
RM
L*
Solvent
T
[8C]
Conv.
[%][a]
7/8/9[a]
ee 7a
[%][b]
1[c]
2[c]
3[d]
4[d]
5[c]
6[c]
7[d]
8[c]
9[d]
EtMgBr
EtMgBr
EtMgBr
EtMgBr
Et2Zn
Et2Zn
Et2Zn
Et3Al
Et3Al
L6
L6
L2
L2
L6
L6
L2
L5
L2
CH2Cl2
Et2O
CH2Cl2
Et2O
CH2Cl2
Et2O
Et2O
À10
À10
À10
À10
À10
À10
À10
À30
À30
100
100
100
100
10
100
60
100
100
91.5:0:8.5
28:n.d.:n.d.[e]
0:100:0
n.d.[e]
85
93
–
–
–
99
–
n.d.
–
RM
L* Solvent
T
[8C]
5/6[b]
Conv. Yield
[%][a] [%]
ee (5/6)
[%][b]
1[c]
2[c]
3[c]
4[d]
Et2Zn
Et3Al
Me3Al
L2 Et2O
L2 Et2O
L3 Et2O
0
0
0
0:100 11
0:100 100
0:100 100
n.d.
–/11
45 (6b) –/69
54 (6a) –/56
73 (5b) 96/–
n.d.[e]
75:25:0
0:100:0
5:95:0
EtMgBr L4 CH2Cl2 À10 98:2
100
94
5[d,e] MeMgBr L4 CH2Cl2 À10
n.d.
n.d.
n.d.
Et2O
Et2O
[a] Determined by GC-MS methods. [b] Determined by chiral GC meth-
ods using a chiral stationary phase. [c] Reaction performed with Cu-
0:100:0
[a] Determined by GC-MS methods. [b] Determined by chiral GC meth-
ods using a chiral stationary phase. [c] Reaction performed with Cu-
G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGRTENN(UNG OTf)2/L*=
were tested in the presence of CuACHTNUTRGNEUNG(OTf)2 and ligand L2. As
expected, the 1,6 adduct was formed exclusively in both
cases (Table 6, entries 1 and 2). However, low reactivity and
stereocontrol were detected with diethylzinc, whereas Et3Al
gave full conversion with an enantioselectivity of 69%.
Me3Al was also tested under these conditions, displaying
identical 1,6 selectivity with an enantioselectivity of 56%
(Table 6, entry 3). When the addition of EtMgBr was tested
under our standard reaction conditions, the 1,4 adduct was
obtained with almost perfect regiocontrol, leading to the for-
mation of bicyclic compound 5b with an excellent enantio-
selectivity of 96% (Table 6, entry 4). MeMgBr gave a mix-
ture of regioisomers, with a large amount of the 1,2 addition
product (Table 6, entry 5).
light, we found that the 1,4 adduct was mainly formed with
an enantioselectivity reaching 85%. This result displays sim-
ilar behavior, in terms of reactivity, to the dienone ana-
logues. We decided to perform the same reaction by using
Et2O in place of CH2Cl2, and were not surprised to observe
a chaotic reaction with only a minor amount of the 1,4
adduct among many other products derived from the 1,2
and 1,6 additions (Table 7, entry 2). This result highlights
the detrimental effect of Et2O on the regioselectivity. The
use of phosphoramidite ligand L2 in CH2Cl2 led to only the
1,6 addition, affording allene 8, which isomerized on workup
into conjugated dienone 8a (Table 7, entry 3). The same re-
action performed in Et2O led to a mixture of compounds
(Table 7, entry 4). We continued our study by using diethyl-
zinc as the organometallic reagent. Applying the standard
reaction conditions (with NHC L6) led to very low conver-
sion (Table 7, entry 5). However, when Et2O was used,
a ratio of 3:1 in favor of 1,4 adduct 7a was detected with an
enantioselectivity of 99% (Table 7, entry 6). Under the
same reaction conditions, L2 afforded only the 1,6 adduct
(Table 7, entry 7). Finally, Et3Al was also tested, affording
mainly the 1,6 adduct (Table 7, entries 8 and 9).
The high regioselectivity displayed with the Grignard re-
agent, as shown in the previous table, motivated us to exam-
ine the scope of the reaction towards nucleophiles with eny-
none S11 (Table 8). After slight modification of the dilution
and addition time of the EtMgBr, 1,4 adduct 7a was ob-
tained as a single regioisomer with an enantioselectivity of
82% (Table 8, entry 1). On the other hand, but-3-enyl mag-
nesium bromide afforded perfect regioselectivity and an ex-
cellent enantioselectivity of up to 95% under the standard
Enynones: To extend our methodology to another class of
substrates, we investigated the reaction of enynone S11.[28b]
This type of polyconjugated Michael acceptor was first stud-
ied by Hulce,[34] who only observed 1,6 addition by use of
a copper reagent. Hayashi et al.[35] reported the rhodium cat-
alyzed 1,6 addition of aryltitanates to this type of substrate,
which results in the formation of chiral allenes. We found
two isolated examples, in different reports, of copper-cata-
lyzed 1,4-addition reactions to this type of substrate by
using diethylzinc[17] and trimethylaluminum[36] by Hoveyda
et al. in the recent literature.
We initially investigated the addition of EtMgBr, Et2Zn,
and Et3Al to enynone S11 by using NHC ligand L6 and
phosphoramidite ligand L2 under various conditions
(Table 7). Intrigued by the potential outcome of our method
with S11, we tested the reaction with EtMgBr under our
standard reaction conditions (Table 7, entry 1). To our de-
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Asymmetric Conjugate Addition Reactions
FULL PAPER
Table 8. Enantioselective 1,4 conjugate addition of several Grignard re-
agents to dienone S11.
S11–S15 were obtained in a one-pot procedure by lithiation
of the corresponding acetylene derivatives and then addition
to ethoxycyclohexenone S2. Compound S16 was synthesized
by deprotection of enynone S13 by using tetra-n-butylam-
monium fluoride (TBAF). The seven- and five-membered
rings S18 and S19 were obtained through the reaction of the
lithium acetylide of hexyne and the corresponding cyclic
enones,[37] followed by a 1,3 rearrangement of the tertiary al-
cohol assisted by (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO).[38] Finally, the alcohol precursor of S17 was ob-
tained through a Sonogashira cross-coupling reaction.[39]
First, we investigated the addition of EtMgBr to S12, pos-
sessing a tert-butyl group. The standard reaction conditions
afforded the exclusive 1,4 addition product in 79% ee
(Table 9, entry 1). The addition of the isopropyl and isobutyl
R
Prod.
Conv.
[%][a]
7/8/9[a]
Yield
[%]
ee 7
[%][b]
1[c,d]
2
Et
7a
7b
7c
7d
7e
100
100
100
100
100
100:0:0
100:0:0
100:0:0
93:3:4
72
90
60
58
82
95
92
89
But-3-enyl
iPr
iBu
3[c,d,e]
4[c,d,e]
5
Me
23:77:0
n.d.
n.d.
[a] Determined by GC-MS methods. [b] Determined by chiral GC meth-
ods using a chiral stationary phase. [c] The solution was twice as diluted
as under the standard reaction conditions. [d] The substrate addition time
was 30 min instead of 15 min. [e] Et2O in the Grignard reagent was re-
placed with CH2Cl2.
Table 9. Enantioselective 1,4 conjugate addition of Grignard reagents to
various enynones S12–19.
reaction conditions (Table 8, entry 2). Isopropyl and isobutyl
Grignard reagents required a slight modification of the reac-
tion conditions. Thus, the Et2O contained within the
Grignard reagent should be replaced by CH2Cl2 to obtain
the 1,4 adduct as the major isomer with high enantioselectiv-
ities (Table 8, entries 3 and 4). These results highlight the
similar behavior of enynones and dienones with these two
Grignard reagents. Despite the fact that methyl Grignard af-
forded 1,6 addition in the dienone series, we investigated
this addition to enynone S11. We were not surprised to
detect mainly the 1,6 adduct. However, in comparison with
the dienones, the 1,4 product was detected in substantial
amounts in this case (Table 8, entry 5).
Substrate
R
Prod. Conv. 7/8/9[a]
Yield ee 7
[%]
[%][a]
[%][b]
1
2
3
4
5
6
7
8
9
S12
S12
S12
S13
S13
S13
S13
S14
S14
Et
7 f
7g
7h
7i
100
100
100
100
100
100
100
100
100
100
100
100
100
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
95:5:0
82
57
87
69
98
72
74
81
87
79
87
93
78
95
91
96
94
93
91
96
97
36
iPr
iBu
Et
iBu
7j
But-3-enyl 7k
Cy
iBu
But-3-enyl 7n
But-3-enyl 7o
But-3-enyl 7p
But-3-enyl 7q
7l
7m
100:0:0
100:0:0
To extend the scope of this reaction, we synthesized a vari-
ety of cyclic enynones (Scheme 5). The six-membered rings
10[c,d] S16
50:50:0 n.d.
11
12
13
S17
S18
S19
100:0:0
100:0:0
n.d.
79
67
n.d.
Et
7r
[a] Determined by GC-MS methods. [b] Determined by chiral GC meth-
ods using a chiral stationary phase. [c] The solution was twice as diluted
as under the standard reaction conditions. [d] Substrate addition time
was 30 min instead of 15 min.
Grignard reagents to S12 displayed the same regioselectivity
with enantioselectivities of up to 93% without any modifica-
tion of the standard reaction conditions (Table 9, entries 2
and 3). Trimethylsilyl (TMS)- and phenyl-substituted sub-
strates S13 and S14 also gave excellent results in terms of re-
gioselectivity with primary and secondary Grignard re-
agents; enantioselectivities, ranging between 78 and 96%,
were detected (Table 9, entries 4–9).
Enynone S16, possessing a terminal alkyne, was synthe-
sized to determine the limitations of the methodology. Slight
modification of the methodology gave a very interesting
result; we observed the formation of the 1,4 and 1,6 adducts
in equal amounts (Table 9, entry 10). An enantioselectivity
of 91% was detected for adduct 7o. This result highlights
the power of this catalytic system because even with the 1,6
position completely unprotected, 1,4 attack occurred. The
Scheme 5. Synthesis and substrate scope (THP=tetrahydropyranyl).
Chem. Eur. J. 2012, 00, 0 – 0
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A. Alexakis, L. Guꢀnꢀe, M. Mauduit et al.
regioselective 1,4 A.C.A was also possible for reagents with
different ring sizes. The seven-membered ring S18 gave our
best results in terms of enantioselectivity (97%) with perfect
regioselectivity (Table 9, entry 12). Unfortunately, five-mem-
bered ring analogue S19 resulted in a disordered reaction,
producing a product mixture containing the 1,4 adduct in
36% ee (Table 9, entry 13). Finally, enynone S17 was tested
under the reaction conditions, affording only the 1,4 adduct
with an enantioselectivity of 96% (Table 9, entry 11).
To complete the study into the scope of this reaction, we
proceeded to a specific investigation of the addition of the
problematic methyl Grignard reagent to various enynones
(Table 10). The addition of MeMgBr to the n-butyl-substi-
tuted enynone S11 exhibited the formation of the 1,4 adduct
as the minor isomer (Table 10, entry 1). To drive the selec-
tivity in favor of the 1,4 adduct, tert-butyl-substituted eny-
none S12 was tested (Table 10, entry 2). As expected, the 1,4
Scheme 6. Synthesis and substrate scope.
Table 10. Enantioselective 1,4 conjugate addition of MeMgBr to various enynones S11–
13 and S15.
The challenging substrates S20–S24, possessing
one or even two additional unsaturated units
compared with the classical enynones, were
tested under the standard reaction conditions
(Table 11). Our first attempt with butyl-substitut-
ed compound S20 afforded the 1,4 adduct as
a single regioisomer with a moderate enantiose-
Substrate
Prod.
Conv.
