Catalytic Asymmetric Intramolecular Bromolactonization of α,β-Unsaturated Ketones

Article abstract of DOI:10.1055/s-0037-1611860

Enantioselective bromolactonization by using an amino-urea catalyst to generate the important bromo-containing 3,4-dihydroisocoumarins is described. Excellent yields and good enantioselectivities could be achieved for various 3,4-dihydroisocoumarin compou

Full text of DOI:10.1055/s-0037-1611860

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
Synlett
S. Liu et al.
Letter
Catalytic Asymmetric Intramolecular Bromolactonization of ,-
Unsaturated Ketones
Shenghui Liua
Hailong Heb
Min Gana
Peng Yia
Me
O
MeO
Me
O
COOH
catalyst (15 mol%), NBS
O
R1
R1
O
R2
N
H
NH
toluene, 15 °C
up to 99% yield
Xiaojian Jiang*a
0
0
0
0-0
0
0
2-1
3
5
5-
3
6
1
1
R2
N
O
Br
,4-dihydroisocumarin
20 examples)
er up to = 10:90)
α, β−unsaturated ketone
= alkyl
R2 = alkyl, aryl
N
H
3
a
1
International Cooperative Laboratory of Traditional Chinese
Medicine Modernization and Innovative Drug Development of
Chinese Ministry of Education (MOE), College of Pharmacy,
Jinan University, Guangzhou 510632, P. R. of China
chemjxj2015@jnu.edu.cn
R
(
(
catalyst
b
Guangzhou Wanglaoji Pharmaceutical Company Limited,
Guangzhou 510450, P. R. of China
Received: 29.04.2019
Accepted after revision: 21.05.2019
Published online: 12.06.2019
lective bromolactonization approach to gain diverse halo-
lactones and isochroman-1,4-diones using organocatalysts
(Scheme 1, a and b).11 Deactivated ,-unsaturated olefins
are used in these reactions. In addition, electron-donating
substituents on the urea moiety and the carbamate moiety
might offer steric and/or electronic effect(s) in the enantio-
determining step.
DOI: 10.1055/s-0037-1611860; Art ID: st-2019-u0240-l
Abstract Enantioselective bromolactonization by using an amino-urea
catalyst to generate the important bromo-containing 3,4-dihydroiso-
coumarins is described. Excellent yields and good enantioselectivities
could be achieved for various 3,4-dihydroisocoumarin compounds.
OH
O
OH
O
Key words 3,4-dihydroisocoumarins, bromolactonization, organocat-
alyst, enantioselectivity, deactivated olefins
O
O
OH
NH2
H
N
COOH
Me
OH
Chiral 3,4-dihydroisocoumarins are isolated from a vari-
Me
O
OH
O
mellein
COOH
ety of natural sources and possess diverse biological activi-
AI-77-B
Me
1
ties. For instance, mullein, a trail pheromone, exhibits an-
O
OH
O
tifungal, antimicrobial, and HCV protease-inhibitory activi-
ties (Figure 1). AI-77-B, isolated from a culture broth of
1b
Bn
N
H
O
Bacillus pumilus, possesses gastroprotective and antiulcero-
Me
MeO
Me
1b,d
ochratoxin A
genic properties.
Ochratoxin A is one of the most abun-
Cl
O
Me
dant food-containing mycotoxins and shows nephrotoxic,
O
hepatotoxic, carcinogenic, and teratogenic properties.1e,f
3-pentyl-3,4-dihydrocoumarin
Chiral 3-pentyl-3,4-dihydrocoumarin has significant cyto-
toxic properties.1 Methods to access this important build-
ing block usually utilize chiral starting materials that can be
converted into the desired molecules by multi-step path-
Figure 1 Examples of biologically active chiral 3,4-dihydroisocoumarins
a,g
Electrophiles such as ,-unsaturated ketones serve as
one of the most widely used precursors in synthetic reac-
tions.12 Considering the 3,4-dihydroisocoumarin frame-
works, we envisioned an intramolecular bromolactoniza-
tion protocol. As depicted in Scheme 1, c, ,-unsaturated
carboxylic acid substrate 3 might be converted into the cor-
responding enantioenriched bromo-substituted 3,4-dihy-
droisocoumarins 4 in the presence of a halogen source, such
as N-bromosuccinimide (NBS) and a suitable chiral catalyst.
