Direct catalytic enantio- and diastereoselective ketone aldol reactions of isocyanoacetates

Article abstract of DOI:10.1002/anie.201411852

A catalytic asymmetric aldol addition/cyclization reaction of unactivated ketones with isocyanoacetate pronucleophiles has been developed. A quinine-derived aminophosphine precatalyst and silver oxide were found to be an effective binary catalyst system and promoted the reaction to afford chiral oxazolines possessing a fully substituted stereocenter with good diastereoselectivities and excellent enantioselectivities.

Full text of DOI:10.1002/anie.201411852

Angewandte
Chemie
DOI: 10.1002/anie.201411852
Asymmetric Catalysis
Direct Catalytic Enantio- and Diastereoselective Ketone Aldol
Reactions of Isocyanoacetates**
Raquel de la Campa, Irene Ortꢀn, and Darren J. Dixon*
[
7]
Abstract: A catalytic asymmetric aldol addition/cyclization
reaction of unactivated ketones with isocyanoacetate pronu-
cleophiles has been developed. A quinine-derived aminophos-
phine precatalyst and silver oxide were found to be an effective
binary catalyst system and promoted the reaction to afford
chiral oxazolines possessing a fully substituted stereocenter
with good diastereoselectivities and excellent enantioselectiv-
ities.
reaction has been widely studied using aldehydes, to date,
no enantioselective example using unactivated ketones has
been reported despite its potential to provide an elegant
asymmetric route to a-amino acid derivatives possessing
a chiral tertiary alcohol in the b-position (Scheme 1). In
a related study, the asymmetric aldol addition reaction of
isothiocyanato esters and unactivated ketones, which
afforded oxazolidinethione products with a fully substituted
[
10]
[11]
b-stereocenter, was described.
T
he aldol reaction is one of the most powerful methods for
[
1]
the construction of b-hydroxy carbonyl compounds. The
importance of these building blocks, contained in a wide
variety of biologically relevant compounds, has promoted the
development of several catalytic asymmetric methods for
[
2]
their production. However, despite enormous progress in
the aldol addition arena, its application to the synthesis of
tertiary alcohols still remains a major challenge, principally
owing to a lack of reactivity and the fact that the differ-
entiation of the enantiotopic faces is more difficult with
ketone electrophiles than with the corresponding aldehydes.
Furthermore, deleterious side reactions, such as retro-aldol
reactions, can predominate when a ketone moiety is
[
3]
involved. Although a few catalytic asymmetric aldol reac-
[
4]
tions with unactivated ketones have been reported, the
development of new and efficient catalytic asymmetric
methods to access chiral tertiary alcohols remains an impor-
[5]
tant goal in modern asymmetric catalysis.
Scheme 1. a) Catalytic asymmetric addition reactions of isocyanoace-
tate pronucleophiles to carbonyl or imine electrophiles. b) Aminophos-
phine/silver(I) binary catalyst system applied in this work.
Along these lines, we recognized that the catalytic
asymmetric ketone aldol reaction of isocyanoacetate pronu-
[
6]
cleophiles could be a synthetically powerful approach.
[
7]
Isocyanoacetate ester addition reactions to carbonyl or
[
8,9]
imine electrophiles directly afford the respective oxazoline
or imidazoline heterocycles, which can be ring-opened under
mild hydrolytic conditions to yield b-substituted a-amino
acids. Although the catalytic asymmetric version of this
For promoting and controlling various addition reactions,
our group has developed an effective binary catalyst system
comprising a “soft” metal ion, such as a silver (I) ion, and
a cinchona-derived aminophosphine precatalyst of type 1.
This system promotes the highly diastereo- and enantioselec-
[
7l]
tive aldol reaction of isocyanoacetates with aldehydes, and
[
*] Dr. R. de la Campa, Dr. I. Ortꢀn, Prof. Dr. D. J. Dixon
Department of Chemistry, Chemistry Research Laboratory
University of Oxford
[
8e]
[9a]
Mannich reactions of aldimines
and ketimines.
The
precatalyst is equipped with Brønsted basic and Lewis basic
sites and also possesses a hydrogen-bond donor group located
in the proximity of the chiral pocket that is created by the
Mansfield Road, Oxford OX1 3TA (UK)
E-mail: darren.dixon@chem.ox.ac.uk
I
[**] We thank the EPSRC (Leadership Fellowship to D.J.D.), the EC [IEF
cinchona scaffold (Scheme 1). In conjunction with Ag ions,
to R.C. (PIEF-GA-2012-329689) and IEF to I.O. (PIEF-GA-2010-
these features provide remarkable catalytic activity in reac-
tions of isocyanoacetate pronucleophiles and accordingly
prompted us to address the challenging enantioselective aldol
reaction of unactivated ketones.
