Asymmetric bromolactonization using amino-thiocarbamate catalyst

Article abstract of DOI:10.1021/ja1048972

A novel amino-thiocarbamate-catalyzed bromolactonization of unsaturated carboxylic acids has been developed. The scope of the reaction is evidenced by 22 examples of γ-lactones with up to 99% yield and 93% ee. The protocol was applied in the enantioselective synthesis of the key intermediates of VLA-4 antagonists.

Full text of DOI:10.1021/ja1048972

Published on Web 10/14/2010
Asymmetric Bromolactonization Using Amino-thiocarbamate Catalyst
Ling Zhou, Chong Kiat Tan, Xiaojian Jiang, Feng Chen, and Ying-Yeung Yeung*
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3, Singapore 117543, Singapore
Received June 4, 2010; E-mail: chmyyy@nus.edu.sg
bromolactonization of alkenoic acid 1b (Table 1, R ) Ph) was
Abstract: A novel amino-thiocarbamate-catalyzed bromolacton-
carried out using a stoichiometric amount of NBS and 10 mol %
ization of unsaturated carboxylic acids has been developed. The
of thiocarbamate 3b in CH2Cl2 at -78 °C. Bromolactone 2b was
scope of the reaction is evidenced by 22 examples of γ-lactones
isolated in 95% yield; however, no enantioselectivity was observed,
with up to 99% yield and 93% ee. The protocol was applied in
and the reaction was sluggish (Table 1, entry 4). Subsequent
the enantioselective synthesis of the key intermediates of VLA-4
attempts to accelerate the reaction by increasing the nucleophilicity
antagonists.
of the carboxylate group were unsuccessful (Table 1, entry 5).9
The failure to achieve any enantioselectivity might be attributed to
the following reasons: (1) the chiral moiety linked to the thiocar-
bamate may be too remote from the olefin to effect stereocontrol;10
Halocyclization of olefins is an important class of organic
transformations. Reactions involving halolactonization, haloetheri-
fication, and polyene cyclization are well documented. Among these
(2) the enantiomerically enriched bromonium-olefin intermediate
may racemize through a rapid olefin-olefin halogen exchange.11
reactions, halolactonization has been studied extensively and applied
in the synthesis of many bioactive molecules.1 However, the
catalytic and enantioselective version of halolactonization, especially
bromolactonization, is still lacking because a suitable catalytic
system is elusive.2,3 Herein we describe an efficient, enantioselec-
tive, and organocatalytic bromolactonization using an amino-
thiocarbamate as the catalyst.
Toward these problems, we reasoned that encapsulating the
electrophilic bromonium ion and the olefinic substrate into a pocket
might provide a solution. We therefore decided to incorporate a
Br activator (a thiocarbamate) and a carboxylate activator (an amine)
into a rigid skeleton, and the resulting amino-thiocarbamate
bifunctional catalyst was investigated. A simple experiment was
conducted using a prolinol-derived amino-thiocarbamate, 4a (10
mol %), to catalyze the bromolactonization of 1b, which allowed
us to achieve a -14% ee of 2b (Table 2).
Inexpensive and commercially available N-bromosuccinimide
(NBS) is a halogen source commonly used in bromolactonization
reactions. Various NBS activators such as Lewis acids,4 hydrogen-
bonding-type catalysts,5 amides,6 and aryl iodides7 have been
reported. Recently, Denmark and co-workers reported the use of a
sulfur Lewis basic catalyst in the activation of a phenylselenium
group for the electrophilic lactonization.8 We rationalized that the
sulfur Lewis base should also be able to activate a halogen for the
bromolactonization (Table 1, complex A). Thus, we screened some
sulfur Lewis bases and found that thiocarbamates were exceptionally
active in catalyzing the bromolactonization reactions (Table 1). In
addition, modification of the thiocarbamate through the replacement
of S with O (Table 1, entry 6) or N-H with N-Me (Table 1, entry
7) resulted in a decrease in efficiency, which indicated that both
the S and the N-H were responsible for the reactivity. Keeping
this in mind, we attempted to incorporate the thiocarbamate into a
chiral scaffold, for instance into (-)-menthol, to form a chiral
catalyst for the enantioselective bromolactonization. Initially, the
Table 2. Amino-thiocarbamate-Catalyzed Bromolactonization
Table 1. Thiocarbamate-Catalyzed Bromolactonization
a Isolated yield. b Reactions were conducted at -78 °C for 5 h. c 10
mol % of Et3N was added.
