Synthesis of Novel C 2-Symmetric Sulfur-Based Catalysts: Asymmetric Formation of Halo- and Seleno-Functionalized Normal- and Medium-Sized Rings

Article abstract of DOI:10.1055/s-0037-1610715

The synthesis of novel, highly functionalized, C ₂ -symmetric sulfur-based catalysts is developed and their catalytic applications are explored in asymmetric bromo-, iodo- and seleno-functionalizations of alkenoic acids. This protocol provides

Full text of DOI:10.1055/s-0037-1610715

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
cluster
A
en
S. Jana et al.
Cluster
Synlett
Synthesis of Novel C2-Symmetric Sulfur-Based Catalysts: Asymmetric
Formation of Halo- and Seleno-Functionalized Normal- and Medium-
Sized Rings
O
Sadhan Jana
Ajay Verma
0
0
0
0-0
0
0
2-
7
7
3
6-0
5
6
0
X
Cat (5 mol%), NXS (1.2 equiv)
CHCl3/Hexane (1:2)
–78 °C, N2 atm
O
0
0
0
0-0
0
0
1-
8
0
8
5-7
3
5
1
O
n
Ph
Ph
O
Vandana Rathore
0
0
0
0-0
0
0
1-7
8
1
5-6
5
1
3
OH
n
X = Br, I, SePh
98% (up to 83% ee)
O
O
O
Sangit Kumar*
0
0
0
0-
0
0
0
3-0
6
5
8-8
7
0
9
N
N
n = 1, 2
OH
S
O
N
O
Department of Chemistry, Indian Institute of Science
Education and Research (IISER) Bhopal, Bhopal Bypass
Road, Bhauri, Bhopal 462066 Madhya Pradesh, India
sangitkumar@iiserb.ac.in
O
N
Br/I
Y
O
O
H
3
3
Y
Y = O and S
82% (up to 31% ee)
Published as part of the Cluster Organosulfur and
Organoselenium Compounds in Catalysis
C2-symmetric bifunctional chiral catalyst
Received: 20.04.2019
Accepted after revision: 25.04.2019
Published online: 29.05.2019
Sulfide-catalyzed electrophilic bromination of various
substrates has been achieved. Yeung and co-worker report-
ed the triphenylphosphine sulfide catalyzed bromocycliza-
tion of amides to afford oxazolidines and oxazines.8 Similar-
ly, Mukherjee and Tripathi described selective oxidation of
secondary alcohols with NBS using a thiourea derivative as
the catalyst.9 Moreover, Denmark and Burk accomplished
the iodolactonization of alkenoic acids with N-iodosuccin-
imide catalyzed by the Lewis base, n-Bu3P=S.3c
DOI: 10.1055/s-0037-1610715; Art ID: st-2019-w0086-c
Abstract The synthesis of novel, highly functionalized, C2-symmetric
sulfur-based catalysts is developed and their catalytic applications are
explored in asymmetric bromo-, iodo- and seleno-functionalizations of
alkenoic acids. This protocol provides the corresponding normal- and
medium-sized bromo, iodo and selenolactones in up to 98% yield and
83% stereoselectivity.
Numerous methodologies have been reported for the
catalytic, enantioselective bromofunctionalization of
alkenes.1d,6c,10 In 2010, Yeung et al. developed a thiocarba-
mate which acts as a Lewis base for the enantioselective
bromofunctionalization of alkenes. This sulfur-based cata-
lyst has been employed in the cyclization of various disub-
stituted alkenes to obtain enantioenriched halolactones, 3-
bromopyrrolidines, and 3,4-dihydroisocoumarins.10h,11
Our group has also been actively involved in selenium-
catalyzed halocyclizations of alkenoic acids, where seleni-
um plays a vital role in the transformation.12 Inspired by our
recent development of the regioselective synthesis of medi-
um-sized bromo/iodolactones and bromooxepanes using a
catalytic amount of a monoselenide (Scheme 1a),12b herein
we present our results on the stereoinduction of normal-
and medium-size rings (Scheme 1b). Studies on catalytic,
enantioselective, chalcogenide-catalyzed medium-sized ha-
logenation reactions are still lacking. Furthermore, the cy-
clization of linear-chain alkenoic acids is not a favorable
process due to enthalpic and entropic factors.12b Substrates
with an alkyl chain possess a high degree of flexibility that
brings a negative entropy change during intramolecular cy-
clization reactions.13 Therefore, significant research is still
required for the preparation of new chiral Lewis bases and
diverse structural analogues.