Herein, we describe an organocatalytic process that gives
brominated 3,4-dihydroisocoumarins upon bromolacton-
ization of prochiral ,-unsaturated olefinic precursors.
2
ways. However, enantioselective catalytic approaches to
achieve chiral 3,4-dihydroisocoumarins are still very limit-
3
ed. Therefore, developing useful methods to obtain diverse
enantioenriched 3,4-dihydroisocoumarins is highly re-
quired.
Catalytic enantioselective halocyclization of olefinic
substrates is an important strategy to obtain diverse useful
4
heterocyclic backbones. Various mono- and bifunctional
organocatalysts have been widely applied in the asymmet-
ric halocyclization of diverse activated or unactivated ole-
3g,5–10
finic substrates.
Recently, we developed an enantiose-
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
S. Liu et al.
Letter
Since an amino-urea catalyst had been beneficial in the
previous bromolactonization of ,-unsaturated carboxylic
acids, we tested several cinchona alkaloid-derived urea cat-
alysts. Scheme 2 shows that quinine-derived urea catalyst
Subsequent studies focused on optimizing the reaction
conditions. As illustrated in Table 1, the enantioselectivity
decreased when the reaction was conducted at room tem-
perature (entry 1). The effect of additives, such as BzOH and
5a led to an enantiomeric ratio (er) of 57:43. Its quasienan-
NsNH on the asymmetric bromolactonization of substrate
2
tiomer, quinidine-derived urea catalyst 5b, increased the er
value. Catalyst 6a, which bears a cinchonine framework,
provided the product with a higher er of 36:64. Other mod-
ifications of the urea moiety, such as thio-urea, sulfonyl-
urea, and carbamate (6b–d) failed to deliver an acceptable
enantioselectivity.
3a was detrimental, leading to lower enantioselectivities
(Table 1, entries 2–3). Utilization of other solvents, such as
Et O, EtOAc, CH Cl , and CHCl failed to provide a higher er
value (Table 1, entries 4–7). The enantioselectivity in-
creased when the temperature was lowered to 15 °C (Table
1, entry 8). However, further decreasing the temperature to
2
2
2
3
0
°C proved to be harmful to the enantioselectivity (Table 1,
O
O
O
1
(15 mol%), NBS
O α
O
R
O
a)
b)
R
α
OH
toluene, 15 °C
up to 99% yield
β
Br
COOH
catalyst (15 mol%), NBS
toluene, 15 °C, 12 h
O
β
O
O
O
Ph
R2
R2
Ph
2
(15 mol%), NBS
Br
O
R1
R1
3a
4a Br
toluene, 15 °C
up to 99% yield
O
COOH
O
O
ischroman-1,4-dione
Ph
R1
PhHN
H
N
NH
H
H
OEt
N
electron-rich
carbamate
N
N
electron-rich
urea
N
Me
Me
O
MeO
N
H
N
H
EtO
Me
O
Me
N
OMe
HN
O
H
N
O
5a (er 57:43)
5b (er 37:63)
6
H
HN
N
R1
=
N
S
O
O
O
N
H
MeO
Ph
Ph
Ts
Ph
N
NH
N
NH
N
H
NH
N
O
H
H
H
N
1
2
6a (er 36:64)
6b (er 49:51)
6c (er 41:59)
6d (er 47:53)
MeO
EtO
MeO
this work
c)
O
O
O
O
COOH
N
N
H
N
N
H
MeO
N
N
H
asymmetric
O
H
H
H
R1
bromolactonization R1
O
6f (er 29:71)
6g (er 23:77)
R2
6e (er 28:72)
R2
EtO
EtO
O
3
O
4
Br
O
O
3
,4-dihydroisocoumarins
O
N
N
H
N
H
N
H
H
Scheme 1 Bromolactonization of deactivated olefinic acids
6
h (er 22:78)
6i (er 23:77)
O
O
O
EtO
Me
O
Electron-rich substituents, such as methoxyl and ethox-
yl groups provided better er values (Scheme 2, 6e and 6f).
