Biomimetic asymmetric reduction of benzoxazinones and quinoxalinones using ureas as transfer catalysts

Article abstract of DOI:10.1039/d0cc03091k

Using ureas as transfer catalysts through hydrogen bonding activation, biomimetic asymmetric reduction of benzoxazinones and quinoxalinones with chiral and regenerable NAD(P)H models was described, giving chiral dihydrobenzoxazinones and dihydroquinoxalin

Full text of DOI:10.1039/d0cc03091k

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Biomimetic Asymmetric Reduction of Benzoxazinones and Quino-
xalinones Using Ureas as Transfer Catalysts
Zi-Biao Zhao,a,c Xiang Li,a Mu-Wang Chen,b Zongbao K. Zhao*b and Yong-Gui Zhou*a,b,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Using ureas as transfer catalysts through hydrogen bonding reduction10 (Scheme 1b). The readily available and bench-
activation, biomimetric asymmetric reduction of benzoxazinones stable achiral Lewis acids10 and Brønsted acids11 could be used
and quinoxalinones with chiral and regenerable NAD(P)H models as transfer catalysts. These two types of transfer catalysts have
was described, giving the chiral dihydrobenzoxazinones and different activation modes.11 However, these catalysts have
dihydroquinoxalinones with high yields and excellent enantiose- limited compatibility with acid-labile or polyfunctional
lectivities. A key dihydroquinoxalinone intermediate of BRD4 substrates and tandem transformations.12 Therefore, more
inhibitor was synthesized using biomimetric asymmetric reduction. mild and general transfer catalysts remain to be developed,
especially those with potentially new activation modes, to
The development of biomimetic science has brought great
benefits to human life. The reduced nicotinamide adenine
dinucleotide (NADH) and nicotinamide adenine dinucleotide
phosphate (NADPH) as crucial redox coenzymes play a vital
role in the cells. The interconversion of the pyridine nucleotide
coenzymes NAD(P)+ /NAD(P)H is widespread in over 400
enzymatic reactions (Scheme 1a).1 Because these coenzymes
are expensive and labile, synthetic NAD(P)H mimics have been
continuously emerged over the past decades. Early works
mainly focused on development of the stoichiometric NAD(P)H
models such as dihydronicotinamide derivatives2, Hantzsch
esters (HEH)3 and benzothiazolines4 etc. The utilization of the
stoichiometric models limits its further regeneration and leads
to low atomic economy. Subsequently, regenerable NAD(P)H
models were devised and the processes were realized by in
situ regeneration mediated by homogeneous catalysts
including rhodium5, ruthenium6, iron catalyst7 and sodium
dithionate8, etc.9 In terms of biomimetic asymmetric reduction,
stereocontrol is mainly from chiral transfer catalysts.6,7b
Nevertheless, chiral transfer catalyst screening is quite tedious
in each biomimetic reduction. Very recently, a chiral and
regenerable NAD(P)H model based on ferrocene-derived motif
was designed and employed to biomimetic asymmetric
further expand the generality of biomimetic asymmetric
reduction.
(a) NAD(P)H-mediated Metabolism Process in the Cell
Substrates
NAD(P)H
CONH2
TCA Cycle
N
Enzyme I (regeneration) Enzyme II (transfer)
RO
Glycolysis
O
.....
NAD(P)H
NAD(P)+
Products
OH OH
(b) Biomimetic Reduction with Chiral and Regenerable NAD(P)H Models
Chiral
NH
Substrates
NAD(P)H Model
Fe
Transfer Catalyst (achiral)
Regeneration Catalyst
Chiral
NAD(P)+ Model
Chiral NAD(P)H
Model (FENAM)
H2
Products
(c) The Evolution of Transfer Catalysts in Biomimetic Reduction
Chiral
Brønsted Acid
Simple
Lewis Acid
Organocatalyst
Urea
Simple
Brønsted Acid
This work
.
