C3-symmetric cinchonine-squaramide-catalyzed asymmetric chlorolactonization of styrene-type carboxylic acids with 1,3-dichloro-5,5- dimethylhydantoin: An efficient method to chiral isochroman-1-ones

Article abstract of DOI:10.1002/adsc.201300915

A more practical and efficient catalytic asymmetric chlorolactonization of styrene-type carboxylic acids with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) using C₃-symmetric cinchonine-squaramide (CSCS) as organocatalyst has been developed. A series of chiral chloro-substituted isochroman-1-ones was obtained in excellent yields (up to 95%) and enantioselectivities (up to 99% ee), whwereby the results for chloro-substituted isochroman-1-ones are the best ever achieved. The catalyst can be recovered and reused for six cycles. Moreover, the chlorolactonization product 3b was further transformed to optically active bicyclic isochroman-1-one derivatives in high yield without losing the enantioselectivity. Furthermore, compounds 3e and 2n proved to be highly potent inhibitors of the HIV-1 in TZM-bl cells.

Full text of DOI:10.1002/adsc.201300915

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DOI: 10.1002/adsc.201300915
C3-Symmetric Cinchonine-Squaramide-Catalyzed Asymmetric
Chlorolactonization of Styrene-Type Carboxylic Acids with 1,3-
Dichloro-5,5-dimethylhydantoin: An Efficient Method to Chiral
Isochroman-1-ones
Xin Han,a Chune Dong,a and Hai-Bing Zhoua,*
a
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan
University School of Pharmaceutical Sciences, Donghu Road 185#, Wuhan, Peopleꢀs Republic of China
Fax : (+86)-27-6875-9850; e-mail: zhouhb@whu.edu.cn
Received: October 13, 2013; Revised: January 17, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300915.
Abstract: A more practical and efficient catalytic over, the chlorolactonization product 3b was further
asymmetric chlorolactonization of styrene-type car- transformed to optically active bicyclic isochroman-
boxylic acids with 1,3-dichloro-5,5-dimethylhydan- 1-one derivatives in high yield without losing the
toin (DCDMH) using C3-symmetric cinchonine- enantioselectivity. Furthermore, compounds 3e and
squaramide (CSCS) as organocatalyst has been de- 2n proved to be highly potent inhibitors of the HIV-
veloped. A series of chiral chloro-substituted iso- 1 in TZM-bl cells.
chroman-1-ones was obtained in excellent yields (up
to 95%) and enantioselectivities (up to 99% ee),
whwereby the results for chloro-substituted isochro- Keywords: asymmetric chlorolactonization; C3-sym-
man-1-ones are the best ever achieved. The catalyst metrical cinchonine-squaramides; carboxylic acids;
can be recovered and reused for six cycles. More- isochroman-1-ones
Introduction
tonization of alkenoic acids that proceeds in high
yields and excellent ees.[12] More recently, Hansenꢀs
Halolactonization is one of the most important reac- group discovered a novel organocatalytic asymmetric
tions in organic chemistry due to the fact that the re- iodolactonization that afforded chiral iodolactones in
sulting halogenated lactones are among the most ver- up to 96% ee value in the presence of NIS.[13] At the
satile building blocks in organic synthesis.[1,2] Over the same time, Martin and co-workers reported that 5-exo
years, the reaction has been applied in the context of and 6-endo bromolactones could be obtained by the
various heterocyclic syntheses, and it continues to be asymmetric bromolactonization of alkenecarboxylic
a significant focus of research.[3,4] Given its impor- acids with TBCO and BINOL ligand.[14] Despite
tance, asymmetric halolactonization has been actively a wealth of accomplishments in asymmetric bromolac-
pursued since Bartlett and co-workers described the tonization and iodolactonazition, reports on chloro-
first stereoselective iodolactonization,[5] in particular, lactonizations remain scarce, mainly because of the
bromolactonization and iodolactonization have low reactivity of the chlorinating agent. Only a few
become well established in recent years (Figure 1).[6,7] examples of asymmetric chlorolactonization have
The rapid development has still continued, and been described so far. Borhan and co-workers report-
a number of newly structured organocatalysts such as ed the first dimeric Cinchona alkaloid derivative
thiocarbamate, urea, trisimidazoline etc. have been (DHQD)2PHAL-catalyzed enantioselective chlorolac-
developed by several other groups.[8–10] For example, tonizations of alkenoic acids.[15] However, regarding
in 2010, Tang and co-workers reported a highly enan- this type of asymmetric chlorolactonization reaction,
tioselective bromolactonization of conjugated (Z)- there are still some limitations. For instance, the reac-
enynes governed by a cinchonidine-based urea orga- tion conditions are not practical, the catalyst is non-
nocatalyst.[11] In the same year, Veitch and Jacobsen recyclable, and the substrate scopes are rather limited
disclosed an aminourea-mediated asymmetric iodolac- and lack generality. Furthermore, to the best of our
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Xin Han et al.