[%][a]
7/8/9[a]
Yield
[%]
ee 7
[%][b] lectivity of 79% (Table 11, entry 1). Adducts
S21–S24 also gave perfect 1,4 selectivity, despite
the possible 1,2, 1,6, and 1,8 additions pathways
(Table 11, entries 2–5). Even the 10 position re-
mained unaffected when the highly extended
compound S22 was tested, affording only product
10c with an enantioselectivity of 87% (Table 11,
entry 3). Substrate S23, possessing two conjugat-
ed triple bonds, resulted in perfect regioselectivi-
1
2
3
4
S11
S12
S13
S15
7s
7t
7u
7v
100
100
100
100
23:77:0
71:17:11
71:23:7
100:0:0
n.d.
29
n.d.
78
n.d.
83
84
90
[a] Determined by GC-MS methods. [b] Determined by chiral GC methods using a chiral
stationary phase.
addition became the dominant reaction pathway and,
moreover, an enantioselectivity of 83% was detected
Table 11. Enantioselective 1,4 conjugate addition of Grignard reagents to various eny-
nones S20–24.
for adduct 7t. However, 1,2 and 1,6 addition also oc-
curred, lowering the isolated yield. The use of the
TMS-substituted enynone S13 gave a similar regiose-
lectivity to S12 with an enantioselectivity of 84%
(Table 10, entry 3). Finally, enynone S15, bearing
a very bulky TIPS substituent, allowed 1,4 addition
exclusively with high enantioselectivity (90%;
Table 10, entry 4).
Substrate
R
Prod.
Conv.
[%][a]
10/11[a]
Yield
[%]
ee 10
[%][b]
1
2
3
4
5
6
7
S20
S21
S22
S23
S24
S24
S24
S24
S24
S24
Et
Et
Et
Et
10a
10b
10c
10d
10e
10 f
10g
10g
10h
10i
100
100
100
100
100
100
100
100
100
100
100:0
100:0
100:0
100:0
100:0
100:0
33:47[d]
65:24[d]
100:0
100:0
60
75
73
68
81
65
n.d.
n.d.
80
79
83
87
77
87
93
89
90
85
90
In the first section of this paper, we described the
first catalytic 1,4 conjugate addition to trienones S8
and S9. The high regio- and enantioselectivity of this
reaction led us to examine the corresponding enynone
derivatives in detail. First, we synthesized a small li-
brary of substrates through a simple two-step proce-
dure. The corresponding aldehydes were converted
into the dibromodienes by using the Corey–Fuchs
methodology.[40] After treatment of the dibromodienes
with BuLi, followed by addition to S2, the desired
compounds S20–24 were obtained in good yield
(Scheme 6).
Et
But-3-enyl
Me
Me
Cy
8[c]
9
10
iPr
72
[a] Determined by GC-MS methods. [b] Determined by chiral GC methods using
a chiral stationary phase. [c] The solution was twice as diluted as under the standard re-
action conditions. [d] Side product could not be identified.
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Asymmetric Conjugate Addition Reactions
FULL PAPER
ty and an enantioselectivity of 77% (Table 11, entry 4). The
scope of the reaction with respect to the nucleophile was
then examined with substrate S24. The linear ethyl and bu-
tenyl Grignard reagents resulted in perfect regioselectivity
(Table 11, entries 5 and 6). The 3-butenyl Grignard achieved
a higher enantioselectivity of 93%. Secondary Grignard re-
agents also gave exclusively the 1,4 adducts with enantiose-
lectivities of 90 and 85% for iPrMgBr and CyMgBr, respec-
tively (Table 11, entries 9 and 10). Unfortunately, MeMgBr
remained problematic with a mixture of regioisomers being
detected and providing mainly the 1,6 adduct, although a sig-
nificant amount of the 1,4 adduct was produced (Table 11,
entry 7). Of the many unsuccessful attempts to direct the se-
lectivity in favor of the 1,4 addition reaction, modification
of the concentration afforded the best result in terms of re-
gioselectivity, with the 1,4 adduct being obtained as the
major regioisomer (Table 11, entry 8).
Scheme 9. Synthetic transformations of enol acetate 14.
More recently in our laboratory, we have developed the
in situ trapping of magnesium enolates with different elec-
trophiles (allyliodide, Br2, MeI, and benzaldehyde).[19c] Com-
pared with the methodology described above, this methodol-
ogy opens a straightforward route to an a-functionalized
product. We decided to apply this useful methodology in
our system and attempt to enlarge the scope of electrophiles
that can be utilized (Table 12).
Synthetic applications: Next, we focused on the develop-
ment of synthetic methods to demonstrate the value of our
methodology by using the olefinic and acetylenic appendag-
es of the 1,4 adduct. For example, adduct 2i was cyclized by
ring-closing metathesis (Scheme 7) to give spiro compound
12.
Table 12. In situ trapping of the magnesium enolate.
Scheme 7. Ring-closing metathesis on adduct 2i.
Alternatively, the remaining double bond on adduct 2j
was oxidatively cleaved to give ketoester 13 (Scheme 8). As
well as its synthetic versatility, this transformation allowed
us to determine the ee value of adduct 2j.
R
Product
Conv.
d.r.[a]
[%][a,b]
1
2
3
E1
E2
E3
19
20
21
92
95
82
83:17
82:18
87:13
[a] Determined by GC-MS methods. [b] The conversion was calculated
from the 1,4-addition adduct.
First, we investigated the electrophilic trapping with allyl
iodide (E1). The formation of a-alkylated product 19 pro-
ceeded at room temperature, in the presence of hexamethyl-
phosphoramide (HMPA, 10 equiv) and the electrophile
(2 equiv). A good diastereomeric ratio (d.r.) was detected,
however, a small amount (<5%) of the a’-alkylated product
was also detected. Unfortunately, it was not possible to sep-
arate this isomer from the a-alkylated diastereomeric mix-
ture. Subsequently, we explored the reactivity of benzyl bro-
mide (E2) and the TMS-protected propargylic bromide E3.
The reaction conditions gave the desired a-alkylated diaste-
reoisomers 20 and 21, respectively, and a small amount of
the a’-alkylated products were also detected. Moreover, in
all of these reactions, a small amount of the 1,4 adduct 7i
was recovered, highlighting the possible generation of
Scheme 8. Oxidative cleavage of adduct 2j (TMS=trimethylsilyl).
We also took advantage of the magnesium enolate inter-
mediate resulting from the 1,4 A.C.A. by trapping it with
Ac2O (Scheme 9). Enol acetate 14 was transformed into the
lithium enolate, which upon allylation gave a 3:1 ratio of
monoallylated adduct 15 (as a cis/trans mixture) and bisally-
lated 16. Both compounds 15 and 16 underwent a facile
ring-closing methathesis reaction to yield products 17 and
18, respectively. Although compound 15 was a mixture of
isomers, a single product, 17, was obtained; presumably the
one incorporating the cis ring junction.
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A. Alexakis, L. Guꢀnꢀe, M. Mauduit et al.
a proton source during the reaction. This observation could
explain the formation of the a’-alkylated products.
In addition, applications of the triple bond remaining in
products 7 were also developed. This functionality allowed
for many transformations, giving access to more com-
plex molecules. Our first experiment resulted in an
ene–yne methathesis/Diels–Alder/aromatization sequence
(Scheme 10). After deprotection of 7k with TBAF, com-
pound 7o was submitted to the Grubbs I catalyst in the
presence of an atmosphere of ethene.[41] Spirobicyclic com-
pound 22 was formed in 65% yield. This intermediate was
Scheme 12. Huisgen reaction with adduct 7p.
A crystalline product was obtained that enabled us to
solve the crystal structure and prove that the absolute con-
figuration of product 16 is (R) (Figure 3).
Scheme 10. Ene–yne metathesis/Diels–Alder/aromatization sequence
(TBAF=tetra-n-butylammonium fluoride, G-I=Grubbꢄs catalyst 1st
generation, DMAD=dimethyl acetylenedicarboxylate, DDQ=2,3-di-
chloro-5,6-dicyano-1,4-benzoquinone).
submitted to the Diels–Alder reaction by using dimethyl
acetylenedicarboxylate (DMAD) as the dienophile. Un-
fortunately, a 1:1 diastereomeric mixture was observed for
compound 23. This system was then easily rearomatized to
give compound 24 in a quantitative yield. No loss of enan-
tioselectivity was detected with compound 24 displaying an
enantioselectivity of 91%.
The synthesis of adduct 7o encouraged us to perform the
well-known Pauson–Khand reaction[42] by treating com-
pound 7o with cobalt octacarbonyl, followed by the addition
of N-methylmorpholine N-oxide (NMO) as an inducer of
decarbonylation.[43] We were glad to obtain tricyclic com-
pound 25 in a 1:1 diastereomeric ratio (Scheme 11).
Finally, we performed the cycloaddition of azide 26 and
keto–enyne 7o, namely, the Huisgen reaction[44]
(Scheme 12). The efficient methodology developed by
Sharpless et al.[45] that uses catalytic amounts of copper al-
lowed the formation of the triazole-substituted quaternary
stereogenic center in 27.
Figure 3. Single-crystal X-ray structure of compound 16. Thermal ellip-
soids shown at the 40% probability level.[46]
Mechanistic aspects: Our counterintuitive observations
prompted us to attempt to get a better understanding of the
mechanism of this reaction, which goes against the general
trend observed with copper reagents.[21] After further inves-
tigation, we proposed a catalytic cycle that could rationalize
the observed regioselectivity in the A.C.A. reaction to the
polyconjugated cyclic enones described in this article
(Figure 4). Our reaction conditions for the 1,4 A.C.A. reac-
tion to the polyconjugated cyclic enones involves the addi-
tion of the substrate as the last step. This observation means
that the hydroxy group of the NHC is deprotonated by the
Grignard reagent, leading to the formation of a transcient
complex A0, followed by the formation of the heterocuprate
complex (Figure 4). The recent characterization of a magne-
sium organocuprate complex by Davies et al.[47] derived
from Grignard reagents shows that they have a dimeric con-
tact-ion-pair (CIP) structure in weakly coordinating solvents,
such as Et2O. This group found that this species is isostruc-
tural with the previously reported lithium diphenyl cupra-
te.[1b,48] For this reason, we propose the dimeric heterocup-
rate A1 as the copper complex in this reaction. However,
the large excess of Grignard reagents cannot exclude that
Scheme 11. Pauson–Khand reaction of adduct 7o (NMO=N-methylmor-
pholine N-oxide).
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Asymmetric Conjugate Addition Reactions
FULL PAPER
tion of a b-cuprioACTHNUTRGNEUNG(III) enolate intermediate C (Figure 5). At
this point, two pathways can be envisaged with this species.
Complex C can reductively eliminate to afford the 1,4
adduct, enolate E (pathway I) or the heterocuprate complex
can migrate to the triple bond to form a new organocopper-
AHCTUNGTREG(NNNU III) intermediate D (pathway II), followed by reductive
elimination to afford the 1,6 adduct, enolate F. Both enolate
species E and F were transformed upon hydrolysis into the
corresponding 1,4 and 1,6 adducts, respectively.
The groups of Nakamura[49] and Krause[50] have been in-
volved in investigating the conjugate addition of organocop-
per reagents to polyconjugated carbonyls. Density functional
calculations have been performed to explain the reason
behind the formation of a remote conjugate addition prod-
uct in the reaction of a lithium organocuprate (R2CuLi) with
polyconjugated carbonyl compounds. Indeed, the calcula-
tions showed that the 1,4 reductive elimination of the b-
Figure 4. Carbenoid–metal complexes.
instead of having a heterocuprate complex, such as A1, this
reaction involves the presence of a high-order heterocuprate
A2. The formation of these two possible heterocuprates
complexes (A1 or A2) appeared to be beneficial for the re-
gioselectivity. Indeed, as described previously, when the
Grignard reagent is added last, the regioselectivity becomes
in favor of the 1,6 adduct. In this case, the addition of the
Grignard reagent to the reaction mixture would generate
a organocopper species, rather than a heterocuprate, which
might explain the 1,6 selectivity. We attempted to experi-
mentally observe complexes A1 or A2 through a 13C NMR
experiment in solution (see the Experimental Section) by
mixing the Grignard reagent in the presence of NHC L6
and (CuOTf)2·C6H6 (copper(I)). We observed a signal at
205 ppm, which probably corresponds to the chemical shift
of a carbenoid/magnesium A0 complex, and a signal at
201 ppm, corresponding to the chemical shift of heterocup-
rate complex A1 or A2. The carbon atom signal of the imida-
zolinium salt (160 ppm) was no longer observed due to total
deprotonation of the NHC by the Grignard and complete
complexation to the metal.
cuprioACTHNURTGNEU(GN III) intermediate is kinetically disfavored compared
with the migration to the C6 position. This could be ex-
plained by the disruption of conjugation if the reductive
elimination occurred at the C4 position. This observation
led them to postulate that the copper migration is the rate-
determining step. Moreover, the activation barrier for the
1,6 reductive elimination is lower than the activation barrier
for the 1,4 reductive elimination. In our case, the 1,4 addi-
tion trend observed with our catalytic system implies that
the 1,4 reductive elimination is faster than the migration to
form complex D. We postulate that the NHC L6/Cu com-
plex lowers the activation barrier of this 1,4 reductive-elimi-
nation step and thus disfavors the migration to the 1,6 posi-
tion. As demonstrated by the ligand screening, the structural
features of NHC L6 are very important for the outcome of
this reaction.