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15474 J. AM. CHEM. SOC. 2010, 132, 15474–15476
10.1021/ja1048972  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 4. Asymmetric Bromolactonization of 1
Table 3. Optimization of The Asymmetric Bromolactonization
entrya
halogen source
X
additive (mol %)
time (h)
yield,b ee (%)
entrya
acid
R
time (h)
yield,b ee (%)
1
2
3
4
5
6
7
8
NBS
NCS
NIS
Br
Cl
I
Br
Br
Br
Br
Br
Br
-
-
-
-
-
17
48
80
16
12
14
17
21
84
40
40
45
19
96, 87
0
1
2
3
4
5
6
7
8
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
4-Cl-C6H4
4-F-C6H4
40
26
56
96
60
24
36
36
30
44
36
48
96
46
36
20
67
66
126
60
36
88, 91
93, 91
71, 85
85, 83
98, 87
85, 90
87, 84
67, 28
71, 70
99, 90
89, 86
98, 87
88, 90
92, 82
95, 52
98, 90
91, 80
93, 84
81, 41
99, 82
97, 93
80, 20
99, 82
71, 53
55, 82
28, 0
86, 73
80, 89
98, 90
99, 90
99, 90
96, 86
4-CF3-C6H4
4-NO2-C6H4
4-EtOCO-C6H4
4-CF3O-C6H4
4-Me-C6H4
4-MeO-C6H4
4-Ph-C6H4
3-F-C6H4
3-CF3-C6H4
3,5-F2-C6H3
3,5-(CF3)2-C6H3
3-MeO-C6H4
2-Me-C6H4
2-naphthyl
3-thienyl
NBP
DBDMH
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
BzOH (100)
TFA (100)
CF3SO2NH2 (100)
NsNH2 (100)
9
9
10
11c
12d
13
Br NsNH2 (50)
Br NsNH2 (50)
Br NsNH2 (50)
10
11
12
13
14
15
16
17
18
19
20
21
Br
NsNH2 (20)
a Reactions were carried out with acid 1b (0.1 mmol), catalyst 5e
(0.01 mmol), additive, and halogen source (0.12 mmol) in CHCl3/
toluene (1:2) (3 mL). b Isolated yield. c 1 mmol of acid 1b was used. d 2
mmol of acid 1b was used.
1t
3-furanyl
methyl
cyclohexyl
tert-butyl
1u
1v
1w
a Reactions were carried out with acid 1 (0.1 mmol), catalyst 5e (0.01
mmol), NsNH2 (0.05 mmol), and NBS (0.12 mmol) in CHCl3/toluene
(1:2) (3 mL). b Isolated yield.
the use of additive. On the basis of complex A, we reasoned that
a weak hydrogen-bonding donor could coordinate to the carbonyl
group of succinimide and further enhance the electrophilicity of
Br. Thus, some weak acids were screened, and the results are listed
in Table 3. Relatively acidic additives were found to have a
detrimental effect on the yield and the enantioselectivity of the
reaction (Table 3, entries 6-8). In the case of strongly acidic TFA,
the enantioselectivity plunged to 0%. This result is a likely
indication of a disruption to the ion-pairing of alkenoic acid 1 and
catalyst 5e. To our surprise, the addition of 1.0 equiv of NsNH2
was found to increase the enantioselectivity to 89% ee, but with
retardation of the reaction rate (Table 3, entry 9). Reducing the
amount of NsNH2 to 0.5 equiv could regain some of the reaction
efficiency with similar enantioselectivity (Table 3, entry 10). Further
reducing the amount of NsNH2 resulted in no effect on the yield
and the ee (Table 3, entry 13). Apparently, the effect of NsNH2 on
the reaction time implied that the role of NsNH2 might not be as a
hydrogen-bonding donor. Alternatively, we suspect that NsNHBr,
a compound generated through the Br exchange between NBS and
NsNH2, could contribute to the increase in ee.13,14 In fact, the
existence of NsNHBr was described in the literature15 and was
confirmed by our 1H NMR study on a mixture of NBS and
NsNH2.12 Finally, the reaction was readily scalable without losing
any efficiency and enantioselectivity (Table 3, entries 11 and 12).