Results and Discussion
Using 2-(prop-1-en-2-yl)benzoic acid 1a as model sub-
strate, we began to screen conditions for the asym-
metric chlorolactonization of 1a. The results are sum-
marized in Table 1. To our surprise, the reaction pro-
ceeded smoothly to give the racemic product 2a in
95% yield in the presence of 10 mol% CSCS
(entry 1). In order to achieve the optically active
product, various additives were screened in toluene
with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH)
as the chloro source at À788C in the presence of
10 mol% CSCS; NsNH2 was the best providing the
desired product in 51% ee (entries 2–9). Increasing
the amount of NsNH2 to 5 equivalents resulted in
64% ee (entry 13). With 5 equiv. of NsNH2 as the ad-
ditive, various solvents and chloro sources such as
NCS (N-chlorosuccinimide), TCCA (trichloroisocya-
nuric acid), DCDPH (1,3-dichloro-5,5-diphenylhydan-
toin), NCP (N-chlorophthalimide) and DCDHH (1,3-
dichlorohydantoin), have also been examined for this
reaction (Table 1, entries 15–25), the use of chloro-
form was determined to be the most appropriate sol-
vent and DCDMH gave the highest ee value for this
study. No further improvement was observed by in-
creasing the catalyst loading to 20 mol% (Table 1,
entry 28). Much to our delight, 83% ee was obtained
when the reaction was run in CHCl3 at À608C for
16 h in the presence of 5 equivalents of additive
NsNH2 and 10 mol% of CSCS (entry 21).
Figure 1. Representative chiral organic catalysts in asymmet-
ric halolactonization.
knowledge, there is no report on the enantioselective
With the optimized reaction conditions in hand,
chlorolactonization of styrene-type carboxylic acids. CSCS was employed in the asymmetric chlorolactoni-
Therefore, the development of more practical, recy- zation of a series of carboxylic acids bearing different
clable, highly efficient organocatalysts for enantiose- substituent groups; the results are summarized in
lective chlorolactonization of styrene-type carboxylic Table 2. In general, the desired products were formed
acids is highly desirable.
in excellent yields (entries 1–14, Table 2). As might be
For some time, we have been interested in the de- expected, the nature of the substrates plays an impor-
velopment of novel C3-symmetric chiral squaramide tant role in this reaction. As can be seen in Table 2,
organocatalysts and their applications in a series of carboxylic acids with terminal alkenes favored the 5-
asymmetric transformations.[16] Building on our previ- exo products; while, carboxylic acids with internal al-
ous success with the C3-symmetric chiral cinchonine- kenes preferentially provided more 6-endo products.
squaramide (CSCS), we discovered that application of For instance, when R2 was hydrogen, the products re-
this readily available C3-symmetric cinchonine-squara- turned with high 5-exo selectivity (up to 99:1) (en-
mide in the asymmetric chlorolactonization of sty- tries 1, 8, 10–12, 14). A 3:1 ratio of the 6-endo/5-exo
rene-type carboxylic acids results in a drastic im- (3:2) mixture was obtained in excellent enantioselec-
provement in enantioselectivity.