Presumably, the addition of the dienone to complex A led
to the formation of a p complex B followed by the genera-
Figure 5. Proposed catalytic cycle.
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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A. Alexakis, L. Guꢀnꢀe, M. Mauduit et al.
GC-MS using a Hewlett Packard (EI mode) HP6890–5973 spectrometer.
Optical rotations were measured at 208C in a 1 cm cell in the stated sol-
vent; [a]D values are given in 10À1 8cm2 gÀ1 (concentration c given as g
per 100 mL). Enantiomeric excesses were determined by chiral GC (ca-
pillary column, 10 psi H2). Temperature programs are described as fol-
lows: initial temperature [8C]—initial time [min]—temperature gradient
[8CminÀ1]—final temperature [8C]; retention times (RT) are given in min.
All Grignard reagents except ethyl and methyl magnesium bromide (Al-
drich) were synthesized in Et2O by addition of the corresponding bro-
mide to magnesium. Flash column chromatography was performed by
using silica gel (32–63 mm, 60 ꢅ). The syntheses of starting substrates are
described in the Supporting Information.
Conclusion
We have developed a highly regio- and enantioselective 1,4
conjugate addition of Grignard reagents to polyconjugated
cyclic enones. The exceptional and unusual 1,4 selectivity
corresponds to a conjugate addition at the most hindered
position, giving access to all-carbon quaternary stereogenic
centers with an excellent level of enantioselectivity (99%).
It is remarkable to note that experiments conducted with
phosphorus or simpler NHC ligands (Arduengoꢄs carbene)
and Grignard reagents gave exclusively the 1,6 addition,
whereas the use of our NHC L6, containing a chelating hy-
droxyl group, afforded the 1,4 adduct. For dienones, excel-
lent regioselectivities and enantioselectivities (up to 99%)
were obtained with primary and secondary Grignard re-
agents on S1. However, MeMgBr gave only 1,6 addition. It
seems that the natural trend for 1,6 addition and the prefer-
ence for the less substituted position are difficult to over-
come in this case. The methodology was successfully extend-
ed to trienones, displaying perfect 1,4 selectivity. We also
successfully applied our methodology to enynone deriva-
tives. Seven-membered rings displayed the best enantiose-
lectivity for this family of substrates (97%), reacting with
perfect regiocontrol, whereas five-membered rings gave low
regio- and enantioselectivity. By increasing the bulk of the 6
position, the addition of methyl Grignard reagents can be
exclusively directed to 1,4 adduct formation. The scope of
the reaction towards substrates with additional unsaturation
attached to the triple bond was also tested, demonstrating
an excellent level of regioselectivity with good enantioselec-
tivity.
Typical procedure for 1,4 addition reactions: A flame-dried Schlenk tube
was charged with copper salt (6.0 mol%) and the chiral ImH+ salt
(9.0 mol%). The system was flushed with N2 and dry CH2Cl2 (1.5 mL)
was added. The mixture was cooled to À108C in an ethanol cold bath.
The Grignard reagent (2 equiv) in Et2O was added dropwise to the solu-
tion over 5 min.
A solution of the dienone or enynone (0.5 mmol,
1 equiv) in CH2Cl2 (5 mL) was then added dropwise to the solution at
À108C over 15 min and the solution was stirred for 1 h. The reaction was
hydrolyzed at the reaction temperature by addition of NH4Cl (1m, 3 mL)
and the aqueous layer was separated and extracted further with CH2Cl2
(3ꢆ10 mL). The combined organic layers were dried with MgSO4, fil-
tered, and concentrated in vacuo to give an oily residue. The crude was
purified by flash column chromatography on a silica column with cylo-
hexane/EtOAc to give the pure product.
AHCTUNGTRENNUNG
(S,E)-3-Ethyl-3-(prop-1-enyl)cyclohexanone (2a): 1H NMR (100 MHz,
CDCl3): d=5.34 (dq, J1 =6.0, J2 =16.0 Hz, 1H), 5.15 (d, J=16 Hz, 1H),
2.46 (d, J=14.0 Hz, 1H), 2.33–2.16 (m, 2H), 2.12 (d, J=14.0 Hz, 1H),
1.84–1.76 (m, 1H), 1.69–1.61 (m, 6H), 1.37 (q, J=7.5, 2H), 0.78 ppm (t,
J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=212.0, 136.6, 125.3,
49.8, 44.2, 41.2, 35.2, 34.2, 21.8, 18.3, 7.9 ppm; HRMS (EI) calcd for
C11H18O: 166.1357 [M]+; found: 166.1360; [a]2D0 = +72.24 (c=1.4 in
CHCl3), 95% ee. The enantiomeric excess was determined on the hydro-
genated compound by GC analysis employing LIPODEX-E (75–40–1–
100): RT =36.88, RT =39.09 min.
1
2
AHCTUNGTRENNUNG
(S,E)-3-Butyl-3-(prop-1-enyl)cyclohexanone (2b): 1H NMR (300 MHz,
À
In terms of synthetic applications, the remaining C C
CDCl3): d=5.38–5.30 (m, 1H), 5.16 (d, J=16.5 Hz, 1H), 2.45 (d, J=
14.0 Hz, 1H), 2.32–2.18 (m, 2H), 2.13 (d, J=14.0 Hz, 1H), 1.84–1.75 (m,
2H), 1.70–1.60 (m, 5H), 1.34–1.10 (m, 6H), 0.87 ppm (t, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=212.0, 137.1, 124.9, 50.4, 44.0, 41.6, 41.2,
35.5, 25.7, 23.3, 21.8, 18.3, 14.1 ppm; HRMS (EI) calcd for C13H22O:
194.16706 [M]+; found: 194.1670; [a]D20 = +67.0 (c=1.34 in CHCl3),
97.4% ee. The enantiomeric excess was determined on the hydrogenated
double bond in the 1,4 adducts allowed useful transforma-
tions, such as ring-closing metathesis, affording interesting
bicyclic building blocks. We also took advantage of the for-
mation of a magnesium enolate intermediate and trapped it
with different electrophiles, allowing for the formation of
useful synthons. The acetylenic appendage was also useful
for synthetic transformations. Adduct 7p was cyclized by
ring-closing ene–yne metathesis and the Pauson–Khand re-
action. The Huisgen reaction was also applied to this useful
intermediate to confirm the absolute configuration of the
1,4 adducts. We also attempted to explain the selectivity out-
come of our reaction through the elaboration of a proposed
catalytic cycle highlighting reductive elimination as the rate-
determining step.
compound by GC analysis employing LIPODEX-E (75–40–1–100): RT
=
1
56.58, RT =57.78 min.
2
A
(2c):
1H NMR
(400 MHz, CDCl3): d=5.83–5.72 (m, 1H), 5.35 (dq, J1 =16.0 J2 =6.0 Hz,
1H), 5.18 (d, J=16.0 Hz, 1H), 5.30–4.90 (m, 2H), 2.50 (d, J=14.0 Hz,
1H), 2.34–2.19 (m, 2H), 2.15 (d, J=14.0 Hz, 1H), 1.99–1.92 (m, 2H),
1.84–1.78 (m, 2H), 1.77–1.61 (m, 6H), 1.45–1.30 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=211.7, 138.9, 136.5, 125.6, 114.4, 50.1, 44.0, 41.2,
41.0, 35.6, 28.0, 21.7, 18.3 ppm; HRMS (ESI+) calcd for C13H21O:
193.1586 [M+H]+; found: 193.1588; [a]D20 = +70.0 (c=0.955 in CHCl3),
>99% ee. The enantiomeric excess was determined on the hydrogenated
compound by GC analysis employing LIPODEX-E (75–40–1–100): RT
=
1
56.58, RT =57.78 min.
2
AHCTUNGTRENNUNG
(S,E)-3-Butyl-3-(prop-1-enyl)cyclohexanone (2e): 1H NMR (300 MHz,
Experimental Section
CDCl3): d=5.31 (dq, J1 =6.0, J2 =16.0 Hz, 1H), 5.11 (d, J=16.0 Hz, 1H),
2.50 (d, J=14.0 Hz, 1H), 2.34–2.19 (m, 2H), 2.15 (d, J=14.0 Hz, 1H),
1.99–1.92 (m, 2H), 1.84–1.78 (m, 2H), 1.77–1.61 (m, 6H), 1.45–1.30 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3): d=212.0, 137.5, 125.0, 51.4, 50.7,
44.6, 41.2, 36.3, 25.2, 25.1, 24.0, 21.7, 18.3 ppm; HRMS (EI) calcd for
C13H22O: 194.1671 [M]+; found: 194.1667; [a]2D0 = +61.2 (c=1.26 in
CHCl3), 98.7% ee. The enantiomeric excess was determined on the hy-
drogenated compound by GC analysis employing HYDRODEX B3-P
(70–50–1–120): RT =98.34, RT =98.94 min.
General procedures: All reactions were conducted under an inert atmos-
phere. Unless otherwise stated, all reagents were purchased from com-
mercial suppliers and used without further purification. All solvents em-
ployed in the reactions were dried on alumina columns and degassed
prior to use. Organic solutions were concentrated under reduced pressure
on a Bꢁchi rotary evaporator. 1H (400 MHz) and 13C (100 MHz) NMR
spectra were recorded in CDCl3, and chemical shifts (d) are given in ppm
relative to residual CHCl3. The evolution of the reaction was followed by
1
2
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ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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Asymmetric Conjugate Addition Reactions
FULL PAPER
A
(2 f):
1H NMR
tiomeric excess was determined on the hydrogenated compound by GC
(400 MHz, CDCl3): 5.32 (dq, J1 =6.0, J2 =16.0 Hz, 1H), 5.14 (d, J=
16.0 Hz, 1H), 2.49 (dt, J1 =2.0, J2 =14.0 Hz, 1H,), 2.31–2.24 (m, 1H),
2.19–2.12 (m, 1H), 2.11 (d, J=14.0 Hz, 1H), 1.85–1.62 (m, 7H), 1.54
(sept, J=6.8 Hz, 1H), 0.83 (d, J=2.8 Hz, 3H), 0.81 ppm (d, J=2.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=212.5, 134.2, 126.8, 47.6, 46.9, 41.2,
37.1, 33.6, 21.8, 18.5, 17.5, 17.0 ppm; HRMS (EI) calcd for C12H20O:
180.1514 [M]+; found: 180.1513; [a]D20 = +88.14 (c=1 in CH3Cl),
95.5% ee. The enantiomeric excess was determined by GC analysis em-
ploying LIPODEX-E (100–12): RT =8.31, RT =9.37 min.
analysis employing LIPODEX-E (80–25): RT =16.71, RT =19.87 min.
