Synthesis of chiral butenolides using amino-thiocarbamate-catalyzed asymmetric bromolactonization

Article abstract of DOI:10.1016/j.tetlet.2014.01.009

The asymmetric cyclization of 4,4-disubstituted 3-butenoic acids is studied. Amino-thiocarbamates are used as the catalysts and N-bromosuccinimide is used as the stoichiometric halogen source. The resulting γ-butanolide products are readily converted into the corresponding γ-butenolides (up to 58% ee) derivatives in one-pot.

Full text of DOI:10.1016/j.tetlet.2014.01.009

Tetrahedron Letters 55 (2014) 1243–1246
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of chiral butenolides using amino-thiocarbamate-
catalyzed asymmetric bromolactonization
⇑
Chong Kiat Tan, Jun Cheng Er, Ying-Yeung Yeung
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric cyclization of 4,4-disubstituted 3-butenoic acids is studied. Amino-thiocarbamates are
Received 20 October 2013
Revised 3 December 2013
Accepted 2 January 2014
Available online 8 January 2014
used as the catalysts and N-bromosuccinimide is used as the stoichiometric halogen source. The resulting
c-butanolide products are readily converted into the corresponding
c-butenolides (up to 58% ee) deriv-
atives in one-pot.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Bromolactonization
Catalysis
Lewis base
Asymmetric reaction
The area of enantioselective synthesis of halolactones from pro-
chiral olefins has witnessed a recent flurry of reports to tackle this
long-standing problem.1 In our laboratory, we discovered that the
cinchona alkaloid derived amino-thiocarbamates offer a frame-
work for catalyst modification to accommodate a number of
olefinic acids of various substitution patterns (Scheme 1).2
co-workers.3c Aldehyde 6 could readily be prepared from ketone
4 through a 4?5?6 sequence (Scheme 3). Alternatively, olefinic
acid 1 could be furnished in one-step from ketone 4 by reacting
with Wittig salt 7 using sodium bis(trimethylsilyl)amide as the
base, although the yield was not promising.6
In the initial phase, amino-thiocarbamates derived from four
cinchona alkaloid cores were evaluated for their potential to cata-
lyze asymmetrically the bromolactonization. Alkenoic acid 1a was
used as the model substrate and the reaction was conducted in
chloroform at À50 °C (Table 1). The work-up of the reaction
revealed not only the formation of the bromolactone 2a, but also
the elimination product 3a (2a:3a = 10:1). The product mixture
containing 2a and 3a was duly converted into 3a by adding trieth-
ylamine during the work-up process. Consequently, evaluation of
the enantioselectivity of the reaction was based on that of
butenolide 3a.
The result of the catalyst screening showed that the cinchonine
derived catalyst 8a was the best with 46% ee (Table 1, entry 1). The
amino-thiocarbamates with the pseudo enantiomeric cinchonidine
and quinine cores afforded 3a of opposite stereo-configuration
(entry 3). Contrary to our previous reports, the presence of a 6-alk-
oxy substituent on the catalyst framework did not lead to positive
enhancement of the ee of the reaction (Table 1, entry 1 vs 2, entry 3
vs 4). We also found that carbamate catalyst 12 returned a much
lower ee, which verifies the importance of the Lewis basic sulfur
atom.
While the advances have enabled the synthesis of various useful
chiral halolactone motifs, reports on asymmetric halolactoniza-
tions of alkenoic acids with
a tri-substituted olefin remain
scarce.3,4 Herein we describe our recent progress on the asymmet-
ric bromocyclization of 4,4-disubstituted 3-butenoic acids 1.
Amino-thiocarbamate and N-bromosuccinimide (NBS) were used
as the catalyst and the stoichiometric halogen source, respectively.
The result is a stereochemically defined
readily be converted into a -butenolide 3 by a simple base-med-
iated elimination (vide infra) (Scheme 2).