tivity (up to 99% ee for the major isomer) for the R2
Herein, we report the first, highly efficient, recycla- as a methyl group (entry 2). Further investigation in-
ble C3-symmetric cinchonine-squaramide-catalyzed dicated that, for carboxylic acids with internal al-
asymmetric chlorolactonization of styrene-type car- kenes, the presence of electron-rich or electron-defi-
boxylic acids affording the corresponding isochroman cient R1 groups on the aryl ring has little effect on the
derivatives in up to 99% ee and excellent yields, enantioselectivity (entries 3–5). However, for terminal
which are potential bioactive substances with anti- alkenes, a better ee was obtained when changing R1
HIV activity.[17] Furthermore, this methodology was to an electron-deficient group (entries 10 vs. 12). In
extended to the synthesis of enantiomerically pure comparison, when R2 was an ethyl group, the desired
fully substituted isochroman-1-one derivatives.
product was obtained with good 6-endo selectivity but
poorer enantioselectivity (entry 13). Finally, we were
delighted to find that when NBS (N-bromosuccini-
2
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C3-Symmetric Cinchonine-Squaramide-Catalyzed Asymmetric Chlorolactonization
mide) was used as halo source, the corresponding bro-
To determine the recycling ability of our C3-sym-
molactonization product was also obtained in excel- metric catalyst in this type of reaction, CSCS was re-
lent yield and enantioselectivity (entry 15).
covered after the catalytic process and was reused in
the asymmetric chololactonization of 1b with
DCDMH under the optimized reaction conditions. As
illustrated in Table 3, catalyst CSCS can be recovered
in high yields (90–93%) and be reused without signifi-
cant loss of activity. It is gratifying our CSCS catalyst
maintained its catalytic activity even after six cycles
(94–99% ees).
Table 1. Screening conditions for the enantioselective chlor-
olactonization of carboxylic acid 1a.[a]
Lactone derivatives are notable because of their ex-
tensive bioactivities, including anti-tumor promoting,
anti-platelet aggregation and so on.[18] Even so, re-
ports on potent anti-HIV agents based on the chiral
lactone skeleton are rare. Therefore, our compounds
were evaluated for anti-HIV activity by using an HIV-
1IIIB/TZM-bl indicator cell culture system as previous-
ly described,[19] and the results are summarized in
Table 4. Following a TZM-bl cell assay, we were sur-
prised to see that 3e and 2n showed excellent anti-
HIV-1 activity on HIV-1 strains with an EC50 value as
low as 15 mM (Table 4). This work opens new pros-
pects on the design and synthesis of highly efficient
anti-HIV agents. Further investigations to clarify the
structure–activity relationships (SARs) of these com-
pounds, which are currently underway, will be report-
ed in due course.
Entry Additive
(equiv.)
Solvent
Yield ee
G
[%][b] [%][c]
1
2
3
4
–
toluene
toluene
toluene
toluene
95
94
95
93
0
3
51
5
Furthermore, in order to expand the utility of this
reaction protocol, the chlorolactonization product 3b
was treated with alkynes in the presence of
TsNH2 (0.5)
NsNH2 (0.5)
4-methylbenzoic acid
(0.5)
PdACHTNURTGNEUGN(PPh3)Cl2/CuI to provide fully substituted isochro-
5
6
phenylhydrazine (0.5)
ortho-toluenesulfona-
mide (0.5)
toluene
toluene
97
91
8
17
man-1-ones 4a–d in 92–95% yields and 98–99% ees,
which have potential activity in the inhibition of vari-
ous bacteria and fungi species (Scheme 1).[20]
7
8
hydroxypyrrolidine-2,5- toluene
dione (0.5)
4-sulfamoylbenzoic
acid (0.5)
93
92
17
7
toluene
Conclusions
9k
NsNH2 (0.5)
NsNH2 (2.5)
NsNH2 (1)
NsNH2 (2)
NsNH2 (5)
NsNH2 (7.5)
NsNH2 (10)
NsNH2 (5)
NsNH2 (5)
NsNH2 (5)
NsNH2 (5)
NsNH2 (5)
NsNH2 (5)
NsNH2 (5)
NsNH2 (5)
NsNH2 (5)
NsNH2 (5)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
CHCl3
DCM
CHCl3
C2H5Br
AcOEt
DCE
CHCl3/tolu-
ene (1:1)
CHCl3
90
94
95
90
92
93
91
92
92
91
92
95
95
90
94
95
94
37
40
51
62
64
47
57
In conclusion, we have developed the first highly
enantioselective chlorolactonization of styrene-type
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
[a]
Reaction conditions: 0.1 mmol of 1a, 0.5 mmol of addi-
tive, indicated amount of catalyst in 2.0 mL of appropri-
ate solvent for 30 min at room temperature and then
0.12 mmol of DCDMH was added at low temperature
for 16 h.
