C2-Symmetric Chiral Bisoxazolines as Hydrogen-Bond-Acceptor Catalysts in Enantioselective Aldol Reaction of β-Carbonyl Acids with Trifluoroacetaldehyde Hemiacetals

Article abstract of DOI:10.1021/acs.orglett.6b03256

A simple C₂-symmetric chiral bisoxazoline is demonstrated to use hydrogen bonding to catalyze an important family of aldol reactions of trifluoroacetaldehyde hemiacetals with various β-carbonyl acids. This reaction is highly enantioselective, delivering chiral nonracemic trifluoromethylated alcohols with excellent optical purity and good isolated yields. This concept of relaying chiral information via a chiral hydrogen-bond acceptor should be applicable to a vast number of organocatalytic processes.

Full text of DOI:10.1021/acs.orglett.6b03256

Letter
pubs.acs.org/OrgLett
C2‑Symmetric Chiral Bisoxazolines as Hydrogen-Bond-Acceptor
Catalysts in Enantioselective Aldol Reaction of β‑Carbonyl Acids with
Trifluoroacetaldehyde Hemiacetals
Zhen-Yan Yang,† Jun-Liang Zeng,† Nan Ren,† Wei Meng,‡ Jing Nie,† and Jun-An Ma*,†
†Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, and Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. China
‡Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
S
* Supporting Information
ABSTRACT: A simple C2-symmetric chiral bisoxazoline is demonstrated to use hydrogen bonding to catalyze an important
family of aldol reactions of trifluoroacetaldehyde hemiacetals with various β-carbonyl acids. This reaction is highly
enantioselective, delivering chiral nonracemic trifluoromethylated alcohols with excellent optical purity and good isolated yields.
This concept of relaying chiral information via a chiral hydrogen-bond acceptor should be applicable to a vast number of
organocatalytic processes.
A myriad of chiral metal complexes of bisoxazolines have
spawned countless asymmetric reaction classes, thereby
dramatically expanding the synthetic toolbox available to
researchers in the chemical and biological sciences (Figure
1a).5 In contrast, little progress has made in the direct use of
ydrogen bonding is a special type of electrostatic
Hattraction between the hydrogen atom bonded to the
donor and the lone electron pair on the acceptor.1 In biological
systems, hydrogen bonding is one of the most dominant forces
for molecular interaction and recognition, such as protein
folding, DNA base-pairing, receptor−ligand binding, and
enzyme catalysis.2 In addition to the eminent importance of
hydrogen bonding for the intricate architecture and function-
ality of biological molecules, the potential benefits that
hydrogen bonding offers in asymmetric catalysis have been
appreciated by organic chemists in recent years. Accordingly, a
great number of hydrogen-bond donors3 have been invented as
small organic molecule catalysts and demonstrated useful levels
of enantioselectivity for a wide range of different asymmetric
transformations. The unique characteristic of hydrogen-
bonding catalysis is that the catalyst not only activates the
reactants and stabilizes the transition states through hydrogen-
bonding interactions but also orients them in close proximity
with the desired relative geometry, and therefore, the reaction is
often facilitated in a synergistic way, in a manner similar to that
of enzymatic catalysis. In addition to a hydrogen donor, an
acceptor with a lone electron pair is another partner in
hydrogen bonding. However, no example has emerged of
asymmetric catalysis using chiral hydrogen-bond acceptors as
organocatalysts4 to promote chemical reactions.
Figure 1. Use of C2-symmetric chiral bisoxazolines (a) as ligands in
metal complexes and (b) as acceptors in hydrogen-bonding complexes.
Calculated hydrogen-bond lengths L (N···H−O−R3) [Å] and
interaction energies ΔE [kcal/mol] for complexes of oxazoline with
H2O, MeOH, and HCO2H are also shown (see SI-Figure 1).
C2-symmetric bisoxazolines as chiral organocatalysts for
enantioselective synthesis, and only one report by Gobel and
̈
co-workers has addressed a bisoxazoline-catalyzed Diels−Alder
reaction of N-substituted maleimides with anthrones through
ion-pair intermediates.6 The design of chiral bisoxazolines was
originally inspired by the ligand framework of vitamin B12.
Therefore, every now and then chiral bisoxazolines would be
prepared, but usually only as metal ligands on the road toward
Over the past several decades C2-symmetric chiral bisoxazo-
lines have proved to be one of the most successful and
commonly used classes of ligand structures for asymmetric
catalysis because of their ready accessibility and modular nature.