Initially, the reaction of acetophenone (3a) and tert-butyl
isocyanoacetate (2a) in EtOAc at À208C was selected as
a model system, and the performance of our previously
described silver oxide/aminophosphine catalytic system,
2
75788)] for funding, Allegra Franchino of the Department of
Chemistry, University of Oxford for the preparation of precatalyst
b, Pablo Garcꢀa of the Department of Chemistry, University of
1
Oviedo and Matt Rattley and Yinchao Yang of the Department of
Chemistry, University of Oxford for X-ray analysis, and the Oxford
Chemical Crystallography Service for use of their instrumentation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411852.
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1
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Communications
which was employed in a 2:1 molar ratio of aminophosphine
precatalyst to metal, was assessed. Pleasingly, using cincho-
nidine-derived aminophosphine 1c, trans-oxazoline (4R,5S)-
Subsequently, the effect of lowering the catalyst loading
was studied (Table 2). trans-Oxazoline 4a was obtained with
marginally lower levels of enantioselectivity when the loading
was reduced to 5 and 1 mol% of 1a while maintaining
a precatalyst/metal ratio of 2:1 ratio (entries 2 and 3).
However, diastereo- and enantioselectivities that are com-
parable to the best values reported in Table 1 were achieved
[
7l]
4
a was obtained as the major product with significant
diastereo- and enantiocontrol (Table 1, entry 1; 89:11 d.r.,
Table 1: Optimization studies.
I
when precatalyst 1a and Ag were employed in a 1:1 ratio at
a precatalyst loading of 5 mol% (entry 1).
Table 2: Variations of the catalyst loading.
[
a]
[b]
[c]
Entry 1a (mol%) Ag O (mol%) t [h] Yield [%] d.r.
e.r.
2
1
2
3
5
5
1
2.5
1.25
0.25
72
96
96
84
85
73
94:6
90:10 93:7
86:14 90:10
94:6
[
a]
[b]
[c]
Entry
1
[Ag]
T [8C] Solvent t [h] Yield [%] d.r.
e.r.
1
2
3
4
5
6
7
8
9
1c Ag O
1a Ag O
1b Ag O
À20 EtOAc
À20 EtOAc
À20 EtOAc
60 78
60 93
60 82
24 64
48 55
36 74
36 63
36 79
96 84
48 84
89:11 90:10
95:5 94:6
90:10 90:10
91:9 94:6
88:12 91:9
88:12 94:6
79:12 85:15
89:11 93:7
90:10 94:6
89:11 92:8
2
[a] Combined yield of both diastereomers after flash column chroma-
2
1
[
d]
tography. [b] Given as the trans/cis ratios and determined by H NMR
analysis of the crude reaction mixture. [c] Determined by HPLC analysis
on a chiral stationary phase.
2
1a Ag CO3 À20 EtOAc
2
1a AgOAc À20 EtOAc
1a Ag O
À20 TBME
2
1a Ag O
1a Ag O
1a Ag O
1a Ag O
1a
–
À20 CH Cl2
2
2
À20 iPrOAc
À30 EtOAc
2
With the optimized conditions established, we proceeded
to study the scope of the reaction of tert-butyl isocyanoacetate
(2a) with different alkyl aryl ketones in the presence of
2
10
11
12
0
EtOAc
2
–
À20 EtOAc 120
0
0
–
–
–
–
Ag O
2
À20 EtOAc 120
quinine-derived aminophosphine precatalyst 1a and Ag O
2
(Table 3). Several substituted methyl aryl ketones with either
[
a] Combined yield of both diastereomers after flash column chroma-
tography. [b] The diastereomeric ratio (d.r.) is given as the trans/cis ratio
and was determined by H NMR analysis of the crude reaction mixture.
electron-withdrawing or -donating groups afforded the trans-
configured oxazolines 4b–4 f as the major products with good
diastereoselectivities and very good enantioselectivities
1
[c] The enantiomeric ratios (e.r.) were determined by HPLC analysis on
a chiral stationary phase. [d] Enantiomeric (4S,5R)-4a was obtained.
M.S.=molecular sieves, TMBE=tert-butyl methyl ether.
