Mechanistic investigations into the enantioselective Conia-ene reaction catalyzed by cinchona-derived amino urea pre-catalysts and CuI

Article abstract of DOI:10.1002/chem.201200832

The enantioselective Coniaene cyclization of alkyne-tethered β-ketoesters is efficiently catalyzed by the combination of cinchona-derived amino-urea pre-catalysts and copper(I) salts. The reaction scope is broad and a series of substrates can be efficiently cyclized with high yields and enantioselectivities. Herein, we present a detailed mechanistic study based on experimental considerations and quantum mechanical calculations. Several variables, such as the nature of the organic pre-catalyst and the metal-ion source, have been thoroughly investigated. Kinetic studies, as well as kinetic isotope effects and deuterium labeling experiments have been used to gain further insights into the mechanism and prove the cooperative nature of the catalytic system. Our studies suggest that the rate-limiting step for the reaction involves the β-ketoester deprotonation and that the active species responsible for the enantiodeterming step is monomeric in amino-urea pre-catalyst. Computational studies provide a quantitative understanding of the observed stereoinduction and identify hydrogen bonding from the urea group as a crucial factor in determining the observed enantioselectivity.

Full text of DOI:10.1002/chem.201200832

FULL PAPER
DOI: 10.1002/chem.201200832
Mechanistic Investigations into the Enantioselective Conia-Ene Reaction
Catalyzed by Cinchona-Derived Amino Urea Pre-Catalysts and CuI
Filippo Sladojevich,[a] ꢀngel L. Fuentes de Arriba,[b] Irene Ortꢁn,[a] Ting Yang,[c]
Alessandro Ferrali,[d] Robert S. Paton,*[a] and Darren J. Dixon*[a]
Abstract: The enantioselective Conia-
ene cyclization of alkyne-tethered b-
ketoesters is efficiently catalyzed by
the combination of cinchona-derived
amino-urea pre-catalysts and copper(I)
salts. The reaction scope is broad and a
series of substrates can be efficiently
cyclized with high yields and enantiose-
lectivities. Herein, we present a de-
tailed mechanistic study based on ex-
perimental considerations and quantum
mechanical calculations. Several varia-
bles, such as the nature of the organic
pre-catalyst and the metal-ion source,
have been thoroughly investigated. Ki-
netic studies, as well as kinetic isotope
effects and deuterium labeling experi-
ments have been used to gain further
insights into the mechanism and prove
the cooperative nature of the catalytic
system. Our studies suggest that the
rate-limiting step for the reaction in-
volves the b-ketoester deprotonation
and that the active species responsible
for the enantiodeterming step is mono-
meric in amino-urea pre-catalyst. Com-
putational studies provide a quantita-
tive understanding of the observed
stereoinduction and identify hydrogen
bonding from the urea group as a cru-
cial factor in determining the observed
enantioselectivity.
Keywords: asymmetric catalysis
·
cinchona alkaloids · Conia-ene re-
action · quantum mechanical calcu-
lations · reaction mechanism
Introduction
bining organocatalytic activation (such as enamine activa-
tion or acid/base activation) with transition-metal-ion-cata-
lyzed processes. We reasoned that cinchona-derived struc-
tures, such as 1a–d[1d,3] could perform, in combination with
different transition-metal ions, as cooperative catalytic sys-
tems (Figure 1).
Cooperative catalysis is a powerful tool in asymmetric syn-
thesis, allowing access to new chemical reactivity and pro-
viding high stereocontrol in a wide range of reactions.
Through mutual activation and organization of reagents, this
concept has been applied widely to reactions of nucleophilic
and electrophilic species, by the combination of (Lewis/
Brønsted) acids and bases distributed around a chiral scaf-
fold.[1] A thriving research area in the field of cooperative
catalysis has emerged, in which organocatalysts and transi-
tion-metal ions are combined.[2] This combination presents
the opportunity to explore new reaction pathways by com-
[a] Dr. F. Sladojevich, Dr. I. Ortꢀn, Dr. R. S. Paton, Prof. D. J. Dixon
Chemistry Research Laboratory, Department of Chemistry
University of Oxford
Figure 1. Pseudoenantiomeric cinchona-derived potential pre-catalysts
1a–d.
Mansfield Road, Oxford, OX1 3TA (U.K.)
E-mail: robert.paton@chem.ox.ac.uk
darren.dixon@chem.ox.ac.uk
Since bifunctional catalysts 1a–d are effective in promot-
ing nucleophilic addition of active methylene compounds,[1d]
we hypothesized that 1a–d could be effective in generating
enolates of b-ketoesters and we postulated that such eno-
lates, in the presence of appropriate metal ions, would ex-
hibit reactivity towards an alkyne functionality. We recently
examined the asymmetric Conia-ene reaction of b-keto-
[b] ꢁ. L. Fuentes de Arriba
Organic Chemistry Department
University of Salamanca
Plaza de los Caꢀdos 1-5, Salamanca, 37008 (Spain.)
[c] Dr. T. Yang
GlaxoSmithKline (China) R&D
Building No. 3, 898 Halei Road Zhangjiang Hi-tech Park,
Pudong Shanghai 201203 (China.)
AHCTUNGTRENNUNG
esters as a platform for this cooperative catalysis concept.[4]
[d] Dr. A. Ferrali
We demonstrated that the combination of 1b and
CuOTf·1/2 C6H6 is an effective catalytic system for the enan-
tioselective cyclization of alkyne-linked b-ketoesters and b-
ketoamides.[5] Notably, this new catalytic system represents
Enantia S.L.
C/Baldiri Reixac, 1008028 Barcelona (Spain.)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200832.
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

one of the few examples able to promote the carbocycliza-
tion at room temperature. Intrigued by this new reactivity,
we decided to start further studies to prove the cooperativity
of the catalytic system and gain a better picture of the acti-
vation mode. We believed that the knowledge gained could
be insightful for future research projects in the field of
asymmetric cooperative catalysis.
