Enantioselective Intramolecular Hydroacylation of Unactivated Alkenes: An NHC-Catalyzed Robust and Versatile Formation of Cyclic Chiral Ketones

Article abstract of DOI:10.1002/anie.201412302

A highly enantioselective intramolecular N-heterocyclic carbene (NHC)-catalyzed hydroacylation reaction gives access to a range of cyclic ketones from unactivated olefin-substituted aldehydes (up to 99% ee). Remarkably, aliphatic aldehydes were also transformed efficiently in an NHC-catalyzed hydroacylation reaction for the first time. 100% Organic: A highly enantioselective N-heterocyclic carbene (NHC)-catalyzed intramolecular hydroacylation of aromatic and, more interestingly, aliphatic aldehydes with unactivated olefins offers access to a range of cyclic α-chiral ketones bearing quaternary centers. The reaction was found to be highly robust and proceeds with excellent yield in the presence of a diverse range of functional groups.

Full text of DOI:10.1002/anie.201412302

Angewandte
Chemie
DOI: 10.1002/anie.201412302
Enantioselective Organocatalysis
Enantioselective Intramolecular Hydroacylation of Unactivated
Alkenes: An NHC-Catalyzed Robust and Versatile Formation of Cyclic
Chiral Ketones**
Daniel Janssen-Mꢀller, Michael Schedler, Mirco Fleige, Constantin G. Daniliuc, and
Frank Glorius*
Abstract: A highly enantioselective intramolecular N-hetero-
cyclic carbene (NHC)-catalyzed hydroacylation reaction gives
access to a range of cyclic ketones from unactivated olefin-
substituted aldehydes (up to 99% ee). Remarkably, aliphatic
aldehydes were also transformed efficiently in an NHC-
catalyzed hydroacylation reaction for the first time.
NHCs have been used to catalytically transform electro-
philic aldehydes into nucleophilic species, thereby enabling
their reaction with various electrophiles.[6] The Stetter reac-
tion, the NHC-catalyzed addition of an aldehyde to a Michael
acceptor,[6b–c,e–g,l,7] is formally a hydroacylation of an electron-
=
deficient C C bond. While the Stetter reaction is limited to
electron-deficient olefins, several hydroacylation reactions of
electron-neutral olefins have been discovered and these make
the NHC-catalyzed hydroacylation synthetically more versa-
tile and widely applicable.[8–10] The resulting a-functionalized
ketones are structurally important motifs in biologically
active molecules, such as the loop diuretic drug Indacrinone[11]
and the antidepressant drug Nafenodone[12] (Figure 1).
H
ydroacylation, the formal insertion of unsaturated func-
À
tionalities such as olefins into the C H bond of an aldehyde, is
a useful method for the formation of carbon–carbon bonds
since both starting materials are abundant and important
functional groups in organic chemistry. Catalysis of this
transformation has been achieved with transition metals,
including rhodium, ruthenium, and cobalt, as well as with N-
heterocyclic carbenes (NHCs)[1] as organocatalysts.[2] Transi-
tion-metal-catalyzed hydroacylation reactions often suffer
from decarbonylation of the acyl metal species, thereby
resulting in catalytically inactive carbonyl complexes, and
they therefore require an additional coordinating group on
one of the substrates. While there are some approaches to
prevent decarbonylation of non-chelating substrates, this
deactivation pathway remains a general challenge in the
field of hydroacylation.[2c,3]
Figure 1. Two biologically active a-chiral ketones.
The use of NHCs as organocatalysts for hydroacylation
avoids this issue but is still underdeveloped.[2d] Additionally,
the NHC-catalyzed intramolecular hydroacylation reaction is
complementary to the metal-catalyzed variant, providing exo-
cyclized products where the transition-metal-catalyzed trans-
formation usually affords endo-cyclization.[4] The NHC-cata-
lyzed reaction therefore often efficiently offers access to
a quaternary stereocenter, the synthesis of which is generally
In 2009, our group reported the intramolecular NHC-
catalyzed hydroacylation of electroneutral olefins with the
cyclization of O-allylated salicylaldehydes to afford chroma-
nones (Scheme 1).[8a,9] We then developed a highly enantio-
selective variant of this reaction in 2011, however, the
À
considered challenging owing to the steric repulsion in the C
C bond forming step.[5]
[*] D. Janssen-Mꢀller, Dr. M. Schedler, M. Fleige, Dr. C. G. Daniliuc,
Prof. Dr. F. Glorius
Westfꢁlische Wilhelms-Universitꢁt Mꢀnster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢀnster (Germany)
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
[**] We are grateful to Karin Gottschalk for skilful technical assistance.
