Biomimetic Asymmetric Reduction of Quinazolinones with Chiral and Regenerable NAD(P)H Models

Article abstract of DOI:10.1002/cjoc.202000045

A facile approach to chiral dihydroquinazolinone derivatives has been described via biomimetic asymmetric reduction of quinazolinones with chiral and regenerable NAD(P)H models. The utility of this method was demonstrated by a concise synthesis of the bromodomain protein divalent inhibitor.

Full text of DOI:10.1002/cjoc.202000045

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Biomimetic Asymmetric Reduction of Quinazolinones with Chiral and
Regenerable NAD(P)H Models
Authors: Zi-Biao Zhao, Xiang Li, Bo Wu, and Yong-Gui Zhou*
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Biomimetic Asymmetric Reduction of Quinazolinones with Chiral and
Regenerable NAD(P)H Models
Zi-Biao Zhao,a Xiang Li,a Bo Wu,a and Yong-Gui Zhou*, a,b
a State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. China.
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion: A facile approach to chiral dihydroquinazolinone derivatives has been described via biomimetic
asymmetric reduction of quinazolinones with chiral and regenerable NAD(P)H models. The utility of this method was demonstrated by a concise synthesis
of the bromodomain protein divalent inhibitor.
synthesis of chiral dihydroquinazolinones. In 2013, Zhou, Ma and
Background and Originality Content
[8]
co-workers
reported palladium-catalyzed asymmetric
Dihydroquinazolinones are identified as significant and
prevalent structural motifs in bioactive and pharmaceutical
molecules.[1] It is well known that these molecules could be
served as agonists, inhibitors, and antitumor agents. In addition,
these molecules also possess a wide variety of pharmacological
activities such as antiviral, antibacterial and antimalarial activity
(Figure 1).[1] For example, a series of dihydroquinazolinone
derivatives have been used as selective M1 and M4 muscarinic
hydrogenation of the fluorinated quinazolinones, providing the
chiral products with excellent enantioselectivity. Subsequently,
[9]
Zhou and coworkers
developed an iridium-catalyzed
asymmetric hydrogenation of quinazolinones. This method has a
broad scope of substrates, excellent yields and up to 98%
enantioselectivities. Despite the above advance, it is still
necessary to develop new and effective approaches to the
optically active dihydroquinazolinones.
acetylcholine receptors agonist.[1l] They could also be used as
[1e,j]
Scheme 1 Biomimetic asymmetric reduction of quinazolinones.
sodium/calcium exchanger inhibitor
(II) and PDE7 inhibitor
(III).[1f,g] Bromodomain protein divalent inhibitor (IV) with
antitumor activity[1m] has the core structure towards the dihydro-
quinazolinones.
t i HEH by hi13
a
s mme r c rans er
ro ena on w s o c ome r c
A y
t i
t
f
hyd
g
ti
ith
t
i hi
S
)
H
N
H
N
O
O
-
,
e
e
M O2C
CO2M
HEH
CPA
)
R
(
r
r
A
A
NH
N
en ac oroe ane
p
t
hl
30 o
th
e
M
e
M
t
CO2E
N
H
HEH
-
N
,
R
C
12 h
R
Ph
N
Ph
N
u
o
ee
p t 94%
N
N
om me c re uc on w
Bi ti ti
c
ra an re enera
e
mo e s
d l
( )
b
)
i
d
ith hi
l
d
g
bl NAD P H
N
O
N
H
O
ra
Chi
l
H
u s ra es
t
t
S b
o
e
a+ a2+ exc an e n
or
g
i hibit
( )
NAD P H M d l
an
m
a on s
A hR i t
C g
I
( )
M1 d M4
II
( )
N
/
h
C
rans er a a
s
ac ra
hi l
)
e enera on a a
s
T
f
C t ly t
R g
ti C t ly t
(
N
N
Cl
O
O
ra
Chi
NH
N
N
l
H2
NAD P +
M
ro uc s
P
d
t
o e
d l
O
N
O
N
(
)
N
O
H
c
s
Thi
or : om me c as mme r c re uc on o u nazo nones
W
k
Bi
i
ti
y
t i
d
ti
f q
i
li
Cl
)
-
n
or
romo oma n ro e n va en
n
or
u
c mene
y
I
)
]
III PDE7 i hibit
IV B
( )
d
i
p
t i di t i hibit
l
N
R
p
(
)
[
(
H
N
H
,
O
N
mo e 2 c2
O
NAD P H
d l A id
(
)
r
r
Figure 1 Bioactive molecules containing the dihydroquinazolinone motifs.