Herein, we report a detailed mechanistic study based on
various experimental and computational data. In particular,
we elucidate the effect of the pre-catalystꢃs structure on the
reaction rate and enantioselectivity and elucidate the effects
of the urea hydrogen-bonding capability on acceleration of
the reaction rate. A kinetic study, kinetic isotope effects,
nonlinear and titration studies are used to gain insight into
the mechanism and demonstrate the cooperativity of the
new catalytic system and to identify the rate-determining
step. Finally, computational studies contribute to elucidate
the mechanistic steps and origin of enantioselectivity from a
qualitative and quantitative point of view.
Interestingly, the enantioselectivity was not influenced by
the nature of the counteranion, which suggested that in all
cases the same, highly organized stereodetermining transi-
tion structure is formed, independent of the counteranion.
When CuCN was used, the reaction rate decreased consider-
ably but the enantiomeric excess of the product was 91%,
which suggested that the rate-determining step differs from
the enantiodetermining step (the carbocyclization). It is im-
portant to note that the cyclization of 2a in the presence of
CuOTf·1/2 C6H6 yields the desired product 3a with the same
enantioselectivity and yield as CuCl, CuBr or CuI and each
salt can be used indifferently. CuOTf·1/2 C6H6 was selected as
the copper source in subsequent studies (even though it dis-
played a slightly diminished reaction rate relative to CuCl
and CuBr) to allow direct comparisons with earlier results
obtained using the same copper source.
Pre-catalyst screen: A substantial screen of pre-catalysts
was carried out (Table 2) to gain further mechanistic insights
and identify structure–activity relationships.
Different hydrogen-bond donors were compared. Ureas
1b and 1d–l were found to be the most effective pre-cata-
lysts but amides 1m–q were also moderately effective in
promoting the carbocyclization of substrate 2a to afford 3a
with appreciable levels of enantioselectivity, although with
decreased reaction rate. Sulphonamide 1r was found to be a
poor pre-catalyst, giving rise to only traces of product after
24 h. Also thiourea 1a and pseudoenantiomeric 1c were not
active, presumably due to strong ligation of the copper cata-
lyst by the sulphur atom of the thiourea group. Different
substituents on the urea aromatic ring were also investigat-
ed. When the series of para-substituted ureas 1g–l was con-
sidered, it was clear that electron-withdrawing groups have
a remarkable effect in accelerating the reaction: p-OMe-
substituted urea 1i gave 26% conversion after 1 day, where-
as urea 1l, bearing a p-nitro group, gave rise to 87% conver-
sion in the same amount of time. These results strongly sug-
Results and Discussion
Initially, the influence of various metal sources, pre-catalysts
and solvents on the reaction outcome was investigated and
the reaction scope surveyed by using the optimal conditions
identified.
Metal screening: A metal screen was carried out on the
easily synthesized substrate 2a (Table 1). Different transi-
Table 1. Screening of metal sources.
Entry
N
t [h]
Conv. [%]
ee [%]
1
2
3
4
5
6
7
8
9
(PPh3)]/AgOTf
18
18
18
18
18
18
18
18
18
0
0
–
–
+6
À30
+92
+92
+92
+92
+91
A
31
68
82
99
98
94
11
(dppe)]
CuOTf·1/2 C6H6
CuCl
À
gest that the acidity of the urea N H bonds is correlated
with reactivity. Finally, the relative stereochemistry at C-8
and C-9 was investigated. For this purpose urea 1s, with in-
verted stereochemistry at C-9 (with respect to 1b), was pre-
pared.[6] Notably, pre-catalyst 1s gave rise to lower conver-
sion and enantioselectivity, proving that the relative orienta-
tion of the bridgehead nitrogen atom and the urea is essen-
tial for the high levels of enantioselectivity and reactivity
observed, consistent with a cooperative mode of action.
tion-metal salts were screened in conjunction with pre-cata-
lyst 1b in dichloromethane. Conversions were measured
after 18 h by H NMR spectroscopy. To our surprise, [AuCl-
1
ACHTUNGTRENNUNG
A
Solvent effect: The influence of solvents on the reaction out-
come was also studied. Dichloromethane was confirmed as
the ideal solvent from a point of view of reactivity and enan-
tioselectivity. Nevertheless, the reaction was tolerant to the
nature of the solvent, showing identical conversion and a
small erosion in enantioselectivity when performed in tol-
uene. A polar protic solvent, such as MeOH, could also be
used without any loss in enantioselectivity, albeit at a lower
reaction rate (Table 3).
CTHUNGTRENNUNG
phenylphosphino)ethane) furnished the enantiomeric prod-
uct in 68% conversion and in 30% ee (entry 4). Pleasingly,
CuOTf·1/2 C6H6 gave 92% ee with 82% conversion (entry 5).
Once copper(I) was identified as the metal ion of choice, a
wide range of copper sources was tested in the reaction.
Similar reactivity was observed with different copper(I) salts
(entries 5–8).
&
2
&
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Conia-Ene Reaction
Table 2. Screening of pre-catalysts.
FULL PAPER
it was used as the solvent, presumably due to quenching of
the metal ion Lewis acidity resulting from complexation of
the highly coordinating DMSO.[7] Alternatively, DMSO
might interfere with the urea hydrogen-bonding capability.[8]
Substrate scope: With optimal reactivity and enantiocontrol
established, the scope of the reaction was surveyed by using
20 mol% of either pre-catalyst 1b or pseudoenantiomeric
1d and 5 mol% of CuOTf·1/2 C6H6 in dichloromethane at
room temperature. A range of pentynyl b-ketoesters incor-
porating significant structural and electronic diversity to
both the ester and ketone group was investigated and the re-
sults are presented in Table 4.
The reaction was general for aliphatic and (electron-rich
or -poor) aromatic b-ketoester substrates. The steric demand
of the ester group had little effect on the reaction enantiose-
lectivity (Table 4, entries 1–3). Similarly, aryl amides were
also good substrates in the process (entry 18). Reaction
times reflected in part the acidity of the substrates with the
fastest finishing after one day and slowest after 10 days.