(Table 3, entries 2–6; 93:7–96:4 e.r.). Pleasingly, methyl
ketone substrates 3i and 3j, which feature five- and six-
membered heteroaromatic rings, were also well tolerated
giving products 4i and 4j with good stereoselectivities
(entries 9 and 10). An important success was observed when
aryl ethyl ketones 3k–3n were used in the reaction. trans-
Oxazolines 4k–4n were obtained as the major products with
good diastereoselectivities and excellent enantioselectivities
(entries 11-14; 98:2–99:1 e.r.). Aryl propyl ketones 3o–3p
were also excellent substrates and afforded the trans-config-
ured oxazoline products 4o–4p in high yields and in good to
excellent enantioselectivities (entries 15 and 16). Finally,
isovalerophenone 3q afforded trans-oxazoline 4q in 75%
yield, 96:4 d.r., and 97:3 e.r. (entry 17), demonstrating the
broad scope of the reaction with respect to different non-
activated ketones. We also studied the scope of the reaction
with different isocyanoacetates (entries 18–20). With ethyl
isocyanoacetate (2b) or methyl isocyanoacetate (2c), the
trans-configured oxazoline products 4r–4t were obtained
with very good diastereoselectivities and excellent enantio-
selectivities. Unfortunately, under the optimized conditions,
symmetric and unsymmetric aliphatic ketones afforded the
corresponding oxazoline products with poor enantioselectiv-
9
0:10 e.r.). With quinine-derived precatalyst 1a, product 4a
was afforded in higher diastereo- and enantioselectivity
entry 2; 95:5 d.r., 94:6 e.r.), whereas pseudoenantiomeric
b yielded the enantiomeric product (4S,5R)-4a as a 90:10
(
1
mixture of diastereomers with 90:10 e.r. (entry 3). Alternative
silver sources were also tested in conjunction with precatalyst
1
selectivity would be observed. Although the use of silver
carbonate afforded trans-oxazoline product (4R,5S)-4a with
high enantioselectivity (entry 4; 91:9 d.r., 94:6 e.r.), 4a was
formed with enhanced diastereocontrol and yield when
silver(I) oxide was employed (see entry 2). In terms of
diastereoselectivity, EtOAc was found to be the best solvent
compared with TBME, CH Cl , or iPrOAc (entries 2 and 6–
a (entries 4 and 5) in the hope that an increase in the
2
2
8
0
). Changing the temperature of the reaction to À308C or to
8C from À208C made no improvement to the enantioselec-
tivity (entries 9 and 10). Finally, reactions performed in the
absence of Ag O or without precatalyst 1a gave no product
2
after five days at À208C (entries 11 and 12). These results
demonstrate that the active catalyst is made from a combina-
I
[12]
tion of aminophosphine precatalyst 1a and a Ag salt.
ities.
2
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Chemie
[
13]
Table 3: Scope of the ketone aldol/cyclization reaction with isocyanoacetates.
heterocycles, we subsequently explored the con-
version of oxazolines 4 into the corresponding
amino acid derivatives under different reaction
conditions. The hydrolysis of oxazoline 4e using
catalytic amounts of HCl afforded the correspond-
ing N-formyl derivative 6 in quantitative yield
(
Scheme 3a). Similarly, methanolysis of 4e led to
1
2
[a]
[b]
[c]
Entry
2
3
R
R
4
Yield [%]
d.r.
e.r.
the corresponding b-hydroxy-a-amino acid tert-
butyl ester 7 under mild conditions (Scheme 3b).
These transformations highlight the ability of our
method to afford protected serine derivatives with
a doubly substituted b-position. Furthermore, treat-
ment of 7 with thiophosgene under basic conditions
furnished crystalline oxazolidinethione 8 (Sche-
me 3c); its absolute and relative stereochemical
configurations were determined by single-crystal X-
ray diffraction, and those of the other oxazolines
1
2
3
4
5
6
7
8
9
2a 3a Ph
2a 3b p-CH OC H
4
2a 3c 5-Br-thiophen-2-yl
2a 3d p-NO C H
2a 3e p-BrC H4
p-CNC H4
6
2a 3g 4-F,3-BrC H3
2a 3h 3,5-(CF ) C H
3
5-methylthiazol-2-yl Me
pyrazin-2-yl
2a 3k Ph
2a 3l p-MeC
2a 3m p-FC H4
2a 3n p-BrC H4
2a 3o Ph
2a 3p 2-thienyl
2a 3q Ph
2b 3k Ph
Me
Me
Me
Me
Me
Me
Me
Me
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
84
73
78
60
71
80
83
82
55
75
76
81
83
73
79
81
75
81
82
77
94:6
92:8
94:6
94:6
3
6
88:12 93:7
90:10 95:5
89:11 95:5
90:10 96:4
85:15 89:11
86:14 88:12
91:9
91:9
90:10 99:1
91:9 98:2
88:12 99:1
90:10 99:1
87:13 99:1
84:16 96:4
96:4
90:10 99:1
2
6
4
6
2a 3 f
6
[
14]
3
2
6
2a 3i
2a 3j
93:7
91:9
10
11
12
13
14
15
16
17
18
19
20
Me
Et
Et
Et
Et
Pr
Pr
(4a–4v) were assigned by analogy.