The synthesis of -butano- and -butenolides would be partic-
c-butanolide 2 which can
c
c
c
ularly useful as such motifs rank among the most prevalent sub-
units found in natural isolates and pharmaceutically useful
organic molecules.5 Many of these compounds exhibit diverse
biological properties such as anti-inflammatory, antibacterial,
antifungal, or phytotoxic activities, with several having been
described as potential antitumor and anticancer agents, or antima-
larial, antituberculosis, anti-aldosteronic and anti-asthmatic drug
candidates (Fig. 1).
The olefinic acid substrates 1 were synthesized via Knoevenagel
condensation of aldehyde 6, as reported by Rousseau and
The N-aryl substituent on 8 was then varied in an attempt to
improve the ee. It was found that 4- and 3-alkoxyphenyl substitu-
ents had only a small effect on the enantioselectivity (Table 1,
entries 6–9), whereas 2-alkoxyphenyl substitution significantly
⇑
Corresponding author. Tel.: +65 65167760; fax: +65 67791691.
E-mail address: chmyyy@nus.edu.sg (Y.-Y. Yeung).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.009

1244
C. K. Tan et al. / Tetrahedron Letters 55 (2014) 1243–1246
Table 1
O
Evaluation of amino-thiocarbamates as asymmetric catalysts
OH
O
Br
O
R
O
R1
Br
R
S
R
O
O
N
H
Catalyst
O
O
+
N
(10 mol%)
Et3N
O
Br
Br
R
R
OH
O
2a
(E)
H
O
5 min
X-source
(1.2 equiv)
CHCl3
O
N
OH
catalyst
3a
R
R2
O
OH
O
O
O
1a
-50 oC, 15 h
3a
O
Br
N
stoichiometric
halogen source
2a:3a
(
= 10:1)
O
O
Br
R
R
Catalysts
R'
R'
S
OH
S
O
Ar
O
O
O
N
H
N
H
O
H
N
O
N
N
H
Scheme 1. Amino-thiocarbamate-catalyzed asymmetric bromolactonization.
H
N
N
N
S
N
OMe
H
9
10
8
O
OMe
O
H
N
H
N
O
Br
H
R1
amino-thiocarbamate
catalyst
N
R1
R2
R1
R2
base
one-pot
O
R2
N
NBS
O
O
N
O
O
OH
N
H
S
2
3
1
11
12
Scheme 2. Amino-thiocarbamate catalyzed asymmetric bromolactonization of 4,4-
disubstituted 3-butenoic acid 1.
Entrya
Cat.
Ar
X-source
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
8a
9
C6H5
—
—
—
—
4-MeO-C6H4
4-EtO-C6H4
4-(t-BuO)-C6H4
3-MeO-C6H4
2-MeO-C6H4
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
98
99
99
99
95
99
99
99
99
99
99
84
99
96
81
99
99
93
99
NR
15
46
38
À33
À29
12
45
46
44
40
16
14
7
40
20
32
48
40
6
OH
Z
10
11
12
8b
8c
8d
8e
8f
OH
Me
n-C16H33
X
Y
Me
O
O
O
O
-butenolide
γ
Antibiotic
Plakortis halichondriodies (Marine Sponge)
OH
OH
8g
8h
8i
2,4-(MeO)2-C6H3
HO
R
2,4,6-(MeO)2-C6H3
4-Me-C6H4
3,5-(CF3)2-C6H3
4-NO2-C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
HO
O
OH
Ar
O
O
O
8j
OH
(R = n-Pr, i-Pr, Me)
(Ar = Ph, substituted phenyl)
8k
8a
8a
8a
8a
8a
8a
O
OMe
NBP
DBDMH
TABCO
NIS
NCS
DBDMH
Antitumor
Aspergillus terreus (Fungus)
Anti-inflammatory
15
—
0
Figure 1. Selected examples of natural products and potential drug molecules
containing the
c
-butano- or
c
-butenolide moiety.
C6H5
a
Reactions were carried out with alkenoic acid 1 (0.1 mmol), NBS (0.12 mmol),
catalyst 8a (0.01 mmol) in CHCl3/hexane (1:1) (3.0 mL).
R
R
O
Me3SI, NaH
diminished the ee (Table 1, entries 10–12). In addition, relatively
less electron-donating or highly electron-deficient substituents re-
turned lower ees (Table 1, entries 13–15). Thus, catalyst 8a was se-
lected for further development.