Enantiomeric excesses ranged from 79–93% with the high-
est arising from aryl ketone substrates. The substitution of
1b for pseudoenantiomeric pre-catalyst 1d in the cyclization
reaction of 2a afforded (S)-3a in good yield and enantiocon-
trol (entry 19, 92% yield, 89% ee); 2o yielded (S)-3o in an
improved yield but with a slightly diminished ee of 74%
(entry 20 vs. 15). Single-crystal X-ray analysis on 3k and a
spirocyclic derivative of 3o, as well as chemical correlation
studies on 3p established the R configuration of these com-
pounds when pre-catalyst 1b was employed;[4a] the rest were
assigned by analogy. Aromatic b-ketoesters presenting sub-
stitution of the terminal alkyne position (with aromatic or
aliphatic substituents) were found to be unreactive under
the reported reaction conditions. A similar outcome was ob-
served when b-ketoesters giving rise to six- or seven-mem-
bered rings were used. b-Diketones giving rise to five-mem-
bered rings were found to be suitable substrates and were
cyclized under the reported reaction conditions but in mod-
erate enantiomeric excess. For example 2-(pentynyl)-1-phe-
nylbutane-1,3-dione was cyclized completely (98% conver-
sion after two days) under optimal reaction conditions in
45% ee.
Entry
Pre-catalyst
t [h]
Conv. [%]
ee [%]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
0
98
0
–
92
–
92
86
80
39
31
26
58
50
87
2
À89
93
83
81
84
80
85
82
94
61
68
–
9
10
11
12
13
14
15
16
17
18
19
20
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
3
2
3
2
37
53
–
traces
46
25
À5
81
Stereochemical outcome of deuterated substrates: Further
mechanistic insight was gained by repeating the reaction
with monodeuterated substrate 4.
Table 3. Solvent effects.
At low conversion,[9] the predominant monodeuterated
product was (E)-7. This is consistent with the intermediacy
of a ligated copper enolate that undergoes an enantioselec-
tive syn-carbocupration followed by a final protodemetalla-
tion step as shown in Scheme 1.[5b]
Entry
Solvent
t [h]
Conv. [%]
ee [%]
1
2
3
4
CH2Cl2
toluene
MeOH
DMSO
24
24
24
24
98
98
51
0
92
88
93
–
Kinetic measurements: Kinetic profiles were determined at
different copper and pre-catalyst loadings. Conversion was
measured by 1H NMR spectroscopy after 16 h in CD2Cl2.
First, the amount of CuOTf·1/2 C6H6 was fixed at 5 mol%
and a series of reactions were performed whilst the loading
Highly coordinating DMSO was found to be incompatible
with the catalytic system and no product was observed when
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

R. S. Paton, D. J. Dixon et al.
Table 4. Scope of the catalytic asymmetric Conia-ene reaction.
investigated using the initial
rates method (Figure 4). The
rate dependence on the concen-
tration of copper ions was stud-
ied at a fixed concentration of
pre-catalyst 1b of 0.02m
(20 mol% with respect to b-ke-
toester 2a) by varying the per-
centage of CuOTf·1/2 C6H6 in
the region of 0.64–4.00 mol%.
Inhibition due to copper ions
was less pronounced in this
concentration range, as shown
in Figure 2. The reaction order
with respect to CuOTf·1/2 C6H6
was found to be 0.36, confirm-
ing that a series of equilibria is
involved in the reaction mecha-
nism. The reaction order with
respect to pre-catalyst 1b was
studied at a fixed concentration
of CuOTf·1/2 C6H6 (0.005m) in a
5 mol% ratio with respect to b-
ketoester 2a. The reaction
Entry
Product
R1
R2
Pre-cat.
t [days]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3e
(R)-3 f
(R)-3g
(R)-3h
(R)-3i
(R)-3j
(R)-3k
(R)-3l
(R)-3m
(R)-3n
(R)-3o
(R)-3p
(R)-3q
(R)-3r
(S)-3a
(S)-3o
Ph
Ph
Ph
OMe
OEt
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1d
1d
1.5
1.5
1.5
3
2
1
10
1.5
4
1
1
1
1
2
1.5
1.5
3.5
5
2
2
98
82
95
97
99
67
91
96
74
77
87
83
89
84
85
67
77
85
92
90
92
91
89
92
92
87
91
93
92
89
93
92
89
91
83
80
79
OBn
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
3-MeO-C6H4
4-F-C6H4
2-F-C6H4
4-Br-C6H4
3,4-di-Cl-C6H3
4-Ph-C6H4
2-naphthyl
Me
9
10
11
12
13
14
15
16
17
18
19
20
Me
Et
Ph
OMe
OBn
OMe
NHPh
Ph
83
À89
OEt
Me
À74
Scheme 1. Reaction outcome with deuterated substrate 4.
of the pre-catalyst 1b was varied (Figure 2). Next the
amount of pre-catalyst 1b was fixed at 20 mol% and the
CuOTf·1/2 C6H6 was varied in the range of 0–40 mol%.
Interestingly, on increasing the copper loading (above
5 mol%), the reaction rate decreased. We hypothesize that
at high copper loading the basic sites of the pre-catalyst are
preferentially ligated to the metal ion and, therefore, pre-
catalyst 1b is not able to act as a Brønsted base in the de-
protonation of the b-ketoester. Increasing the loading of
pre-catalyst 1b at a fixed 5 mol% of CuOTf·1/2 C6H6 gave
rise to a linear increase in the reaction rate in the range of
5–30 mol% (grey diamonds in Figure 2). Next, the order of
reaction with respect to each of the components was stud-
ied. The reaction was found to be first order in the substrate
Figure 2. Conversion as a function of loading of CuOTf·1/2 C6H6 and pre-
catalyst 1b.
order with respect to pre-catalyst 1b was found to be 1 in
the range of concentration 0.00967–0.0392m (10 to 40 mol%
with respect to b-ketoester 2a). To establish the rate-deter-
mining step in the reaction, kinetic isotope measurements
were considered. Mono- and bis-deuterated substrates 8 and
9 (Figure 5) were tested under the standard reaction condi-
tions (0.1m, 20 mol% of pre-catalyst 1b and 5 mol% of
CuOTf·1/2 C6H6). Here it should be pointed out that deuteri-
as illustrated in Figure 3. With lnACTHNUGTRNEUNG[2a] plotted against time, a
linear relation is clearly shown, typical of a first-order kinet-
ic profile with respect to the substrate. The order of reaction
with respect to CuOTf·1/2 C6H6 and pre-catalyst 1b was then
À
um scrambling is observed between the Ca H of the ke-
toester and the alkyne C–D, so the use of a doubly deuterat-
&
4
&
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Conia-Ene Reaction
FULL PAPER
Figure 3. Substrate reaction order.
ed substrate was envisaged to establish whether or not the
carbon–carbon bond-forming step was rate-determining.