[9b,15]
6
H
4
Based on previous reports
and on the
6
known absolute stereochemical configuration of
oxazoline products 4, a transition-state model
rationalizing the stereochemical outcome of the
ketone aldol reaction between 3a and 2a in the
presence of precatalyst 1a and silver oxide is
proposed in Scheme 4. In the enantiodetermining
carbon–carbon bond-forming step, the phosphorus
and amide nitrogen atoms of 1a, the oxygen atom of
ketone 3a, and the terminal carbon atom of the
isonitrile coordinate to a silver(I) ion in a tetrahedral
6
CH iPr 4q
97:3
2
Et
Et
Et
4r
4s
4t
2b 3l
p-MeC H4
91:9
91:9
98:2
99:1
6
2c 3k Ph
[
[
a] Combined yield of both diastereomers after flash column chromatography.
b] Determined by H NMR analysis of the crude reaction mixture. [c] Determined by
HPLC analysis on a chiral stationary phase.
1
As the stereochemical outcome favored the production of
the trans-configured oxazoline product, and as alkyl groups
larger than a methyl group were well tolerated in the ketone
aldol reaction, our reaction could be applied to the synthesis
of oxazoline-fused g- and d-lactam derivatives. Therefore,
azides 3r and 3s were subjected to the standard reaction
conditions, and pleasingly, oxazolines 4u and 4v were
afforded in good yield and with excellent enantioselectivities.
Subsequently, under standard Staudinger conditions, these
oxazolines were transformed into the target lactam products
5
a and 5b with high yields in a straightforward manner
without compromising stereochemical integrity (Scheme 2).
To demonstrate further synthetic utility whilst expanding
our knowledge on the hydrolytic manipulation of oxazoline
Scheme 3. Synthetic manipulations of the oxazoline products.
arrangement. Additional transition-state stabilization is pro-
vided through hydrogen bonding of the protonated quinucli-
dine to the coordinated ketone oxygen atom. Importantly, this
interaction creates a well-defined chiral pocket that can
readily differentiate the enantiotopic faces of the bound
ketone; unfavorable steric interactions force the aryl group
away from the quinuclidine, and attack of the enolate occurs
preferentially to the Re face.
In conclusion, we have developed the first highly enantio-
and diastereoselective aldol addition/cyclization reaction of
isocyanoacetate esters with unactivated prochiral ketones to
afford functionalized oxazolines with a fully substituted
stereogenic center at the b-carbon atom. The reaction is
Scheme 2. Application of the ketone aldol reaction to the formation of
fused bicyclic lactams.
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.
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Communications
Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2007,
5969 – 5994; d) M. Shibasaki, M. Kanai, Chem. Rev. 2008, 108,
2853 – 2873; e) M. Hatano, K. Ishihara, Synthesis 2008, 1647 –
1675.
[
6] For a review on isocyanoacetates, see: a) A. V. Gulevich, A. G.
Zhdanko, R. V. A. Orru, V. G. Nenajdenko, Chem. Rev. 2010,
1
10, 5235 – 5331; see also: b) W. A. Bçll, F. Gerhart, A.
Nꢂrrenbach, U. Schçllkopf, Angew. Chem. Int. Ed. Engl. 1970,
, 458 – 459; Angew. Chem. 1970, 82, 482 – 483; c) Y. Ito, T.
9
Scheme 4. Proposed transition-state model rationalizing the stereo-
chemical outcome of the reaction of 3a and 2a in the presence of 1a
Matsuura, T. Saegusa, Tetrahedron Lett. 1985, 26, 5781 – 5784.
7] For enantioselective reactions of aldehydes, see: a) Y. Ito, M.
Sawamura, T. Hayashi, J. Am. Chem. Soc. 1986, 108, 6405 – 6406;
b) Y. Ito, M. Sawamura, T. Hayashi, Tetrahedron Lett. 1987, 28,
[
and Ag O.