1
2
(S)-3-Ethyl-3-(prop-1-en-2-yl)cyclohexanone (2n): 1H NMR (400 MHz,
CDCl3): d=4.96 (s, 1H), 4.71 (s, 1H), 2.65 (d, J=14.4, 1H), 2.37–2.27
(m, 1H), 2.25–2.15 (m, 1H), 2.12 (d, J=14.4 Hz, 1H), 1.91–1.84 (m, 1H),
1.83–1.77 (m, 1H), 1.74–1.66 (m, 1H), 1.63 (s, 3H), 1.61–1.51 (m, 1H),
1.39–1.30 (m, 2H), 0.71 ppm (t, J=7.5 Hz, 3H); 13C NMR (101 MHz,
CDCl3): 211.8, 146.8, 114.6, 49.9, 47.3, 41.0, 33.9, 31.3, 21.4, 18.8, 7.7 ppm;
HRMS (EI) calcd for C11H18O: 166.1357 [M]+; found: 166.1357; [a]D20 = +
33.6 (c=1 in CH3Cl), 88% ee. The enantiomeric excess was determined
by GC on a chiral stationary phase (HYDRODEX B-6-TBDM column,
method: 60–0–1–170–5, 45 cmsÀ1): RT =53.78, RT =54.58 min.
1
2
A
(2g):
1H NMR
(400 MHz, CDCl3): d=5.28–5.23 (m, 1H), 5.14 (d, J=16.2 Hz, 1H), 2.49
(d, J=16.2 Hz, 1H), 2.29–2.24 (m, 1H), 2.19–2.11 (m, 2H), 1.84–1.61 (m,
11H), 1.24–1.10 (m, 5H), 0.94–0.84 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=212.5, 135.2, 126.4, 47.8, 47.5, 46.8, 41.3, 33.3, 27.3, 27.0, 26.9,
26.8, 26.6, 21.6, 18.4 ppm; HRMS (EI) calcd for C15H24O: 220.1826 [M]+;
found: 220.1827; [a]2D0 = +74.2 (c=1 in CH3Cl), 86% ee. The enantio-
meric excess was determined by GC on a chiral stationary phase (HY-
1
2
(S)-3-Ethyl-3-[(1E,3E)-4-phenylbuta-1,3-dien-1-yl]cyclohexenone (2o):
1H NMR (400 MHz, CDCl3): d=7.46–7.22 (m, 5H), 6.78 (dd, J=15.7,
10.2 Hz, 1H), 6.56 (d, J=15.7 Hz, 1H), 6.18 (dd, J=15.7, 10.2 Hz, 1H),
5.61 (d, J=15.7 Hz, 1H), 2.60 (d, J=14.1 Hz, 1H), 2.42–2.21 (m, 3H),
1.95–1.71 (m, 3H), 1.51 (q, J=7.3 Hz, 2H), 1.33–1.23 (m, 1H), 0.87 ppm
(t, J=7.4, 2.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=211.5, 140.3,
137.4, 131.5, 130.7, 129.1, 128.7, 127.4, 126.3, 49.7, 44.9, 41.3, 35.2, 34.3,
22.0, 8.1 ppm; HRMS (EI) calcd for C18H22O: 254.1671 [M]+; found:
254.1668; [a]2D0 = +21.4 (c=1 in CH3Cl), 95% ee. The enantiomeric
excess was determined by chiral SFC on a chiral stationary phase (Chiral-
DRODEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): R
=
T1
99.88, R =100.67 min.
T2
ACHTUNGTRENNUNG
(S,E)-3-Ethyl-3-(pent-1-enyl)cyclohexanone (2i): 1H NMR (300 MHz,
CDCl3): d=5.30 (td, J1 =6.5, J2 =16.0 Hz, 1H), 5.12 (d, J=16.0 Hz, 1H),
2.31–2.16 (m, 2H), 2.10 (d, J=14.0 Hz, 1H), 2.00–1.82 (m, 2H), 1.83–1.73
(m, 2H), 1.68–1.60 (m, 2H), 1.40–1.30 (m, 4H), 0.85 (t, J=7.5 Hz, 3H),
0.77 ppm (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): 212.0, 135.6,
130.9, 49.8, 44.2, 41.2, 35.3, 35.0, 34.3, 22.7, 21.8, 13.6, 7.9 ppm; HRMS
(ESI+) calcd for C13H23O: 195.1743 [M+H]+; found: 195.1749; [a]D20 = +
59.4 (c=0.745 in CHCl3), 93% ee. The enantiomeric excess was deter-
mined by GC analysis employing HYDRODEX-B-6TDM (80–1–150):
RT =45.20, RT =45.89 min.
cel AS column, method: MeOH 0%–2–1–15, 58C): RT =5.51, RT
=
1
2
5.88 min.
A
(2p):
1H NMR (400 MHz, CDCl3): d=6.13 (dd, J=15.5, 10.7 Hz, 1H), 5.77 (d,
J=10.4 Hz, 1H), 5.27 (d, J=15.6 Hz, 1H), 2.51 (d, J=14.1 Hz, 1H),
2.43–2.00 (m, 3H), 1.80 (d, J=4.6 Hz, 1H), 1.74 (d, J=3.8 Hz, 6H), 1.69
(d, J=5.6 Hz, 1H), 1.48–0.83 (m, 4H), 0.78 ppm (t, J=7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=211.8, 136.7, 134.6, 126.9, 125.0, 49.9,
44.8, 41.3, 35.3, 34.3, 26.1, 21.9, 18.5, 8.1 ppm; HRMS (EI) calcd for
C14H22O: 206.1671 [M]+; found: 206.1670; [a]D20 = +23.4 (c=1 in CH3Cl),
91% ee. The enantiomeric excess was determined by GC on a chiral sta-
tionary phase (HYDRODEX B-6-TBDM column, method: 60–0–1–170–
5, 45 cmsÀ1): RT =84.67, RT =85.27 min.
1
2
A
(2j):
1H NMR
(300 MHz, CDCl3): d=5.26 (dd, J1 =7.0, J2 =16.0 Hz, 1H), 5.07 (d, J=
16.0 Hz, 1H), 2.45 (d, J=14.0 Hz, 1H), 2.32–2.12 (m, 2H), 2.09 (d, J=
14.0 Hz, 1H), 1.98–1.84 (m, 1H), 1.83–1.73 (m, 2H), 1.72–1.58 (m, 7H),
1.36 (q, J=7.5 Hz, 2H), 1.43–0.96 (m, 5H), 0.76 ppm (t, J=7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): 211.9, 137.0, 132.7, 49.8, 43.9, 41.2, 41.1, 35.3,
34.2, 33.4, 33.3, 26.2, 26.1, 21.8 7.9 ppm; HRMS (ESI+) calcd for
C16H26ONa: 257.1875 [M+Na]+; found: 257.1869; [a]2D0 = +57.67 (c=1.09
in CHCl3), 92% ee. The enantiomeric excess was determined on the cor-
responding d-keto ester 13 by GC analysis employing LIPODEX-E (60–
1–110): RT =47.94, RT =49.31 min.
1
2
8a-Ethyl-3,4,6,7,8,8a-hexahydronaphthalen-2ACTHNUTRGNEUNG
(1H)-one (5b): 1H NMR
(400 MHz, CDCl3): d=5.68 (brs, 1H), 2.54–2.42 (m, 1H), 2.41–2.26 (m,
4H), 2.19 (dd, J1 =2.0, J2 =13.5 Hz, 1H), 2.08–1.92 (m, 2H), 1.77–1.66
(m, 1H), 1.64–1.20 (m, 5H), 0.77 ppm (t, J=7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=212.0, 139.1, 124.2, 53.2, 42.4, 40.8, 33.6, 31.4, 29.9,
25.7, 19.2, 7.7 ppm; HRMS (EI) calcd for C12H18O: 178.1356 [M]+;
found: 178.1358; [a]2D0 =À12.9 (c=1.29 in CHCl3), 96% ee. The enantio-
meric excess was determined on the hydrogenated compound by GC
1
2
ACHTUNGTRENNUNG
(S,E)-3-Ethyl-3-styrylcyclohexanone (2k): 1H NMR (400 MHz, CDCl3):
d=7.37–7.19 (m, 5H), 6.29 (d, J=16.5 Hz, 1H), 5.96 (d, J=16.5 Hz, 1H),
2.63 (d, J=14.2 Hz, 1H), 2.35–2.23 (m, 3H), 1.89–1.74 (m, 4H), 1.55–1.46
(m, 2H), 0.84 ppm (t, J=7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=
211.4, 137.3, 135.8, 130.0, 128.6, 127.3, 126.2, 49.7, 44.7, 41.2, 35.3, 34.2,
21.9, 8.1 ppm; HRMS (EI) calcd for C16H20O: 228.1514 [M]+; found:
228.1516; [a]2D0 = +53.4 (c=1 in CH3Cl), 94% ee. The enantiomeric
excess was determined by chiral SFC on a chiral stationary phase (Chiral-
analysis employing LIPODEX-E (80–1–120): R =29.73, R =32.57 min.
T1
T2
3-Ethyl-3-(hex-1-yn-1-yl)cyclohexanone (7a): 1H NMR (400 MHz,
CDCl3): d=2.50 (d, J=2.04 Hz, 1H), 2.39–2.23 (m, 1H), 2.20–2.00 (m,
5H), 1.99–1.80 (m, 2H), 1.50–1.30 (m, 7H), 1.00 (t, J=7.36 Hz, 3H),
0.87 ppm (t, J=7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=210.1,
85.0, 82.2, 52.8, 41.0, 40.8, 35.9, 35.1, 31.1, 22.8, 21.8, 18.3, 13.6, 8.8 ppm;
HRMS (EI) calcd for C14H22O: 229.1564 [M+Na]+; found: 229.1564;
[a]2D5 = +50.08 (c=1 in CHCl3), 82% ee. The enantiomeric excess was de-
termined by GC on a chiral stationary phase (HYDRODEX B-6-TBDM
column, method: 60–0–1–170–5, 45 cmsÀ1): RT =78.24, RT =78.98 min.
cel OJ column, method: MeOH 0%–2–1–15, 58C): RT =4.27, RT
=
1
2
5.08 min.
(S)-3-Ethyl-3-(2-methylprop-1-enyl)cyclohexanone
(2l):
1H NMR
(400 MHz, CDCl3): d=4.88 (s, 1H), 2.50 (d, J=13.5 Hz, 1H), 2.32–2.22
(m, 2H), 2.16 (d, J=13.5 Hz, 1H), 1.97–1.88 (m, 1H), 1.85–1.80 (m, 3H),
1.69 (s, 3H), 1.68 (s, 3H), 1.64–1.45 (m, 2H), 0.81 ppm (t, J=7.5 Hz,
3H); 13C NMR (101 MHz, CDCl3): d=212.2, 133.6, 128.3, 52.9, 44.4, 41.2,
35.7, 33.2, 28.3, 22.3, 19.1, 8.4 ppm; HRMS (EI) calcd for C12H20O:
180.1514 [M]+; found: 180.1515; [a]D20 = +57.6 (c=1 in CH3Cl), 88% ee.
The enantiomeric excess was determined by GC on a chiral stationary
phase (HYDRODEX B-6-TBDM column, method: 60–0–1–170–5,
45 cmsÀ1): RT =53.78, RT =54.58 min.
1
2
3-(But-3-en-1-yl)-3-(hex-1-yn-1-yl)cyclohexanone
(7b):
1H NMR
(500 MHz, CDCl3): d=5.83–5.79 (m, 1H), 5.00–4.93 (m, 2H), 2.45 (d, J=
13.55 Hz, 1H), 2.35 (m, 1H), 2.20–2.02 (m, 7H), 2.00–1.80 (m, 2H), 1.65–
1.50 (m, 3H), 1.45–1.30 (m, 4H), 0.88 ppm (t, J=7.25 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=209.7, 138.5, 114.6, 85.4, 82.0, 53.1, 41.6, 41.0, 40.2,
36.3, 31.1, 28.9, 22.7, 21.8, 18.3, 13.6 ppm; HRMS (EI) calcd for C16H24O:
255.1719 [M+Na]+; found: 255.1719; [a]D25 = +32.8 (c=1 in CHCl3),
95% ee. The enantiomeric excess was determined by GC on a chiral sta-
tionary phase (HYDRODEX B-6-TBDM column, method: 60–0–1–170–
5, 45 cmsÀ1): RT =95.99, RT =96.41 min.