When mono-deuterated substrate 8 was used, a primary
kinetic isotope effect was observed in the initial rate
(kH/kD=3.9). When doubly deuterated substrate 9 was used,
a primary kinetic isotopic effect was also observed (kH/kD =
4.5), which suggested that the rate-determining step is not
the carbocyclization step. This is further supported by the
fact that no correlation between enantioselectivity and reac-
tion rate is observed. For example, for all the points of the
graphic in Figure 2, the product is always formed with a con-
stant enantiomeric excess of 92%. The observed kinetic iso-
tope effect suggests that the rate-determining step involves
the breaking of a bond to hydrogen. In this case, two possi-
ble scenarios emerge: 1) the rate-determining step is the de-
Figure 4. Reaction order for CuOTf·1/2 C6H6 and pre-catalyst 1b.
ured for the virgin starting material 2a and then for the re-
covered 2a after the reaction was run for 48 h (97% conver-
sion). An enrichment in 13C for a given carbon atom of the
recovered starting material indicates that the carbon atom is
involved in a bond that is broken in the rate-limiting step.
The ratio of integrals between recovered 2a and virgin 2a
(as the average of three runs) is reported in Scheme 2. A
pronounced kinetic isotope effect (1.043) was observed for
the Ca atom of recovered b-ketoester 2a in comparison to
all other carbon atoms (Scheme 2).
To gain further insight into the deprotonation event, the
rate of substrate racemization was also monitored. Initially,
(+)- and (À)-2a were treated separately with pre-catalyst
1b (in the absence of a copper salt) and the specific rota-
tion, [a]D, was measured as a function of time. As shown in
À
protonation of the Ca H bond of b-ketoester 2a or 2) the
rate-determining step is a protonation event occurring after
À
the C C bond formation; in this case the kinetic isotope
À
effect would be related to the breaking of a N D bond of
the protonated bridgehead ammonium enolate formed after
the initial deprotonation of the b-ketoester. To discern be-
tween these two possibilities, we measured the carbon iso-
tope effect employing Singletonꢃs NMR spectroscopic tech-
nique at natural abundance.[10] 13C NMR spectra were meas-
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

R. S. Paton, D. J. Dixon et al.
Figure 6. A) Racemization rate of (+)- and (À)-2a in the presence of
pre-catalyst 1b. B) Racemization rate of (À)-2a in the presence of pre-
catalyst 1b and in the presence of pre-catalyst 1b and CuOTf·1/2 C6H6.
Figure 5. Kinetic isotopic effect for substrates 8 and 9.
(Figure 7A). This idealized system was designed to gain fur-
ther insight into the role of the tertiary amine and the urea
moieties and has been used to understand if the urea is play-
ing an active role or if the active catalytic site on pre-cata-
lyst 1b is only the tertiary amine. Figure 7A shows the reac-
tion conversion at
a
fixed amount of 5 mol% of
Scheme 2. Natural abundance 13C kinetic isotope effect measured at 97%
conversion.
CuOTf·1/2 C6H6 and 20 mol% of organic base (either quinu-
clidine or BEMP), when the loading of ureas 12 or 13 is
varied in the range of 0–50 mol%. This clearly illustrates
that cyclic urea 13 is completely inactive in catalyzing the
À
Figure 6A, the rates of racemization of enantiomeric b-ke-
toesters, (+)- and (À)-2a in the presence of 1b were essen-
tially the same: both substrates were fully racemized within
7 h, forming the same product mixture with 1b. This demon-
strates that enolization by the pre-catalyst in the absence of
Cu is rapid on the timescale of the reaction (typically 24–
48 h). Figure 6B shows the change in specific rotation in the
presence of CuI, with and without the addition of pre-cata-
lyst 1b. Racemization was not observed unless both CuI and
pre-catalyst were present.
reaction, whereas urea 12, with two N H protons capable of
forming hydrogen-bonding interactions, increases the reac-
tion rate upon an increase in loading. A second point that
emerges is that conversion in the presence of BEMP is
much higher than in the presence of quinuclidine. This data
is in good agreement with the difference in pKBH+ between
the two bases[11] and in support of a rate-determining enoli-
zation step. We then looked at the conversion when urea 12
and CuOTf·1/2 C6H6 were fixed at 20 and 5 mol%, respec-
tively, and the amount of BEMP was varied in the range of
0–50 mol% (Figure 7B).
The measured primary D/H and 13C/12C KIEs both indi-
À
cate that the RDS involves breaking the a-C H bond. In
In the absence of base (0 mol% of BEMP) no reaction is
observed and this data is in agreement with the cooperative
nature of the catalytic system, in which both a urea and an
organic base are required for the reaction to occur. Interest-
ingly, when the base loading is higher than the loading of
urea 12, a decrease in the reaction rate is observed. One
possible hypothesis is that deleterious complexation of CuI
with excess BEMP lowers the amount of reactive copper in
the reaction mixture.[12]
the presence of CuI, this suggests that formation of the Cu-
enolate is rate-limiting. Enolization of substrate by pre-cata-
lyst 1b is competitive and does not require CuI; however,
this is unproductive and does not lead to cyclization.
Pre-catalyst role: To further understand the role of pre-cata-
lyst 1b in the reaction mixture, we decided to replace 1b
with a combination of an organic base (either quinuclidine
or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diazaphosphorine (BEMP)) and model urea 12 or 13
The graphics in Figure 7 demonstrate that the observed
rate acceleration due to amino-urea 1b is not simply a
&
6
&
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Conia-Ene Reaction
FULL PAPER
Figure 8. Nonlinear effect between ee of pre-catalyst 1t and ee of product
3a in CH2Cl2 and MeOH.
ciation of the pre-catalyst into diastereomeric aggregated
species in solution. Given the formation of precipitates in
the reaction mixture (especially when CH2Cl2 is used as the
solvent), two sets of experiments were performed, using
either CH2Cl2 or MeOH.