Examination of other halogenation sources was also conducted.
N-Bromophthalimide (NBP) afforded a minor enhancement in the
enantioselectivity, while the more reactive Br-sources, 1,3-dibro-
mo-2,2-dimethylhydantoin (DBDMH) and 2,4,4,6-tetrabromo-2,5-
cyclohexadienone (TABCO) returned eroded ees (Table 1, entries
16–18). Similar to our previous observation,2 the iodinating agent
N-iodosuccinimide (NIS) gave a much lower ee, and the use of chlo-
rinating agents gave sluggish reactions (Table 1, entries 19–21).
BF3 Et2O
O
O
DMSO/THF, 0 o
~50%
C
Ar
THF, 25 o
~90%
C
Ar
Ar
R
H
6
4
5
CH2(CO2H)2
Et3N, reflux
~30%
Br Ph3P
OH
R
7
O
OH
O
Ar
NaHMDS (2 equiv), THF/PhMe, reflux
2 days, ~20%
1
Scheme 3. Synthesis of olefinic acid substrates 1.

C. K. Tan et al. / Tetrahedron Letters 55 (2014) 1243–1246
1245
Table 2
protocol allows for the facile synthesis of enantioenriched
nolides which are fundamental units of many pharmaceutically
important molecules.
c
-bute-
Substrate scope of the asymmetric bromolactonization of 1
R1
8a
1.
(10 mol%), NBS
R1
R2
CHCl3/hexane (1:1), -78 o
2. Et3N, 5 min
C
O
Acknowledgments
R2
O
O
OH
3
We are grateful for the financial support from ASTAR-Public
Sector Funding (grant no. 143-000-536-305) and ETRP NEA (grant
no. 143-000-547-490). We also acknowledge the scholarship to
C.K. Tan (NUS President’s Graduate Fellowship).
1
Entrya
Acid
R1
R2
Time (h)
Yield (%)
ee (%)
References and notes
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Me
H
Ph
Ph
38
13
15
40
60
36
36
36
98
93
99
99
98
97
97
99
52
7
1. For recent reviews, see: (a) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew.
Chem., Int. Ed. 2012, 51, 10938; (b) Hennecke, U. Chem. Asian J. 2012, 7, 456; (c)
Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Synlett 2011, 1335; (d) Snyder, S. A.; Treitler, D.
S.; Brucks, A. P. Aldrichim. Acta 2011, 44, 27; (e) Smith, A. M. R.; Hii, K. K. Chem.
Rev. 2011, 111, 1637; (f) Tan, C. K.; Yeung, Y.-Y. Chem. Commun. 2013, 7985; (g)
Murai, K.; Fujioka, H. Heterocycles 2013, 87, 763; (h) Castellanos, A.; Fletcher, S.
P. Chem. Eur. J. 2011, 17, 5766.
Me
Me
Me
Me
Me
Me
2-Naphthyl
4-F-C6H4
4-Br-C6H4
4-MeO-C6H4
3-MeO-C6H4
2-Benzofuranyl
58
54
56
19
51
58
1g
1h
2. For the efforts from our research group, see: (a) Zhou, L.; Tan, C. K.; Jiang, X.;
Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474; (b) Tan, C. K.; Zhou, L.;
Yeung, Y.-Y. Org. Lett. 2011, 13, 2738; (c) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y.
J. Am. Chem. Soc. 2011, 133, 9164; (d) Chen, J.; Zhou, L.; Tan, C. K.; Yeung, Y.-Y. J.
Org. Chem. 2012, 77, 999; (e) Chen, J.; Zhou, L.; Yeung, Y.-Y. Org. Biomol. Chem.
2012, 10, 3808; (f) Tan, C. K.; Le, C.; Yeung, Y.-Y. Chem. Commun. 2012, 5793; (g)
Jiang, X.; Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2012, 51, 7771;
(h) Zhou, L.; Tay, D. W.; Chen, J.; Leung, G. Y. C.; Yeung, Y.-Y. Chem. Commun.
2013, 4412; (i) Chen, F.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2013, 135, 1232;
(j) Zhao, Y.; Jiang, X.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2013, 52, 8597.
