2-Hydroxybenzophenone as a Chemical Auxiliary for the Activation of Ketiminoesters for Highly Enantioselective Addition to Nitroalkenes under Bifunctional Catalysis

Article abstract of DOI:10.1002/anie.201800435

An organocatalytic system is presented for the Michael addition of monoactivated glycine ketimine ylides with a bifunctional catalyst. The ketimine bears an ortho hydroxy group, which increases the acidity of the methylene hydrogen atoms and enhances the reactivity, thus allowing the synthesis of a large variety of α,γ-diamino acid derivatives with excellent stereoselectivity.

Full text of DOI:10.1002/anie.201800435

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: 2-Hydroxybenzophenone as Chemical Auxiliary for the Activation
of Ketiminoesters in the Highly Enantioselective Addition to
Nitroalkenes under Bifunctional Catalysis
Authors: José Alemán, Alberto Fraile, Andrea Guerrero, Francisco
Esteban, Mario Parra, Manuel Iniesta, Ana Somer, and Sergio
Diaz-Tendero
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800435
Angew. Chem. 10.1002/ange.201800435
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10.1002/anie.201800435
Angewandte Chemie International Edition
COMMUNICATION
2-Hydroxybenzophenone as Chemical Auxiliary for the Activation
of Ketiminoesters in the Highly Enantioselective Addition to
Nitroalkenes under Bifunctional Catalysis†‡
Andrea Guerrero-Corella,+ Francisco Esteban,+ Manuel Iniesta, Ana Martín-Somer, Mario Parra, Sergio
Díaz-Tendero, Alberto Fraile* and Jose Alemán*
Abstract: An organocatalytic system for the Michael addition of
mono-activated glycine ketimine ylide using a bifunctional catalyst
is presented. The ketimine bears an ortho hydroxy group, which
increases the acidity of the methylenic protons and enhances the
reactivity, allowing the synthesis of a large variety of α,γ-diamino
acid derivatives with excellent stereocontrol.
for this class of ylides, two EWGs are needed to increase the
acidity to promote the organocatalytic addition.
In our investigations with bifunctional catalysis,[10] we
speculated that it might be possible to overcome this
organocatalytic limitation in the synthesis of α,γ-diamino acid
derivatives. Recently, different authors such as Takemoto,[11]
Vicario,[12] Palomo,[13] and Krische[14] among others[15] (top,
Scheme 1), have published excellent examples showing how
different chemical auxiliaries using hydrogen bond activation can
increase the electrophilicity of amides or ketones, or be used in
the control of the stereochemistry and reactivity (nitroalkenes and
aldehydes). However, only a few studies have been reported
regarding the increase in nucleophilicity.
α-Amino acids are essential molecules in many fields. They are
used in the synthesis of peptides and proteins, as chiral catalysts,
as a source of chirality in the design of ligands and in total
synthesis.[1] Such is the application and demand for
enantiomerically enriched α-amino acids that synthetic organic
chemists continue to develop new methods of synthesis.[2]
Especially important and relevant are α,γ-diamino acid derivatives,
The low reactivity in the azomethine ylides in the
organocatalytic area is due to the low acidity of the CH2 protons.
Therefore, we wondered if an intramolecular hydrogen bond
activation would help in the addition to nitroalkenes and provide
good reactivity and enantioselectivity. However, in order to find an
appropriate scaffold, the chemical auxiliary must fulfill the
following requirements: i) be recyclable; ii) inexpensive; and iii)
easily removable. Taking these factors into consideration, we
hypothesized that 2-hydroxybenzophenone may be a suitable
candidate due to the easy intramolecular six membered-ring via
hydrogen bond formation, and the easy ketimine hydrolysis
(bottom, Scheme 1). As part of our work to extend the use of the
hydrogen bond activation, we describe here a new direct process
for the synthesis of γ,α-diamino acid derivatives, using a new
chemical auxiliary that is easily recovered, activates the glycine
which are present in
a large number of natural and
pharmaceutical products.[3] For example, DABA analogues are
used as drugs e.g. anticonvulsants, sedatives, and anxiolytics.[3a]
HA-966 and L687414 are used as NMDA antagonists,[3b-c] and
cucurbitine, a natural product found in pumpkins, is used against
the parasite Schistosoma japonicum[3d] (middle-right, Scheme 1).