Figure 8 shows that a linear correlation is observed when
MeOH is used as the solvent, whereas a slight positive non-
linear relationship between the two enantiomeric values is
obtained using CH2Cl2. This suggests that the active catalytic
species responsible for asymmetric induction is monomeric;
however, the nonlinear effect observed in CH2Cl2 is most
likely due to solubility effects,[15] which are particularly ac-
centuated in the chlorinated solvent (when catalyst 1t was
mixed with an equimolar amount of its enantiomer in
CH2Cl2 the formation of a crystalline precipitate is clearly
observed).
Figure 7. A) Conversion studies at different loadings of ureas 12 and 13
in the presence of BEMP or quinuclidine. B) Conversion studies at differ-
ent loadings of BEMP in the presence of 20 mol% of urea 12.
ligand effect on the Cu: when pre-catalyst 1b is ꢄsplitꢃ into
two separate chemical entities the presence of both urea
and basic functional groups are essential in maintaining cat-
alytic activity, which suggests that pre-catalyst 1b is promot-
ing enolization by acting as a Brønsted base and as a hydro-
gen-bond donor.
Modeling studies: To aid in the interpretation of our experi-
mental studies and to shed light on the origins of enantiose-
lectivity, we performed quantum chemical calculations by
using DFT with Gaussian 09.[16] The M06-2X meta-hybrid
GGA density functional[17] was used for geometry optimiza-
tion and, along with B3LYP,[18] for single-point energy calcu-
lations. The M06-2X functional was chosen in this study as it
has been parameterized to treat dispersion interactions, that
are entirely absent from the (older) hybrid GGA function-
als.[19] Such non-covalent interactions are expected to be im-
portant for asymmetric induction,[20] barrier heights and re-
action energies over an uncorrected hybrid GGA functional,
such as B3LYP.
Origins of enantioselectivity: Further experiments were re-
quired to gain a better understanding of the enantio-deter-
mining step and an investigation of possible nonlinear ef-
fects[13] was performed. The enantiomer of pre-catalyst 1b
was not readily available. Therefore, we performed these ex-
periments with pre-catalyst 1t,[14] easily available in both
enantiomeric forms. The ee value of product 3a was studied
as a function of the ee value of pre-catalyst 1t (Figure 8). A
linear correlation would imply that the chiral species re-
sponsible for asymmetric induction is monomeric in the
enantio-determining step. In contrast, a nonlinear relation-
ship implies that the active chiral catalyst is formed by asso-
Restricted Kohn–Sham DFT calculations were used
throughout.[21] For all geometry optimizations the Pople all-
electron 6-31G(d) double-z valence basis set was employed
for C, H, N, O and F atoms in combination with the Hay
Wadt LANL2DZ effective core potential[22] (ECP) and
double-z valence basis for Cu. A larger 6-311+GACHTUNGTRENNUNG(d,p)
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

R. S. Paton, D. J. Dixon et al.
triple-z valence basis set and LANL2TZ(f) ECP plus triple-
z valence basis combination was used for single-point
energy calculations.[23] An ultrafine (99,590) grid containing
99 radial shells and 590 angular points per shell was used for
the numerical integration in the calculation of single-point
energetics.[24] Stationary points were verified as minima
(zero imaginary frequencies) or transition structures (a
single imaginary frequency) with harmonic frequency calcu-
lations at the same level of theory as optimizations, and
Gibbs free energies were computed at 298 K after shifting
very low frequencies below 50 cmÀ1 to a value of 50 cmÀ1 to
prevent spuriously large vibrational entropic terms. Due to
the insensitivity of conversion and enantioselectivity with re-
spect to the solvent observed in our experiments, optimiza-
tions were performed in the gas phase; however, the effects
of solvation have been included through single-point energy
calculations with a CPCM model by using UAKS radii.[25]
Where applicable, all possible efforts were made to find the
lowest-energy conformations by performing geometry opti-
mizations from different starting points. Natural bond orbi-
tal (NBO) calculations were performed with NBO 3.1[26] and
Wiberg bond orders computed.[27]
Figure 9. Top: Optimized M062X/6-31G(d) structures of lowest-energy
À
competing TSs for C C bond formation of 2a catalyzed by a simplified
version of 1b (H atoms are omitted for clarity). ZPE-inclusive M062X/6-
31G(d) relative energies, with M062X/6-311+GACTHNUTRGNE(NUG d,p) in parentheses,
To gain a qualitative and quantitative understanding of
the observed stereoinduction we modeled competing stereo-
shown in kcalmolÀ1. Bottom: Wiberg bond orders and distances (ꢅ) for
key interactions in the TSs and for a simplified model.
À
determining C C bond-forming transition structures (TSs)
by using quantum chemical calculations. The nature and ge-
ometry of this TS were established by performing calcula-
tions on a model system: a syn-carbocupration TS in which
observed stereoselectivity of deuterium incorporation in
Scheme 1. Pre-catalyst coordination to CuI occurs through
the quinuclidine nitrogen atom, leaving the urea group to
hydrogen bond with one of the oxygen atoms. Coordination
of the urea oxygen to Cu is disfavored by ca. 13 kcalmolÀ1,
and other H-bonding modes were calculated; however, the
pre-catalyst scaffold evidently favours the mode shown in
Figure 9. The optimized TS geometries for enolate Re and
Si face attack show the former is favored by 1.3 kcalmolÀ1,
in accord with experiment in which this is the major enan-
tiomer in 92% ee (the M062X/6-31G(d) computed ee from
competing Boltzmann factors is 82%).