1
2
(S)-3-Methyl-3-(2-methylprop-1-enyl)cyclohexanone
(2m): 1H NMR
(300 MHz, CDCl3): d=5.03 (s, 1H), 2.46 (d, J=13.5 Hz, 1H), 2.29–2.21
(m, 2H), 2.19 (d, J=13.5 Hz, 1H), 1.97–1.81 (m, 3H), 1.70 (d, J=1.0 Hz,
3H), 1.67 (d, J=1.0 Hz, 3H), 1.65–1.55 (m, 1H), 1.16 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=212.9, 133.2, 130.4, 55.2, 41.0, 40.5, 37.8,
28.1, 27.4, 22.6, 19.2 ppm; HRMS (EI) calcd for C11H18O: 166.1357 [M]+;
found: 166.1356; [a]2D0 = +48.16 (c=0.995 in CHCl3), 92% ee. The enan-
1
2
3-(Hex-1-yn-1-yl)-3-isopropylcyclohexanone (7c): 1H NMR (400 MHz,
CDCl3): 2.50 (d, J=2.04 Hz, 1H), 2.34–2.32 (m, 1H), 2.20–2.05 (m, 5H),
2.00–1.89 (m, 2H), 1.60–1.50 (m, 2H), 1.45–1.30 (m, 4H), 1.00 (m, 6H),
0.87 ppm (t, J=1.52 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=210.5,
85.8, 80.8, 51.0, 44.5, 40.9, 37.3, 33.9, 31.2, 22.8, 21.8, 18.3, 18.1, 17.7,
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
13
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These are not the final page numbers!

A. Alexakis, L. Guꢀnꢀe, M. Mauduit et al.
13.6 ppm; HRMS (EI) calcd for C15H24O: 243.3402 [M+Na]+; found:
243.3400; [a]2D5 = +56.8 (c=1 in CHCl3), 92% ee. The enantiomeric
excess was determined by GC on a chiral stationary phase (HYDRO-
9H); 13C NMR (100 MHz, CDCl3): 210.0, 108.5, 89.7, 50.4, 46.6, 44.7,
41.0, 33.3, 35.9, 27.7, 27.4, 26.6, 26.55, 26.4, 22.5, 0.2 ppm; HRMS (ESI)
calcd for C15H24OSi: 277.1982 [MÀH]; found: 277.1985; [a]2D0 = +19.1
(c=1 in CH3Cl), 96% ee. The enantiomeric excess was determined by
GC on a chiral stationary phase (Hydrodex B-3P, method: 60–0–1–170–5,
45 cmsÀ1): RT =96.05, RT =96.62 min.
DEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): RT =85.48,
1
RT =86.85 min.
2
3-(Hex-1-yn-1-yl)-3-isobutylcyclohexanone (7d): 1H NMR: (500 MHz,
CDCl3): 2.50 (d, J=1.9 Hz, 1H), 2.40–2.21 (m, 1H), 2.20–2.03 (m, 5H),
1.99–1.80 (m, 3H), 1.65–1.50 (m, 1H), 1.48–1.30 (m, 6H), 0.98–0.95 (m,
6H), 0.87 ppm (t, J=7.25 Hz, 3H); 13C NMR (100 MHz, CDCl3): 210.0,
85.1, 82.7, 53.8, 51.1, 40.9, 39.9, 37.0, 31.0, 24.9, 24.66, 24.62, 22.6, 21.8,
18.3, 13.6 ppm; HRMS (EI) calcd for C16H26O 257.1876 [M+Na]+;
found: 247.1876; [a]2D5 = +48.3 (c=1 in CHCl3), 95% ee. The enantiomer-
ic excess was determined by GC on a chiral stationary phase (HYDRO-
1
2
(R)-3-Isobutyl-3-(2-phenylethynyl)cyclohexanone
(7m):
1H NMR
(400 MHz, CDCl3): 7.41–7.25 (m, 5H), 2.63 (d, J=13.8 Hz, 1H), 2.42 (d,
J=13.8 Hz, 1H), 2.31–2.16 (m, 3H), 2.05–1.95 (m, 2H), 1.71–1.66 (m,
1H), 1.54–1.52 (m, 1H), 1.05–1.02 ppm (m, 6H); 13C NMR (100 MHz,
CDCl3): 131.6, 128.2, 127.9, 123.4, 92.6, 85.1, 53.4, 50.7, 41.0, 40.4, 36.9,
26.7, 25.1, 24.6, 24.5, 22.7 ppm; HRMS (EI) calcd for C18H22O: 254.1671
[M]+; found: 254.1673; [a]D20 = +51.7 (c=1 in CH3Cl), 94% ee. The enan-
tiomeric excess was determined by GC on a chiral stationary phase (HY-
DEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): RT =90.44,
1
RT =90.74 min.
DRODEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): RT
=
2
1
3-(3,3-Dimethylbut-1-yn-1-yl)-3-ethylcyclohexanone
(7 f):
1H NMR
111.10, RT =111.74 min.
2
(400 MHz, CDCl3): d=2.43–2.39 (m, 1H), 2.37–2.30 (m, 1H), 2.2–2.00
(m, 3H), 1.95–1.80 (m, 2H), 1.55–1.40 (m, 2H), 1.28–1.20 (m, 1H), 1.10
(s, 9H), 0.90 ppm (t, J=7.32 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
210.0, 94.1, 80.4, 52.8, 41.0, 40.5, 35.9, 35.0, 31.3, 27.3, 22.8, 8.8 ppm;
HRMS (EI) calcd for C14H22O: 229.1563 [M+Na]+; found: 229.1561;
[a]2D5 = +36.5 (c=1 in CHCl3), 79% ee. The enantiomeric excess was de-
termined by GC on a chiral stationary phase (HYDRODEX B-6-TBDM
column, method: 60–0–1–170–5, 45 cmsÀ1): RT =116.03, RT =116.50 min.
(R)-3-(But-3-enyl)-3-(2-phenylethynyl)cyclohexanone (7n): 1H NMR
(400 MHz, CDCl3): 7.38–7.35 (m, 2H), 7.28–7.27 (m, 3H), 5.82–5.81 (m,
1H), 5.05 (dd, 1H, J=13.6 Hz), 2.62 (d, J=13.6 Hz, 1H), 2.44–1.97 (m,
7H), 1.73–1.67 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): 138.3, 131.6,
128.3, 128.2, 123.2, 114.9, 91.7, 85.3, 52.8, 41.3, 41.0, 40.8, 36.2, 29.0, 27.0,
22.8 ppm; HRMS (EI) calcd for C18H20O: 251.1436 [MÀH]; found:
251.1433; [a]2D0 = +50.4 (c=1 in CH3Cl), 95% ee. The enantiomeric
excess was determined by SFC on a chiral stationary phase (Chiralcel
1
2
3-(3,3-Dimethylbut-1-yn-1-yl)-3-isopropylcyclohexanone (7g): 1H NMR
(500 MHz, CDCl3): d=2.43–2.39 (m, 1H), 2.37–2.30 (m, 1H), 2.20–2.10
(m, 2H), 2.09–2.00 (m, 1H), 1.98–1.85 (m, 2H), 1.65–1.55 (m, 1H), 1.52–
1.48 (m, 1H), 1.10 (s, 9H), 0.96 ppm (q, J=6.65 Hz, 6H); 13C NMR
(400 MHz, CDCl3): 210.4, 94.8, 79.1, 51.0, 44.1, 40.9, 37.1, 33.9, 31.3, 27.4,
22.7, 18.0, 17.6 ppm; HRMS (EI) calcd for C15H24O: 220.1827 [M]À;
found: 220.1830; [a]2D5 = +45.2 (c=1 in CH3Cl), 87% ee. The enantiomer-
ic excess was determined by GC on a chiral stationary phase (HYDRO-
OD column, method: MeOH 0%–2–1–15, 58C), RT =5.15, RT
5.67 min.
=
1
2
(R)-3-(But-3-enyl)-3-ethynylcyclohexanone (7o): 1H NMR (400 MHz,
CDCl3): d=5.85–5.75 (m, 1H), 5.05–4.93 (m, 2H), 2.50 (d, J=12.0 Hz,
1H), 2.39–2.34 (m, 1H), 2.26–2.18 (m, 5H), 2.13–2.05 (m, 1H), 1.98–1.92
(m, 2H), 1.64–1.56 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): 209.0,
138.0, 114.9, 86.3, 72.9, 52.6, 41.0, 40.9, 40.0, 35.8, 28.7, 22.5 ppm; HRMS
(EI) calcd for C12H16O: 176.1201 [M]+; found: 176.1189; [a]D20 = +26.4
(c=1 in CH3Cl). The enantiomeric excess was determined by GC on
a chiral stationary phase (HYDRODEX B-6-TBDM column, method:
60–0–1–170–5, 45 cmsÀ1): RT =66.22, RT =66.47 min.
DEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): RT =60.76,
1
RT =63.41 min.
2
3-(3,3-Dimethylbut-1-yn-1-yl)-3-isobutylcyclohexanone (7h): 1H NMR
(500 MHz, CDCl3): 2.40 (d, J=13.25 Hz, 1H), 2.36–2.33 (m, 1H), 2.23–
2.10 (m, 2H), 1.95–1.80 (m, 3H), 1.55–1.45 (m, 1H), 1.40–1.30 (m, 2H),
1.10 (s, 9H), 0.96 ppm (t, J=6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d=209.9, 93.9, 81.1, 53.8, 51.0, 40.9, 39.5, 37.0, 31.1, 31.0, 27.3, 24.9, 24.57,
24.56, 22.6 ppm; HRMS (EI) calcd for C16H26O: 257.1876 [M+Na]+;
found: 257.1879; [a]2D5 = +39.4 (c=1 in CH2Cl2), 93% ee. The enantio-
meric excess was determined by GC on a chiral stationary phase (HY-
1
2
(R)-3-(But-3-enyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)but-1-ynyl]cyclo-
hexanone (7p): 1H NMR (400 MHz, CDCl3): 5.87–5.77 (m, 1H), 5.05–
4.94 (m, 2H), 4.61 (s, 1H), 3.88–3.83 (m, 1H), 3.78–3.72 (m, 1H), 3.52–
3.44 (m, 2H), 2.48–2.35 (m, 3H), 2.24–2.04 (m, 5H), 1.95–1.90 (m, 2H),
1.85–1.78 (m, 1H), 1.73–1.47 ppm (m, 9H); 13C NMR (100 MHz, CDCl3):
209.5, 138.4, 114.6, 98.8, 83.1, 82.0, 66.1, 62.1, 53.0, 41.5, 41.0, 40.2, 36.2,
30.6, 28.9, 25.5, 22.7, 20.2, 19.4 ppm; HRMS (EI) calcd for C19H28O3:
324.4136 [M+Na]+; found: 324.4138; [a]D20 = +50.4 (c=1 in CH3Cl),
96% ee. The enantiomeric excess was determined on the deprotected al-
cohol by GC on a chiral stationary phase (HYDRODEX B-6-TBDM
column, method: 60–0–1–170–5, 45 cmsÀ1): RT =39.67, RT =40.39 min.
DRODEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): RT
=
1
68.92, RT =69.95 min.