Generous financial support by the Fonds der Chemischen Industrie
(M.S.) and the Deutsche Forschungsgemeinschaft (SPP 1179, IRTG
2027, Leibniz Award) are gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412302.
Scheme 1. Intramolecular enantioselective NHC-catalyzed hydroacyla-
tion.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
substrates are limited to salicylaldehyde derivatives.[8b] As
a result, this potentially useful transformation was restricted
to aromatic aldehydes, the formation of heterocycles, and
monoaryl-substituted olefins. Motivated by our recent suc-
cessful development of the intermolecular hydroacylation of
cyclopropenes and styrenes,[10] we wanted to reexamine the
intramolecular hydroacylation in more detail. Herein, we
report the use of a N-2,6-dimethoxyphenyl-substituted NHC
as an organocatalyst in an intramolecular enantioselective
hydroacylation reaction for the construction of a variety of
cyclic a-chiral ketones. This reaction is general and remark-
ably robust, and even the more challenging aliphatic alde-
hydes can be used.
Since all known substrates for NHC-catalyzed intramo-
lecular hydroacylation contain a heteroatom bridge between
the aromatic aldehyde and the olefin, we commenced our
studies by exploring whether this constraint could be removed
(1a) to allow the synthesis of 5-membered carbocycles, such
as 2a (Table 1).
62% ee. When using catalyst 3c, temperatures between 08C
and 1408C were tolerated for this reaction, but 808C proved
to be optimal for most substrates. The catalyst loading could
be reduced to 5 mol%.
With these conditions in hand, an additive-based robust-
ness screen[14] was performed to test the functional group
tolerance of this reaction. Gratifyingly, nearly all of the tested
additives, including the standard set of functional groups
(entries A1–10) and heterocycles (entries B1–10), did not
affect the hydroacylation (Table 2). Moreover, the additives
did not decompose under the reaction conditions, thus
suggesting that the reaction is well suited for the use of
highly functionalized substrates. Only the additives dodecyl-
amine, N-pivaloylpyrrol, and 2-chloroquinoline (see Table 2,
entries A9, B7, and B10) reduced the yield of the product
slightly, but even in the presence of these highly reactive
functional groups, hydroacylation was possible, which prob-
ably makes this reaction the most robust reaction examined
with this robustness screen to date.[14,15] Furthermore, none of
the additives had any significant influence on the enantiose-
lectivity.
To demonstrate the scalability of this transformation, we
performed the reaction on a 2 g scale. This allowed us to
decrease the amount of precatalyst 3c at room temperature to
2 mol%. The yield of isolated product even increased to 99%
and the ee was unaffected by the scale-up, remaining at 98%.
Having established the high functional-group tolerance of this
reaction, we went on to study the substrate scope, focusing
especially on the influence of the ring size and the necessity of
the aromatic rings. We started investigating different aromatic
aldehydes including 1b, a substrate that bears an electron-rich
enol ether rather than an electro-neutral olefin. This substrate
was previously used in a non-enantioselective transformation
by She et al.[9] Pleasingly, we were able to isolate the product
2b with good yield and enantioselectivity (Table 3). This
methodology could also be extended to the formation of 6-
membered carbocycles (2c) with excellent enantioselectivity.
Next, replacement of the olefin substituent R, which had
previously only tolerated aryl substituents, with an ethyl
group was explored and ketone 2d was formed with good
yield and selectivity. The introduction of a fluorine atom to
the aromatic aldehyde (1e) resulted in a 99% yield and an
even higher ee of 99%.
We also investigated whether heteroaromatic aldehydes
are tolerated in this reaction and hence we performed
hydroacylation with the two nitrogen-containing heteroaro-
matic compounds 1 f and 1g. Hydroacylation of 1 f provided
an efficient and highly enantioselective route to pyrrolizine
2 f, an import structural motif found in alkaloids and drugs.[16]
The structure and absolute configuration of hydroacylation
product 2g was confirmed by single-crystal X-ray diffraction
analysis (see Table 3).[17] The reaction was found to tolerate
both electron-donating (1h, 1i, and 1j) and electron-with-
drawing (1l and 1m) substituents on the phenyl ring of the
olefin, as well as pyridyl substituents (1k), in all cases
providing the product with 97% ee or higher. The trisub-
stituted olefin substrates 1n and 1o gave products 2n and 2o
in 77% and 14% yield and with 97% and 88% ee,
respectively. 1,3-Diene containing substrate 1p gave the
Table 1: Screening of chiral NHC catalysts.[a]
Precat.