The other tested electron-donating systems failed to im-
prove the er value substantially (Scheme 2, 6g–k). Methyl
substituents offered a higher enantiomeric induction. The
er value increased to 23:77 when additional 2-methyl and
MeO
O
O
O
N
N
H
H
N
H
N
H
N
H
N
6
j (er 22:78)
H
6
k (er 28:72)
6l (er 23:77)
Me
EtO
EtO
Me
O
O
3
-methyl substituents were applied (Scheme 2, 6l and 6m).
N
N
H
Me
N
N
H
H
H
Further screening led us to use one more methyl group at
the benzene ring for the catalyst 6n, which increased the er
value to 25:75. The er value increased to 20:80 when the
position of the methyl substituents was fine-tuned
6m (er 23:77)
6n (er 25:75)
Me
Me
CF3
EtO
Me
MeO
Me
O
O
O
N
H
N
H
N
H
N
H
F3C
N
H
N
H
(Scheme 2, 6o). Finally, catalyst 6p gave the desired product
6
o (er 20:80)
6p (er 19:81)
6
q (er 41:59)
with a 19:81 er value. An electron-withdrawing substitu-
ent, such as the CF group provided a low enantioselectivity
Scheme 2 Study on the effect of the catalyst. a Reactions were con-
ducted with substrate 4a (0.1 mmol), catalyst (0.01 mmol), and NBS
0.12 mmol) in toluene (5 mL) at 15 °C for 12 h in the absence of light.
3
(Scheme 2, 6q).
(
Ts = p-tolulenesulfonyl. The er value was determined by chiral HPLC.
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
Synlett
S. Liu et al.
Letter
entry 9). Use of other bromine sources such as N-bromoph-
thalimide (NBP), 1,3-dibromo-5,5-dimethylhydantoin
DBDMH), and 2,4,4,6-tetrabromo-2,5-cyclohexadienone
TBCHD) showed inferior effects on the enantiomeric in-
duction (Table 1, entries 10–12). The enantioselectivity in-
creased when the catalyst loading was increased to 15 mol%
Table 1 Optimization of the Reaction Conditionsa
O
(
(
COOH
6p, halogen source
O
O
Ph
solvent
Ph
O
X
3a
4
a, X = Cl, Br, I
(Table 1, entry 13). The er value decreased when the
amount of catalyst was 20 mol% (Table 1, entry 14). It is
noteworthy to mention that although the corresponding
iodo-substituted 3,4-dihydroisocoumarin product could be
obtained in an excellent yield, the enantioselectivity was
poor when N-iodosuccinimide (NIS) was used instead of
NBS (Table 1, entry 15).
Entry
Halogen
source
Conditions
erb
Yield
(%)c
1
2
3
4
5
6
7
8
9
NBS
toluene, r.t.
22:78
24:76
31:69
32:68
29:71
36:64
25:75
19:81
23:79
21:79
22:78
39:61
18:82
19:81
47:53
–
98
96
97
97
99
99
99
99
98
97
98
96
99
99
99
<5
83
99
NBS
BzOH (1.0 equiv), toluene, r.t.
NBS
NsNH (1.0 equiv), toluene, r.t.
2
1,3-Dichloro-5,5-dimethylhydantoin (DCDMH) was able
NBS
Et
EtOAc, r.t.
CH Cl , r.t.
CHCl , r.t.