2
3-Isobutyl-3-[(trimethylsilyl)ethynyl]cyclohexanone
(7j):
1H NMR
(400 MHz, CDCl3): d=2.50–2.40 (m, 1H). 2.39–2.30 (m, 1H), 2.20–2.10
(m, 2H), 2.09–2.00 (m, 1H), 1.95–1.80 (m, 3H), 1.60–1.50 (m, 1H), 1.45–
1.35 (m, 2H), 1.08–0.90 (m, 6H), 0.08 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): 209.2. 109.6, 88.9, 53.2, 50.3, 40.8, 40.4, 36.6, 24.9, 24.53, 24.50,
22.4, 0.1 ppm; HRMS (EI) calcd for C15H26OSi: 273.1645 [M+Na]+;
found: 273.1648; [a]2D5 = +40.4 (c=1 in CH3Cl), 95% ee. The enantiomer-
ic excess was determined by GC on a chiral stationary phase (HYDRO-
1
2
(R)-3-(But-3-enyl)-3-(hex-1-ynyl)cycloheptanone
(7q):
1H NMR
(400 MHz, CDCl3): d=5.86–5.76 (m, 1H), 5.04–4.93 (m, 2H), 2.63–2.58
(m, 4H), 2.23–2.14 (m, 4H), 1.96–1.82 (m, 4H), 1.51–1.34 (m, 8H),
0.89 ppm (t, 3H, J=7.3 Hz); 13C NMR (100 MHz, CDCl3): 212.4, 138.5,
114.5, 85.8, 82.4, 55.0, 43.8, 43.1, 42.6, 36.7, 31.2, 29.2, 26.5, 24.1, 22.0,
18.4, 13.6 ppm; HRMS (EI) calcd for C17H26O: 245.1905 [MÀH]; found:
245.1907; [a]2D0 = +84.0 (c=1 in CH3Cl), 97% ee. The enantiomeric
excess was determined by GC on a chiral stationary phase (HYDRO-
DEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): RT =72.12,
1
RT =72.80 min.
2
DEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): RT =96.45,
3-(But-3-enyl)-3-[2-(trimethylsilyl)ethynyl]cyclohexanone (7k): 1H NMR
(400 MHz, CDCl3): d=5.88–5.78 (m, 1H), 5.75–5.06 (m, 2H), 2.50 (d,
1H, J=12 Hz), 2.38–2.35 (d, 1H, J=12 Hz), 2.24–2.02 (m, 5H), 1.97–1.90
(m, 2H), 1.63–1.54 (m, 3H), 0.10 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): 209.0, 138.3, 114.7, 108.6, 89.2, 52.6, 40.9, 40.7, 35.9, 28.9, 22.5,
0.1 ppm; HRMS (EI) calcd for C15H24OSi: 247.1518 [MÀH]; found:
247.1517; [a]2D0 = +34.9 (c=1 in CH3Cl), 91% ee. The enantiomeric
excess was determined by GC on a chiral stationary phase (HYDRO-
1
RT =96.76 min.
2
(S)-3-(3,3-Dimethylbut-1-yn-1-yl)-3-methylcyclohexanone (7t): 1H NMR
(400 MHz, CDCl3): d=2.45–2.35 (m, 1H), 2.33–2.27 (m, 1H), 2.20–2.02
(m, 2H), 1.99–1.79 (m, 2H), 1.70–1.55 (m, 2H), 1.20 (s, 3H), 1.10 ppm (s,
9H); 13C NMR (100 MHz, CDCl3): 209.7, 92.6, 82.0, 54.7, 40.6, 38.0, 35.9,
31.3, 30.3, 29.7, 22.9 ppm; HRMS (EI) calcd for C13H20O: 215.2870
[M+Na]+; found: 215.2870; [a]D25 = +27.3 (c=1 in CHCl3), 83% ee. The
enantiomeric excess was determined by GC on a chiral stationary phase
(HYDRODEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1),
RT =41.53, RT =43.00 min.
DEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): RT =76.32,
1
RT =76.97 min.
2
(S)-3-Cyclohexyl-3-[2-(trimethylsilyl)ethynyl]cyclohexanone
(7l):
1
2
1H NMR (400 MHz, CDCl3): d=2.47 (d, 1H, J=12 Hz), 2.36 (d, 1H, J=
16 Hz), 2.21 (d, 1H, J=16 Hz), 2.09–2.05 (m, 2H), 1.96–1.91 (m, 2H),
1.86–1.77 (m, 4H), 1.67–1.53 (m, 3H), 1.27–1.10 (m, 6H), 0.11 ppm (s,
(S)-3-Methyl-3-[2-(triisopropylsilyl)ethynyl]cyclohexanone (7v): H NMR
(400 MHz, CDCl3): d=2.48 (d, J=13.7 Hz, 1H), 2.39–2.32 (m, 1H),
2.26–2.08 (m, 3H), 1.97–1.88 (m, 2H), 1.64–1.60 (m, 8.3 Hz, 1H), 1.32 (s,
1
&
14
&
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Conjugate Addition Reactions
FULL PAPER
3H), 1.08–0.93 ppm (m, 21H); 13C NMR (100 MHz, CDCl3): 208.9, 112.1,
83.1, 54.2, 40.5, 37.8, 37.0, 29.5, 22.8, 18.6, 11.1 ppm; HRMS (EI) calcd
for C18H32OSi: 292.2222 [M]+; found: 292.2225; [a]2D0 = +44.3 (c=1 in
CH3Cl), 90% ee. The enantiomeric excess was determined by GC on
a chiral stationary phase (HYDRODEX B-6-TBDM column, method:
60–0–1–170–5, 45 cmsÀ1): RT =98.97, RT =98.97 min.
(S)-1-(4-Methylpent-3-en-1-yn-1-yl)-[1,1’-bi(cyclohexan)]-3-one
(10h):
1H NMR (400 MHz, CDCl3): d=5.22 (s, 1H), 2.52 (d, J=13.4 Hz, 1H),
2.41–2.33 (m, 1H), 2.26 (d, J=13.4 Hz, 1H), 2.23–2.01 (m, 2H), 2.00–1.93
(m, 2H), 1.91–1.84 (m, 2H), 1.82 (s, 3H), 1.81–1.76 (m, 2H), 1.75 (s, 3H),
1.69–1.55 (m, 2H), 1.27–1.07 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=210.4, 147.6, 105.3, 93.3, 83.8, 50.9, 47.3, 44.9, 41.2, 33.8, 28.0, 27.7,
26.7, 26.6, 26.5, 24.8, 22.9, 21.0 ppm; HRMS (EI) calcd for C18H26O:
258.1984 [M]+; found: 258.1984; [a]D20 = +56.1 (c=1 in CH3Cl), 85% ee.
The enantiomeric excess was determined by chiral SFC on a chiral sta-
tionary phase (Chiralcel OD column, method: MeOH 0%–2–1–15, 58C,
RT =5.11, RT =5.57 min.
1
2
A
(10a):
1H NMR
(400 MHz, CDCl3): d=6.02 (dt, J=15.8, 7.0 Hz, 1H), 5.41 (dt, J=15.8,
1.6 Hz, 1H), 2.48 (dt, J=13.6, 1.8 Hz, 1H), 2.40–2.33 (m, 1H), 2.26–2.16
(m, 2H), 2.10–2.01 (m, 3H), 1.98–1.87 (m, 2H), 1.63–1.48 (m, 3H), 1.36–
1.23 (m, 4H), 0.99 (t, J=7.4 Hz, 3H), 0.87 ppm (t, J=7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=209.8, 144.3, 109.4, 90.1, 83.6, 52.5, 41.3,
41.1, 35.8, 34.9, 32.7, 30.9, 22.8, 22.3, 14.0, 9.0 ppm; [a]2D0 = +49.3 (c=1 in
CH3Cl), 79% ee. The enantiomeric excess was determined by GC on
a chiral stationary phase (LIPODEX-E column, method: 60–0–1–170–5,
45 cmsÀ1): RT =75.9, RT =77.01 min.
1
2
(S)-3-Isopropyl-3-(4-methylpent-3-en-1-ynyl)cyclohexanone
(10i):
1H NMR (400 MHz, CDCl3): d=5.22 (s, 1H), 2.53 (d, J=16 Hz, 1H),
2.39–2.35 (m, 1H), 2.25–2.09 (m, 3H), 1.99–1.94 (m, 2H), 1.82 (s, 3H),
1.76 (s, 3H), 1.72–1.55 (m, 2H), 1.03–0.98 ppm (m, 6H); 13C NMR
(100 MHz, CDCl3): d=210.2, 147.6, 105.2, 92.5, 83.7, 51.0, 45.3, 40.9, 37.4,
34.0, 24.7, 22.8, 20.9, 18.2, 17.85 ppm; HRMS (EI) calcd for C15H22O:
218.1671 [M]+; found: 218.1670; [a]D20 = +75.5 (c=1 in CH3Cl), 90% ee.
The enantiomeric excess was determined by GC on a chiral stationary
phase (HYDRODEX B-6-TBDM column, method: 60–0–1–170–5,
45 cmsÀ1): RT =91.59, RT =92.59 min.
1
2
A
(10b):
1H NMR (400 MHz, CDCl3): d=7.36–7.22 (m, 5H), 6.85 (d, J=16.3 Hz,
1H), 6.13 (d, J=16.2 Hz, 1H), 2.55 (dt, J=13.6, 1.9 Hz, 1H), 2.46–2.37
(m, 1H), 2.32–2.19 (m, 2H), 2.17–2.05 (m, 1H), 2.03–1.92 (m, 2H), 1.71–
1.53 (m, 3H), 1.05 ppm (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3):
d=209.7, 140.8, 136.5, 128.8, 128.5, 126.2, 108.3, 94.3, 84.1, 52.5, 41.7,
41.1, 35.8, 35.0, 22.9, 9.1 ppm; HRMS (EI) calcd for C18H20O: 252.1514
[M]+; found: 252.1514; [a]D20 = +55.7 (c=1 in CH3Cl), 83% ee. The enan-
tiomeric excess was determined by chiral SFC on a chiral stationary
1
2
(S)-SpiroACTHNUTRGNEUNG
[4.5]dec-1-en-7-one (12): 1H NMR (400 MHz, CDCl3): d=5.71–
5.69 (m, 1H), 5.56–5.54 (m, 1H), 2.39–2.30 (m, 5H), 2.23 (d, J=13.5 Hz,
1H), 1.97–1.77 (m, 3H), 1.69–1.62 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3): d=211.5, 137.6, 130.4, 53.8, 52.6, 41.3, 36.4, 35.2, 31.3, 23.6 ppm;
HRMS (EI) calcd for C10H14O: 150.1045 [M]+; found: 150.1044; [a]2D0
À49.5 (c=1.485 in CHCl3).
=
phase (Chiralcel AS column, method: MeOH 0%–2–1–15, 58C): R
=
T1
5.62, RT =6.29 min.
2
7a-Ethyl-3,3a,5,6,7,7a-hexahydroinden-4-one (17): 1H NMR (400 MHz,
CDCl3): d=5.72 (d, J=11.0 Hz, 1H), 5.51–5.44 (m, 1H), 2.60–2.51 (m,
2H), 2.48 (dd, J1 =2.0, J2 =18.0 Hz, 1H), 2.37–2.30 (m, 1H), 2.21 (d, J=
18.0 Hz, 1H), 2.11–1.93 (m, 3H), 1.65–1.58 (m, 1H), 1.38 (q, J=7.5 Hz,
2H), 0.88 ppm (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
216.1, 138.6, 127.1, 52.1, 46.5, 36.5, 36.1, 35.4, 34.1, 24.7, 8.2 ppm; HRMS
(EI) calcd for C11H16O: 164.1201 [M]+; found: 164.1202; [a]D20 = +53.19
(c=0.97 in CHCl3).
(S)-3-Ethyl-3-[(3E,5E)-hepta-3,5-dien-1-yn-1-yl]cyclohexenone
(10c):
1H NMR (400 MHz, CDCl3): d=6.32 (dd, J=15.6, 10.7 Hz, 1H), 5.97–
5.86 (m, 1H), 5.62 (td, J=13.7, 6.8 Hz, 1H), 5.30 (d, J=15.6 Hz, 1H),
2.41–2.31 (m, 1H), 2.25 (d, J=15.0 Hz, 1H), 2.15–2.05 (m, 3H), 1.86–1.78
(m, 2H), 1.63 (d, J=6.7 Hz, 3H), 1.49–1.39 (m, 3H), 0.88 ppm (t, J=
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=209.7, 141.6, 132.0, 131.0,
108.5, 93.5, 84.2, 52.4, 41.5, 41.0, 35.7, 34.9, 22.8, 18.4, 8.9 ppm; HRMS
(EI) calcd for C15H20O: 216.1514 [M]+; found: 216.1512; [a]D20 = +39.9
(c=1 in CH3Cl), 87% ee. The enantiomeric excess was determined by
GC on a chiral stationary phase (DEX CB column, method: 140–100,
45 cmsÀ1): RT =48.33, RT =49.32 min.