A
A
e
F
s
NH
N
H2 500 p i
(
)
-
H1
,
R
exam es u
o
ee
(
)
21
pl
p t 98
%
R
R
mo e
d l
Owing to the remarkable importance of dihydroquinazoli-
nones, a variety of powerful approaches have been developed for
the synthesis of dihydroquinazolinones including organocatalytic
aza-Henry reaction,[2] Mannich reaction,[3] organocatalytic
Strecker reaction,[4] allylic C-H amination,[5] decarboxylative [4+2]
cycloaddition[6] and other reactions.[7] Apart from these methods,
asymmetric hydrogenation of easy available quinazolinones
would be one straightforward and atom- economical way for
NAD P H
(
)
♣
♣
a a c amoun
C t lyti
o
mo e s
d l
)
♣
♣
ommerc a ava a e ac s
i lly il bl id
t
f NAD P H
C
(
roa su s ra es sco
b t
e
p
reac on con ons
ti
diti
B
d
t
Mild
Biomimetic asymmetric reduction (BMAR) has attracted much
attention and gradually become one of the most important
choices. NADP/NADPH couple [10] driven reduction reactions have
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Zhao et al.
Report
also been studied in recent years. A series of NAD(P)H models
were designed and utilized.[11] In these models, the most
representative example is Hantzsch esters (HEH).[12] In 2019, Shi’s
group reported a chiral phosphoric acid catalyzed asymmetric
transfer hydrogenation of quinazolinones with HEH as hydrogen
atom donor (Scheme 1).[13] However, this reaction required the
stoichiometric amount of models and suffered from restriction on
regeneration, leading to low atomic economy. The regeneration
of the consumed models will also bring many benefits such as
increasing conversion and omitting NAD(P)H models separation
from the complex system. Due to the importance of regeneration
of models, researchers have invested great scientific interest in
the regeneration of NAD(P)H models.[14] Recently, our group
reported the synthesis of chiral and regenerable NAD(P)H models
based on the planar-chiral ferrocene and their application in
biomimetic asymmetric reduction of tetrasubstituted olefins and
imines.[15] Inspired by this work, we envisaged that biomimetic
asymmetric reduction of quinazolinones with regenerable and
chiral NAD(P)H models would be another straightforward
approach for synthesis of chiral dihydroquinazolinones. Herein,
we present biomimetic asymmetric reduction of quinazolinones,
giving the chiral products with high yields and up to 98% ee. The
utility of this method was demonstrated by a concise synthesis of
the bromodomain protein divalent inhibitor.
3d
4e
5f
Brønsted acid
Brønsted acid
Urea catalyst
(R)-H1
(R)-H1
(R)-H1
>95
>95
10
88
89
43
a
Conditions: 1a (0.10 mmol), [Ru(p-cymene)I2]2 (0.5 mol%), NAD(P)H
models (10 mol%), EtOAc (2.0 mL), H2 (500 psi), 35 oC, 24 h. b Measured by
analysis of 1H NMR. c Determined by chiral HPLC. d Brønsted acid (5 mol%).
e Brønsted acid (10 mol%). f Urea catalyst (20 mol%), CHCl3 (2.0 mL).
Subsequently, we turned our attention to screening of the
transfer catalyst Brønsted acids. A series of Brønsted acids were
evaluated (Table 2, entries 1-5). In case of the acid-2 with
electron-withdrawing nitro group, a high conversion and 88% ee
were observed (entry 2). Next, the solvent effects were examined
with acid-2. Initially, full conversion and moderate enantioselec-
tivity could be obtained in THF (entry 6). When the solvents was
changed to the toluene, the reaction could provide the target
product in 92% ee and full conversion (entry 7). It was worth
noting that solvent trifluorotoluene was the best choice in terms
of conversion and enantioselectivity (entry 8). In addtion, t-butyl
methyl ether and chloroform were also proved to be beneficial for
enantiocontrol (entries 9 and 11). When acetonitrile was used as
solvent, no desired product was observed (entry 10).
Table 2 The evaluation of reaction parameters.a
Results and Discussion
H
N
H
N
-
-
O
O
,
H1
R
( )
2 2
u
c mene
y
R
p
(
I
)
[
]
+
H2
Initially, we investigated background reaction with ruthenium
catalyst [Ru(p-cymene)I2]2 (Table 1, entry 1). This reaction barely
gave the desired product in low 17% conversion. The conversion
could be slightly improved using the chiral and regenerable
NAD(P)H models without transfer catalysts (entry 2). Delightedly,
the biomimetic asymmetric reduction performed smoothly using
commercially available simple Brønsted acid as transfer catalyst,
giving the desirable product in 88% enantioselectivity and full
conversion (entry 3). Meanwhile, when we increased the amount
of Brønsted acid, no obvious improvement in enantioselectivity
was observed (entry 4). Urea catalysts which are capable of
activating substrates through hydrogen-bonding activation have
received significant attention. Unfortunately, the biomimetic
reduction reaction could not give the satisfied result (entry 5).