Key words alkenoic acids, organosulfur catalysts, asymmetric cataly-
sis, halolactones, selenolactones
The group 16 donor atoms sulfur (S), selenium (Se) and
tellurium (Te) act as Lewis bases. The Lewis base catalyzed
halogenation of organic substrates, in which an n–* inter-
action between a Lewis base chalcogenide and a Lewis
acidic halogen source leads to an electrophilic halogen spe-
cies, has been well documented in the literature.1 Denmark
et al. established a variety of chiral and achiral Lewis bases,
such as selenides and sulfides, for the activation of halo-
gens.2 In recent decades, various research groups have been
involved in the development of catalytic halocyclization re-
actions by utilizing chalcogenide-based catalysts.3,4 In 2012,
Yeung and co-workers reported the synthesis of medium-
ring-sized seven-membered bromolactones using a sulfur-
based organocatalyst.5 However, catalytic asymmetric halo-
genation of medium-sized rings has not yet been explored.
In contrast to the enantioselective halogenation of five- and
six-membered rings,6 enantioenriched medium-sized halo-
lactones are rare, despite their potential applications in the
synthesis of biologically relevant molecules.7
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

B
S. Jana et al.
Cluster
Synlett
(a) Previous work
Selenide-catalyzed
Se
O
O
Y
n
O
OH
O
O
(ref 12b)
Y
n = 0, 1–5
Br/I
DMAP, NBS/NIS
0 °C
n
n = 0, 1-5
5-11 membered
(b) This work
Sulfur-catalyzed
cat (5 mol%), NBS/NIS
CHCl3/Hexane (1:2)
–78 °C, N2 atm
O
Ph
O
n
Ph
O
OH
O
X
n
Br/I
H
O
N
N
O
O
n = 1, 2
Y
S
O
OH
X = Br, I, SePh
98% (83% ee)
n = 1, 2
Y = O, S
82% (31% ee)
O
O
Y
N
N
O
O
3
3
C2-symmetric bifunctional chiral catalyst
Scheme 1 Chalcogenide-catalyzed halogenation with formation of medium-sized rings
In continuation of our studies on organochalcogen
chemistry,12,14 we rationalized that the Lewis base sulfur
would be able to activate a halogen for the synthesis of
highly strained, medium-sized rings. Thus, we have de-
signed a range of novel C2-symmetric sulfur-based chiral
catalysts for the synthesis of enantioenriched bromolac-
tones. Initially, the bromolactonization of 4-phenyl-4-pen-
tenoic acid (1a) was carried out using 1.2 equivalents of
NBS and 5 mol% of the chiral catalyst in dichloromethane at
–78 °C. We screened thiophene dicarboxylates such as (–)-
menthol-based cat 1 and found that it catalyzed the bromo-
lactonization reaction, however, no enantioselectivity was
observed (Scheme 2).
O
chiral catalyst (5 mol%)
CH2Cl2 (0.01 M), –78 °C
OH
NBS
O
Br
N2 atm, 6 h
O
80–90% yield
2a
(0.1 mmol)
(0.12 mmol)
1a
O
O
S
O
O
O
O
O
N
N
S
O
cat 1, 75% (racemic)
N
N
Further, we attempted to incorporate a nitrogen-based
chiral scaffold to make an effective chiral catalyst and chose
various cinchona alkaloid as skeletons. However, the result-
ing catalysts, quinine cat 2 and cinchonine cat 3 (Scheme
2), had no effect on the enantioselectivity and only racemic
mixtures were obtained. Surprisingly, changing the skele-
ton to dihydroquinine (DHQN) cat 4 (Scheme 2) resulted in
an enantioselectivity (ee) of 31%. To further improve the
enantioselectivity, we explored the impact of the ligand on
the structure of the catalyst. Two sites in the catalyst were
tuned: (i) the ester and amide units, and (ii) the O-alkoxy
substituents on the hydroquinine unit, which was accom-
plished by demethylation followed by alkylation. The C2-
symmetry of the scaffold also simplified the catalyst design
and modification. Moreover, different substituents have
been introduced to tune the steric hindrance. The catalyst
was modified by demethylation using sodium ethylthiolate
followed by incorporation of different alkyl chains such as
n-butyl, n-hexyl, tert-butyl, iso-butyl, 2-butane and 2-
methylpropane15 (Scheme 3). Similarly, the azide formed
from the O-mesylated derivative of DHQN followed by azide
O
O
O
O
N
N
cat 2, 76% (racemic)
S
O
O
N
N
O
O
N
N
cat 3, 70% (racemic)
S
O
N
O
N
O
O
cat 4, 73% (31% ee)
Scheme 2 Catalyst screening
reduction and hydrolysis provided 9-amino-(9-deoxy)-epi-
cinchona alkaloids (DHQN-NH2).16 Thus, the alkoxy or
amine derivative of the cinchona alkaloid was treated with
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