2
6
215 – 6218; c) S. D. Pastor, A. Togni, J. Am. Chem. Soc. 1989,
efficient and broad in scope and effectively promoted by
a binary catalyst system that consists of a cinchona-derived
aminophosphine precatalyst and silver oxide. In combination
with hydrolytic transformations of the oxazoline heterocycles,
this method enables the transformation of simple ketones into
the corresponding amino acid derivatives possessing a tertiary
alcohol in the b-position. Further studies towards the discov-
ery and application of new asymmetric isocyanoacetate
addition reactions are ongoing in our laboratories, and the
results will be reported in due course.
111, 2333 – 2334; d) T. Hayashi, Y. Uozumi, A. Yamzaki, M.
Sawamura, H. Hamashima, Y. Ito, Tetrahedron Lett. 1991, 32,
2
799 – 2802; e) T. Hayashi, M. Sawamura, Y. Ito, Tetrahedron
992, 48, 1999 – 2012; f) V. A. Soloshonok, T. Hayashi, Tetrahe-
1
dron Lett. 1994, 35, 2713 – 2716; g) V. A. Soloshonok, A.
Kacharov, T. Hayashi, Tetrahedron 1996, 52, 245 – 254; h) J. M.
Longmire, X. Zhang, Organometallics 1998, 17, 4374 – 4379;
i) M. Sawamura, Y. Nakayama, T. Kato, Y. Ito, J. Org. Chem.
1995, 60, 1727 – 1732; j) S. Gosiewska, M. H. Veld, J. J. M.
de Pater, P. C. A. Bruijnincx, M. Lutz, A. L. Spek, G. van Koten,
R. J. M. K. Gebbink, Tetrahedron: Asymmetry 2006, 17, 674 –
686; k) M. Xue, C. Guo, L. Gong, Synlett 2009, 2191 – 2197;
l) H. Y. Kim, K. Oh, Org. Lett. 2011, 13, 1306 – 1309; m) F.
Sladojevich, A. Trabocchi, A. Guarna, D. J. Dixon, J. Am. Chem.
Soc. 2011, 133, 1710 – 1713.
Received: December 9, 2014
Revised: January 23, 2015
Published online: && &&, &&&&
[
8] For enantioselective reactions of aldimines, see: a) X. Zhou, Y.
Lin, L. Dai, J. Sun, L. Xia, M. Tang, J. Org. Chem. 1999, 64,
Keywords: aldol reaction · asymmetric catalysis ·
1331 – 1334; b) X. Zhou, Y. Lin, L. Dai, Tetrahedron: Asymmetry
.
enantioselectivity · isocyanoacetates · oxazolines
1999, 10, 855 – 862; c) J. Aydin, A. Ryden, K. J. Szabꢃ, Tetrahe-
dron: Asymmetry 2008, 19, 1867 – 1870; d) Z. Zhang, G. Lu, M.
Chen, N. Lin, Y. Li, T. Hayashi, A. S. C. Chan, Tetrahedron:
Asymmetry 2010, 21, 1715 – 1721; e) P. Shao, J. Liao, Y. A. Ho, Y.
Zhao, Angew. Chem. Int. Ed. 2014, 53, 5435 – 5439; Angew.
Chem. 2014, 126, 5539 – 5543.
[
1] For reviews on asymmetric aldol reactions, see: a) R. Mahrwald
in Modern Aldol Reactions, Wiley-VCH, Weinheim, 2004;
b) B. M. Trost, C. S. Brindle, Chem. Soc. Rev. 2010, 39, 1600 –
1
632; c) C. Palomo, M. Oiarbide, J. M. Garcꢀa, Chem. Soc. Rev.
[9] For enantioselective reactions of ketimines, see: a) I. Ortꢀn, D. J.
Dixon, Angew. Chem. Int. Ed. 2014, 53, 3462 – 3465; Angew.
Chem. 2014, 126, 3530 – 3533; b) M. Hayashi, M. Iwanaga, N.
Shiomi, D. Nakane, H. Masuda, S. Nakamura, Angew. Chem. Int.
Ed. 2014, 53, 8411 – 8415; Angew. Chem. 2014, 126, 8551 – 8555.
[10] For the racemic reaction, see: a) V. A. Soloshonok, A. D.