One marked structural difference between the diastereo-
meric TSs that could account for the facial selectivity is the
lack of any ester O–Cu interaction in the disfavored TS. The
metal plays a dual role in the Conia-ene TS: to coordinate
strongly to the charged b-dicarbonyl enolate while also acti-
vating the h2-coordinated alkyne. It is the former of these
two roles that differs between the Re and Si TS. Relative to
a trimethylamine: a CuI model system lacking any hydro-
gen-bonding contributions, the effect of the two H-bonding
interactions formed between the urea group and one of the
oxygen atoms is to weaken the strength of the correspond-
ing O–Cu interaction. This is evident from bond distances
and calculated bond orders (BOs) in Figure 9, in which rela-
tive to a model TS, the ketone O–Cu interaction lengthens
by 0.13 ꢅ and loses 0.05 in terms of BO in the major TS,
and the ester O–Cu interaction effectively disappears in the
minor TS. The strength of hydrogen-bonding interactions is
very similar for the two TSs, as judged by O–H distances
and computed BOs, and serves to compensate for the loss of
À
the two C O bonds are aligned was computed to be ener-
getically preferred over isomeric Cu enolates and alternative
mechanisms involving hydrogen-transfer to the terminal
alkyne from an enol nucleophile (Figure S1). Models were
also considered in which the Cu counterion (chloride) was
still present in the carbocylization step; however, the com-
À
puted activation free-energy barrier of C C bond formation
is around 10 kcalmolÀ1 higher than for a Cu/amine complex
(see Figure S2 in the Supportig Information) and thus these
other models were discounted. We thus focussed on the
computational description of the carbocyclization step
shown in Figure 9. In our model, a simplified structure lack-
ing the olefin substituent on the quinuclidine was used to
describe the pre-catalyst 1b. This modelling assumption is
justified by the similar ee (with opposite sign) obtained
when using pseudoenantiomeric pre-catalyst 1d, differing
only in the positioning of the vinyl substituent. For substrate
2a and model pre-catalyst 1b, we performed a number of
optimizations starting from different geometries of the pre-
catalyst with respect to the cyclic core of the TS. This search
process yielded eight unique conformations (four enolate Re
face attack, four enolate Si face) from which the lowest-
energy and thus most important diastereomeric pair, making
up 87% of the conformer distribution at 298 K, are shown
below in Figure 9.
The low-energy TSs are both characterized by a six-mem-
bered cyclic TS in which the alkyne and enolate are both co-
ordinated to CuI. The syn-carbometallation across the
alkyne of these models is consistent with the experimentally
&
8
&
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Conia-Ene Reaction
FULL PAPER
À
Cu O bonding. However, critically in the major TS urea co-
ordination occurs at the more electron-rich ketone oxygen,
which is able to remain bound to Cu, whereas in the minor
TS the ester oxygen atom is unable to do both and sacrifices
Cu coordination to engage in hydrogen bonding. Further
calculations on the model of pre-catalyst 1b with a substrate
possessing an aliphatic ketone (c.f. Table 4, methyl ketones
3o, 3p, and ethyl ketone 3q) yield a computed selectivity of
93% in favour of Re-face attack, in accord with experiment
(79–83% ee). Pre-catalyst 1t gives comparable selectivity in
experiment (81% ee) and the computed selectivity again is
in good agreement, albeit slightly overestimated, at 95% ee.
Competing transition structures are shown below in
Figure 10. A common mode of stereoinduction is seen for
Scheme 3. Proposed catalytic cycle.
is involved in two distinct roles: ligating to the CuI and pro-
moting enolization and subsequent formation of a reactive
copper enolate that undergoes syn-carbocupration. The for-
mation of a 1:1 [Cu]/[pre-catalyst] complex is supported by
nonlinear studies (see Figure 8). Background enolization in-
volving 1b without Cu is possible, but ultimately unproduc-
tive. Cu is certainly present in the rate-limiting enolization
step (since the order with respect to Cu is non-zero), which
is then followed by syn-carbocupration, a cyclization mecha-
nism supported by deuterium labeling and predicted by
DFT studies to be the lowest energy pathway. Ligation of
1b to the Cu-enolate imparts asymmetry in the stereode-
À
terming C C bond-forming step. Computed relative ener-
getics for the diasteromeric transition structures are in good
agreement with observed levels of enantioselectivity. Final
protodemetallation furnishes the cyclized product 8 and re-
generates pre-catalyst 1b. The urea group of the pre-catalyst
plays a key role through hydrogen-bonding interactions with
the oxygen atom of the enolized ketone, which provides ad-
ditional organization to discriminate the diastereomeric
transition structures.
Figure 10. Optimized M062X/6-31G(d) structures of lowest-energy com-
À
peting TSs for C C bond formation (H atoms are omitted for clarity) of
3o catalyzed by simplified 1b (top) and of 3a catalyzed by 1t (bottom).
ZPE-inclusive M062X/6-31G(d) relative energies, with M062X/6-311+G-
ACHTUNGTRENNUNG
(d,p) in parentheses, shown in kcalmolÀ1, distances in (ꢅ).
all of the substrates and pre-catalysts studied computational-
ly: in enolate Si-face attack the ester carbonyl O–Cu inter-
action is lost at the expense of two hydrogen bonds to the
urea of the pre-catalyst, whereas the major pathway pre-
serves both of these stabilizing interactions.
Experimental Section
General procedure for Conia-ene cyclizations: The b-ketoester or b-ke-
toamide 2a–r (0.2 mmol) was added to a solution of CuOTf·1/2 C6H6
(2.5 mg, 0.01 mmol) and 1a–t (22 mg, 0.04 mmol) in dry CH2Cl2 (2 mL).
The mixture was stirred at room temperature until complete consump-
tion of the b-ketoester or b-ketoamide was indicated by TLC analysis.
The solvent was then removed under reduced pressure and the crude
product obtained was purified by flash column chromatography.
Conclusion
On the basis of the experimental evidence and computation-
al modeling described above, we propose the catalytic cycle
shown in Scheme 3, in which the amino urea pre-catalyst 1b
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!

R. S. Paton, D. J. Dixon et al.
[6] See the Supporting Information for details.
Acknowledgements
[7] For selected examples of the DMSO effect in transition-metal catal-
ysis, see: a) K. K. Spektor, G. L. Starova, Y. M. Skripkin, L. V. Ste-
pakova, Russ. J. Gen. Chem. 2011, 81, 1772–1777; <lit b>M. S.
Chen, M. C. White, J. Am. Chem. Soc. 2004, 126, 1346–1347.