C
S. Jana et al.
Cluster
Synlett
O
O
N
N
N
Cl
OH
Cl
N
N
S
O
O
S
OH
OH
NaSEt, DMF
R=Br, Cs2CO3
O
O
O
HO
O
R
N
110 °C, 4–6 h
DMF, 60 °C, 24 h
R = alkyl chain
Et3N, CH2Cl2
0 °C to rt, 6 h
N
O
R
O
R
N
N
N
(3)
(4)
(5aa–ee)
R = n-butyl, cat 5 (66%)
R = n-hexyl, cat 6 (63%)
R = Isopentyl, cat 7 (59%)
R = 2-butane, cat 8 (61%)
O
O
MsCl, NEt3
THF, 0 °C
S
HN
NH
R = 2-methylpropane, cat 9 (57%)
cat 10 (72%)
Cl
Cl
O
O
N
N
S
N
S
N
NaN3, DMF
65 °C, 24 h
N
PPh3, THF
65 °C, 4 h
O
O
NH
HN
OMs
N3
NH2
Et3N, CH2Cl2
0 °C to rt, 6 h
O
O
N
N
O
O
O
N
N
N
cat 11 (60%)
Quinine bisamide cat 12 (56%)
(6)
(7)
(8)
(9) Quinine–NH2
Scheme 3 Synthesis of modified catalysts
2,5-thiophenedicarbonyl dichloride under basic conditions
to afford catalysts cat 5–9 and cat 10–12, respectively.
These bifunctional sulfur-based catalysts were then sub-
jected to the asymmetric bromocyclization reaction.
When the reaction of 1a and NBS was conducted with
C2-symmetric sulfur-based cat 5 (5 mol%) in dichlorometh-
ane (CH2Cl2), the desired bromolactone 2a was obtained in
88% yield with poor enantioselectivity (36% ee) within 16
hours (Table 1, entry 1). Next, various solvent systems were
explored to improve the selectivity of the reaction. We ob-
served that among several solvents, including dichloro-
methane, chloroform and toluene, the reaction in the less
polar solvent hexane proceeded with modest enantioselec-
tivity (45% ee) (entries 2–4). On varying the polarity with
mixed solvent systems, CHCl3/hexane (1:2) showed the
highest efficiency with an optimum 83% ee being obtained
(entries 5–9). The nonpolar solvent mixture reduced the
noncatalyzed reaction and strengthened the polar interac-
tion among the alkenoic acid, NBS, and the catalyst, result-
ing in enhancement of the enantioselectivity. The hexyl
substitution on the quinolone moiety of thiophene dicar-
boxylate cat 6, under the same conditions, gave a lower en-
antioselectivity (entry 10). Similarly, reactions with cat 7,
cat 8 and cat 9 occurred with low enantioselectivity (en-
tries 11–13). Furthermore, screening the efficient isopino-
campheylamine/cinchonine framework, endeavoring to in-
crease the acidity of the carboxylate in cat 10–12 by re-
placement with an amide functional group, however,
resulted in a racemic mixture for cat 10, moderate 52% ee
for cat 11 (entry 14), and 43% ee for cat 12, respectively. Al-
so, the use of additives failed to improve the stereoselectivi-
ty.
Table 1 Optimization of the Reaction Conditionsa
O
cat (5 mol%)
OH
NBS
solvent (0.01 M), –78 °C
O
Br
O
1a
2a
Entry Cat.