Received: October 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03256
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Organic Letters
Letter
more efficient and hopefully unpatented metal complexes. In
point of fact, oxazolines are typical weak bases, and the nitrogen
atom of oxazolines can act as a hydrogen-bond acceptor (Figure
1b).7 Thus, we envisioned that chiral bisoxazolines should
program the assembly of reaction partners with appropriately
oriented hydrogen bonds that are activated toward useful
chemical transformations.
Table 1. Optimization of the Organocatalytic Aldol
Reaction
a
catalyst (mol %)/
solvent/temp (°C)/
yield
b
ee
(%)
Here we report an implementation of this strategy using C2-
symmetric chiral bisoxazolines as small-molecule hydrogen-
bond-acceptor catalysts. Specifically, the aldol reaction between
trifluoroacetaldehyde hemiacetals and β-carbonyl acids was
employed as an ideal platform to test the catalytic ability of
chiral bisoxazolines.8,9 Because of the unique physicochemical
and biological properties of organofluorine compounds,
stereoselective construction of chiral fluorine-containing
molecules under mild reaction conditions has been highly
desirable in organic synthesis, medicinal chemistry, and
materials science.10 It was recognized that the accompanying
aldol products with a trifluoromethyl group have been
established as important chiral synthons for several biologically
active compounds of medicinal and agrochemical interest.11,12
The studies were initiated by evaluating the catalytic activity
of a series of readily accessible chiral bisoxazoline catalysts I−
IX13 in the aldol reaction of 3-oxo-3-phenylpropanoic acid (1a)
and trifluoroacetaldehyde methyl hemiacetal (2a) in dichloro-
methane. Under these reaction conditions, the aldol product 3a
was obtained in high yield with variable enantioselectivity
(Table 1, entries 1−9), with catalyst III giving the best
performance (entry 3). These results clearly validated the
strategy and suggested that additional improvement of the
enantioselectivity might be feasible through further optimiza-
tion of the conditions. The solvent was found to have an
important effect on the reactivity (entries 10−15). Among the
solvents tested, toluene was found to be the solvent of choice
for this reaction with respect to both catalytic activity and
asymmetric induction (entries 14 and 15), whereas the use of
methanol did not furnish the desired product (entry 12). Under
the standard reaction conditions, the catalyst loading was
lowered to 5 mol % without deteriorating the yield and
enantioselectivity (entry 16). Even at a loading of 1 mol %,
catalyst III still delivered comparable results (90% yield with
90% ee) when the reaction was run with a prolonged reaction
time (entry 17). With an increase in temperature, significant
amounts of byproduct acetophenone, formed from a competing
decarboxylation pathway, was recovered during the course of
the reaction (entries 18 and 19). To corroborate further the
reactivity and enantioselectivity of the bisoxazoline catalyst III,
trifluoroacetaldehyde hydrate (2b) and trifluoroacetaldehyde
ethyl hemiacetal (2c) were also tested under the optimized
reaction conditions. The target product 3a was also obtained in
high yield and enantioselectivity (entries 20 and 21).
c
entry
substrate 2
time (h)
(%)
1
2
I (10)/2a
CH2Cl2/0/48
CH2Cl2/0/48
CH2Cl2/0/48
CH2Cl2/0/48
CH2Cl2/0/48
CH2Cl2/0/48
CH2Cl2/0/48
CH2Cl2/0/48
CH2Cl2/0/48
THF/0/48
89
90
91
88
89
86
88
85
90
92
89
0
26
11
88
47
17
10
6
II (10)/2a
III (10)/2a
IV (10)/2a
V (10)/2a
VI (10)/2a
VII (10)/2a
VIII (10)/2a
IX (10)/2a
III (10)/2a
III (10)/2a
III (10)/2a
III (10)/2a
III (10)/2a
III (10)/2a
III (5)/2a
III (1)/2a
III (5)/2a
III (5)/2a
III (5)/2b
III (5)/2c
3
4
5
6
7
8
16
10
84
64
0
9
10
11
12
13
14
15
16
17
18
19
20
21
Et2O/0/48
MeOH/0/48
hexane/0/48
toluene/0/48
toluene/0/96
toluene/0/96
toluene/0/120
toluene/10/96
toluene/25/96
toluene/0/96
toluene/0/96
72
92
98
98
90
88
80
95
95
78
95
95
95
90
90
83
90
93
a
The reactions were carried out using 1a (0.3 mmol, 49.2 mg), 2a−c
(0.2 mmol), and chiral bisoxazoline catalysts I−IX (1−10 mol %) in
b
the solvent at the stated temperature for the stated time. Isolated
c
yields obtained as averages of two runs. Determined by chiral-phase
HPLC. The absolute configuration of 3a is based on a comparison of