In recent years, ketiminoesters derived from glycine have
become increasingly important because they provide a starting
material for the synthesis of optically pure α-amino acid
derivatives.[4] The alkylation of glycine ketimines with different
alkylating reagents under PTC conditions has been well
developed by the excellent works of O´Donnell,[5] Maruoka,[6] and
others.[7] However, the number of examples related to their
addition to nitroalkenes, that would give access to -diamino
acid derivatives, is scarce (middle, Scheme 1).[8,9] There are no
highly asymmetric examples of the organocatalytic approach to
these additions in the literature, where the corresponding adducts
in the addition of mono-activated ketimines to nitroalkenes can be
obtained.[9b] The reason for this absence of reactivity, especially
in the field of the bifunctional thiourea catalysis,[9a-b] is related to
the lack of acidity of the protons of the α-methylene ester. In fact,
a
Some Known Catalytic Intramolecular Hydrogen Bond Activation
O
O
H
O
O
O
O
R1
N
N
H
O
R2
R2
O
H
R1
NBoc
H
O
H
R1
R1
Takemoto (2005)
Palomo (2014)
Identification of the Limitation
CO2R1
Vicario (2012)
Krische (2006)
R
R
b
H2N
CO2H
H2N
N
N
NH2
OH
DABA analogues
O
Ph
R2
HA-966 (R= H)
L687414 (R= Me)
organo-
catalysis
access to
amino-

-aminoacids
[a]
A. Guerrero-Corella, F. Esteban, M. Iniesta, M. Parra Prof. Dr. A.
Fraile, Prof. Dr. J. Alemán
not acidic enough
NH2
CO2H
+

R5
Organic Chemistry Department, Módulo 1
derivatives
HN
R3
NO2
Universidad Autónoma de Madrid, Madrid-28049, Spain
E-mail: jose.aleman@uam.es, www.uam.es/jose.aleman
Prof. Dr. S. Díaz-Tendero, Dr. A. Somer-Martín
Chemistry Department
Cucurbitine
R4
c
[b]
Design of a New Chemical Auxiliary
CH2 Acidity
increase
Universidad Autónoma de Madrid, 28049, Spain
Prof. Dr. J. Alemán, Prof. Dr. A. Fraile, Prof. Dr.S. Diaz-Tendero
Institute for Advanced Research in Chemical Sciences (IAdChem),
Prof. Dr. S. Díaz-Tendero
Easy Recover
OH
O
After Use
Inexpensive
H
[c]
[d]
Strong
Hydrogen
CO2R1
Easy Imine formation
High ee´s and dr´s
Good Yieds
O
N
Ph
Activation
1g= 10€
Condensed Matter Physics Center (IFIMAC),
Universidad Autónoma de Madrid, 28049 Madrid, Spain.
C=N Bond:
Easy Hydrolysis
After Addition
[+]
These authors contributed equally to this work.
Supporting information is given via a link at the end of the document
Scheme 1. Background and strategy for the synthesis of a novel chemical
auxiliary in the organocatalytic synthesis of α,γ-diamino acid derivatives.
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10.1002/anie.201800435
Angewandte Chemie International Edition
COMMUNICATION
ketimine and provides excellent yields, diastereo- and enantio-
selectivities.
polar solvents such as CH3CN and MeOH produced worse results
(entries 9 and 10). Interestingly, ethereal solvents provided good
results, especially in the case of THF which resulted in the product
4b as a single diastereoisomer with a 98% ee (entry 7 and 8). The
conversion with the THF solvent was 83% after 4 hours and this
was increased to a full conversion after 15 hours (result between
brackets, entry 8). With these conditions defined, the scope of the
reaction was studied using different substituted nitroalkenes
(Table 2), and ketimines (Scheme 3).
The reaction worked with EDGs and EWGs (4c-4f) with high
enantiomeric excess (92-97% ee) and good yields (74-81%). The
addition reaction was also performed with aromatic groups
containing halogens in the ortho (4g) and para position (4h),
bulkier groups such as naphthyl (4i) and heterocycles in different
positions (4j and 4k) from good to excellent ee (90-99% ee).
Interestingly, alkyl groups at the nitroalkene, which are difficult to
obtain by other methods, were also tolerated, yielding the amino
acid derivative 4l, but longer reaction times of 4 days were needed.
A double bond substitution at the nitroalkene led to the final
product 4m in a good yield (83%) and excellent ee (98% ee).
We analyzed other groups at the azomethine ylides in place
of the carboxylate group (Scheme 3). This catalytic system with
the hydroxy group allowed the addition of nitrile ylide 1n and
yielded the product 4n in moderate enantiomeric excess.