[8] For example, DMSO titration experiments are used to estimate the
strength of hydrogen-bonding in solution: a) T. P. Pitner, D. W. Urry,
J. Am. Chem. Soc. 1972, 94, 1399–1400; b) M. Iqbal, P. Balaram, J.
Am. Chem. Soc. 1981, 103, 5548–5552; c) P. A. Raj, P. Balaram, Bio-
polymers 1985, 24, 1131–1146.
We thank the EPSRC (Leadership Fellowship to D.J.D., postdoctoral fel-
lowships to F.S.), the Oxford University Press John Fell fund (R.S.P.) the
European Community (IEF to F.S. (PIEF-GA-2009-254068)), the Spanish
Ministerio de Educaciꢆn (MEC) for a FPU and a summer stay fellowship
to A.L.F.A. We are grateful to T. Claridge and B. Odell of the Depart-
ment of Chemistry, University of Oxford, for essential and precious assis-
tance with the use of NMR spectroscopy for kinetic measurements and
data interpretation. We acknowledge the use of the EPSRC UK National
Service for Computational Chemistry Software (NSCCS) at Imperial Col-
lege London and contributions from its staff in carrying out this work.
[9] The reaction was quenched and analyzed after 3 h (25% conversion,
E/Z 94:6) to minimize the extent of CuI-promoted H/D exchange
processes in 4 prior to cyclization.
[10] a) D. A. Singleton, A. A. Thomas, J. Am. Chem. Soc. 1995, 117,
9357–9358; b) K.-H. Kwon, D. W. Lee, C. S. Yi, Organometallics
2010, 29, 5748–5750; c) Y. Wu, R. P. Singh, L. Deng, J. Am. Chem.
Soc. 2011, 133, 12458–12461.
[1] a) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–5743;
b) M. Shibasaki, M. Kanai, S. Matsunaga, N. Kumagai, Acc. Chem.
Res. 2009, 42, 1117–1127; c) S. Matsunaga, M. Shibasaki, Bull.
Chem. Soc., Jpn. 2008, 81, 60–75; d) R. M. Haak, S. J. Wezenberg,
A. W. Kleij, Chem. Commun. 2010, 46, 2713–2723; e) S. J. Connon,
Chem. Commun. 2008, 2499–2510; f) E. N. Jacobsen, Acc. Chem.
Res. 2000, 33, 421–431; g) S. Saito, H. Yamamoto, Acc. Chem. Res.
2004, 37, 570–579; h) A. Lattanzi, Chem. Commun. 2009, 1452–
1463; i) F. Giacalone, M. Gruttadauria, P. Agrigento, R. Noto,
Chem. Soc. Rev. 2012, 41, 2406–2447; j) A. E. Allen, D. W. C. Mac-
Millan, Chem. Sci. 2012, 3, 633–658.
[2] a) L. Stegbauer, F. Sladojevich, D. J. Dixon, Chem. Sci. 2012, 3, 942–
958; b) P. de Armas, D. Tejedor, F. Garcꢀa-Tellado, Angew. Chem.
2010, 122, 1029–1032; Angew. Chem. Int. Ed. 2010, 49, 1013–1016;
c) J. R. Gareth, Tetrahedron 2001, 57, 1865–1882; d) Y. J. Park, J.-W.
Park, C.-H. Jun, Acc. Chem. Res. 2008, 41, 222–234; e) M. Rueping,
R. M. Koenigs, I. Atodiresei, Chem. Eur. J. 2010, 16, 9350–9365;
f) C. Zhong, X. Shi, Eur. J. Org. Chem. 2010, 2999–3025; g) D. T.
Cohen, K. A. Scheidt, Chem. Sci. 2012, 3, 53–57; h) C. Grondal, M.
Jeanty, D. Enders, Nat. Chem. 2010, 2, 167–178; i) C. C. J. Loh, D.
Enders, Chem. Eur. J. 2012, 18, 10212–10225; j) Z. Du, Z. Shao,
Chem. Soc. Rev. 2013, 42, 1337–1378; k) W. Tang, S. Johnston, J. A.
Iggo, N. G. Berry, M. Phelan, L. Lian, J. Bacsa, J. Xiao, Angew.
Chem. 2013, 125, 1712–1716; Angew. Chem. Int. Ed. 2013, 52, 1668–
1672.
[11] Reported BEMP PKbH+
er, H. Schlemper, Angew. Chem. 1987, 99, 1212; Angew. Chem. Int.
Ed. Engl. 1987, 26, 1167 and quinuclidine PKbH+(H2O) is 11.4 ac-
ACHTUNGTRENUN(NG MeCN) is 27.6 according to: R. Schwesing-
AHCTUNGTRENNUNG
cording to: E. A. Castro, M. Aliaga, P. Campodꢆnico, J. G. Santos, J.
Org. Chem. 2002, 67, 8911; no PKbH+ measurement for the two com-
pounds in the same solvent were found by the authors. As a compar-
ison the PKbH+ACTHNUGTRNEUNG(MeCN) values for some representative nitrogen
bases are as following: NEt3 (18.82), N-methyl-piperidine (18.25),
sparteine (21.66), DBU (24.34), TMG (23.3). All values according
to: E. I. Rꢇꢇm, A. Kꢈtt, I. Kaljurand, I. Koppel, I. Leito, I. A.
Koppel, M. Mishima, K. Goto, Y. Miyahara, Chem. Eur. J. 2007, 13,
7631–7643.
[12] V. Chandrasekhar, P. Thilagar, B. Murugesa Pandian, Coord. Chem.
Rev. 2007, 251, 1045–1074.
[13] C. Girard, H. B. Kagan, Angew. Chem. 1998, 110, 3088–3127;
Angew. Chem. Int. Ed. 1998, 37, 2922–2959.
[14] a) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119–125; b) A. Berkessel, F. Cleemann, S.
Mukherjee, T. N. Mueller, J. Lex, Angew. Chem. 2005, 117, 817–821;
Angew. Chem. Int. Ed. 2005, 44, 807–811.
[15] a) N. Iwasawa, Y. Hayashi, H. Sakurai, K. Narasaka, Chem. Lett.
1989, 18, 1581–1584; b) C. Bolm, G. Schlingloff, K. Harms, Chem.