N
NH
oC
,
,
24 h
s
o ven
S l
500 P i
t 35
(
)
a
r
s e ac
øn
t d id
a
2
1
Ph
B
Ph
O2N
NO2
•
H2O
OH
O
O
O
O
O
O
O
P
P
P
O
OH
O
H
O
OH
S
O
O
COOH
O2N
-
-
-
c
-
-
c
5
A id
c
c
A id
c
1
2
A id
A id
4
A id 3
entry
1
Brønsted acid
Acid-1
Acid-2
Acid-3
Acid-4
Acid-5
Acid-2
Acid-2
Acid-2
Acid-2
Acid-2
Acid-2
solvent
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
THF
conv. (%)b
70
ee (%)c
34
88
29
3
2
>95
79
3
Table 1 Initial result on biomimetic reduction of quinazolinones.a
4
27
H
H
N
-
-
N
O
O
,
H1
R
( )
u
R
c mene
y
I
)
2 2
p
[
(
]
5
>95
>95
>95
>95
>95
<5
77
58
92
95
90
--
+
H2
N
NH
rans er a a s s
EtOA 35 oC 24 h
T
f
,
C t ly t
,
s
500 P i
(
)
6
c
a
1
a
2
Ph
Ph
7
Toluene
N
CF3
CF3
-
-
8
PhCF3
O
4 O2NC6H4O
O
P
4 O2NC6H4O OH
tBuOMe
CH3CN
CHCl3
e
F
F
3C
N
N
C
F
3
9
H
H
-
r
B
s e ac
øn
t d id
rea ca a
U
s
H1
)
t ly t
R
(
10
11
>95
91
transfer
catalysts
NAD(P)H
models
entry
conv. (%)b
ee (%)c
a
Conditions: 1a (0.10 mmol), [Ru(p-cymene)I2]2 (0.5 mol%), (R)-H1 (10
mol%), Brønsted acid (5 mol%), solvent (2.0 mL), H2 (500 psi), 35 oC, 24 h. b
Measured by analysis of 1H NMR. c Determined by chiral HPLC.
1
2
--
--
--
17
25
--
2
(R)-H1
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Biomimetic Asymmetric Reduction of Quinazolinones
Chin. J. Chem.
Next, we conducted the reaction with different kinds of chiral
and regenerable NAD(P)H models (Table 3). The reaction gave the
better result with NAD(P)H models with planar chirality. When
electron-donating group such as methoxy was introduced, the
expected product could be obtained in 93% ee (entry 2).
Compared to the electron-donating group, electron-withdrawing
group obviously slowed down the reduction reaction, affording
the product in low 38% conversion and moderate 79% ee (entry
3). In addition, the NAD(P)H models with axial chirality proved to
be ineffective in terms of reactivity and enantioselectivity (entries
4-6). To our delight, when the temperature was decreased to 25
°C, full conversion and 96% ee were still obtained. Thus, the
optimized conditions were established as: substrate quinazoli-
none 1a (0.20 mmol), [Ru(p-cymene)I2]2 (0.5 mol%), (R)-H1 (10
mol%), acid-2 (5 mol%), H2 (500 psi), PhCF3, 25 oC, 24 h.
After optimizing the reaction conditions, substrate generality
was investigated (Table 4). Firstly, the effect of methyl group on
the different positions of 4-phenyl on the enantioselectivity and
reactivity was screened, all performed very well with 93-95% ee
(2b-2d). When the methyl group was replaced with more
electron-donating group such as methoxy group, slightly lower
90% ee was achieved (2e). Similar result was also observed with
electron-withdrawing fluorine group (2f). Notably, disubstituted
substrates obviously affected the enantioselectivity and yield
(2g-2h). For the 4-biphenylquinazolinone (1i), moderate 73% yield
and 85% ee was obtained. For the 4-naphthylquinazolinone (1j),
the desirable product was obtained moderate 67% yield and 90%
ee. For the alkyl substituted substrates, high yields were
obtained, albeit with moderate enantioselectivities (2k-2l).
analysis of 1H NMR. c Determined by chiral HPLC. d 25 oC.