3. For selected examples of the catalytic enantioselective halocyclization of tri-
substituted olefinic acids, see: (a) Murai, K.; Nakamura, A.; Matsushita, T.;
Shimura, M.; Fujioka, H. Chem. Eur. J. 2012, 18, 8448; (b) Ikeuchi, K.; Ido, S.;
Yoshimura, S.; Asakawa, T.; Inai, M.; Hamashima, Y.; Kan, T. Org. Lett. 2012, 14,
6016; (c) Garnier, J. M.; Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2007, 3281; (d)
den Hartog, T.; Maciá, B.; Minnaard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2010,
352, 999; (e) Garnier, J.-M.; Robin, S.; Guillot, R.; Rousseau, G. Tetrahedron:
Asymmetry 2007, 18, 1434; (f) Paull, D. H.; Fang, C.; Donald, J. R.; Pansick, A. D.;
Martin, S. F. J. Am. Chem. Soc. 2012, 134, 11128.
4. For related studies, see: (a) Cambie, R. C.; Rutledge, P. S.; Somerville, R. F.;
Woodgate, P. D. Synthesis 1988, 1009; (b) Balkrishna, S. J.; Prasad, C. D.; Panini,
P.; Detty, M. R.; Chopra, D.; Kumar, S. J. Org. Chem. 2012, 77, 9541; (c)
Mellegaard, S. R.; Tunge, J. A. J. Org. Chem. 2004, 69, 8979; (d) Genovese, S.;
Epifano, F.; Pelucchini, C.; Procopio, A.; Curini, M. Tetrahedron Lett. 2010, 51,
5992; (e) López-López, J. A.; Guerra, F. M.; Moreno-Dorado, F. J.; Jorge, Z. D.;
Massanet, G. M. Tetrahedron Lett. 2007, 48, 1749; (f) Yu, H.; Simon, H.
Tetrahedron 1991, 47, 9035; (g) Rao, Y. S. Chem. Rev. 1964, 64, 353; (h) Rao, Y.
S. Chem. Rev. 1976, 76, 625.
a
Reactions were carried out with alkenoic acid 1 (0.1 mmol), NBS (0.12 mmol),
catalyst (0.01 mmol) in CHCl3 (3.0 mL).
Prior to the examination of the substrate scope with catalyst 8a,
extensive solvent screening was performed. The reaction using
CHCl3/hexane (1:1) was found to offer an improved ee of 52% for
the bromolactonization of 1a (Table 2, entry 1). Using the opti-
mized conditions, other derivatives of olefinic acid
1 were
examined.7
The replacement of methyl with a hydrogen atom in the R1
position (substrate 1b) resulted in a drastic decrease in ee to 7%
(Table 2, entry 2). Introduction of bulkier substituents at the R2
position proved to be favorable; butenolides 3c and 3h bearing
2-naphthyl and 2-benzofuranyl substituents were both obtained
with 58% ee (Table 2, entries 3 and 8). Variation of the electronic
demand of the phenyl ring system at R2 was found not to affect
the ee adversely (Table 2, entries 4, 5, and 7). However, olefinic
acid 1f bearing a 4-methoxyphenyl substituent was found to offer
only 19% ee (Table 2, entry 6). This observation is also consistent
with our findings in previous reports.1,2 The absolute configura-
tions of products 3 were established based on the X-ray crystallo-
graphic study of 2h (Fig. 2).8
5. (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,
1192; (b) Bermejo, A.; Figadere, B.; Zafra-Polo, M. C.; Barrachina, I.; Estornell, E.;
Cortes, D. Nat. Prod. Rep. 2005, 22, 269; (c) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L.