2
O, r.t.
to perform the chlorolactonization and produced the de-
sired chloro-substituted 3,4-dihydroisocoumarin com-
pound with 83% yield (Table 1, entry 17). Unfortunately, the
reaction with N-chlorosuccinimide (NCS) was sluggish (Ta-
ble 1, entry 16). The optimal conditions were found when a
NBS
NBS
2
2
NBS
3
NBS
toluene, 15 °C
toluene, 0 °C
toluene, 15 °C
toluene, 15 °C
toluene, 15 °C
toluene, 15 °C
toluene, 15 °C
toluene, 15 °C
toluene, 15 °C
toluene, 15 °C
toluene/CHCl (4:1) solvent system was used and resulted
NBS
3
in a 15:85 er value (Table 1, entry 18).
1
0
1
NBP
The scope of current bromolactonization reaction is
demonstrated by the examples in Scheme 3. First, the effect
1
DBDMH
TBCHD
NBS
2
12
of substituents at different positions on the phenyl ring (R )
1
3d
was investigated. We observed that the enantioselectivity
2
14e
increased when the R group was a 1-naphthyl group (4b,
NBS
er = 14:86). However, the enantioselectivity decreased
when a 2-naphthyl group was applied (4c, er = 21:79).
Moderate enantioselectivities were obtained when 2-, 3-
and 4-methyl-substituted phenyl rings were utilized (4d–f).
We found that the electron-donating 2-methoxyl substitu-
ent delivered a high er value of 10:90 along with an excel-
lent yield (4g), whereas 3- and 4-methoxyl substituents re-
sulted in lower er values (4h and 4i). The enantioselectivity
dropped considerably when a 2-ethoxyl substituent (4j, er
5f
NIS
1
1
1
6
NCS
7g
8d
DCDMH
NBS
40:60
15:85
1
3
toluene/CHCl (4:1), 15 °C
a
Reactions were carried out with substrate 3a (0.1 mmol), catalyst 6p
0.01 mmol), and halogen source (0.12 mmol) in solvent (5.0 mL) in the
(
absence of light. The amount of BzOH or NsNH
2
was 1.0 equiv.
b
The er value was determined by chiral HPLC.
Isolated yield.
The amount of catalyst 6p was 0.015 mmol.
The amount of catalyst 6p was 0.02 mmol.
c
d
e
=
80:20) was used, possibly because of the increased steric
f
N-Iodosuccinimide (NIS) was used as halogen source. The corresponding
hindrance. Electron-withdrawing substituents, such as F, Cl,
and CF3 induced only moderate enantioselectivities (4k–
m). Good er values could be obtained when the phenyl sub-
stituent was located at the o-position (4n, er = 12:88). The
cyclohexyl group delivered a much lower er value (4o, er =
iodolactone was obtained instead of bromolactone.
g
1,3-Dichloro-5,5-dimethylhydantoin (DCDMH) was used as halogen
source. The corresponding chlorolactone was obtained instead of bromo-
lactone.
3
6:64), indicating that a – interaction is beneficial to the
To demonstrate the synthetic utility of this process, fur-
ther transformations were carried out as shown in Scheme
enantioselective induction. A thiophene substituent had a
negative effect on the stereocontrol, leading to a low er val-
ue (4p, er = 25:75). Next, we evaluated the effect of R sub-
stituents. We discovered that 2-, 3-, and 4-methyl-substi-
tuted phenyl rings resulted in moderate enantioselectivi-
ties, though excellent yields were achieved (Scheme 3, 4q,
4. Substitution of Br by using NaN readily gave the desired
3
1
product 7 in 99% yield without loss of enantiomeric excess
(Scheme 4, a). Starting from 4g, an efficient synthesis of
product 8 with high er value was conducted in the presence
of NaHCO and EtOH (Scheme 4, b).
3
4
r, and 4s). The reaction was scalable with an equal er value
Because electron-withdrawing amino-urea catalyst 6q
offered a much lower enantioselectivity (Scheme 2), we as-
sumed that a classical di-hydrogen bond activation process
might not be involved in this reaction. On the basis of our
previous control experiments,1 electron-rich urea catalyst
(Scheme 3, 4a, er = 15:85). The absolute configuration of 4b
13
was determined to be S by X-ray crystallographic analysis.