Solvent
CH2Cl2
Time (h) Yield (%)b ee (%)c
1
2
cat 5
cat 5
cat 5
cat 5
cat 5
cat 5
cat 5
cat 5
cat 5
cat 6
cat 7
cat 8
cat 9
cat 11
16
20
28
30
35
32
10
24
31
88
68
80
50
40
88
75
85
80
87
85
81
90
97
92
87
89
92
85
36
15
34
45
38
62
44
60
83
60
55
66
45
52
toluene
3
CHCl3
4
hexane
5
toluene/CH2Cl2 (1:1)
CHCl3/toluene (1:1)
CHCl3/toluene (1:2)
CHCl3/hexane (1:1)
CHCl3/hexane (1:2)
CHCl3/hexane (1:2)
CHCl3/hexane (1:2)
CHCl3/hexane (1:2)
CHCl3/hexane (1:2)
CHCl3/hexane (1:2)
6
7
8
9
10
11
12
13
14
a All reactions were carried out with 1a (0.1 mmol), NBS (0.12 mmol) and the
chiral catalyst (5 mol%) in 2 mL of solvent at –78 °C in a 10 mL Schlenk tube
under nitrogen. The reaction progress was monitored by TLC.
b Yield of isolated 2a.
c Enantiopurity was determined by HPLC analysis using a ChiralPak IC-3 column.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

D
S. Jana et al.
Cluster
Synlett
Having optimized the catalyst and reaction conditions,
we next investigated the substrate scope. A broad range of
4-phenyl-4-pentenoic acids containing aromatic substitu-
ents on the olefin was converted into the corresponding
bromolactones with high yields and good to moderate en-
antioselectivities (Figure 1). In particular, better results
were obtained with the substrates 1b and 1c having elec-
tron-rich methyl and methoxy groups at the para positions
of the aromatic rings, with the lactones 2b and 2c being ob-
tained with 82% and 66% ee, respectively. Electron-deficient
fluoro-, chloro-, and difluoro-substituted substrates 1d–f
provided bromolactones 2d–f with good enantioselectivi-
ties (43–66%). The X-ray crystal structure of 4-fluorophenyl
-lactone 2d is shown in Figure 1. Biphenyl-substituted
alkenoic acid 1g provided bromolactone 2g with moderate
selectivity (27% ee).
ing the developed protocol. Lactones 3b–i having an addi-
tional heteroatom in the chain were obtained in good to ex-
cellent yields (22–82%) and moderate to low enantiomeric
excesses, which can be attributed to the reduction of tran-
sannular strain in the presence of the heteroatom. Electron-
withdrawing Cl and NO2 substituents on the aromatic rings
yielded products 3d,e with low enantioselectivities (<20%).
Interestingly, electron-donating Me and OMe substituents
induced slightly higher enantioselectivities (>30%) in prod-
ucts 3f,g. Polyaromatic bromolactone 3h containing a
naphthyl ring was obtained with 14% ee.
O
O
O
O
O
O
Br
I
Br
H
H
H
O
O
3a, 81% (racemic)
3b, 33% (25% ee)
3c, 22% (10% ee)
(34 h)
(49 h)
(66 h)
R
X
O
O
O
O
O
O
Cl
Br
Br
Br
O
O
H
H
H
O
Br
O
O
Br
O
Br
O
O
O
NO2
2a, 97%
(83% ee)
(31 h)
2b, R = Me; 98% (82% ee) (23 h)
2c, R = OMe; 95% (66% ee) (18 h)
2d, X = F; 86% (64% ee) (24 h)
2e, X = Cl; 88% (66% ee) (41 h)
3e, 82% (10% ee)
3d, 60% (20% ee)
3f, 77% (31% ee)
(93 h)
(74 h)
(47 h)
O
O
O
O
O
F
O
Br
Br
Br
H
H
H
O
O
S
F
O
O
O
Br
3g, 71% (29% ee)
3h, 52% (14% ee)
O
3i, 22% (racemic)
Br
O
(54 h)
(77 h)
(63 h)
2d
2f, 89% (43% ee)
2g, 83% (27% ee)
Figure 2 Scope of the enantioselective formation of seven-membered
(39 h)
(63 h)
CCDC 1573525
bromo/iodolactones
O
O
We speculate that the halocyclization reaction proceeds
through a rigid transition state model, in which the olefin–
olefin halogen exchange18 and the transannular strain in
the ring13 could be suppressed through Lewis basic sulfur1
or via hydrogen bond activation. The n-butyl moiety on the
quinine scaffold leads to a pocket in which the carboxylic
acid of the substrate was deprotonated by the quinine ni-
trogen of cat 5 to form an ion pair (Scheme 4). Cat 5 serves
as a bifunctional catalyst by interacting with both the car-
boxylate nucleophile and the NBS electrophile, facilitating
5-exo cyclization to form desired five- to seven-membered
halolactones.