Once the optimized conditions were identified (Table 3, entry 10),
other substrates were examined, and the scope of the bromolacton-
ization is indicated by the examples listed in Table 4.12 The reactions
were all performed smoothly with high yields and ee’s. For aromatic-
substituted acid substrates, the highest enantioselectivity of 91% ee
was obtained with 1c and 1d (Table 4, entries 1 and 2), both bearing
para-substituted halogens. In general, electron-rich aryl substituents
gave lower enantioselectivities, which could be ascribed to the
enhanced background reaction (Table 4, entries 1-6, 10-13 vs 7-9,
14). In some cases, the steric effect appeared to have negative effects
on the ee values (Table 4, entries 3-5, 15). For 4-methyl and
4-cyclohexyl alkenoic acids, reactions gave good yields and moderate
Figure 1. Proposed mechanism of the bromolactonization.
Further screening for efficient amino-thiocarbamate frameworks
led us to identify the cinchonine skeleton 5, and a 37% ee of 2b
was observed when catalyst 5b was used. Attempts to increase the
acidity of the thiocarbamate proton by replacing the phenyl ring
with an electron-deficient 3,5-bis(trifluoromethyl)phenyl group,
however, resulted in a negative effect on the enantioselectivity (5c,
-29% ee). Surprisingly, an increase in the electron density of the
phenyl group has an enhancing effect on the enantioselectivity.
4-Methoxyphenyl catalyst 5d gave 40% ee, and the more electron-
rich 2,4-dimethoxyphenyl catalyst 5e afforded 50% ee. Changing
the skeleton to quinidine furnished the same ee (6, 50% ee), while
saturation of the olefin in 6 resulted in a lower ee (7, 40% ee).
Replacing the phenyl group with other units such as tBu (Table 2,
5f) or Ph2CH (Table 2, 5g) resulted in a total loss of enantiose-
lectivity. Finally, an exactly opposite ee was achieved when 8
(-49% ee) was used (compared to 5e).12
After identifying the suitable catalyst 5e, we attempted to
optimize the reaction by varying different parameters systematically.
Initially, various solvents including CH2Cl2, CHCl3, toluene, ethanol,
and ethyl acetate were screened,12 and we eventually discovered
that a CHCl3/toluene (1:2) system dramatically enhanced the
enantioselectivity to 87% ee (Table 3, entry 1). The enhanced ee
in nonpolar solvents could be a result of reduced noncatalyzed
reaction and/or strengthened polar interaction among substrate,
NBS, and catalyst (cf. Figure 1). We have also investigated other
halogen sources including N-chlorosuccinimide (NCS), N-iodosuc-
cinimide (NIS), N-bromophthalimide (NBP), and 1,3-dibromo-5,5-
dimethylhydantoin (DBDMH), none of which was found to be as
effective as NBS in terms of ee and reaction yield (Table 3, entries
2-5). Further attempts to improve the reaction led us to explore
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C O M M U N I C A T I O N S
Scheme 1. Asymmetric Synthesis of 11
In summary, we have developed a novel amino-thiocarbamate-
catalyzed enantioselective bromolactonization for asymmetric synthesis
of γ-lactones. Further investigations on other applications, including
δ-lactone formation, and on mechanistic studies are underway.