To further demonstrate the generality of our method, we
explored the substrate scope of different substituents on the
benzo ring (Scheme 2). It was worth noting that methyl group on
the different positions of the basic skeleton could deliver the
products with high yields and 89%-98% ee (2m-2o). Dimethoxy
substituted substrates could lead to excellent yield, albeit with
low 19% of enantioselectivity (2p). The reason might ascribe to
electronic effect. A series of electron-withdrawing substrates
performed very well in the optimized conditions (2q-2u). Halogen
group at different positions had marginal effect on reactivities
and enantioselectivities (2s-2u). The halogen group could provide
more opportunities for further transformations.
Table 4 Substrate scope.a
H
H
-
-
,
c
N
O
N
O
u
c mene
y
2
R
[
p
I
)
A id
(
]
2 2
+
H2
-
PhCF3 25 oC
,
NH
,
N
H1
)
R
(
s
500 P i
(
)
-
36 72h
2
R
1
R
entry
1
2
3
4
5
6
7
8
R
yield (%)b
94 (2a)
90 (2b)
96 (2c)
96 (2d)
92 (2e)
97 (2f)
46 (2g)
<5 (2h)
73 (2i)
67 (2j)
91 (2k)
87 (2l)
ee (%)c
95
Ph
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-FC6H4
3,5-Me2C6H3
3,5-(MeO)2C6H3
4-PhC6H4
93
93
94
90
88
85
--
85
Table 3 The evaluation of NAD(P)H models.a
H
N
H
N
9
O
O
2,
Acid-
p
,
]
-cymene)I2 2
[Ru(
10
11
12
Naphthyl
Cyclohexyl
Isopropyl
90
74
73
+
H2
Psi
N
NH
models
NAD(P)H
PhCF3 24 T,
(500
)
1a
,
h,
2a
Ph
Ph
a
Conditions: 1 (0.20 mmol), [Ru(p-cymene)I2]2 (0.5 mol%), (R)-H1 (10
N
mol%), acid-2 ( 5 mol%), PhCF3 (2.0 mL), H2 (500 psi), 25 oC, 36-72 h.
Isolated yields. c Determined by chiral HPLC.
b
R
N
Fe
N
R
R
:
:
:
=
=
=
H1
H2
H3
R
)-
R
)-
R
)-
R
R
R
H
OCH3
F
(
(
(
:
:
=
CH3
OCH3
H4
R
S
R
R
(
(
)-
H5
:
=
CH3
H6
R
)-
R
=
(
)-
NAD(P)H
models
entry
conv. (%)b
ee (%)c
1
2
(R)-H1
(R)-H2
(R)-H3
(R)-H4
(S)-H5
(R)-H6
(R)-H1
>95
>95
38
95
93
79
31
6
3
4
70
5
>95
14
6
7d
5
>95
96
a
Conditions: 1a (0.10 mmol), [Ru(p-cymene)I2]2 (0.5 mol%), NAD(P)H
model (10 mol%), PhCF3 (2.0 mL), H2 (500 psi), 35 oC, 24 h. b Measured by
Chin. J. Chem. 2019, 37, XXX－XXX
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Zhao et al.
Report
Scheme 2 Substrate scopea
Scheme 3 The synthesis of three pharmaceutically active molecules a
H
H
H
H
N
N
N
N
O
S
S
N
O
O
-
-
c
.
.
e
f
R 10
u
c mene
y
,
2
R
p
I
)
A id
e
R
f
10
[
(
]
2 2
N
r
A
r
A
NH
NH
+
H2
N
NH
-
PhCF3 25 o
C
,
,
,
e
s
H1
M
R
500 P i
(
(
)
)
-
2
1
36 72 h
Ph
Ph
- -
-
H
H
N
H
N
a
2
n
or
7 489
SDZ 26
Eg5 I hibit
( )
e
M
N
O
O
O
NH
NH
NH
H
N
O
B
O
e
N
O
M
O
N
O
e
o
M
2
,
s
C
e
M
2SO4
2CO3
NH
NH
m
n
r
B
2
2
r
B
,
a
CH3CN
e
Pd PPh
o uene
N
2CO3
(
l
)
3
4
,
,
,
79 yi ld
%
T
/EtOH/H2O
e
ee
e
ee
e
ee
96% yi ld 94%
92% yi ld 89%
H
92% yi ld 98%
e
83% yi ld
H
H
,
u
>
99%
e
ee
ee
99%
2
3
M O
N
O
F
N
N
O
C
l
O
NH
NH
NH
N
N
O
O
e
M O
N
O
r
r
CH 4B
)
2
B
N
N
(
NH
r
O
N
O
N
2p
2q
2
O
N
,
a
N
H
DMF
e
63% yi ld
,
,
,
e
ee
O
e
ee
O
e
ee
97% yi ld 92%
95% yi ld 93%
95% yi ld 19%
H
N
H
N
H
N
O
ee
romo oma n ro e n va en
n
or
i hibi
t
4
5
t
t
99%
B
d
i
p
i
di
l
ee
99%
NH
NH
NH
r
B
Cl
F
To further demonstrate synthetic utility of this methodology,
three pharmaceutically active molecules containing dihydroquina-
u
s
2
2
2t
zolinone motifs could be concisely synthesized (Scheme 3). For
,
,
,
e
ee
e
ee
97% yi ld 97%
91% yi ld 93%
e
ee
91% yi ld 93%
[16]
instance, human potent Eg5 inhibitor
and a serum HDL
[17]
cholesterol raising agent such as SDZ 267-489
, which play
considerable role in human physical activity. The above two
bioactive molecules could be formally synthesized in simple one
or two steps from chiral dihydroquinazolinones (2a). In addition,
bromodomain protein divalent inhibitors could interfere the
combination with the Brd 4 and acetylated histones.[1m] The
