Enantioselective Bromolactonization of Deactivated Olefinic Acids

Article abstract of DOI:10.1021/acs.orglett.8b01125

A novel enantioselective bromolactonization of α,β-unsaturated ketones using bifunctional amino-urea catalysts has been developed. The scope of the reaction is evidenced by 23 examples of halolactones bearing various functionalities with up to 99% yield a

Full text of DOI:10.1021/acs.orglett.8b01125

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Bromolactonization of Deactivated Olefinic Acids
Xiaojian Jiang,*,† Shenghui Liu,† Si Yang,† Mei Jing,† Lipeng Xu,† Pei Yu,† Yuqiang Wang,†
and Ying-Yeung Yeung*,‡
†Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardiocerebrovascular
Diseases, Jinan University College of Pharmacy, Guangzhou 510632, People’s Republic of China
‡Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
S
* Supporting Information
ABSTRACT: A novel enantioselective bromolactonization of
α,β-unsaturated ketones using bifunctional amino-urea cata-
lysts has been developed. The scope of the reaction is
evidenced by 23 examples of halolactones bearing various
functionalities with up to 99% yield and 99:1 er. Unlike typical
urea catalysts that require electron-deficient substituents to
enhance the hydrogen bond strength, it is interesting to realize
that electron-rich ureas are essential for high enantioselectivity
in this case. Moreover, experimental data reveals that the
halolactone compounds exhibit considerable anti-inflammatory effects on LPS-induced RAW 264.7 cells.
Scheme 1. Bromolactonization of Deactivated Olefinic Acids
Catalyzed by Electron-Rich Urea Organocatalyst
atalytic enantioselective halocyclization of olefinic sub-
Cstrates is an important approach to achieve various useful
heterocyclic building blocks.1 Various mono- and bifunctional
organocatalysts have been widely applied in the asymmetric
halocyclization of diverse olefinic substrates.2−7 Activated or
unactivated olefins are typically used in these reactions.
A separated class of substrates is deactivated olefins, which are
less studied. Deactivated olefins such as α,β-unsaturated enones
are relatively inert toward electrophilic halogenation reactions,
attributed to the relatively low reactivity of the electron-deficient
olefin as a π-donor in the α,β-unsaturated enone system. For
example, olefinic acid 1 was capable of performing the
bromolactonization reaction with N-bromosuccinimide (NBS)
at room temperature, allowing for an efficient synthesis of
bromolactone 2 in the absence of catalyst (Scheme 1, eq 1). In
contrast, bromolactonization of α,β-unsaturated ketone 3a under
the identical conditions was found to be sluggish (Scheme 1, eq
2).
Sporadic studies were documented, which a metal-catalyzed
system can be applied to the halogenation of deactivated olefins.
Representative research works on the transition metal-catalyzed
haloamidation and related reactions of β-substituted enones
reported by Feng et al. have been documented.6a,8 It has been
proposed that the reaction might go through a haliranium
intermediate or a Michael addition mechanism.1f However, to
the best of our knowledge, asymmetric organocatalytic
halocyclization of deactivated olefins with nucleophile attacking
the α-carbon remains unknown. Herein, we report the
halocyclization of deactivated olefinic substrates using a
nonclassical urea organocatalyst that bears an electron-donating
substituent. The resulting halolactone compounds were found to
exhibit significant anti-inflammatory effect on LPS-induced RAW
264.7 cells.
At the initial stage of investigation, enone substrate 3a was
examined with toluene as the reaction media. Chiral catalysts
including (DHQ)2PHAL (5), BINOL-derived phosphoric acid
6, and L-proline- and cinchona alkaloid-derived S- and O-
thiocarbamate catalysts 7−9 were examined,1 but the yields were
moderate with negligible enantioselectivity. However, cinchona
alkaloid derived-ureas 10a, 11a, and 12 were found to be effective
in promoting the cyclization of 3a. In particular, urea 10a gave
the desired product 4a with er 62:38 (Figure 1).
Next, ureas with different substituents were evaluated.