J. Nat. Prod. 1999, 62, 504; (d) Hanson, J. R. Nat. Prod. Rep. 2002, 19, 381; (e)
Rodriguez, A. D. Tetrahedron 1995, 51, 4571; (f) Wright, A. D.; de Nys, R.;
Angerhofer, C. K.; Pezzuto, J. M.; Gurrath, M. J. Nat. Prod. 2006, 69, 1180; (g)
Jiménez-Romero, C.; Ortiz, I.; Vicente, J.; Vera, B.; Rodríguez, A. D.; Nam, S.; Jove,
R. J. Nat. Prod. 2010, 73, 1694; (h) Staroske, T.; Hennig, L.; Welzel, P.; Hofmann,
H.-J.; Müller, D.; Häusler, T.; Sheldrick, W. S.; Zillikens, S.; Gretzer, B.; Pusch, H.;
Glitsch, H. G. Tetrahedron 1996, 52, 12723; (i) Dogné, J. M.; Supuran, C. T.;
Pratico, D. J. Med. Chem. 2005, 48, 2251.
In summary, we have reported that tri-substituted olefinic acids
1 are amenable to amino-thiocarbamate catalyzed asymmetric
bromolactonization offering moderate ees of the products. This
6. (a) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481; (b) Vakulya, B.;
Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967; (c) McCooey, S. H.;
Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367; (d) Li, B.-J.; Jiang, L.; Liu, M.;
Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603.
7. General procedure: to an oven-dried 10 mL Schlenk flask were added alkenoic
acid 1 (0.05 mmol, 1.0 equiv) and amino-thiocarbamate catalyst 8a (0.005, 0.1
equiv) in CHCl3/hexane (1:1, 1.5 mL) under N2. The solution was cooled to
À78 °C and recrystallized NBS (10.8 mg, 0.06 mmol, 1.2 equiv) was added. The
resulting mixture was stirred at the same temperature for 15 h. Upon
completion, the reaction was quenched with saturated Na2SO3 (2 mL) and
warmed to 25 °C. Et3N (1 mL) was added and the solution was stirred for 5 min.
The resultant mixture was diluted with H2O (3 mL) and extracted with CH2Cl2
(3 Â 5 mL). The combined organic extracts were washed with aqueous HCl (1 M,
3 Â 5 mL) and brine (15 mL), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 3:1) to afford the corresponding c-butenolide 3.
Selected data: 5-(benzofuran-2-yl)-4-bromo-5-methyldihydrofuran-2(3H)-one
(2h): white solid; 1H NMR (300 MHz, CDCl3): d = 7.59 (d, J = 8.0 Hz, 1H), 7.49
(d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 6.80 (s, 1H), 4.96
(dd, J = 7.0, 3.8 Hz, 1H), 3.44 (dd, J = 18.3, 7.0 Hz, 1H), 3.00 (dd, J = 18.3, 3.8 Hz,
1H), 2.00 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 155.0, 154.1, 127.3, 125.3, 123.4,
121.5, 111.4, 104.6, 84.3, 53.4, 48.7, 40.3, 24.2; MS (EI): m/z [M]+ = 295.0.
5-(Benzofuran-2-yl)-5-methylfuran-2(5H)-one (3h): yellow solid; 1H NMR
Figure 2. X-ray crystal structure of 2h (CCDC: 818046).

1246
C. K. Tan et al. / Tetrahedron Letters 55 (2014) 1243–1246
(300 MHz, CDCl3): d = 7.60 (d, J = 5.6 Hz, 1H), 7.56 (ddd, J = 8.1, 1.3, 1.0 Hz, 1H),
chiral HPLC (CHIRALPAKÒ IB Column, i-PrOH/hexane = 15:85, 0.6 mL/min, 214
nm): t1 = 14.5 min (major), t2 = 15.3 min (minor).
8. CCDC 818046 (2h) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
7.46 (ddd, J = 8.0, 1.1 Hz, 1H), 7.31 (ddd, J = 8.1, 8.0, 1.3 Hz, 1H), 7.24 (ddd, J = 8.1,
8.0, 1.1 Hz, 1H), 6.74 (d, J = 1.0 Hz, 1H), 6.21 (d, J = 5.6 Hz, 1H), 1.93 (s, 3H); 13C
NMR (75 MHz, CDCl3): d = 171.3, 157.3, 154.9, 154.1, 127.3, 125.1, 123.2, 121.4,
121.1, 111.4, 104.1, 84.5, 23.0; MS (EI): m/z [M]+ = 214.2. Determination of ee by