However, the use of derivatives 1o and 1p, with a ketone and
amide, respectively, resulted in better enantiomeric excesses
(both with 93% ee). The use of CF3 or an aryl group did not enable
Initially, we synthesized the ketimines 1a and 1b (see. S.I.)
in good yields from commercially available starting materials
(Scheme 2). The stability of ketimine 1b is very high, and it could
be stored at room temperature for months. As a proof of concept,
we performed the reaction with the ketimine 1a, without a hydroxy
group. No reaction took place using the ketimine 1a and after 24
hours no trace of the corresponding product 4a was detected.
However, when the ketimine 1b was used with Takemoto’s
catalyst 3a, a complete conversion to 4b occurred in only 4 hours.
These preliminary results prompted us to screen the reaction and
determine the best catalytic conditions in terms of
enantioselectivity, diastereoselectivity and yield (Table 1).
CF3
S
F3C
N
N
R
H
H
R
NO2
Ph
N
3a
N
COOMe +
, 10 mol%
N
O2N
Ph
p-xylene, rt, 4 or 24h
Ph
Ph COOMe
1a
2a
(R= H)
1b (R= OH)
4a
no reaction (R= H)
4b conversion= 100% (R= OH)
Scheme 2. Proof of concept for the intramolecular H-bond activation.
Different thiourea and squaramide catalysts (3a-3b), and
cinchona thioureas (3c and 3d) were tested (entries 1-4, Table 1).
Similar results were found with all the thiourea catalysts (ee>95%,
entries 1 and 3-4), but the reaction resulted in a very low
conversion with the squaramide catalyst 3b (entry 2). We then
followed the optimization with the commercially available
Takemoto catalyst 3a. Different apolar solvents such as DCE or
p-xylene produced similar results (entries 5 and 6), whereas the
Table 2. Reaction of glycine ketimine 1b with different nitroalkenes 2.[a]
Table 1. Screening of reaction conditions for the synthesis of 4b.[a]
N
H
N
H
N
OMe
OMe
F3C
H
H
N
X
N
X
S
CF3
3a
N
N
3d
3c
N
H
H
CF3
S
N
N
N
H
X=
N
H
F3C
O
O
CF3
OH
3b
Ph COOMe
O
H
N
NO2
Ph
N
catalyst 3 (10 mol%)
+
COOMe
solvent, 4h, r.t.
Ph
O2N
Ph
1b
4b
2a
Ee
Conversion[b] d.r.[b]
Entry
Solvent
Cat.
[%][c]
1
2
3a
3b
3c
3d
3a
3a
3a
3a
3a
3a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
100
10
90:10
80:20
92:8
97
n.d.[d]
3
89
95
4
100
95:5
97
5
p-Xylene
DCE
92
92:8
95
96
96
98
6
100
88:12
85:15
>98:2
7
Et2O
84
THF
83 (100)[e]
8
9
CH3CN
MeOH
94
52
90:10
91:9
96
74
10
[a] All the reactions were performed at 0.2 mmol scale in 0.4 mL THF. Ee
(enantiomeric excess) of 4 were determined by SFC. D.r. (diastereomeric ratio)
was determined by 1H NMR: Yield isolated after flash chromatography. [b]
Reaction time: 4 days. [c] Reaction time: 5 days.
[a] Conditions: 0.2 mmol of 1b, 0.24 mmol of 2a, 10 mol% of catalyst 3 in 0.4
mL of the indicated solvent. [b] Determined by 1H NMR analysis. [c] Determined
by SFC. [d] Not determined. [e] Determined after 15 h reaction.
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10.1002/anie.201800435
Angewandte Chemie International Edition
COMMUNICATION
the corresponding products 4q and 4r, and we only observed the
Figure 1. We then evaluated the effect of the different substituents
in the acidity of the ketimine 1 towards the formation of the ylide
4A-complex. The G in 1b (with an OH group) is 5.9 kcal/mol
lower than in 1a (without an OH group), which demonstrates the
importance of the intramolecular H bond in increasing the acidity.