Typically, it is believed that urea performs as a dihydrogen-
bond catalyst and an electron-withdrawing substituent, which
Received: April 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01125
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With the optimized conditions in hand, the substrate scope
was examined. In general, the reactions proceeded with excellent
yield and good-to-excellent enantioselectivity (Table 1). The
a
Table 1. Substrate Scope
c
entry
4, R
4a, C6H5
time (h)
yield (%)
er
1
40
48
40
40
42
42
42
36
36
40
36
48
48
40
48
36
60
60
60
60
60
48
36
36
96
87
99
99
98
97
96
99
99
97
95
96
98
97
96
99
98
99
99
99
99
98
97
98
90:10
80:20
92:8
2
4b, 1-naphthyl
4c, 2-naphthyl
4d, 4-Me-C6H4
4e, 3-Me-C6H4
4f, 2-Me-C6H4
4g, 2,4-Me2-C6H3
4h, 4-MeO-C6H4
4i, 4-EtO-C6H4
4j, 3-MeO-C6H4
4k, 2-MeO-C6H4
4l, 4−F-C6H4
4m, 4−Cl-C6H4
4n, 4−Br-C6H4
4o, 4-CF3−C6H4
4p, 2-thienyl
4q
3
4
90:10
85:15
80:20
82:18
94:6
5
6
7
8
9
92:8
10
11
12
13
14
15
16
17
18
19
20
21
86:14
59:41
90:10
93:7
93:7
86:14
88:12
95:5
4s
96:4
4r
96:4
4t
>99:1
>99:1
94:6
4u
Figure 1. Study on effect of the substituent on the urea catalyst.
b
22
4h, 4-MeO-C6H4
ent-4h, 4-MeO-C6H4
4v, 4-MeO-C6H4
c
23
7:93
d
24
91:9
should enhance the hydrogen-bond strength and could lead to a
better selectivity.2,9 Unexpectedly, both urea catalysts 10c and
10d, which have electron-donating substituents gave better
enantioselectivity than that of the relatively electron-deficient
urea 10b. Further examination of different catalysts indicated
that the enantioselectivity increased with the electron-donating
and steric effects; the enantioselectivity increased significantly
with the urea catalyst bearing a 2,4-dimethoxyphenyl (10e) or a
2-methyl-4-methoxyphenyl (10f) group. However, substitution
at the meta-position (urea 10g, 10j) failed to return a higher
enantioselectivity. Changing the 4-methoxy to a 4-ethoxy
substitution generally improved the enantioselectivity (10h
and 10i). Finally, a 88:12 er was obtained with catalyst 10k. The
antipode of 4a could be obtained with comparable efficiency
when the pseudoenantiomeric quinidine-derived urea 11b was
used. A survey on the halogen source, solvent, and reaction
temperature revealed that the use of NBS in toluene at 15 °C was
optimal.10
a
Reactions were carried out with substrate 3 (0.2 mmol), catalyst 10k
(0.03 mmol), and NBS (0.26 mmol) in PhMe (8 mL) at 15 °C in the
absence of light. The yield was isolated yield, and the er was
determined by chiral HPLC. 1 mmol scale. Catalyst 11b was used
instead of 10k. NIS was used instead of NBS. The corresponding
b
c
d
iodolactone was obtained instead of bromolactone.
reaction worked well with substrates bearing electron-donating
substituents at the para-, meta-, or ortho-positions of the aryl
systems (entries 1−10). In particular, the 4-methoxyphenyl
substituted substrate 3h gave the desired product 4h in er 94:6
(entry 8). Diminished enantioselectivity was encountered for
substrate 3k, presumably due to the presence of a sterically
congested substituent (entry 11). The reaction was also found to
be compatible with electron-deficient substrates 3l−3o (entries
12−15). Thiophene-containing substrate 3p gave the corre-
sponding product 4p smoothly, and the thiophene remained
B
DOI: 10.1021/acs.orglett.8b01125
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
intact (entry 16). Substrates bearing alkyl side-chains including
methyls (3q, 3r), cyclopentyl (3s, 3t), and cyclohexyl (3u)
returned excellent enantioselectivity (entries 17−21), attribute
to the crucial role of the Thorpe−Ingold effect.11 The reaction
was found to be readily scalable, and comparable enantiose-
lectivity was obtained (entry 8 vs 22). The antipode of 4 could be
obtained by employing the pseudoenantiomeric catalyst 11b
(entry 8 vs 23). Iodolactonization of 3 could be achieved by
replacing NBS with N-iodosuccinimide (NIS) as the halogen
source (entry 24). The absolute configuration of lactone 4 was
determined on the basis of an X-ray crystallographic study on a
single crystal of 4u.10
Scheme 3. Proposed Mechanism
The synthetic utility was demonstrated by the transformation
using lactone 4h. As illustrated in Scheme 2, heating 4h at 60 °C
Scheme 2. Synthetic Application
enone. These interactions might distort the geometry in such a
way that the carbonyl group could not effectively conjugate with
the olefin. However, an intensive study is underway in order to
gain a better understanding of this new class of catalysts.