In conclusion, we have developed a novel C2-symmetric
sulfur-based chiral catalyst for the enantioselective bromo-
lactonization of alkenoic acids.19 This protocol allows for
the asymmetric synthesis of -, - and -lactones and sele-
nolactones. Further mechanistic studies and investigations
of this class of catalysts in another asymmetric electrophilic
cyclization reactions are underway.
Br
O
Ph
O
SePh
I
O
O
2h, 77% (31% ee)
2i, 62% (13% ee)
2aa, 85% (34% ee)
(52 h)
(36 h)
(69 h)
Figure 1 Scope of catalytic enantioselective halo/seleno lactonization
When N-iodosuccinimide (NIS) was used as the halogen
source, -iodolactone 2h was formed with 31% enantiomer-
ic excess. By utilizing this protocol, five-membered seleno-
lactone 2i17 was also prepared with 13% enantioselectivity
and 62% yield. Furthermore, when 5-phenyl-5-hexanoic
acid was subjected to the bromocyclization with NBS in the
presence of 5 mol% of chiral catalyst 5 in CHCl3/hexane
(1:1) at –60 °C, the desired product 2aa was obtained with
34% ee.
Next, the synthesis of various seven-membered bromo-
and iodolactones was explored starting from the corre-
sponding alkenoic acids (Figure 2). Bromolactone 3a with a
phenyl ring attached was obtained as a racemic mixture us-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

E
S. Jana et al.
Cluster
Synlett
2010, 107, 20655. (d) Snyder, S.; Treitler, A. D. S.; Brucks, A. P. J.
Am. Chem. Soc. 2010, 132, 14303. (e) Chen, F.; Tan, C. K.; Yeung,
Y.-Y. J. Am. Chem. Soc. 2013, 135, 1232. (f) Sawamura, Y.;
Nakatsuji, H.; Sakakura, A.; Ishihara, K. Chem. Sci. 2013, 4, 4181.
(g) Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2014,
136, 5627. (h) Kawato, Y.; Kubota, A.; Ono, H.; Egami, H.;
Hamashima, Y. Org. Lett. 2015, 17, 1244. (i) Ke, Z.; Tan, C. K.; Liu,
Y.; Lee, K. G. Z.; Yeung, Y.-Y. Tetrahedron 2016, 72, 2683. (j) See,
J. Y.; Yang, H.; Zhao, Y.; Wong, M. W.; Ke, Z.; Yeung, Y.-Y. ACS
Catal. 2018, 8, 850.
O
O
N
H
O
O
S
N
O
N
Pocket
O
N
cat 5
(4) Catalytic halocyclization reactions by sulfur-based catalysts:
(a) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8, 171.
(b) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321.
(c) French, A. N.; Bissmire, S.; Wirth, T. Chem. Soc. Rev. 2004, 33,
354. (d) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.;
Jayaraman, N. Tetrahedron 2004, 60, 5273. (e) Laya, M. S.;
Banerjee, A. K.; Cabrera, E. V. Curr. Org. Chem. 2009, 13, 720.
(f) Montana, A. M.; Batalla, C.; Barcia, J. A.; Montana, A. M.;
Batalla, C. Curr. Org. Chem. 2009, 13, 919. (g) Chung, W.-j.;
Vanderwal, C. D. Angew. Chem. Int. Ed. 2016, 55, 4396.
O
N
H
O
O
O
S
N
O
Br
N
H
O
O
O
N
(5) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2012, 134, 16492.
cat 5 + substrate complex
Scheme 4 Proposed working model
(6) For reviews on enantioselective halofunctionalization, see:
(a) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem. Int.
Ed. 2012, 51, 10938. (b) Tan, C. K.; Yeung, Y.-Y. Chem. Commun.
2013, 49, 7985. (c) Cheng, Y. A.; Yu, W. Z.; Yeung, Y.-Y. Org.
Biomol. Chem. 2014, 12, 2333.
Funding Information
(7) (a) Boye, A. C.; Meyer, D.; Ingison, C. K.; French, A. N.; Wirth, T.