NR[d]
17[e]
65[f]
36[g]
45
83
24
3
5
[b]
Isolated yield.
[c]
The ee values were determined by HPLC analysis using
a Chiralpac AD-H column.
NCS or NCP was used in the reaction, no ee was ob-
[d]
served.
TCCA was used.
DCDPH was used.
DCDHH was used.
[e]
[f]
[g]
66
[h]
When the C3-symmetric cinchonidine-squaramide was
used, the opposite configuration was observed.
5 mol% CSCS were used.
20 mol% CSCS were used.
96 h.
26
27
28
NsNH2 (5)
NsNH2 (5)
NsNH2 (5)
95
95
90
61[h]
65[i]
80[j]
[i]
CHCl3
CHCl3
[j]
[k]
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Table 2. Asymmetric chlorolactonization of
1
with
Table 3. Catalyst recovery.[a]
DCDMH.[a]
Cycle
Recovery rate [%]
Yield [%][b]
ee [%][c]
0
1
2
3
4
5
91
92
90
93
90
90
93
93
92
92
90
91
99
98
99
99
98
94
Entry R1
R2
Yield [%][b] (2:3) ee [%][c]
1
Me
H, 1a
Me, 1b 92 (1:3)
Me, 1c 94 (1:99)
Me, 1d 93 (1:2)
Me, 1e 93 (1:3)
Me, 1f
93 (>99:1)
83
99
95
92
90
84
83
82
80
77
67
62
33
57
92
[a]
All reactions were carried out with 0.6 mmol 1b,
0.72 mmol DCDMH in 5 mL of CHCl3 in the presence of
10 mol% CSCS for 16 h.
2
3
4-BrC6H4
H
4
5
6
4-FC6H4
4-ClC6H4
Me
[b]
[c]
Isolated yield.
ee values were determined by HPLC analysis using a chir-
alpac OD-H column.
92 (99:1)
7
8
9
4-IC6H4
4-ClC6H4
Ph
Me, 1g 93 (1:4)
H, 1h
Me, 1i
H, 1j
93 (99:1)
92 (1:99)
92 (99:1)
95 (99:1)
92 (99:1)
90 (1:5)
Table 4. Anti-HIV activity of 3e and 2n in TZM-bl cells.[a]
10
11
12
13
14
15[d]
4-FC6H4
H
4-MeC6H4 H, 1l
4-BrC6H4
Ph
H, 1k
Et, 1m
H, 1n
Me, 1b 93 (1:4)
92 (99:1)
4-BrC6H4
Compounds
[a]
Unless otherwise noted, the reactions were carried out
with 0.1 mmol of 1, 0.5 mmol of NsNH2, 0.12 mmol of
DCDMH, 0.01 mmol of CSCS in 2.0 mL of CHCl3 at
À608C for 16 h.
EC50 (mM)
NA[b]
29.33
15.46
[b]
[c]
Isolated yield of 2 and 3.
[a]
EC50: effective concentration (mM) for 50% inhibition of
HIV-1 (HIV-1IIIB strain) as evaluated with the luciferase
activity in TZM-bl cells.
Tha ee values were determined by HPLC analysis using
a chiralpac OD-H, AD-H or AS-H column.
NBS as the halo source.