In summary, we described a catalytic asymmetric halolacto-
nization of deactivated olefinic acids. A range of keto-lactones
were furnished in good-to-excellent enantioselectivity and yield.
Instead of classical electron-deficient ureas, electron-rich urea
organocatalyst was found to be necessary to achieve high
enantioselectivity. Moreover, the lactone compounds were found
to be potent anti-inflammatory agents.
in ethanoic sodium hydrogen carbonate gave the chiral ether
derivative 16 in a yield of 99%. However, treatment of 4h with
NaN3 led to the formation of the azide derivative 17. More
importantly, no erosion of enantioselectivity was observed in
both reactions. To investigate the potential use of these products,
we evaluated the effects of 4h, 16, 17, and ent-4h on the
production of ROS and NO in LPS-stimulated RAW 264.7 cells.
The results show that 4h considerably reduced the production of
ROS and NO, while the effects of 16 and 17 were less
significant,10 indicating that 4h could be a potent anti-
inflammatory agent.12 Elaboration of these compounds is
underway in order to develop potential lead compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01125.
Based on the results shown in Figure 1, it appears that the
reaction might not go through a classical dihydrogen bond
activation mechanism and the bulky, electron-donating sub-
stituent in 10k might offer steric and/or effect(s) in the enantio-
determining step. Some control experiments were performed in
order to shed light on the mechanistic picture. Upon mixing urea
18 with NBS, in CDCl3, the 13C NMR signals corresponding to
NBS and 18 disappeared, and new signals corresponding to
succinimide appeared. Concurrently, a white precipitate was
formed. HRMS analysis on the white precipitate returned a m/z
peak at 228.9974, which might correspond to the species 18-Br
(Scheme 3).10 However, no observable interaction was detected
between urea 18 and enone 3a on the basis of the NMR study.
Although a more detailed study is required to elucidate a clearer
mechanistic picture, a plausible reaction mechanism is depicted
in Scheme 3 on the basis of the reaction observations. Instead of
acting as a dihydrogen-bond catalyst, we postulate that the
electron-rich urea 10k might mainly serve as a Lewis base in
activating the electrophilic halogen to give species 10k-Br.13
Since efficiency of the electrophilic halogenation was high as
reflected by the reaction rate and yield, the olefin moiety in
substrate 3 appears to be more electron-rich than expected; this
could be a result of inefficient π-conjugation between the
carbonyl and the olefinic groups. We suspect that one of the
possible transition states might involve dual interactions between
the putative species 10k-Br and the enone moiety in the
substrate: (1) the electrophilic Br in 10k-Br might interact with
the olefin to form the bromiranium ion; (2) the N−H group of
the urea might hydrogen-bond to the carbonyl oxygen of the
Experimental details and spectroscopic and analytical data
for new compounds (PDF)
Accession Codes
CCDC 1816471 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chemjxj2015@jnu.edu.cn.
*E-mail: yyyeung@cuhk.edu.hk.
ORCID
Xiaojian Jiang: 0000-0002-1355-3611
Ying-Yeung Yeung: 0000-0001-9881-5758
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of Guangdong
Province (Grant No. 2017B050506006), National Natural
Science Foundation of China (Grant No. 21502068), and
ITSP-Guangdong-Hong Kong Technology Cooperation Fund-
ing Scheme (Grant No. GHP/008/17GD) for financial support.
C
DOI: 10.1021/acs.orglett.8b01125
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(13) The attempt to generate pure 10k-Br was unsuccessful. A
comprehensive study is underway to elucidate a more detailed
mechanism.
(6) Selected recent endeavors on the development of asymmetric
haloaminocyclization: (a) Cai, Y.; Zhou, P.; Liu, X.; Zhao, J.; Lin, L.;
D
DOI: 10.1021/acs.orglett.8b01125
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