Org. Lett. 2003, 5, 2157. (b) Saito, B.; Fu, G. C. J. Am. Chem. Soc.
2007, 129, 9602. (c) Kambe, N.; Iwasaki, T.; Terao, J. Chem. Soc.
Rev. 2011, 40, 4937. (d) Shiina, I. Chem. Rev. 2007, 107, 239.
(e) Gao, W.-C.; Xiong, Z.-Y.; Pirhaghani, S.; Wirth, T. Synthesis
2019, 51, 276.
We are grateful for the financial support from the Science and Engi-
neering Research Board (SERB), Department of Science & Technology
(DST), New Delhi (EMR/2015/000061). S.J., A.V. and V.R. acknowledge
the Indian Institute of Science Education and Research (IISER) Bhopal
and UGC, New Delhi for fellowships.
S
c
i
e
n
c
e
a
n
d
E
n
g
i
n
e
eri
n
g
R
esearc
h
B
o
ard(E
M
R/2
0
1
5/0
0
0
0
6
1)
(8) (a) Wong, Y.-C.; Ke, Z.; Yeung, Y.-Y. Org. Lett. 2015, 17, 4944.
(b) Ke, Z.; Wong, Y.-C.; See, J. Y.; Yeung, Y.-Y. Adv. Synth. Catal.
2016, 358, 1719.
Supporting Information
Supporting information for this article is available online at
(9) (a) Tripathi, C. B.; Mukherjee, S. J. Org. Chem. 2012, 77, 1592.
(b) Tripathi, C. B.; Mukherjee, S. Angew. Chem. Int. Ed. 2013, 52,
8450. (c) Tripathi, C. B.; Mukherjee, S. Synlett 2014, 25, 163.
(10) (a) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang,
W. J. Am. Chem. Soc. 2010, 132, 3664. (b) Murai, K.; Matsushita,
T.; Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka, H.
Angew. Chem. Int. Ed. 2010, 49, 9174. (c) Zhou, L.; Chen, J.; Tan,
C. K.; Yeung, Y. Y. J. Am. Chem. Soc. 2011, 133, 9164.
(d) Castellanos, A.; Fletcher, S. P. Chem. Eur. J. 2011, 17, 5766.
(e) Jiang, X.; Tan, C. K.; Zhou, L.; Yeung, Y. Y. Angew. Chem. Int.
Ed. 2012, 51, 7771. (f) Hennecke, U. Chem. Asian J. 2012, 7, 456.
(g) Zhang, W.; Liu, N.; Schienebeck, C. M.; Decloux, K.; Zheng, S.;
Werness, J. B.; Tang, W. Chem. Eur. J. 2012, 18, 7296. (h) Tan, C.
K.; Le, C.; Yeung, Y. Y. Chem. Commun. 2012, 48, 5793. (i) Zhou,
L.; Tay, D. W.; Chen, J.; Leung, G. Y.; Yeung, Y. Y. Chem. Commun.
2013, 49, 4412. (j) Fujioka, H.; Murai, K. Heterocycles 2013, 87,
763. (k) Armstrong, A.; Braddock, D. C.; Jones, A. X.; Clark, S. Tet-
rahedron Lett. 2013, 54, 7004. (l) Tan, C. K.; Yu, W. Z.; Yeung, Y.-
Y. Chirality 2014, 26, 328. (m) Zheng, S.; Schienebeck, C. M.;
Zhang, W.; Wang, H.-Y.; Tang, W. Asian J. Org. Chem. 2014, 3,
366. (n) Tay, D. W.; Leung, G. Y.; Yeung, Y. Y. Angew. Chem. Int.
Ed. 2014, 53, 5161. (o) Tan, C. K.; Er, J. C.; Yeung, Y.-Y. Tetrahe-
dron Lett. 2014, 55, 1243. (p) Denmark, S. E.; Burk, M. T. Chirality
2014, 26, 344. (q) Chen, T.; Foo, T. J. Y.; Yeung, Y.-Y. ACS Catal.
2015, 5, 4751. (r) Samanta, R. C.; Yamamoto, H. J. Am. Chem. Soc.
2017, 139, 1460. (s) Gieuw, M. H.; Ke, Z.; Yeung, Y. Y. Chem. Rec.