R1
R2
X
Yield [%][b]
ee [%][c]
3a
H
Mes
Cl
100
4
100
95
100
100
100
100
100
93
n.d.
98
62
98
98
98
98
98
3b
3c
3d
Me
H
Me
H
H
H
Mes
BF4
BF4
Cl
BF4
BF4
BF4
Cl
2,6-(MeO)2C6H3
2,6-(MeO)2C6H3
2,6-(MeO)2C6H3
2,6-(MeO)2C6H3
2,6-(MeO)2C6H3
Mes
3c[d]
3c[e]
3c[f]
3a[g]
3c[g]
H
H
2,6-(MeO)2C6H3
BF4
[a] Conditions: 1a (0.1 mmol), chiral precatalyst (20 mol%), base
(40 mol%), 1,4-dioxane (0.5m), 1208C, 2 h. [b] The yield of 2a was
1
determined by H NMR spectroscopy with CH2Br2 as an internal
standard. [c] The ee value was determined by HPLC using a chiral
stationary phase. DBU=1,8-diazabicyclo [5.4.0]undec-7-ene, n.d.=not
determined. [d] Temperature 08C. [e] Temperature 1408C. [f] Chiral
precatalyst (5 mol%) and DBU (10 mol%), 808C. [g] With aliphatic
substrate 1q instead of 1a.
Chiral catalyst 3a, which bears a mesityl substituent at the
triazole core and a benzyl group as the stereo-inducing unit,
gave full conversion to the product with high enantioselec-
tivity (93% ee).[8a] The more sterically demanding catalyst 3b
was found to be less reactive, giving only 4% conversion.
Moving from 3a to 3c by simply changing the mesityl
substituent to the 2,6-dimethoxyphenyl substituent improved
the ee to 98%. This confirms the previously reported
tendency of improved selectivity with these new 2,6-dime-
thoxyphenyl-substituted triazolium salts.[10c,d,13] Catalyst 3d,
the gem-dimethyl derivative of catalyst 3c, exhibited high
activity for the reaction but a reduced enantioselectivity of
2
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Table 2: Results of the robustness screen.[a]
Table 3: Substrate scope of the enantioselective hydroacylation.[a]
Entry Additive
Yield of
ee of
Additive
1a
2a [%][b] 2a [%][c] remaining remaining
[%][b]
[%][b]
A0
A1
none
>95
98
98
–
0
92
95
95
0
0
A2
82
98
A3
A4
92
98
98
>95
>95
0
0
>95
A5
>95
98
>95
0
A6
A7
>95
97
98
76
91
0
0
92
A8
92
98
>95
0
A9
60
93
97
98
95
0
0
A10
>95
B1
B2
>95
>95
97
98
>95
>95
0
0
B3
94
98
89
0
[a] 0.5 mmol of aldehyde was stirred at 808C for 16 h in 1.0 mL 1,4-
dioxane with 5 or x mol% triazolium salt 3c and 10 or 2x mol% DBU.
Yields given are yields of isolated product after column chromatography.
The ee was determined by HPLC with a chiral stationary phase. [b] x=2.
[c] x=20 and reaction-time 48 h. [d] x=20. [e] x=20 and reaction at
1408C. [f] x=10. [g] x=10, reaction at room temperature. [h] Molecular
structure of 2g.
B4
B5
B6
B7
91
95
98
98
98
98
92
>95
94
0
0
>95
61
0
92
21
reported as substrates for intramolecular hydroacylation and
which represent the biggest known restriction in this class of
NHC-catalyzed transformation. Gratifyingly, the subjection
of substrate 1q to the reaction conditions resulted in the
formation of the desired product 2q in 89% yield with an
outstanding enantioselectivity of 98% ee. Once again, we
investigated whether different substituents on the phenyl ring
had an influence on the reaction and found they were well
tolerated (2r–s). Upon incorporation of an oxygen atom into
the aliphatic bridge (1t), the furanone 2t was produced with
a lower ee of 81% and in a much lower yield of 19% as the
result of an NHC-catalyzed side reaction (see the Supporting
Information). This side reaction can be reduced by lowering
the temperature to room temperature, which allowed the
product 2t to be obtained in 49% yield compared to 19%
yield compared to 19% yield at 808C.