O
Ar
Ar
N
H
N
H
Ureas as Transfer
Catalysts
R3
N
R1
Hydrogen Bonding
Activation
R2
Scheme 1. Biomimetic asymmetric reduction (BMAR) based on
the coenzyme NAD(P)H and transfer catalysts.
a. Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian 116024,
P. R. China. E-mail: ygzhou@dicp.ac.cn
b. State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China. E-mail: zhaozb@dicp.ac.cn
c. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
Hydrogen-bonding interaction plays an important role in the
molecular recognition and activation processes of various
biologically important reactions. (Thio)urea based bifunctional
catalysts capable of activating substrates through hydrogen-
bonding activity have received much attention.13 (Thio)urea
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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derivatives feature good functional group tolerance, cheap, observed (Entry 1). To our delight, the reactiVoienw AcroticuleldOnlbinee
DOI: 10.1039/D0CC03091K
moisture-insensitive, and readily accessible. Therefore, carried out smoothly using the urea derivatives. The desired
catalysis through hydrogen-bonding interaction has been product was obtained in 92% enantioselectivity albeit with low
introduced as
a powerful methodology for asymmetric 10% yield (Entry 2). Next, a number of solvents were
reaction.13 However, no report on the application of this extensively examined. It was found that CHCl3 was the best
method to biomimetic reduction with chiral NAD(P)H models choice in terms of yields and enantioselectivities (Entries 2-7).
appeared. Hence, the development of a novel activation Subsequently, considering the effect of temperature on the
method in biomimetic reduction with chiral and regenerable reaction, we tried to increase the temperature. When the
NAD(P)H models is significant in organic chemistry. In this reaction was carried out at 70 oC, the reaction gave the desired
paper, we present the biomimetric asymmetric reduction product with 82% yield and 96% ee value (Entry 9). However,
through hydrogen-bonding activation strategy with urea when the reaction temperature is further increased, NAD(P)H
derivatives (Scheme 1c).
model based on ferrocene-derived structure will be inactivated
(Entry 10). Subsequently, we turned our attention to a series
of organic hydrogen-bonding catalysts. While replacing urea
with thiourea, the reaction didn’t occur (Entry 11), which
might ascribe to the strong poisonous effect of thiourea to
ruthenium regeneration catalyst. We found that the urea and
squaramide catalysts could make the reaction proceed
smoothly and urea OC-3 proved to be the best (Entries 9, 12-
14). Besides, it was noted that the desirable hydrogenation
product could be obtained albeit with low conversion using
mono hydrogen bonding donor OC-6 (58% conversion, 94% ee)
and full N-methyl protected urea OC-7 (11% conversion, 87%
ee) as transfer catalyst (Entries 15-16).
Table 1. Optimization of reaction parametersa
N
[Ru(p-cymene)I2]2
Chiral NAD(P)H Model (R)-
O
O
O
N
O
H1
Fe
N
H
2a
Ph
H2 (500 psi), T, OC, Solvent
Ph
1a
CF3
-H1
(R)
CF3
CF3
CF3
F
F
O
O
S
N
H
N
H
F3C
CF3 F3C
CF3
N
H
N
N
H
N
H
H
1
2
3
OC-
OC-
OC-
O
F3C
CF3
O
N
O
F
F
O
N
H
N
H
N
R
N
Me
N
F3C
CF3
H
H
6
7
OC- , R = H
OC- , R = Me
4
5
OC-
OC-
Table 2. Optimization of chiral NAD(P)H modelsa
F
F
T (oC)
50
50
50
50
50
50
50
60
70
80
70
70
70
70
70
70
Convn (%)b Ee (%)c
O
Entry
1
OC
--
Solvent
Toluene
O
O
N
H
N
H
O
O
<5
10
12
28
24
35
<5
30
82
60
<5
85
30
33
58
11
--
N
H
2a
Ph
N
Ph
[Ru(p-cymene)I2]2, 70 oC, 24-48 h
2
OC-1 Toluene
OC-1 Benzene
92
95
93
96
91
--
NAD(P)H models, CHCl3, H2 (500 psi )
1a
3
N
4
OC-1
OC-1
OC-1
OC-1
OC-1
OC-1
OC-1
OC-2
OC-3
OC-4
OC-5
OC-6
OC-7
DCM
CHCl3
DCE
R
N
N
R
Fe
5
R
6
H1
(R)- : R = H
H2
(R)- : R = OCH3
H3
(R)- : R = F
H4
(R)- : R = CH3
H5
(S)- : R = OCH3
7
THF
H6
(R)- : R = CH3
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
96
96
92
--
Entry
Chiral NAD(P)H model
(R)-H1
Convn (%)b
Ee (%)c
96
9
1
2
85
45
18
9
10
11
12
13
14
15
(R)-H2
94
3
(R)-H3
83
96
94
97
94
87
4
(R)-H4
14
5
(S)-H5
29
<5
94
53
6
7d
(R)-H6
--
(R)-H1
95
16
a Reaction conditions: 1a (0.10 mmol), [Ru(p-cymene)I2]2 (0.5
mol%), Chiral NAD(P)H model (10 mol%), OC-3 (20 mol%),
a
Reaction conditions: 1a (0.10 mmol), [Ru(p-cymene)I2]2 (0.5
mol%), (R)-H1 (10 mol%), OC (20 mol%), Solvent (2 mL), H2
CHCl3 (2 mL), H2 (500 psi), 70 oC, 24 h. Conversion was
b
o
b
(500 psi), 50 C, 24 h. Conversion was measured by analysis
of 1H NMR spectra. c Determined by HPLC.
c
measured by analysis of 1H NMR spectra. Determined by
HPLC. d 48 h.