Electron-withdrawing substituents such as COPh (1o), CN (1n),
CONMe2 (1p), CO2Me (1b) present both inductive (–I) and
mesomeric (–M) effects; however, 1q (CF3) possesses only –I
and 1r (Ph) exclusively –M effect. As was predicted, the reactants
that present groups with both effects showed a lowerG (higher
acidity). For groups at the ketimine 1 showing only one of the
effects, the G was increased, (lower acidity). Consequently,
these latter cases (1q and 1r) did not react. Therefore, a
combination of these factors is needed to increase the acidity: the
intramolecular hydrogen bond (C=N---HO-Ar), and the
appropriated substituents at the ketimine 1 (R groups with both –
I and –M effects).
unaltered starting materials in the crude mixture.
OH
OH
R
N
R
3a
cat.
(10 mol%)
O2N
+
Ph
Ph
THF, rt, 2-4d
N
O2N
1
4
2a
OH
OH
OH
CONMe2
CN
[b]
COPh
N
N
N
O2N
O2N
4n
O2N
4o
4p
(76%)
(59%)
93% ee, dr>98:2
(59%)
93% ee, dr>98:2
51% ee, dr>98:2
OH
OH
Ph
CF3
N
N
O2N
O2N
4q
4r
no reaction
no reaction
O
H
N
Scheme 3. Use of different glycine ketimines [a] 0.2 mmol (1), 0.24 mmol (2),
10 mol% of 3a in 0.4 mL of THF. [b] Yield based on recovered material.
3a + 2a
+
R
Ph
1
In addition, the reaction was scaled up and the hydroxyketone
and catalyst 3a were easily recovered (Scheme 4). The reaction
at this scale (5.6 mmol) took 22 h to complete and using a fast
percolate of the crude mixture the compound 4b (98% ee) was
obtained, and catalyst 3a was recovered with a 75% yield (right,
Scheme 4). Compound 4b was treated with HCl (10%) in smooth
conditions, and after a simple extraction, the hydroxyketone 5 was
recovered with a 96% yield. The amino acid salt derivative 6 was
washed with NaHCO3, and the free amino acid 7 (left, Scheme 4)
obtained. The absolute configuration of the asymmetric centres of
6 was unequivocally assigned as 2S, 3S (left, top-Scheme 4) by
X-ray crystallographic analysis and it was assumed to have the
same stereochemical outcome as the other compounds 4.
G

CF3
S
N
N
H
F3
C
H
N
O
N
H
O
Ph
O
H
N
O
MeO
Ph
4A-complex
Figure 1. G of proton transfer reactions with different nucleophiles 1.
C-C Bond Formation
Proton Transfer
CF3
S
CF3
S
N
H
N
F3C
N
N
F3C
Ph
H
H
H
N
NO2
N
O
OH Ph
O
N
N
3a, (R,R)-Takemoto
thiourea (10 mol%)
H
N
CO2Me
H
O
O
H
O
a) NH3, MeOH
Ph
248 mg (0.56 mmol)
O
H
N
O
O
b)
Cl
2a, 1 g (6.7 mmol)
1b, 1.5 g (5.6 mmol)
N
O
MeO
MeO
H3N
Ph
Ph
O
DCE/ 80ºC
83% yield
CO2Me
H2N
O2N
75%
recovered
(185 mg)
OH
O
7
84% yield
1.17 g
ee = 98%
5
Percolate
AcOEt/MeOH
(9:1)
1) NaHCO3
2) Extraction
AcOEt
OH
96% yield
1.07 g
Et2O phase
Cl
CO2Me
Ph
H3N
Hydrolysis
HCl (10%)
CO2Me
Extraction
Aqueous
phase
N
O2N
6
O2N
4b
Scheme 4. Scale up and catalyst and chemical auxiliary recovery.
The reaction mechanism of the nitroalkene 2a with the
glycine ketimine 1b in presence of catalyst 3a was studied using
DFT calculations (see S.I. for details).[17] Initially, we investigated
the reasons for the lack of reactivity of the three nucleophiles 1a,
1q and 1r in comparison with 1b and 1n-p (Figure 1). We
considered the acid-base equilibrium in which the proton is
transferred from the ketimine 1 to the catalyst 3a and a molecular
hydrogen bonded 4A-complex is formed.[18] The relative Gibbs
free energy (G) in the proton transfer equilibrium is presented in
Figure 2. G and energy profile of the two step mechanism.