[4.5]dec-2-en-6-one (18): 1H NMR
ACHUTNGREN(NUG R,E)-10-Ethyl-10-(prop-1-enyl)spiroACHTUNGTRENNUGN
(400 MHz, CDCl3): d=5.60–5.57 (m, 1H), 5.50–5.46 (m, 1H), 5.39–5.31
(dq, J1 =6.5, J2 =16.0 Hz, 1H), 5.16 (dd, J1 =1.5, J2 =16.0 Hz, 1H), 3.05–
2.98 (m, 1H), 2.66–2.60 (m, 1H), 2.49 (dd, J1 =2.0, J2 =14.0 Hz, 1H), 2.32
(m, 1H), 2.26 (d, J=14.0 Hz, 1H), 2.00 (m, 1H), 1.77–1.60 (m, 8H), 1.33
(q, J=7.5, 2H), 0.77 ppm (t, J=7.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=216.1, 136.6, 128.9, 126.9, 125.1, 54.9, 47.5, 44.3, 42.5, 41.3,
35.4, 34.0, 32.4, 18.4, 8.0 ppm; HRMS (EI) calcd for C15H22O: 218.1671
[M]+; found: 218.1671; [a]D20 = +3.11 (c=1.57 in CHCl3).
1
2
(S)-3-Ethyl-3-(phenylbuta-1,3-diyn-1-yl)cyclohexenone (10d): 1H NMR
(400 MHz, CDCl3): d=7.50–7.27 (m, 1H), 2.57 (dt, J=13.9, 1.8 Hz, 1H),
2.48–2.37 (m, 1H), 2.31–2.19 (m, 1H), 2.16–1.93 (m, 1H), 1.74–1.54 (m,
1H), 1.05 ppm (t, J=7.5 Hz, 1H); 13C NMR (101 MHz, CDCl3): d=
208.8, 132.6, 129.1, 128.5, 128.4, 121.9, 86.1, 73.9, 69.1, 51.9, 41.8, 41.0,
35.5, 34.6, 22.7, 9.0 ppm; HRMS (EI) calcd for C18H18O: 250.1358 [M]+;
found: 250.1357; [a]2D0 = +56.2 (c=1 in CH3Cl), 77% ee. The enantiomer-
ic excess was determined by chiral SFC on a chiral stationary phase
(S)-2-Allyl-3-ethyl-3-[2-(trimethylsilyl)ethynyl]cyclohexanone
(19):
1H NMR (500 MHz, CDCl3) for the major diastereoisomer: d=5.96–5.75
(m, 1H), 5.05–4.91 (m, 2H), 2.66–2.56 (m, 1H), 2.42–2.36 (m, 1H), 2.28–
2.20 (m, 2H), 2.04–1.87 (m, 4H), 1.77–1.63 (m, 2H), 1.53 (m, 1H), 0.98
(t, J=7.4 Hz, 3H), 0.12 ppm (s, 9H);13C NMR (100 MHz, CDCl3): d=
209.9, 137.7, 115.3, 107.9, 89.4, 58.2, 45.4, 40.8, 33.9, 32.0, 29.7, 22.9, 8.7,
0.1 ppm; HRMS (EI) calcd for C16H26OSi: 262.1753 [M]+; found:
262.1753.
(Chiralcel AS column, method: MeOH 0%–2–1–15, 58C): RT =6.49,
1
RT =7.45 min.
2
(S)-3-Ethyl-3-(4-methylpent-3-en-1-yn-1-yl)cyclohexenone
(10e):
1H NMR (400 MHz, CDCl3): d=5.20 (s, 1H), 2.49 (d, J=13.6 Hz, 1H),
2.40–2.33 (m, 1H), 2.26–2.16 (m, 2H), 2.15–2.01 (m, 1H), 1.98–1.88 (m,
2H), 1.81 (s, 3H), 1.74 (s, 3H), 1.59–1.51 (m, 3H), 1.01 ppm (t, J=
7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=209.8, 147.8, 134.0, 105.1,
93.8, 82.9, 52.7, 41.6, 41.1, 35.9, 35.1, 24.8, 22.9, 20.9, 9.0 ppm; HRMS
(EI) calcd for C14H20O: 204.1514 [M]+; found: 204.1513; [a]D20 = +59.6
(c=1 in CH3Cl), 87% ee. The enantiomeric excess was determined by
GC on a chiral stationary phase (Hydrodex B-3P, method: 60–0–1–170–5,
45 cmsÀ1): RT =84.03, RT =84.67 min.
(S)-2-Benzyl-3-ethyl-3-[2-(trimethylsilyl)ethynyl]cyclohexanone
(20):
1H NMR (400 MHz, CDCl3) for the major diastereoisomer: d=7.27–7.10
(m, 5H), 3.30–3.21 (m, 1H), 2.76 (dd, J=14.3, 2.6 Hz, 1H), 2.51 (dd, J=
9.1, 2.5 Hz, 1H), 2.44–2.40 (m, 1H), 2.24–2.14 (m, 1H), 2.06–1.82 (m,
4H), 1.72–1.55 (m, 2H), 1.02 (t, J=7.4 Hz, 3H), 0.16 ppm (s, 9H);
13C NMR (100 MHz, CDCl3): d=209.3, 141.8, 129.1, 128.3, 125.8, 107.8,
89.7, 60.5, 46.1, 41.2, 34.4, 32.5, 30.8, 23.2, 8.8, 0.2 ppm; HRMS (EI) calcd
for C20H28OSi: 312.1909 [M]+; found: 312.1907.
1
2
(R)-3-(But-3-enyl)-3-(4-methylpent-3-en-1-ynyl)cyclohexanone
(10 f):
1H NMR (400 MHz, CDCl3): d=5.88–5.78 (m, 1H), 5.21 (s, 1H), 5.06–
4.94 (m, 2H), 2.52 (d, J=12 Hz, 1H), 2.40–2.35 (m, 1H), 2.27–2.19 (m,
4H), 2.16–2.07 (m, 1H), 1.99–1.93 (m, 2H), 1.82 (s, 3H), 1.76 (s, 3H),
1.66–1.59 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=209.4, 148.0,
138.4, 114.7, 105.0, 93.4, 83.1, 53.0, 41.5, 41.0, 40.9, 36.3, 29.0, 24.7, 22.8,
20.9 ppm; HRMS (EI) calcd for C16H22O: 230.1671 [M]+; found:
230.1659; [a]2D0 = +62.9 (c=1 in CH3Cl), 93% ee. The enantiomeric
excess was determined by GC on a chiral stationary phase (LIPODEX-E
column, method: 60–0–1–170–5, 45 cmsÀ1): RT =92.30, RT =92.89 min.
(S)-3-Ethyl-3-[2-(trimethylsilyl)ethynyl]-2-[3-(trimethylsilyl)prop-2-ynyl]-
1
cyclohexanone (21): H NMR (500 MHz, CDCl3) for the major diastereo-
isomer: d=2.96 (m, 1H), 2.53–2.50 (m, 1H), 2.46–2.42 (m, 1H), 2.35–
2.28 (m, 1H), 2.27–2.21 (m, 1H), 2.02–1.91 (m, 4H), 1.88–1.83 (m, 1H),
1.71–1.63 (m, 1H), 1.01 (t, J=7.4 Hz, 3H), 0.11 (s, 9H), 0.10 ppm (s,
9H); 13C NMR (100 MHz, CDCl3): 207.5, 107.1, 106.8, 90.2, 84.5, 57.7,
46.5, 41.0, 34.5, 32.5, 23.1, 15.6, 8.9, 0.1 ppm; HRMS (EI) calcd for
C19H32OSi2: 332.1991 [M]+; found: 332.1991.
1
2
Chem. Eur. J. 2012, 00, 0 – 0
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A. Alexakis, L. Guꢀnꢀe, M. Mauduit et al.
(R)-1-Vinylspiro
G
[3] a) C. Hawner, A. Alexakis, Chem. Commun. 2010, 46, 7295–7306;
b) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347, 1473–1482;
c) Quaternary Stereocenters (Eds.: J. Christoffers, A. Baro), Wiley-
VCH, Weinheim, 2006.
[4] E. Fillion, A. Wilsily, J. Am. Chem. Soc. 2006, 128, 2774–2775.
[5] A. Wilsily, E. Fillion, Org. Lett. 2008, 10, 2801–2804.
[6] A. Wilsily, E. Fillion, J. Org. Chem. 2009, 74, 8583–8594.
[7] J. Wu, D. M. Mampreian, A. H. Hoveyda, J. Am. Chem. Soc. 2005,
127, 4584–4585.
d=6.25–6.18 (dd, 1H, J1 =12.0, J2 =16.0 Hz), 5.79 (s, 1H), 5.44 (d, 1H,
J=16.0 Hz), 5.09 (d, J=12.0 Hz, 1H), 2.56 (d, J=16.0 Hz, 1H), 2.37–2.24
(m, 4H), 2.12–1.99 (m, 3H), 1.84–1.72 (m, 2H), 1.69–1.62 (m, 1H),
1.53 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=211.7, 146.9, 130.5,
128.2, 115.1, 53.8, 50.3, 41.3, 35.4, 34.4, 29.4, 23.3 ppm; HRMS (EI) calcd
for C12H16O: 176.1201 [M]+; found: 176.1200; [a]2D0 =À43.8 (c=1 in
CH3Cl).
(R)-Dimethyl-3-oxo-2’,3’-dihydrospiro(cyclohexane-1,1’-indene)-4’,5’-di-
carboxylate (24): 1H NMR (400 MHz, CDCl3): d=7.79 (d, J=8.0 Hz,
1H), 7.26 (d, J=8.0 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 2.95 (t, J=
7.3 Hz, 2H), 2.50 (d, J=13.8 Hz, 1H), 2.45–2.41 (m, 2H), 2.36 (d, J=
13.8 Hz, 1H), 2.10–2.03 (m, 2H), 1.97 (q, J1 =13.8, J2 =6.8 Hz, 2H), 1.91–
1.86 (m, 1H), 1.77–1.73 ppm (m, 1H); 13C NMR (100 MHz, CDCl3):
210.1, 169.0, 166.7, 154.3, 141.7, 131.3, 128.9, 127.9, 123.8, 52.6, 52.3, 52.2,
51.8, 41.2, 36.5, 35.5, 28.5, 22.9. HRMS (EI) calcd for C12H16O: 339.12029
[M+Na]+; found: 339.12010; [a]D20 =À25.2 (c=1 in CH3Cl); [a]2D0 =À25.6
(c=1 in CH3Cl), 92% ee. The enantiomeric excess was determined by
chiral SFC on a chiral stationary phase (Chiralcel AD column, method:
MeOH 0%–2–1–15, 58C): RT =10.30, RT =11.86 min.
[8] A. W. Hird, A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127, 14988–
14989.
[9] M. dꢄAugustin, L. Palais, A. Alexakis, Angew. Chem. 2005, 117,
1400–1402; Angew. Chem. Int. Ed. 2005, 44, 1376–1378.
[10] a) M. Vuagnoux-dꢄAugustin, A. Alexakis, Eur. J. Org. Chem. 2007,
5852–5860; b) M. Vuagnoux-dꢄAugustin, A. Alexakis, Chem. Eur. J.
2007, 13, 9647–9662.
[11] L. Palais, I. S. Mikhel, C. Bournaud, L. Micouin, C. A. Falciola, M.
Vuagnoux-dꢄAugustin, S. Rosset, G. Bernardinelli, A. Alexakis,
Angew. Chem. 2007, 119, 7606–7609; Angew. Chem. Int. Ed. 2007,
46, 7462–7465.
[12] M. Vuagnoux-dꢄAugustin, S. Kehrli, A. Alexakis, Synlett 2007, 2057–
2060.