[d]
[b]
NA: no activity.
carboxylic acids catalyzed by recoverable C3-symmet-
ric cinchonine-squaramide (CSCS) providing the iso-
chroman derivatives in up to 99% ee. The chlorolacto-
nization product was further transformed to optically
active bicyclic isochroman-1-one derivatives in high
yield without loss of the enantioselectivity. Further-
more, compounds 3e and 2n proved to be highly
potent inhibitors of the HIV-1 in TZM-bl cells. This
work not only expands the application of chiral C3-
symmetric catalysts in asymmetric chlorolactoniza-
tion, but also opens new prospects for the design and
synthesis of highly specific anti-HIV agents.
further purification. All solvents were purified according to
reported procedures. Reactions were monitored by thin
layer chromatography (TLC) and column chromatography
purifications were performed using 230–400 mesh silica gel.
Carboxylic acids 1 were prepared according to the literature
procedure.[21]
Typical Procedure for the Enantioselective
Chlorolactonization of Carboxylic Acids
A solution of 2-(prop-1-en-2-yl)benzoic acid 1a (32.4 mg,
0.2 mmol), CSCS (25.6 mg, 0.02 mmol) and additive NsNH2
(204 mg, 1 mmol) in dry CHCl3 (1 mL) was stirred for
30 min at room temperature and then the resulting solution
was cooled to À608C, DCDMH (47.3 mg, 0.24 mmol) was
then added in one portion to the solution and the reaction
mixture was stirred at À608C for 16 h. Upon completion,
the solvent was removed and the residue was purified by
Experimental Section
Unless otherwise noted, reagents and materials were ob-
tained from commercial suppliers and were used without
4
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C3-Symmetric Cinchonine-Squaramide-Catalyzed Asymmetric Chlorolactonization
4b: 1H NMR (400 MHz, CDCl3): d=7.92 (d, J=7.5 Hz,
1H), 7.79 (d, J=7.5 Hz, 1H), 7.74 (t, J=6.6 Hz, 1H), 7.58
(t, J=7.2 Hz, 3H), 7.55–7.48 (m, 3H), 7.38 (t, J=9.3 Hz,
1H), 7.05 (t, J=8.6 Hz, 2H), 4.90–4.78 (m, 1H), 1.46 (d, J=
6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=167.87, 161.59
(d, 1JC,F =248.0 Hz), 147.83, 136.31, 133.32, 132.57, 132.49,
130.73, 129.09, 125.32, 124.95, 122.74, 122.38, 114.68 (d,
2JC,F =22.0 Hz), 108.95, 89.25, 88.47, 87.10, 59.96, 18.62; HR-
MS (ESI): m/z=391.0900, calcd. for C24H16ClFO2 [M]+:
391.0901. The enantiomeric excess was determined by
HPLC with a Chiralpak OD-H column (90:10 hexane:2-
propanol, 1.0 mLminÀ1, 220 nm); tmajor =13.470 min, tminor
17.100 min; >99% ee; [a]2D0: +90.1 (c=0.74, CHCl3).
=
4c: 1H NMR (400 MHz, CDCl3): d=7.92 (t, J=6.5 Hz,
1H), 7.79 (d, J=7.6 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.63–
7.46 (m, 5H), 7.44–7.32 (m, 2H), 7.31–7.26 (m, 1H), 4.90–
4.80 (m, 1H), 1.46 (d, J=6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=169.36, 149.99, 134.43, 134.29, 132.10, 131.85,
129.74, 128.97, 128.80, 127.14, 125.91, 125.40, 125.21, 122.80,
122.72, 92.02, 90.31, 90.07, 61.18, 19.83; HR-MS (ESI):
m/z=379.0553, calcd. for C22H15ClSO2 [M]+: 379.0559. The
enantiomeric excess was determined by HPLC with a Chiral-
pak OD-H column (90:10 hexane:2-propanol, 1.0 mLminÀ1,
220 nm);
tmajor =9.282 min, tminor =12.197 min; >99% ee;
[a]2D0: +79.1 (c=0.87, CHCl3).