The configurations of the other products were assigned by
analogy.
1a
6p might react with NBS to form species 6p-Br (Scheme 5),
which could be responsible for the enantioselective induc-
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
Synlett
S. Liu et al.
Letter
O
tion. We suspect that one of the possible transition states
might involve several interactions between the putative
species 6p-Br and ,-unsaturated ketone substrate 3: (1)
the electrophilic Br in 6p-Br might interact with the alkene
to form the bromiranium ion; (2) the N–H group of the urea
might form a hydrogen bond with the ketone moiety in 3;
COOH
O
R1
R1
O
6p (15 mol%), NBS
R2
toluene/CHCl3 (4:1),
15 °C
R2
O
Br
3
a–u
4a–u
O
O
(3) an electrostatic attraction between the basic quinucli-
O
O
O
O
dine moiety in 6p and the carboxylic acid in 3 might be
formed. However, the reason why the ketone moiety failed
to conjugate with the alkene effectively in this type of ,-
unsaturated substrate remains unclear.
R2
S
Br
Br
a,b R2 = Ph, 98% yield, er = 15:85
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4p
b, R2 = 1-naphthyl, 97% yield, er = 14:86
c, R2 = 2-naphthyl, 98% yield, er = 21:79
d, R2 = 2-Me-C6H4, 99% yield, er = 11:89
e, R2 = 3-Me-C6H4, 99% yield, er = 18:82
f, R2 = 4-Me-C6H4, 98% yield, er = 17:83
g, R2 = 2-MeO-C6H4, 99% yield, er = 10:90
h, R2 = 3-MeO-C6H4, 99% yield, er = 19:81
i, R2 = 4-MeO-C6H4, 99% yield, er = 14:86
j, R2 = 2-EtO-C6H4, 95% yield, er = 80:20
98% yield, er = 25:75
Me
O
Me
O
O
MeO
Me
O
NBS
6p
3
Ph
NR
N
N
H
Br
4q
Br
9
8% yield, er = 13:87
6p-Br
k, R2 = 4-F-C6H4, 95% yield, er = 16:84
O
electrostatic attraction
l, R2 = 4-Cl-C6H4, 97% yield, er = 16:84
m, R2 = 4-CF3-C6H4, 98% yield, er = 19:81
n, R2 = 2-Ph-C6H4, 99% yield, er = 12:88
n, R2 = 2-Ph-C6H4, 99% yield, er = 12:88
o, R2 = cyclohexyl, 95% yield, er = 36:64
Me
O
O
hydrogen
bond
R1
OOC
2
Ph
Br
N
H
R
O
O
4r
O
99% yield, er = 86:14
N
Br
Lewis base
Ar
O
O
Me
Scheme 5 Proposed mechanism
Ph
Br
4s
9
9% yield, er = 14:86
In summary, we have described an enantioselective pro-
tocol to produce various synthetically valuable brominated
3,4-dihydroisocoumarins with excellent yields and moder-
ate to good enantioselectivities.14 Studies on the reaction
mechanism as well as further application of this strategy
are ongoing in our laboratory.
Me
O
O
O
OMe
Br
X-ray of 4b
4t
99% yield, er = 30:70
Scheme 3 Substrate scope. a Reactions were conducted with substrate
a (0.1 mmol), catalyst 6p (0.015 mmol), and NBS (0.12 mmol) in tolu-
Funding Information
3
We thank the Natural Science Foundation of Guangdong Province
(Grant No. 2017B050506006) and Fundamental Research Funds for
ene/CHCl (4:1) (5 mL) at 15 °C for 12 h in the absence of light. Isolated
3
yields are given. The er value was determined by chiral HPLC. b Reaction
was carried out on an 1.0 mmol scale.
the Central University (Grant No. 21617470) for financial support.