Kacharov, D. V. Avilov, T. Hayashi, Tetrahedron Lett. 1996, 37,
7845 – 7848; b) V. A. Soloshonok, A. D. Kacharov, D. V. Avilov,
K. Ishikawa, N. Nagashima, T. Hayashi, J. Org. Chem. 1997, 62,
3470 – 3479.
2004, 33, 65 – 75; d) L. M. Geary, P. G. Hultin, Tetrahedron:
Asymmetry 2009, 20, 131 – 173.
[
2] a) K. C. Nicolaou, C. N. C. Boddy, S. Brꢁse, N. Winssinger,
Angew. Chem. Int. Ed. 1999, 38, 2096 – 2152; Angew. Chem.
1
999, 111, 2230 – 2287; b) M. K. Renner, Y. Shen, X. Cheng, P. R.
Jensen, W. Frankmoelle, C. A. Kauffman, W. Fenical, E.
Lobkovsky, J. Clardy, J. Am. Chem. Soc. 1999, 121, 11273 –
1
2
1276; c) B. Herbert, I. H. Kim, K. L. Kirk, J. Org. Chem.
001, 66, 4892 – 4897.
[
3] a) J. P. Guthrie, J. Am. Chem. Soc. 1991, 113, 7249 – 7255; b) M.
Hatano, E. Takagi, K. Ishihara, Org. Lett. 2007, 9, 4527 – 4530.
4] For examples of Lewis base catalysis, see: a) S. E. Denmark, Y.
Fan, J. Am. Chem. Soc. 2002, 124, 4233 – 4235; b) S. E. Denmark,
Y. Fan, M. D. Eastgate, J. Org. Chem. 2005, 70, 5235 – 5248; for
reactions with enol silanes, see: c) K. Oisaki, D. Zhao, M. Kanai,
M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 7164 – 7165; d) K.
Oisaki, Y. Suto, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2003,
[11] a) T. Yoshino, H. Morimoto, G. Lu, S. Matsunaga, M. Shibasaki,
J. Am. Chem. Soc. 2009, 131, 17082 – 17083; b) S. Matsunaga, T.
Yoshino, Chem. Rec. 2011, 11, 260 – 268.
[12] Experiments with pentan-3-one, propanone, and cyclohexyl
methyl ketone gave oxazoline products 4x, 4y, and 4z with
enantiomeric ratios of 61:39, 47:53, and 67:33, respectively; see
the Supporting Information for details.
[
[13] D. Hoppe, U. Schçllkopf, Angew. Chem. Int. Ed. Engl. 1972, 11,
432 – 433; Angew. Chem. 1972, 84, 435 – 436.
125, 5644 – 5645; e) X. Moreau, B. Bazan-Tejada, J. Campagne, J.
Am. Chem. Soc. 2005, 127, 7288 – 7289; for reductive aldol
reactions, see: f) H. W. Laim, P. M. Joensuu, Org. Lett. 2005, 7,
[14] CCDC 1036558 (8) 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.
[15] a) W. Zeng, G. Chen, Y. Zhou, Y. Li, J. Am. Chem. Soc. 2007,
129, 750 – 751; b) G. Liang, M. Tong, C. Wang, Adv. Synth. Catal.
2009, 351, 3101 – 3106; c) J. Song, C. Guo, P. Chen, J. Yu, S. Luo,
L. Gong, Chem. Eur. J. 2011, 17, 7786 – 7790.
4225 – 4228; g) J. Deschamp, O. Chuzel, J. Hannedouche, O.
Riant, Angew. Chem. Int. Ed. 2006, 45, 1292 – 1297; Angew.
Chem. 2006, 118, 1314 – 1319; see also: h) S. Adachi, T. Harada,
Eur. J. Org. Chem. 2009, 3661 – 3671.
[
5] a) E. J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed. 1998,
37, 388 – 401; Angew. Chem. 1998, 110, 402 – 415; b) O. Riant, J.
Hannedouche, Org. Biomol. Chem. 2005, 5, 873 – 888; c) P. G.
4
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric Catalysis
R. de la Campa, I. Ortꢁn,
D. J. Dixon*
&&&& — &&&&
Direct Catalytic Enantio- and
Diastereoselective Ketone Aldol
Reactions of Isocyanoacetates
A stereoselective aldol reaction of unac-
tivated ketones and isocyanoacetate pro-
nucleophiles is catalyzed by a binary
catalyst system consisting of an amino-
phosphine precatalyst and silver(I) oxide
and affords oxazoline products with
a fully substituted b-carbon atom. The
reaction is efficient and broad in scope
and proceeds with high diastereo- and
enantioselectivity.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!