inhibitors (S,S)-5 have the core structure towards the dihydroqui-
nazolinones. Hence, the bromodomain protein divalent inhibitors
(S,S)-5 could be conveniently synthesized from the dihydroqui-
nazolinones (2u) through three steps (N-methylation, Suzuki
coupling and dialkylation) with good yields and without loss of
optical purity.
a
Conditions: 1 (0.20 mmol), [Ru(p-cymene)I2]2 (0.5 mol%), (R)-H1 (10
mol%), acid-2 (5 mol%), PhCF3 (2.0 mL), H2 (500 psi), 25 oC, 36-72 h.
Isolated yields. c Determined by chiral HPLC.
b
A plausible mechanism for biomimetic asymmetric reduction
was proposed,[15b] firstly, chiral NAD(P)H model (R)-H1 could be in
situ reduced with hydrogen by ruthenium complex. Subsequently,
the reduced chiral NAD(P)H model could realize biomimetic
asymmetric reduction of quinazolinones in the presence of
Brønsted acid. Meanwhile, the chiral NAD(P)H model (R)-H1 was
regenerated for the next catalytic cycle.
Conclusions
In summary, we have developed a facile and efficient protocol
that enables the synthesis of chiral dihydroquinazolinones with
excellent enantioselectivities and high yields through biomimetic
asymmetric reduction. This biomimetic method employs chiral
and regenerable NAD(P)H models and commercially available
achiral Brønsted acid as transfer catalysts under the mild reaction
conditions. Furthermore, this methodology provides a concise
approach to synthesize the pharmaceutically active molecules
such as the bromodomain protein divalent inhibitor. Further
development of these chiral and regenerable NAD(P)H models in
other biomimetic catalytic reactions are under investigation by
our group, and will be reported in due course.
Experimental
General procedure for biomimetic asymmetric reduction of
quinazolinone: A mixture of [Ru(p-cymene)I2]2 (1.0 mg, 0.001
mmol), Brønsted acid acid-2 (3.4 mg 0.01 mmol), NAD(P)H model
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Biomimetic Asymmetric Reduction of Quinazolinones
Chin. J. Chem.
(R)-H1 (5.7 mg, 0.02 mmol,) and quinazolinones 1 (0.20 mmol) in
trifluorotoluene (3.0 mL) was stirred at room temperature for 5
min in glove box and then the mixture was transferred to an
autoclave. The reduction was performed at room temperature
under hydrogen gas (500 psi) for 36-72 h. After careful release of
hydrogen gas, the autoclave was opened and the reaction mixture
was directly purified by column chromatography on silica gel
using dichloromethane/methanol as eluent to give the desired
products 2. The enantiomeric excesses were determined by chiral
HPLC.
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CN107056771, 2017.
The full experimental details can be found in the Supporting
Information
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
Financial support from the National Natural Science Foundation
of China (21532006, 21690074) and Chinese Academy of Sciences
(XDB17020300, QYZDJ-SSW-SLH035) is acknowledged.
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Zhao et al.
Report
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Biomimetic Asymmetric Reduction of Quinazolinones
Chin. J. Chem.
Entry for the Table of Contents
Page No.
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A novel and efficient approach to access chiral dihydroquinazolinone derivatives with excellent
enantioselectivities and high yields via biomimetic reduction with chiral and regenerable NAD(P)H
models has been described. Using the above methodology as the key step, the bromodomain
protein divalent inhibitor could be concisely synthesized.
Zi-Biao Zhao, Xiang Li, Bo Wu, and Yong-Gui
Zhou
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.