B8
92
98
>95
0
B9
>95
98
98
>95
>95
0
B10
77
12
[a] The standard reaction (conditions: 1a (0.1 mmol), 3c (5 mol%),
DBU (10 mol%), 1,4-dioxane (0.5m), 808C, 16 h) is undertaken in the
presence of one molar equivalent of the given additive. [b] The yield of 2a
and the amounts of additive and starting material 1a remaining after
reaction were determined by GC. [c] The ee value was determined by
HPLC using a chiral stationary phase.
product 2p in a slightly lowered yield of 61%, while
maintaining a high (90%) ee. We also investigated the use
of aliphatic aldehydes, which have not yet been previously
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
A limitation of this method is the construction of stable
ternary stereocenters (2u and 2v), since this stereocenter is
prone to racemization under basic conditions. By adding
deuterated methanol to the reaction mixture containing
substrate 1u, we observed the incorporation of deuterium
atom at the stereogenic center, thus suggesting that the
ketone formed is in equilibrium with its enolate. As a result,
racemic hydroacylation products were formed.
In order to study the influence of the aromatic backbone
of substrate 1a compared to the aliphatic aldehyde 1q, we
measured time-dependent NMR spectra for both reactions.
At 808C in deuterated toluene[18] and in the presence of
10 mol% 3c and 20 mol% DBU, the aliphatic aldehyde 1q
reacted slowly to give the corresponding hydroacylation
product 2q (Figure 2, left). When the reaction was repeated
[1] Selected references: a) M. N. Hopkinson, C. Richter, M. Sched-
ler, F. Glorius, Nature 2014, 510, 485; b) N-Heterocyclic Carbenes
in Transition Metal Catalysis (Ed.: C. S. J. Cazin), Springer,
Berlin, 2011; c) T. Drçge, F. Glorius, Angew. Chem. Int. Ed. 2010,
49, 6940; Angew. Chem. 2010, 122, 7094; d) S. Dꢀez-Gonzꢁlez, N.
Marion, S. P. Nolan, Chem. Rev. 2009, 109, 3612; e) F. E. Hahn,
M. C. Jahnke, Angew. Chem. Int. Ed. 2008, 47, 3122; Angew.
Chem. 2008, 120, 3166; f) W. A. Herrmann, C. Kçcher, Angew.
Chem. Int. Ed. Engl. 1997, 36, 2162; Angew. Chem. 1997, 109,
2256.
[2] Metal-catalyzed hydroacylation: a) M. C. Willis, Chem. Rev.
2010, 110, 725; b) C. Gonzalez-Rodriguez, M. C. Willis, Pure
Appl. Chem. 2011, 83, 577; c) J. C. Leung, M. J. Krische, Chem.
Sci. 2012, 3, 2202. For NHC-catalyzed hydroacylation see:
d) A. T. Biju, N. Kuhl, F. Glorius, Acc. Chem. Res. 2011, 44, 1182.
[3] a) Y. J. Park, J. W. Park, C. H. Jun, Acc. Chem. Res. 2008, 41, 222;
b) A. H. Roy, C. P. Lenges, M. Brookhart, J. Am. Chem. Soc.
2007, 129, 2082; c) S. K. Murphy, V. M. Dong, Chem. Commun.
2014, 50, 13645.
[4] a) R. W. Barnhart, X. Q. Wang, P. Noheda, S. H. Bergens, J.
Whelan, B. Bosnich, J. Am. Chem. Soc. 1994, 116, 1821; b) E. V.
Beletskiy, C. Sudheer, C. J. Douglas, J. Org. Chem. 2012, 77,
5884; c) A. Ghosh, L. M. Stanley, Chem. Commun. 2014, 50,
2765.
[5] a) J. P. Das, H. Chechik, I. Marek, Nat. Chem. 2009, 1, 128;
b) Z. L. Chen, J. W. Sun, Angew. Chem. Int. Ed. 2013, 52, 13593;
Angew. Chem. 2013, 125, 13838; c) J. Christoffers, A. Baro,
Quaternary Stereocenters. Challenges and Solutions for Organic
Synthesis, Wiley-VCH, Weinheim, 2005; d) C. J. Douglas, L. E.
Overman, Proc. Natl. Acad. Sci. USA 2004, 101, 5363; e) E. A.
Peterson, L. E. Overman, Proc. Natl. Acad. Sci. USA 2004, 101,
11943; f) B. M. Trost, C. H. Jiang, Synthesis 2006, 369.