We then considered the complete picture of the mechanism
for the reaction between 1b and 2a catalyzed by 3a. Two steps
are involved in this process: a proton transfer leading to the ylide,
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10.1002/anie.201800435
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COMMUNICATION
H. H. Hermkens, L. A. J. M. Sliedregt, H. W. Scheeren, F. P. J. T. Rutjes
Tetrahedron 2009, 65, 5393.
followed by the C–C bond formation (top, Figure 2). The energetic
profile of both steps is presented in Figure 2. In the first stage, a
transition state consists of the direct migration of the proton from
the ketimine 1b to the catalyst 3a. The relative position of the
nitroalkene 2a depends on the relative position of the proton,
because the intrinsic dipole of the nitro group points towards the
positive charge on the proton and assists the proton-migration.
Figure 2 also shows how the coordination by means of hydrogen
bonds is fundamental to the appropriate orientation of the
ketimine 1b with the catalyst 3a, enabling the proton transfer to
be carried out. The second stage due to the subtle movements
involved in the geometric reorganization has a very complex
energy profile and therefore only a scan of the C–C bond distance
is presented (see details of the complete exploration of the
potential energy surface in the S.I.). It implies a reorientation of all
the three benzene rings located in the catalyst, in the electrophile,
and in the nucleophile, for the new conformation that involves the
coordinated rotations of the different dihedral angles. The
intramolecular attack of the nitronate intermediate generated on
the ketimine is hindered because the orientation of the phenyl ring
of the ketimine is blocking this addition, without the formation of
the pyrrolidine core by a formal 1,3-dipolar-cycloaddition. In this
step, the coordination of the nucleophile 1b to the catalyst 3a is
also a crucial point in the stereochemistry of the products.[19]
Overall, the rate limiting step is the proton transfer with a larger
energy barrier than the C-C bond formation (see Figure 2).
[4]
[5]
[6]
a) T. Hashimoto, K. Maruoka Chem. Rev. 2007, 107, 5656; b) M. J.
O’Donnell Acc. Chem. Res. 2004, 37, 506; c) K. Maruoka, T. Ooi Chem.
Rev. 2003, 103, 3013; d) M. J. O’Donnell Aldrichimica Acta 2001, 34, 3.
a) M. J. O'Donnell, F. Delgado, R. S. Pottorf Tetrahedron 1999, 55, 6347;
b) M. J. O'Donnell, W. D. Bennett, S. Wu J. Am. Chem. Soc. 1989, 111,
2353.
a) T. Kano, T. Kumano, R. Sakamoto, K. Maruoka Org. Biomol. Chem.
2013, 11, 271; b) T. Ooi, D. Kato, K. Inamura, K. Ohmatsu, K. Maruoka
Org. Lett. 2007, 9, 3945; c) K. Maruoka, T. Ooi, T. Kano Chem. Commun.
2007, 1487.
[7]
[8]
a) L. Belding, P. Stoyanov, T. Dudding J. Org. Chem. 2016, 81, 553; b)
J. S. Bandar, T. H. Lambert J. Am. Chem. Soc. 2012, 134, 5552; c) W.
He, Q. Wang, Q. Wang, B. Zhang, X. Sun, S. Zhang Synlett 2009, 1311.
Organometallic examples have been described in the literature using
copper and silver catalytic systems. See: a) K. Imae, T. Konno, K. Ogata,
S. –I. Fukuzawa Org. Lett. 2012, 14, 4410; b) H. Y. Kim, J. –Y. Li, S. Kim,
K. Oh J. Am. Chem. Soc. 2011, 133, 20750; c) E. Conde, I. Rivilla, A.
Larumbe, F. P. Cossío J. Org. Chem. 2015, 80, 11755.
[9]
Only two organocatalytic reactions have been described in the addition
of azomethine ylides to nitroalkenes with low enantioselecivities and
moderate reactivity. See: a) J. Xie, K. Yoshida, K. Takasu, Y. Takemoto
Tetrahedron Lett. 2008, 49, 6910; b) M. –X. Xue, X. –M. Zhang, L. –Z.
Gong Synlett 2008, 691.
[10] a) M. Frias, R. Mas-Ballesté, S. Arias, C. Alvarado, J. Alemán J. Am.
Chem. Soc. 2017, 139, 672; b) C. Jarava-Barrera, F. Esteban, C.
Navarro-Ranninger, A. Parra, J. Alemán, Chem. Commun. 2013, 49,
2001; c) V. Marcos, J. Alemán, J. L. García Ruano, F. Marini, M. Tiecco,
Org. Lett. 2011, 13, 3052; d) A. Parra, R. Alfaro, L. Marzo, A. Moreno-
Carrasco, J. L. García Ruano, J. Alemán Chem. Commun 2012, 48, 9759.