ACHTUNGTRENNUNG(1R)-3a’,4’-Dihydro-2’H-spiro(cyclohexane-1,1’-pentalene)-3,5’ACHTUNGTERN(NUGN 3’H)-
dione (25): 1H NMR (400 MHz, CDCl3): d=5.90 (s, 1H), 5.80 (s, 1H),
3.05–3.03 (m, 2H), 2.63–2.56 (m, 2H), 2.50–2.28 (m, 8H), 2.19–2.04 (m,
5H), 2.01–1.78 (m, 11H), 1.26–1.16 ppm (m, 2H); 13C NMR (101 MHz,
CDCl3): d=210.35, 210.24, 209.54, 209.00, 194.58, 194.29, 124.60, 123.23,
52.07, 51.10, 46.83, 46.61, 45.14, 44.79, 42.71, 42.63, 41.01, 41.00, 39.46,
37.64, 36.17, 34.21, 29.46, 29.29, 23.78, 23.08 ppm; [a]2D0 =À22.5 (c=1 in
CH3Cl), 90% ee. The enantiomeric excess was determined by chiral GC
on a chiral stationary phase (LIPODEX-E column, method: 60–0–1–170–
20, 45 cmsÀ1): 1st diastereoisomer: RT =112.07, RT =113.88 min; 2nd dia-
[13] C. Hawner, K. Li, V. Cirriez, A. Alexakis, Angew. Chem. 2008, 120,
8334–8337; Angew. Chem. Int. Ed. 2008, 47, 8211–8214.
[14] a) D. Mꢁller, C. Hawner, M. Tissot, L. Palais, A. Alexakis, Synlett
2010, 1694–1698; b) D. Mꢁller, M. Tissot, A. Alexakis, Org. Lett.
2011, 13, 3040–3043; c) T. L. May, J. A. Dabrowski, A. H. Hoveyda,
J. Am. Chem. Soc. 2011, 133, 736–739.
[15] P. K. Fraser, S. Woodward, Tetrahedron Lett. 2001, 42, 2747–2750.
[16] a) F. Guillen, C. L. Winn, A. Alexakis, Tetrahedron: Asymmetry
2001, 12, 2083–2086; b) J. Pytkowicz, S. Roland, P. Mangeney, Tetra-
hedron: Asymmetry 2001, 12, 2087–2089; c) A. Alexakis, C. L.
Winn, F. Guillen, J. Pytkowicz, S. Roland, P. Mangeney, Adv. Synth.
Catal. 2003, 345, 345–348; d) C. L. Winn, F. Guillen, J. Pytkowicz, S.
Roland, P. Mangeney, A. Alexakis, J. Organomet. Chem. 2005, 690,
5672–5695.
1
2
stereoisomer: RT =115.56, RT =116.91 min.
1
2
(R)-3-[1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl]-3-(but-3-enyl)cyclohexa-
none (26): 1H NMR (500 MHz, DMSO): d=8.69 (s, 1H), 7.92 (d, J=
8.8 Hz, 2H), 7.84 (d, J=8.8 Hz, 2H), 5.80–5.75 (m, 1H), 5.00–4.91 (m,
2H), 2.84 (d, J=14 Hz, 1H), 2.59 (d, J=14 Hz, 1H), 2.43–2.30 (m, 1H),
2.28–2.25 (m, 2H), 2.06–2.01 (m ,1H), 1.93–1.73 (m, 5H), 1.67–1.62 ppm
(m, 1H); 13C NMR (126 MHz, DMSO): d=210.42, 153.57, 139.33, 136.82,
133.67, 122.63, 121.94, 121.18, 115.58, 51.07, 42.50, 41.14, 41.04, 34.75,
28.51, 22.19 ppm; [a]2D0 = +26.4 (c=1 in CH3Cl), 96% ee. The enantio-
meric excess was determined by chiral SFC on a chiral stationary phase
[17] K. S. Lee, M. K. Brown, A. W. Hird, A. H. Hoveyda, J. Am. Chem.
Soc. 2006, 128, 7182–7184.
[18] M. K. Brown, T. L. May, C. A. Baxter, A. H. Hoveyda, Angew.
Chem. 2007, 119, 1115–1118; Angew. Chem. Int. Ed. 2007, 46, 1097–
1100.
(Chiralcel AD column, method: MeOH 0%–2–1–15, 58C): RT =18.48,
1
[19] a) D. Martin, S. Kehrli, M. DꢄAugustin, H. Clavier, M. Mauduit, A.
Alexakis, J. Am. Chem. Soc. 2006, 128, 8416–8417; b) J. Wencel, M.
Mauduit, H. Hꢀnon, S. Kehrli, A. Alexakis, Aldrichimica Acta 2009,
42, 43–50; c) S. Kehrli, D. Martin, D. Rix, M. Mauduit, A. Alexakis,
Chem. Eur. J. 2010, 16, 9890–9904.
RT =19.71 min.
2
Acknowledgements
[20] F. Naef, P. Degen, G. Ohloff, Helv. Chim. Acta 1972, 55, 82–85.
[21] For a review, see: N. Krause, S. Thorand, Inorg. Chim. Acta 1999,
296, 1–11.
[22] Y. Yamamoto, S. Yamamoto, H. Yatagai, Y. Ishihara, K. Maruyama,
J. Org. Chem. 1982, 47, 119–126.
The authors thank the Swiss National Research Foundation (grant No.
200020–126663) and COST action D40 (SER contract No. C07.0097) for
financial support. We also thank Dr. Beth Ashbridge from Rockefeller
Research Laboratories for correction of the manuscript and fruitful dis-
cussions.
[23] For a review, see: A. G. Csꢇkꢈ, G. de La Herrꢇn, M. C. Murcia,
Chem. Soc. Rev. 2010, 39, 4080–4102.
[24] E. Fillion, A. Wilsily, E. T. Liao, Tetrahedron: Asymmetry 2006, 17,
2957–2959.
[25] T. den Hartog, S. R. Harutyunyan, D. Font, A. J. Minnaard, B. L.
Feringa, Angew. Chem. 2008, 120, 404–407; Angew. Chem. Int. Ed.
2008, 47, 398–401.
[26] J. Wencel-Delord, A. Alexakis, C. Crꢀvisy, M. Mauduit, Org. Lett.
2010, 12, 4335–4337.
[27] M. Tissot, D. Mꢁller, S. Belot, A. Alexakis, Org. Lett. 2010, 12,
2770–2773.
[28] a) H. Hꢀnon, M. Mauduit, A. Alexakis, Angew. Chem. 2008, 120,
9262–9264; Angew. Chem. Int. Ed. 2008, 47, 9122–9124; b) M.
Tissot, A. Pꢀrez Hernꢉndez, D. Mꢁller, M. Mauduit, A. Alexakis,
Org. Lett. 2011, 13, 1524–1527.
[1] For reviews on asymmetric conjugate additions, see: a) N. Krause,
A. Hoffmann-Rçder, Synthesis 2001, 0171–0196; b) Modern Orga-
nocopper Chemistry (Ed.: N. Krause), Wiley-VCH, Weinheim, 2002,
and references therein; c) A. Alexakis, C. Benhaim, Eur. J. Org.
Chem. 2002, 3221–3236; d) T. Hayashi, Acc. Chem. Res. 2000, 33,
354–362; e) T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829–
2844; f) J. Christoffers, G. Koripelly, A. Rosiak, M. Rçssle, Synthesis
2007, 1279–1300; g) A. Alexakis, J. E. Backvall, N. Krause, O.
Pamies, M. Dieguez, Chem. Rev. 2008, 108, 2796–2823; h) S. R. Har-
utyunyan, T. den Hartog, K. Geurts, A. J. Minnard, B. L. Feringa,
Chem. Rev. 2008, 108, 2824–2852.
[29] T. Hayashi, S. Yamamoto, N. Tokunaga, Angew. Chem. 2005, 117,
4296–4299; Angew. Chem. Int. Ed. 2005, 44, 4224–4227.
[30] Z. Jin, P. L. Fuchs, J. Am. Chem. Soc. 1994, 116, 5995–5996.
[2] a) A. Alexakis, S. Mutti, P. Mangeney, J. F. Normant, J. Am. Chem.
Soc. 1991, 113, 6332–6334; b) A. Alexakis, J. Frutos, P. Mangeney,
Tetrahedron: Asymmetry 1993, 4, 2427–2430.
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Asymmetric Conjugate Addition Reactions
FULL PAPER
[31] F. Rezgui, M. M. El Gaꢊed, Tetrahedron 1997, 53, 15711–15716.
[32] M. Toyota, Y. Asakawa, Phytochemistry 1992, 32, 137–140.
[33] M. Tori, T. Hamaguchi, K. Sagawa, M. Sono, Y. Asakawa, J. Org.
Chem. 1996, 61, 5362–5370.
[34] M. Hulce, Tetrahedron Lett. 1988, 29, 5851–5854.
[35] T. Hayashi, N. Tokunaga, K. Inoue, Org Lett. 2004, 6, 305–307.
[36] T. L. May, M. K. Brown, A. W. Hird, A. H. Hoveyda, Angew. Chem.
2008, 120, 7468–7472; Angew. Chem. Int. Ed. 2008, 47, 7358–7362.
[37] C. Spino, C. Beaulieu, J. Am. Chem. Soc. 1998, 120, 11832–11833.
[38] M. Shibuya, M. Tomizawa, Y. Iwabuchi, Org. Lett. 2008, 10, 4715–
4718.
[39] X. Fu, S. Zhang, J. Yin, T. L. McAllister, S. A. Jiang, C.-H. Tann,
T. K. Thiruvengadam, F. Zhang, Tetrahedron Lett. 2002, 43, 573–
576.
[40] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769–3772.
[41] M. Mori, N. Sakakibara, A. Kinoshita, J. Org. Chem. 1998, 63,
6082–6083.
[45] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew.
Chem. 2002, 114, 2708–2711; Angew. Chem. Int. Ed. 2002, 41, 2596–
2599.
[46] CCDC-866502 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[47] R. Bomparola, R. P. Davies, S. Hornauer, A. J. P. White, Angew.
Chem. 2008, 120, 5896–5899; Angew. Chem. Int. Ed. 2008, 47, 5812–
5815.
[48] N. P. Lorenzen, E. Weiss, Angew. Chem. 1990, 102, 322–324; Angew.
Chem. Int. Ed. Engl. 1990, 29, 300–302.
[49] S. Mori, M. Uerdingen, N. Krause, K. Morokuma, Angew. Chem.
2005, 117, 4795–4798; Angew. Chem. Int. Ed. 2005, 44, 4715–4719.
[50] a) N. Yoshikai, T. Yamashita, E. Nakamura, Angew. Chem. 2005,
117, 4799–4801; Angew. Chem. Int. Ed. 2005, 44, 4721–4723; b) N.
Yoshikai, T. Yamashita, E. Nakamura, Chem. Asian J. 2006, 1, 322–
330.
[42] P. L. Pauson, Tetrahedron 1985, 41, 5855–5860.
[43] S. Shambayani, W. E. Crowe, S. L. Schreiber, Tetrahedron Lett. 1990,
31, 5289–5292.
[44] R. Huisgen in 1,3-Dipolar Cycloaddition Chemistry (Ed.: A.
Padwa), Wiley, New York, 1984, pp. 1–176.
Received: February 15, 2012
Published online: && &&, 2012
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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A. Alexakis, L. Guꢀnꢀe, M. Mauduit et al.
Asymmetric Synthesis
M. Tissot, D. Poggiali, H. Hꢀnon,
D. Mꢁller, L. Guꢀnꢀe,* M. Mauduit,*
A. Alexakis* .................. &&&& — &&&&
Formation of Quaternary Stereogenic
Centers by NHC–Cu-Catalyzed Asym-
metric Conjugate Addition Reactions
with Grignard Reagents on Polycon-
jugated Cyclic Enones
Along came poly: The copper-cata-
lyzed conjugate addition of Grignard
reagents to polyconjugated cyclic
enones allows for the formation of all-
carbon chiral quaternary centers (see
scheme). An N-heterocyclic carbene
(NHC) acts as an efficient chiral
ligand for this transformation. High
enantioselectivities (up to 99%) and
regioselectivities (1,4 selectivity) were
obtained for a broad range of sub-
strates and nucleophiles.
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