[6] a) K. Zeitler, Angew. Chem. Int. Ed. 2005, 44, 7506 – 7510;
Angew. Chem. 2005, 117, 7674 – 7678; b) N. Marion, S. Dꢀez-
Gonzꢁlez, S. P. Nolan, Angew. Chem. Int. Ed. 2007, 46, 2988;
Angew. Chem. 2007, 119, 3046; c) D. Enders, O. Niemeier, A.
Henseler, Chem. Rev. 2007, 107, 5606; d) E. M. Phillips, A. Chan,
K. A. Scheidt, Aldrichimica Acta 2009, 42, 55; e) J. L. Moore, T.
Rovis, Top. Curr. Chem. 2009, 291, 77; f) H. U. Vora, T. Rovis,
Aldrichimica Acta 2011, 44, 3; g) M. Gravel, J. M. Holmes in
Comprehensive Organic Synthesis II, 2nd ed. (Ed.: P. Knochel),
Elsevier, Amsterdam, 2014, p. 1384; h) K. Hirano, I. Piel, F.
Glorius, Chem. Lett. 2011, 40, 786; i) V. Nair, R. S. Menon, A. T.
Biju, C. R. Sinu, R. R. Paul, A. Jose, V. Sreekumar, Chem. Soc.
Rev. 2011, 40, 5336; j) P. C. Chiang, J. W. Bode, TCI Mail 2011,
149, 2; k) D. T. Cohen, K. A. Scheidt, Chem. Sci. 2012, 3, 53;
l) A. Grossmann, D. Enders, Angew. Chem. Int. Ed. 2012, 51,
314; Angew. Chem. 2012, 124, 320; m) X. Bugaut, F. Glorius,
Chem. Soc. Rev. 2012, 41, 3511; n) J. Izquierdo, G. E. Hutson,
D. T. Cohen, K. A. Scheidt, Angew. Chem. Int. Ed. 2012, 51,
11686; Angew. Chem. 2012, 124, 11854; o) H. U. Vora, P.
Wheeler, T. Rovis, Adv. Synth. Catal. 2012, 354, 1617; p) S. J.
Ryan, L. Candish, D. W. Lupton, Chem. Soc. Rev. 2013, 42, 4906;
q) J. Mahatthananchai, J. W. Bode, Acc. Chem. Res. 2014, 47,
696; see also r) Z. Jin, S. Chen, Y. Wang, P. Zheng, S. Yang, Y. R.
Chi, Angew. Chem. Int. Ed. 2014, 53, 13506; Angew. Chem. 2014,
126, 13724, and references therein.
Figure 2. Acceleration by the aromatic backbone: Formation of prod-
ucts 2q (left) and 2a (right). Conditions: 10 mol% 3c, 20 mol% DBU,
[D8]toluene (0.13m).
with aromatic aldehyde 1a, the temperature was reduced to
08C and the resulting clean conversion of the starting material
1a into the product 2a was still 2.0 times faster than the
reaction of 1q at 808C (Figure 2 right). Taking the elevated
temperature into account, the aromatic substrate 1a would
react about 500 times faster than 1q if using the same
temperature for both substrates.[19] This shows that aliphatic
aldehydes are much more challenging substrates for NHC-
catalyzed hydroacylation than aromatic ones.
In conclusion, we have shown that intramolecular NHC-
catalyzed hydroacylation is a robust and versatile method for
the synthesis of a-chiral cyclic ketones bearing quarternary
stereocenters. Both 6- and 5-membered rings can be synthe-
sized, as well as aromatic and aliphatic ketones. The robust-
ness screen showed a very high tolerance of this reaction to
a diverse range of functional groups.
Received: December 22, 2014
Published online: && &&, &&&&
[7] H. Stetter, Angew. Chem. Int. Ed. Engl. 1976, 15, 639; Angew.
Chem. 1976, 88, 695.
[8] Intramolecular hydroacylation of unactivated alkenes and
alkynes: a) K. Hirano, A. T. Biju, I. Piel, F. Glorius, J. Am.
Chem. Soc. 2009, 131, 14190; b) I. Piel, M. Steinmetz, K. Hirano,
R. Frçhlich, S. Grimme, F. Glorius, Angew. Chem. Int. Ed. 2011,
50, 4983; Angew. Chem. 2011, 123, 5087; c) A. T. Biju, N. E.
Wurz, F. Glorius, J. Am. Chem. Soc. 2010, 132, 5970; d) M.