4d: 1H NMR (400 MHz, CDCl3): d=7.90 (d, J=7.6 Hz,
1H), 7.74 (dd, J=13.3, 7.5 Hz, 2H), 7.57 (d, J=7.3 Hz, 1H),
7.50 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 4.83 (q, J=
6.7 Hz, 1H), 1.44 (d, J=6.7 Hz, 3H), 0.94–0.81 (m, 3H),
0.81–0.75 (m, 2H); 13C NMR (101 MHz, CDCl3): d=168.78,
148.65, 136.12, 134.08, 131.64, 129.87, 126.29, 126.11, 125.64,
124.51, 123.31, 94.78, 90.21, 74.77, 60.88, 19.49, 8.52; HR-MS
(ESI): m/z=337.0999, calcd. for C21H17ClO2 [M]+: 337.0995.
The enantiomeric excess was determined by HPLC with
Scheme 1. Application of the methodology.
SiO2 column chromatography (petroleum ether/AcOEt=
4:1) to give 2a as colorless solid.
Anti-HIV-1 Activity Assays
a
Chiralpak OD-H column (90:10 hexane:2-propanol,
1.0 mLminÀ1, 220 nm); tmajor =9.405 min, tminor =10.222 min;
98% ee; [a]2D0: +71.1 (c=0.83, CHCl3).
The inhibitory activity of the experimental compounds on
primary HIV-1 replication was determined as previously de-
scribed.[19]
General Procedure for the Synthesis of Isochroman-
1-ones 4
Acknowledgements
Under an argon atmosphere, a mixture of 3b (35.2 mg,
This work was supported by the NSFC (91017005, 81172935,
81373255), Key Project of Ministry of Education (313040),
the Scientific and Technological Innovative Research Team of
Wuhan (2013070204020048), and Hubei Provinceꢀs Out-
standing Medical Academic Leader Program. We thank Dr.
Shuwen Wu for performing the anti-HIV activity assays.
0.1 mmol), PdCl2ACHTUNGTRENNUNG(PPh3)2 (3.5 mg, 0.005 mmol, 5%), PPh3
(7.9 mg, 0.03 mmol, 30%), CuI (2 mg, 0.01 mmol, 10%), and
acetylene (0.16 mmol) in 1 mL DMF and 1.5 mL TEA as
mixed solvent was heated to 808C for 24 h. The solvent was
removed and the residue was purified by flash chromatogra-
phy on silica gel, eluting with petroleum ether/ethyl acetate
(8:1) to afford the product 4.
4a: 1H NMR (400 MHz, CDCl3): d=7.92 (t, J=7.1 Hz,
1H), 7.79 (d, J=7.7 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.57
(q, J=8.6 Hz, 5H), 7.52 (dd, J=6.5, 3.0 Hz, 2H), 7.41–7.31 References
(m, 3H), 4.86 (q, J=6.7 Hz, 1H), 1.46 (d, J=6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=169.19, 149.89, 137.99,
134.44, 132.10, 131.67, 129.91, 129.74, 128.99, 128.59, 128.42,
126.20, 126.02, 125.90, 125.36, 125.20, 124.04, 122.86, 122.73,
90.70, 90.11, 88.37, 60.98, 19.81: HR-MS (ESI): m/z=
373.0996, calcd. for C24H17ClO2 [M]+: 373.0995. The enantio-
meric excess was determined by HPLC with a Chiralpak
OD-H column (90:10 hexane:2-propanol, 1.0 mLminÀ1,
220 nm); tmajor =15.357 min, tminor =19.527 min; >99% ee;
[a]2D0: +95.1 (c=0.84, CHCl3).
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These are not the final page numbers!

FULL PAPERS
C3-Symmetric Cinchonine-Squaramide-Catalyzed
Asymmetric Chlorolactonization of Styrene-Type
Carboxylic Acids with 1,3-Dichloro-5,5-dimethylhydantoin:
An Efficient Method to Chiral Isochroman-1-ones
7
Adv. Synth. Catal. 2014, 356, 1 – 7
Xin Han, Chune Dong, Hai-Bing Zhou*
Adv. Synth. Catal. 0000, 000, 0 – 0
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7
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These are not the final page numbers!