the optical rotation with the literature value.11,12
Scheme 1. Several Control Reactions
In order to compare with trifluoroacetaldehyde hydrate and
hemiacetals, we also carried out two control experiments using
acetals 2d and 2e as the substrates. However, no desired
product 3a was observed under the otherwise identical reaction
conditions (Scheme 1a,b). In addition, subjecting trifluoroace-
taldehyde to the optimum reaction conditions delivered the
aldol product 3a in 89% yield, albeit with low enantioselectivity
(28% ee) (Scheme 1c). These experimental results revealed
that the hydroxyl group of the hydrate and hemiacetal
substrates is critically important to both the activity and
enantioselectivity of this aldol reaction, in which the hydrate
and hemiacetals can be activated and oriented by hydrogen
B
DOI: 10.1021/acs.orglett.6b03256
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Letter
bonding with the bisoxazoline catalyst. To probe the interaction
between substrates and catalyst, we conducted some NMR
spectroscopic experiments (see SI-Figures 2−5). When
bisoxazoline catalyst III was added to a solution of
trifluoroacetaldehyde methyl hemiacetal 2a in [D8]-toluene,
the broad singlet of the OH proton of 2a at 2.48 ppm rapidly
disappeared. In addition, as the loading amount of the
bisoxazoline catalyst was increased from 0.1 to 1 equiv, the
quartet signals of the CH proton and carbon of 2a became a
doublet of quartets at 4.34 and 93.40 ppm (1H and 13C NMR),
respectively (SI-Figures 2 and 3), whereas the doublet for the
CF3 group was converted to a triplet signal at −82.38 ppm (19F
NMR) (SI-Figure 4). This indicates that two diastereomeric
complexes stemmed from the interaction of the bisoxazoline
and hemiacetal. Similar 1H NMR experiments were carried out
using a mixture of a β-keto acid and bisoxazoline catalyst III in
[D8]-toluene (SI-Figure 5). It was found that the sharp singlet
of the CO2H proton at 12.35 ppm became a broad singlet.
Furthermore, upon addition of 1 equiv of catalyst III to a
solution of the β-keto acid in [D8]-toluene, two singlet signals
(at 12.35 ppm for the acid proton and at 10.15 ppm for the
enol proton) of the β-keto acid rapidly disappeared, and a new
broad singlet at 8.42 ppm appeared, indicating the formation of
a novel hydrogen-bonding complex.
bisoxazoline III, the reactions of ortho-, meta-, and para-
substituted phenyl β-keto acids with trifluoroacetaldehyde
methyl hemiacetal 2a all proceeded smoothly, thus generating
the aldol products 3a−l in consistently excellent yields (95−
98%) with good to high enantioselectivities (80−95% ee). 1-
Naphthyl-, 2-naphthyl-, 2-thiophenyl-, and 2-furanyl-substituted
β-keto acids were also found to be good substrates, delivering
the desired products 3m−p in high yields and enantioselectiv-
ities. Also, a β-ionone-derived β-keto acid was subjected to this
aldol reaction under the same conditions, and the correspond-
ing product 3q was obtained in 96% yield with 86% ee. It is
noteworthy that alkyl-substituted β-keto acids could also be
used as the nucleophilic partner, and good results were
obtained for the aldol adducts 3r−t. To further define the scope
of our methodology, the reaction of the less reactive malonic
acid half oxyester with 2a was tested. The decarboxylative aldol
condensation of this substrate proceeded efficiently to give the
product 3u in 95% yield with 92% ee.
With the success of the bisoxazoline-catalyzed aldol reaction
as a means to provide chiral trifluoromethylated alcohols with
the carbonyl functionality, we decided to explore the synthetic
scalability and application of this asymmetric transformation
(Scheme 3). As expected, almost the same results were
Scheme 3. Scaled-Up Reaction and Further Transformation
With the optimal conditions in hand, we turned our attention
to an investigation of the substrate scope, and the results are
summarized in Scheme 2. In the presence of 5 mol %
Scheme 2. Scope of This Electrophilic Reaction
obtained when the enantioselective aldol condensation of β-
carbonyl acids 1a and 1u with trifluoroacetaldehyde methyl
hemiacetal 2a was run on a decagram scale. Notably, the chiral
bisoxazoline catalyst was easily recovered by flash chromatog-
raphy in excellent yield (94%). The recovered catalyst could be
reused without any loss of reactivity and enantioselectivity.