Ber. 1992, 125, 1191–1203.
[3] J. Ye, D. J. Dixon, P. S. Hynes, Chem. Commun. 2005, 4481–4483.
[4] a) T. Yang, A. Ferrali, F. Sladojevich, L. Campbell, D. J. Dixon, J.
Am. Chem. Soc. 2009, 131, 9140–9141; b) B. K. Corkey, F. D. Toste,
J. Am. Chem. Soc. 2005, 127, 17168–17169; c) A. Matsuzawa, T. Ma-
shiko, N. Kumagai, M. Shibasaki, Angew. Chem. 2011, 123, 7758–
7761; Angew. Chem. Int. Ed. 2011, 50, 7616–7619.
[16] Gaussian 09, Revision A.02, M. J. Frisch et al., Gaussian, Inc. Wall-
ingford, CT, 2009.
[17] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215–241.
[18] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789; c) S. H. Vosko, L.
Wilk, M. Nusair, Can. J. Phys. 1980, 58, 1200–1211; d) P. J. Stephens,
F. J. Deulin, C. F. Chabalowski, N. J. Frisch, J. Phys. Chem. 1994, 98,
11623–11627.
[19] R. S. Paton, J. M. Goodman, J. Chem. Inf. Model. 2009, 49, 944–955.
[20] R. R. Knowles, E. N. Jacobsen, Proc. Natl. Acad. Sci. USA 2010,
107, 20678–20685.
[21] a) G. O. Jones, P. Liu, K. N. Houk, S. L. Buchwald, J. Am. Chem.
Soc. 2010, 132, 6205–6213; b) H.-Z. Yu, Y.-Y. Jiang, Y. Fu, L. Liu, J.
Am. Chem. Soc. 2010, 132, 18078–18091.
[22] P. J. Hay, W. R. Wadt, J. Chem. Phys. 1985, 82, 299–310.
[23] a) D. Feller, J. Comput. Chem. 1996, 17, 1571–1586; b) K. L. Schu-
chardt, B. T. Didier, T. Elsethagen, L. Sun, V. Gurumoorthi, J.
Chase, J. Li, T. L. Windus, J. Chem. Inf. Model. 2007, 47, 1045–1052.
[24] S. E. Wheeler, K. N. Houk, J. Chem. Theory Comput. 2010, 6, 395–
404.
[5] For selected racemic examples of cyclization of active methylene
compounds into unactivated alkynes, see: a) J. M. Conia, P. Le Per-
chec, Synthesis 1975, 1–19; b) J. J. Kennedy-Smith, S. T. Staben,
F. D. Toste, J. Am. Chem. Soc. 2004, 126, 4526–4527; c) Q. Gao, B.-
F. Zheng, J.-H. Li, D. Yang, Org. Lett. 2005, 7, 2185–2188; d) D.
Bouyssi, N. Monteiro, G. Balme, Tetrahedron Lett. 1999, 40, 1297–
1300; e) W. Hess, J. Burton, Adv. Synth. Catal. 2011, 353, 2966–
2970; f) Y. Liu, R.-J. Song, J.-H. Li, Synthesis 2010, 21, 3663–3669;
g) S. Montel, D. Bouyssi, G. Balme, Adv. Synth. Catal. 2010, 352,
2315–2320; h) C.-L. Deng, R.-J. Song, Y.-L. Liu, J.-H. Li, Adv.
Synth. Catal. 2009, 351, 3096–3100; i) W. Li, X.-Z. Liu, X.-F. Zhou,
C.-S. Lee, Org. Lett. 2010, 12, 548–551; j) S. Hatakeyama, Pure
Appl. Chem. 2009, 81, 217–226; k) Y. Itoh, H. Tsuji, K.-I. Yamagata,
K. Endo, I. Tanaka, M. Nakamura, E. Nakamura, J. Am. Chem. Soc.
2008, 130, 17161–17167; l) C.-L. Deng, T. Zou, Z.-Q. Wang, R.-J.
Song, J.-H. Li, J. Org. Chem. 2009, 74, 412–414; m) K. Takahashi,
M. Midori, K. Kawano, J. Ishihara, S. Hatakeyama, Angew. Chem.
2008, 120, 6340–6342; Angew. Chem. Int. Ed. 2008, 47, 6244–6246;
n) C.-L. Deng, R.-J. Song, S.-M. Guo, Z.-Q. Wang, J.-H. Li, Org.
Lett. 2007, 9, 5111–5114; o) J.-H. Pan, M. Yang, Q. Gao, N.-Y. Zhu,
D. Yang, Synthesis 2007, 16, 2539–2544; p) J. S. Fisk, J. J. Tepe, J.
Am. Chem. Soc. 2007, 129, 3058–3059; q) G. Eglinton, M. C. Whit-
ing, J. Chem. Soc. 1953, 3052–3059.
[25] Y. Takano, K. N. Houk, J. Chem. Theory. Comput. 2005, 1, 70–77.
[26] E. D. Glendening, A. E. Reed, J. E. Carpenter, F. Weinhold, NBO
Version 3.1.
[27] K. A. Wiberg, Tetrahedron 1968, 24, 1083–1096.
Received: March 12, 2012
Revised: June 29, 2013
Published online: && &&, 0000
&
10
&
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Conia-Ene Reaction
FULL PAPER
Reaction Mechanism
F. Sladojevich, ꢀ. L. Fuentes de Arriba,
I. Ortꢁn, T. Yang, A. Ferrali,
R. S. Paton,* D. J. Dixon* . . &&&& — &&&&
Mechanistic Investigations into the
Enantioselective Conia-Ene Reaction
Catalyzed by Cinchona-Derived
Amino Urea Pre-Catalysts and CuI
Cooperation is key! A detailed mecha-
nistic study on the enantioselective
Conia-ene reaction catalyzed by cin-
chona-derived amino urea pre-catalysts
and CuI is reported (see scheme;
combination of experimental consider-
ations and quantum mechanical calcu-
lations has been carried out to prove
the cooperative nature of the system
and propose a plausible catalytic cycle.
Tf=trifluoromethanesulfonate). A
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
11
&
ÞÞ
These are not the final page numbers!