To validate our proposed activation strategy, we chose
benzoxazinone (1a) as the model substrate with chiral and
regenerable NAD(P)H model (R)-H1 and (thio)urea derivatives
as transfer catalysts. The results of condition optimization
were summarized in Table 1. The present study was initiated
by direct biomimetic reduction in the absence of transfer
catalyst, unfortunately, only <5% of the desired product was
Hereafter, further examinations focused on screening of
chiral and regenerable NAD(P)H models (Tabel 2). NAD(P)H
models with planar chirality were favourable and the best
result was achieved with (R)-H1. It is worth noting that the
electronic property of the substituents on the structure have
obvious effect on the results (Entries 2-3). In addition, other
2 | J. Name., 2012, 00, 1-3
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NAD(P)H models with axial chirality including the nitrogen enantioselectivity was slightly decreased when the methyl at
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DOI: 10.1039/D0CC03091K
atom close to the C2 axial stereocenter and the nitrogen atom the para-position (4d). Meanwhile, when the methoxy is at the
far away from the C2 axial stereocenter have also been para-position and ortho-position (4e-4f), the enantioselectivi-
investigated. Unfortunately, these NAD(P)H models only ties were slightly lower than the methyl. Notably, when
deliver the trace amount of product (Entries 4-6). In order to introducing fluorine group to meta-position of aryl structure,
enhance the conversion, the reaction time was increased to 48 the reaction proceeded smoothly, giving the desired product
h with improved activity and almost same ee. Therefore, the with excellent enantioselectivity and yield (4g). Furthermore,
optimal conditions were established.
allyl-substituted substrate was also well compatible to deliver
the corresponding product with 95% yield and 93% enantio-
selectivity (4h). It is worth noting that the alkyl-substituted
substrate was also investigated, 97% yield and 90% enantiose-
lectivity could be obtained under the optimal condition (4i).
Scheme 2. The BMAR of benzoxazinones.a
F
F
O
N
H
N
H
O
N
O
O
O
H2
(500 psi)
+
Ar
Ar
[Ru(p-cymene)I2]2, 70 oC, 48 h
H1
R1
N
H
Scheme 3. The BMAR of quinoxalinones.a
R1
(R)- , CHCl3
1
2
F
F
O
O
O
O
O
O
O
R2
N
R2
N
N
H
N
H
O
O
H2
(500 psi)
N
H
+
N
H
N
[Ru(p-cymene)I2]2, 70 oC, 48 h
H
N
H
R1
N
N
R1
OMe
H1
(R)- , CHCl3
2a
93% yield, 94% ee
2b
94% yield, 93% ee
2c
4
3
92% yield, 88% ee
O
O
O
O
O
O
N
N
O
O
O
N
H
N
H
N
H
N
H
N
H
N
H
F
Cl
Br
Cl
Br
2d
86% yield, 93% ee
2f
82% yield, 90% ee
2e
94% yield, 93% ee
4a
92% yield, 92% ee
4b
4c
92% yield, 93% ee
96% yield, 92% ee
O
O
O
O
O
O
OCH3
N
O
N
O
N
O
OMe
N
H
N
H
N
H
N
H
N
H
N
H
2g
96% yield, 94% ee
2h
95% yield, 91% ee
2i
94% yield, 97% ee
OMe
4d
4e
4f
97% yield, 88% ee
91% yield, 83% ee
86% yield, 83% ee
O
O
O
O
O
O
Allyl
N
O
N
O
N
O
Cl
N
H
2j
N
H
2k
N
H
Me
F
2l
N
H
N
H
N
H
91% yield, 98% ee
83% yield, 90% ee
95% yield, 92% ee
4g
4h
4i
aReaction conditions: 1 (0.20 mmol), [Ru(p-cymene)I2]2 (0.5
mol%), (R)-H1 (10 mol%), OC-3 (20 mol%), CHCl3 (3 mL), H2
(500 psi), 70 oC, 48 h.