Padmanaban, A. T. Biju, F. Glorius, Org. Lett. 2011, 13, 5624.
Keywords: enantioselective catalysis · hydroacylation ·
N-heterocyclic carbenes · organocatalysis
.
4
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[9] Pioneering work on the intramolecular hydroacylation of enol
ethers: a) J. He, J. Zheng, J. Liu, X. She, X. Pan, Org. Lett. 2006,
8, 4637; b) J. He, S. Tang, J. Liu, Y. Su, X. Pan, X. She,
Tetrahedron 2008, 64, 8797.
[10] Intermolecular hydroacylation of alkenes and alkynes: a) A. T.
Biju, F. Glorius, Angew. Chem. Int. Ed. 2010, 49, 9761; Angew.
Chem. 2010, 122, 9955; b) X. Bugaut, F. Liu, F. Glorius, J. Am.
Chem. Soc. 2011, 133, 8130; c) F. Liu, X. Bugaut, M. Schedler, R.
Frçhlich, F. Glorius, Angew. Chem. Int. Ed. 2011, 50, 12626;
Angew. Chem. 2011, 123, 12834; d) M. Schedler, D.-S. Wang, F.
Glorius, Angew. Chem. Int. Ed. 2013, 52, 2585; Angew. Chem.
2013, 125, 2645.
c) K. D. Collins, F. Glorius, Tetrahedron 2013, 69, 7817; d) K. D.
Collins, F. Glorius, Acc. Chem. Res. 2015, DOI: 10.1021/
ar500434f.
[15] a) D.-G. Yu, T. Gensch, F. de Azambuja, S. Vꢁsquez-Cꢂspedes, F.
Glorius, J. Am. Chem. Soc. 2014, 136, 17722; b) D. T. D. Tang,
K. D. Collins, J. B. Ernst, F. Glorius, Angew. Chem. Int. Ed. 2014,
53, 1809; Angew. Chem. 2014, 126, 1840; c) H. A. Malik, B. L. H.
Taylor, J. R. Kerrigan, J. E. Grob, K. N. Houk, J. Du Bois, L. G.
Hamann, A. W. Patterson, Chem. Sci. 2014, 5, 2352; d) T. C.
Atack, R. M. Lecker, S. P. Cook, J. Am. Chem. Soc. 2014, 136,
9521; e) T. Morofuji, A. Shimizu, J.-i. Yoshida, J. Am. Chem. Soc.
2014, 136, 4496.
[11] P. H. Vlasses, J. D. Irvin, P. B. Huber, R. B. Lee, R. K. Ferguson,
J. J. Schrogie, A. G. Zacchei, R. O. Davies, W. B. Abrams, Clin.
Pharmacol. Ther. 1981, 29, 798.
[12] F. Pꢂrez-Vizcaino, R. Carron, E. Delpon, J. Tamargo, Eur. J.
Pharmacol. 1991, 199, 43.
[13] M. Schedler, R. Frçhlich, C.-G. Daniliuc, F. Glorius, Eur. J. Org.
Chem. 2012, 4164.
[14] a) K. D. Collins, F. Glorius, Nat. Chem. 2013, 5, 597; b) K. D.
Collins, A. Rꢃhling, F. Glorius, Nat. Protoc. 2014, 9, 1348;
[16] a) A. Belal, D. El-Gendy Bel, Bioorg. Med. Chem. 2014, 22, 46;
b) W. K. Anderson, Cancer Res. 1982, 42, 2168.
[17] CCDC 1040461 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
[18] The reaction also takes place in toluene or THF, therefore we
used toluene for our kinetic studies.
[19] A Q10 coefficient of 2.0 is assumed..
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Enantioselective Organocatalysis
D. Janssen-Mꢁller, M. Schedler, M. Fleige,
C. G. Daniliuc,
F. Glorius*
&&&& — &&&&
Enantioselective Intramolecular
Hydroacylation of Unactivated Alkenes:
An NHC-Catalyzed Robust and Versatile
Formation of Cyclic Chiral Ketones
100% Organic: A highly enantioselective
N-heterocyclic carbene (NHC)-catalyzed
intramolecular hydroacylation of aro-
matic and, more interestingly, aliphatic
aldehydes with unactivated olefins offers
access to a range of cyclic a-chiral
ketones bearing quaternary centers. The
reaction was found to be highly robust
and proceeds with excellent yield in the
presence of a diverse range of functional
groups.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!