[11] T. Inokuma, Y. Hoashi, Y. Takemoto J. Am. Chem. Soc. 2006, 128, 9413.
[12] G. Talavera, E. Reyes, J. L. Vicario, L. Carrillo, Angew. Chem. Int. Ed.
2012, 51, 4104.
In summary, an organocatalytic strategy for the synthesis of
α,γ-diamino acid derivatives in high enantiomeric excess is
presented. The key to the success is the intramolecular activation
via hydrogen bonding through an ortho hydroxy group, which
allows the Michael addition to take place in the presence of
glycine ylides bearing only one activating group.
[13] E. Badiola, B. Fiser, E. Gómez-Bengoa, A. Mielgo, I. Olaizola, I.
Urruzuno, J. M. García, J. M. Odriozola, J. Razkin, M. Oiarbide and C.
Palomo J. Am. Chem. Soc. 2014, 136, 17869.
[14] C. K. Jung, M. J. Krische J. Am. Chem. Soc. 2006, 128, 17051.
[15] a) S. Park, H. J. Kim Chem. Commun. 2010, 46, 9197; b) N. N. Chipanina,
L. P. Oznobikhina, T. N. Aksamentova, A. R. Romanov, A. Yu. Rulev,
Tetrahedron 2014, 70, 1207; c) D. R. Li, A. Murugan, J. R. Falck J. Am.
Chem. Soc. 2008, 130, 46; d) Z. Wang, X. Bi, P. Liao, R. Zhang, Y. Liang,
D. Dong Chem. Commun. 2012, 48, 7076.
Acknowledgements
Spanish Government (CTQ2015-64561-R, CTQ2016-
76061-P, MDM-2014-0377), ERC (contract number: 647550) and
CCC-UAM (computing time) are acknowledged. A. G and F. E.
thank to MINECO for Ph. D. fellowships (FPI) and A. M. S. to CAM
for a postdoctoral contract (2016-T2/IND-1660).
[16] CCDC 1582030 (6) can be obtained at www.ccdc.cam.ac.uk.
[17] M.J. Frisch, et al. Gaussian 09, revision B.01; Gaussian, Inc.: Wallingford,
CT, 2009.
[18] We considered also the Takemoto's coordination but it was found to have
larger energy thermodynamic and kinetics barriers, (a) T. Okino, Y.
Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am. Chem. Soc. 2006, 128,
13151) than the Pápai-Zhong’s model: b) A. Hamza, G. Schubert, T.
Sóos, I. Pápai, J. Am. Chem. Soc. 2006, 128, 13151; c) B. Tan, Y. Lu, X.
Zeng, P.J. Chua, G. Zhong. G. Org. Lett. 2010, 12, 2682.
Keywords: -amino acids • bifunctional catalysis • hydrogen
bond activation • chemical auxiliary
[1]
As catalyst: a) H. Xie, T. Hayes, N. Gathergood Catalysis of Reactions
by Amino Acids in Amino Acids, Peptides and Proteins in Organic
Chemistry Volume 2 - Modified Amino Acids, Organocatalysis and
Enzymes (Ed.: A. B. Hughes), Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim, Germany, 2009, pp. 281-338; As ligand: b) K. Micskei, T.
Patonaya, L. Caglioti, G. Pályi Chem. Biodivers. 2010, 7, 1660; As
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[19] The opposite prochiral face of the electrophile would be attacked but a
strong steric interaction between the aryl group of the catalyst 3a and the
phenyl group of the nitroalkene 2a could take place. This could be the
reason for the lower enantiomeric excess observed for an alkyl
substituent 4l (see Table 2).
[2]
[3]
a) A. E. Metz, M. C. Kozlowski J. Org. Chem. 2015, 80, 1; b) X. –H. Cai,
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10.1002/anie.201800435
Angewandte Chemie International Edition
COMMUNICATION
Andrea Guerrero-Corella, Francisco
Esteban, Manuel Iniesta, Ana Martín-
Somer, Mario Parra, Sergio Díaz-
Tendero, Alberto Fraile*and Jose
Alemán*
Page No. – Page No.
2-Hydroxybenzophenone as Chemical
Auxiliary for the Activation of
Ketiminoesters
Enantioselective
Nitroalkenes
in
the
Addition
Highly
to
In this communication, a new organocatalytic system for Michael addition of mono-
activated azomethine ylides using a bifunctional catalyst is presented.
under
Bifunctional
This article is protected by copyright. All rights reserved.