96% yield, 94% ee
95% yield, 93% ee
97% yield, 90% ee
a
Reaction conditions: 3 (0.20 mmol), [Ru(p-cymene)I2]2 (0.5
mol%), (R)-H1 (10 mol%), OC-3 (20 mol%), CHCl3 (3 mL), H2
(500 psi), 70 oC, 48 h.
With the optimized conditions in hand, the reaction scope of
benzoxazinones was then evaluated, and the results are
summarized in Scheme 2. These results revealed that this
strategy was suitable for a series of benzoxazinones. The
electronic and steric effect on the phenyl of the substrate
slightly influenced the reactivities and enantioselectivities (2a-
2g). For example, the ee value was decreased to 88% when the
electron-donating group methoxy at the para-position of the
aryl moiety (2c). Gratifyingly, the desirable product could be
obtained with high reactivity and enantioselectivity when the
methoxy group at the ortho-position of the aryl moiety (2g).
Subsequently, we investigated disubstituents at the phenyl
and different groups at the benzoxazinones skeleton (2h-2j).
Moreover, the alkyl-substituted substrates were also
amenable to the present reaction, delivering the products in
high yields and excellent enantioselectivities (2k-2l).
Scheme 4. The BMAR of bromine-substituted quinoxalinone
and synthesis of key intermediate of BRD4 inhibitor.
F
F
O
N
H
N
H
N
O
N
N
O
Br
N
H
[Ru(p-cymene)I2]2, 70 oC, 48 h
H1
Br
(R)- , CHCl3, H2 (500 psi)
3j
4j
92% yield, 94% ee
N
N
O
reference 14
N
O
BRD4 Inhibitor
OMe
As a member of the family of the bromodomain and extra-
terminal domain (BET) proteins, bomodomain-containing
protein 4 (BRD4) is a feasible drug target for cancer treatment
on the basis of recent biological and pharmacological studies.14
A series of novel dihydroquinoxalinone derivatives could be
used as BRD4 inhibitors. Therefore, we performed a concise
synthesis of the key intermediate of BRD4 inhibitor using the
above methodology (Scheme 4). Under the standard condition,
To expand the generality of this strategy, we next focused on
biomimetric asymmetric reduction of quinoxalinones with the
NAD(P)H model and urea catalyst. The results are depicted in
Scheme 3. In the case of aromatic moiety, the reaction
conditions tolerated both electron-donating and electron-
withdrawing substituents (4a-4g). It was found that the
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bromine-substituted quinoxalinone 3j afforded the desired
product with 92% yield and 94% ee, which is a key
intermediate for the synthesis of a BRD4 inhibitor.14a
Based on the experimental results, a plausible mechanism
and transition state model are illustrated in Figure S1 (see
Supporting Information). The urea catalysts promote the
reduction through hydrogen-bonding activation. The chiral
NAD(P)H model transfers the hydrogen atom from less steric
face to the imine, leading to the (R)-products.
Tuttle and D. W. C. MacMillan, J. Am. Chem. SoVci.e,w2A0rt0ic5le,O1n2lin7e,
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Conclusions
In summary, we have disclosed hydrogen-bonding activation
strategy in the biomimetric asymmetric reduction with chiral
and regenerable NAD(P)H models. This methodology could be
extended to benzoxazinones and quinoxalinones substrates for
furnishing chiral products with high yields and excellent
enantioselectivities. A key dihydroquinoxalinone intermediate
of BRD4 inhibitor was synthesized using the biomimetric
asymmetric reduction methodology. This activation method
will further broaden the generality of biomimetic asymmetric
reduction. Further, other activation modes and substrates
scope are under progress and the results will be presented in
due course.
5
6
7
8
9
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We are grateful for the financial support from National Natural
Science Foundation of China (21532006) and Chinese Academy
of Sciences (XDB17020300, QYZDJ-SSW-SLH035).
Notes and references
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DOI: 10.1039/D0CC03091K
Table of Contents:
F
F
O
R'
X
R'
X
N
N
H
N
H
O
R
O
R
Ar
Ar
Fe
[Ru(p-cymene)I2]2
(R)-FENAM, H2, CHCl3
N
N
H
Chiral NAD(P)H
Model (FENAM)
21 Examples
Ee: up to 98% ee
X = O, N
Hydrogen-bonding Activation Strategy in Biomimetic Asymmetric Reduction
Using ureas as transfer catalysts through hydrogen bonding activation, biomimetic asymmetric reduction
of benzoxazinones and quinoxalinones has been developed, giving the chiral dihydrobenzoxazinones
and dihydroquinoxalinones with high enantioselectivities. A key dihydroquinoxalinone intermediate of
BRD4 inhibitor was synthesized using biomimetric asymmetric reduction.