Acknowledgment. We gratefully acknowledge the National
University of Singapore (Grant No. 143-000-428-112) for the
funding of this research. We thank Prof. Tony K. M. Shing and
Dr. T. L. Chan (The Chinese University of Hong Kong) for their
valuable advice.
Supporting Information Available: Experimental procedures and
spectral and X-ray data for reactions products (PDF, CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
to good ee’s (Table 4, entries 19 and 20). Notably, 93% ee was
obtained when acid 1w (R ) tBu) was used (Table 4, entry 21).
Additionally, heteroaromatic substrates (Table 4, entries 17 and 18)
were found to be amenable to our catalytic asymmetric protocol, with
no observation of bromination on the heteroaromatic ring. The absolute
configuration of lactones 2 was assigned on the basis of X-ray
crystallographic structures of 2o and 2w.12
References
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S., Ed; Wiley-VCH: New York, 2010; Vol. 4, pp 951-990.
(2) Two elegant organocatalytic asymmetric halolactonization reactions were
reported during our research program: (a) Whitehead, D. C.; Yousefi, R.;
Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132, 3298–3300. (b)
Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang, W.
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To probe the mechanism, several catalyst analogues of 5e were
examined. The catalyst with S replaced by O (5h), N-H replaced by
O (5i), or N-H replaced by N-Me (5j) was found to be ineffective
in offering appreciable ee in the bromolactonization of 1b (Table 2).
Replacing the thiocarbamate of 5e with the well-known double-
hydrogen-bonding catalyst thiourea (Table 2, 5k) also showed no
enantioselectivity in the 1bf2b transformation. The above results led
us to speculate that either a pure Lewis base8 or a hydrogen-bonding
activation5 of NBS is unlikely to be the sole origin of enantioselectivity
in this bromolactonization. We cannot rule out the possibility of
quinuclidine as a NBS activator,2b but taking into account the
importance of both N-H and S of the thiocarbamate toward enanti-
oselectivity, an intermediate B with dual activation of NBS with the
thiocarbamate is proposed (Figure 1). The quinuclidine can interact
with the carboxylic acid, and the electron-rich 2,4-dimethoxyphenyl
ring can act as a steric screening group and control the acidity of the
thiocarbamate’s N-H (Figure 1, C). The generally high ee results also
support this rigid transition-state proposal, in which the olefin-olefin
halogen exchange racemization could be suppressed.11
To demonstrate the synthetic utility of this methodology, we
transformed bromolactone 2b into a synthetically useful building block
(Scheme 1). Thus, 11 was prepared from 2b through a 2bf9f10f11
sequence, in which carboxylic acid 11 is a key intermediate for the
synthesis of specific VLA-4 antagonists (e.g., 12).16
We have also attempted to apply the optimized protocol in the
formation of δ-lactones. Preliminary studies showed that lactone
14 could be prepared from 13 in good yield and ee.
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Piguel, S.; Wirth, T. Org. Lett. 2002, 4, 297–300. (b) Kang, S. H.; Lee,
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(9) We suspected the catalyst might be poisoned through a weak interaction
between amine and N-H of thiocarbamate, and this is still under
investigation.
(10) Cui, X.-L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653–5658.
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(12) The details are in the Supporting information.
(13) A mixture of NsNH2, NsNHBr, and NsNBr2 was obtained when NsNH2
was reacted with various kinds of brominating agents; attempts to isolate
pure NsNHBr were unsuccessful. Pure NsNBr2 was prepared by treating
NsNH2 with 2.2 equiv of Br2. However, only 48% ee was observed when
NsNBr2 was used.
(14) Since a rapid Br exchange should exist between NBS and NsNH2, we
suspect that NsNHBr could serve as a “Br sink”, in which NBS was
regenerated slowly (as a virtual slow addition) for the bromolactonization
reaction. Attempts to add NBS portionwise into the reaction in the absence
of NsNH2 resulted in a comparable improvement in ee; however, the process
was operationally inconvenient. On the other hand, we also acknowledge
the possibility of NsNHBr acting as a better Br source than NBS. The role
of NsNH2 is still under investigation.
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