N
atural S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
G
u
a
n
g
d
o
n
g
Pro
v
i
n
c
e
(2
0
1
7
B
0
5
0
5
0
6
0
0
6)
O
Supporting Information
O
O
Supporting information for this article is available online at
NaN3, DMF, 60 °C
a)
4g
OMe
https://doi.org/10.1055/s-0037-1611860.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orti
n
g Inform ati
o
n
99% yield
er = 10:90
N3
, er = 10:90
O
7
References and Notes
(
1) For selected examples, see: (a) Guimaràes, K. G.; Souza Filho, J.
D.; Mares-Guia, T. R.; Braga, F. G. Phytochemistry 2008, 69, 439.
b) Sun, H.; Ho, C. L.; Ding, F.; Soehano, I.; Liu, X.-W.; Liang, Z.-X.
O
O
NaHCO3, EtOH, 70 °C
95% yield
b)
4g
OMe
(
er = 10:90
EtO
J. Am. Chem. Soc. 2012, 134, 11924. (c) Shimojima, Y.; Hayashi,
H.; Ooka, T.; Shibukawa, M.; Iitaka, Y. Tetrahedron 1984, 40,
8
, er = 10:90
2
519. (d) Itoh, J.; Shomura, T.; Omoto, S.; Miyado, S.; Yuda, Y.;
Scheme 4 Reactions of 4g
Shibata, U.; Inouye, S. Agric. Biol. Chem. 1982, 46, 1255. (e) Van
der Merwe, K. J.; Steyn, P. S.; Fourie, L.; Scott, D. B.; Theron, J. J.
Nature 1965, 205, 1112. (f) Malir, F.; Ostry, V.; Pfohlleszkowicz,
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2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

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Synlett
S. Liu et al.
Letter
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(
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(13) The details are presented in the Supporting Information. CCDC
1911858 contains supplementary crystallographic data for
compound 4b. The data can be obtained free of charge from The
(k) Zhao, Y.; Jiang, X.; Yeung, Y.-Y. Angew. Chem. Int. Ed. 2013, 52,
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2738. (n) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y.
Cambridge
www.ccdc.cam.ac.uk/getstructures.
(14) General Procedure for Bromolactonization. To a PhMe/CHCl (4
Crystallographic
Data
Centre
via
3
J. Am. Chem. Soc. 2010, 132, 15474. (o) Zhou, L.; Chen, J.; Tan, C.
K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2011, 133, 9164. (p) Chen, J.;
Zhou, L.; Yeung, Y.-Y. Org. Biomol. Chem. 2012, 10, 3808.
mL/1 ml) solution of α,β-unsaturated ketone (0.1 mmol, 1.0
equiv) and catalyst (7.1 mg, 0.15 mmol, 0.15 equiv) at 15°C, in
dark under nitrogen was added halogen source (0.13 mmol, 1.3
equiv). The resulting mixture was stirred at 15°C and monitored
(q) Zhou, L.; Tay, D. W.; Chen, J.; Leung, G. Y. C.; Yeung, Y.-Y.
Chem. Commun. 2013, 49, 4412.
by TLC. The reaction was quenched with saturated Na SO3 (1
2
(
7) Selected recent endeavors on the development of asymmetric
O-type halocyclization: (a) Han, X.; Dong, C.; Zhou, H.-B. Adv.
Synth. Catal. 2014, 356, 1275. (b) Murai, K.; Nakajima, J.;
Nakamura, A.; Hyogo, N.; Fujioka, H. Chem. Asian J. 2014, 9,
mL) at 15oC and then was warm to room temperature. The solu-
tion was diluted with water (3 mL) and extrated with EtOAc,
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (hexane/EtOAc=3:1)
to yield the corresponding lactone. Supporting Information pro-
vides full details and graphical guide.
3511. (c) Murai, K.; Shimizu, N.; Fujioka, H. Chem. Commun.
2014, 50, 12530. (d) Arai, T.; Sugiyama, N.; Masu, H.; Kado, S.;
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E