Both of the aldol products 3a and 3u are versatile synthetic
intermediates and can be readily transformed to the
antidepressant drug befloxatone following literature procedures
(Scheme 3a).11a,b Moreover, the trifluoromethylated β-keto
alcohols are also important intermediates for the synthesis of
biologically active isoxazoles.11c,d For example, a hydroxylami-
nation process using NH2OH·HCl gave rise to the correspond-
ing ketoxime 4, which was then converted into trifluoromethy-
lated isoxazoline 5 by means of a Mitsunobu cyclization.14 In all
of these processes, no loss of enantiomeric purity was observed
(Scheme 3b).
C
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Letter
Rev. 2009, 109, 2505. (d) Desimoni, G.; Faita, G.; Jørgensen, K. A.
Chem. Rev. 2011, 111, PR284.
In summary, we have proved that C2-symmmetric chiral
bisoxazolines can be employed as small-molecule hydrogen-
bond-acceptor catalysts for enantioselective synthesis. The
development of an organocatalytic asymmetric decarboxylative
aldol reaction of β-carbonyl acids with trifluoroacetaldehyde
hemiacetals is especially notable given the high enantioselec-
tivity and the demonstrable applicability of this method to the
facile synthesis of biologically active agents. This study should
encourage further development of novel asymmetric trans-
formations by directly using C2-symmmetric chiral bisoxazo-
lines as organocatalysts. We also anticipate that the hydrogen-
bond-acceptor catalysis will open a new avenue for
enantioselective synthesis.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03256.
Experimental details and NMR data for all new
compounds (PDF)
AUTHOR INFORMATION
(10) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis,
Reactivity, Applications; Wiley-VCH: Weinheim, Germany, 2004.
■
Corresponding Author
*E-mail: majun_an68@tju.edu.cn.
ORCID
(b) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
̈
(c) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;
́
́
̃
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev.
2014, 114, 2432.
Jun-An Ma: 0000-0002-3902-6799
Notes
(11) (a) Rabasseda, X.; Sorbera, L. A.; Castaner, J. Drugs Future
̃
1999, 24, 1057. (b) Ishii, A.; Kanai, M.; Higashiyama, K.; Mikami, K.
Chirality 2002, 14, 709. (c) Kawai, H.; Tachi, K.; Tokunaga, E.; Shiro,
M.; Shibata, N. Angew. Chem., Int. Ed. 2011, 50, 7803. (d) Huang, Y.-
Y.; Yang, X.; Chen, Z.; Verpoort, F.; Shibata, N. Chem. - Eur. J. 2015,
21, 8664.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(12) (a) Funabiki, K.; Yamamoto, H.; Nagaya, H.; Matsui, M.
Tetrahedron Lett. 2006, 47, 5507. (b) Zhang, F.; Peng, Y.; Liao, S.;
Gong, Y. Tetrahedron 2007, 63, 4636. (c) Funabiki, K.; Itoh, Y.;
Kubota, Y.; Matsui, M. J. Org. Chem. 2011, 76, 3545. (d) Cotman, A.
E.; Cahard, D.; Mohar, B. Angew. Chem., Int. Ed. 2016, 55, 5294.
(13) Bisoxazolines I−VII were directly purchased and used without
further purification. VIII and IX were synthesized according to the
literature. See: (a) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q.-
L. J. Am. Chem. Soc. 2007, 129, 5834. (b) Zhu, S.-F.; Song, X.-G.; Li,
Y.; Cai, Y.; Zhou, Q.-L. J. Am. Chem. Soc. 2010, 132, 16374.
(14) Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
(b) Mitsunobu, O. Synthesis 1981, 1981, 1. (c) Swamy, K. C.; Kumar,
N. N.; Balaraman, E.; Kumar, K. V. Chem. Rev. 2009, 109, 2551.
This work was supported financially by the National Natural
Science Foundation of China (21225208, 21472137, and
21532008), the National Basic Research Program of China
(973 Program) (2014CB745100), and the Tianjin Municipal
Science & Technology Commission (14JCZDJC33400).
Professor Qi-Lin Zhou (Nankai University) is gratefully
acknowledged for kindly providing chiral spiro-bisoxazolines.
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