2017, 17, 287.
https://doi.org/10.1055/s-0037-1610715.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References and Notes
(1) (a) Mellegaard-Waetzig, S. R.; Wang, C.; Tunge, J. A. Tetrahedron
2006, 62, 7191. (b) Ahmad, S. M.; Braddock, D. C.; Cansell, G.;
Hermitage, S. A. Tetrahedron Lett. 2007, 48, 915. (c) Castellote, I.;
Morón, M.; Burgos, C.; Alvarez-Builla, J.; Martin, A.; Gómez-Sal,
P.; Vaquero, J. J. Chem. Commun. 2007, 1281. (d) Zhang, W.; Xu,
H.; Xu, H.; Tang, W. J. Am. Chem. Soc. 2009, 131, 3832. (e) Cao, L.;
Ding, J.; Yin, G.; Gao, M.; Li, Y.; Wu, A. Synlett 2009, 1445.
(f) Lewis Base Catalysis in Organic Synthesis, 1st ed; Vedejs, E.;
Denmark, S. E., Ed.; Wiley-VCH: Weinheim, 2016. (g) Perin, G.;
Barcellos, A. M.; Peglow, T. J.; Nobre, P. C.; Cargnelutti, R.;
Lenardão, E. J.; Marini, F.; Santi, C. RSC Adv. 2016, 6, 103657.
(h) Sancineto, L.; Mangiavacchi, F.; Tidei, C.; Bagnoli, L.; Marini,
F.; Gioiello, A.; Scianowski, J.; Santi, C. Asian J. Org. Chem. 2017,
6, 988.
(2) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47,
1560. (b) Denmark, S. E.; Kalyani, D.; Collins, W. R. J. Am. Chem.
Soc. 2010, 132, 15752. (c) Denmark, S. E.; Burk, M. T. Org. Lett.
2012, 14, 256.
(3) Electrophilic halogenation catalyzed by Lewis basic chalcogens:
(a) Mellegaard, S. R.; Tunge, J. A. J. Org. Chem. 2004, 69, 8979.
(b) Snyder, S. A.; Treitler, D. S. Angew. Chem. Int. Ed. 2009, 48,
7899. (c) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U.S.A.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

F
S. Jana et al.
Cluster
Synlett
(11) Catalytic asymmetric bromolactonization: (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) Chen, J.; Zhou, L.; Yeung, Y.-Y. Org. Biomol. Chem. 2012,
10, 3808. (d) Chen, J.; Zhou, L.; Tan, C. K.; Yeung, Y.-Y. J. Org.
Chem. 2012, 77, 999.
(12) (a) Balkrishna, S. J.; Prasad, C. D.; Panini, P.; Detty, M. R.;
Chopra, D.; Kumar, S. J. Org. Chem. 2012, 77, 9541. (b) Verma, A.;
Jana, S.; Durga Prasad, C.; Yadav, A.; Kumar, S. Chem. Commun.
2016, 52, 4179. (c) Balkrishna, S. J.; Kumar, S.; Kumar, A.; Panini,
P.; Kumar, S. Proc. Natl. Acad. Sci., India Sect. A: Phys. Sci. 2016,
86, 589.
(13) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(14) (a) Kumar, S.; Yan, J.; Poon, J.-F.; Singh, V. P.; Lu, X.; Ott, M. K.;
Engman, L.; Kumar, S. Angew. Chem. Int. Ed. 2016, 55, 3729.
(b) Prasad, Ch. D.; Sattar, M.; Kumar, S. Org. Lett. 2017, 19, 774.
(c) Rathore, V.; Upadhyay, A.; Kumar, S. Org. Lett. 2018, 20,
6274.
(15) (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126,
9906. (b) Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167.
(c) Choudhury, A. R.; Mukherjee, S. Org. Biomol. Chem. 2012, 10,
7313.
(16) Cassani, C.; Martín-Rapún, R.; Arceo, E.; Bravo, F.; Melchiorre, P.
Nat. Protoc. 2013, 8, 325.
(17) (a) Khokhar, S. S.; Wirth, T. Eur. J. Org. Chem. 2004, 4567.
(b) Khokhar, S. S.; Wirth, T. Angew. Chem. Int. Ed. 2004, 43, 631.
(c) Niu, W.; Yeung, Y.-Y. Org. Lett. 2015, 17, 1660.
(18) (a) Brown, R. S.; Nagorski, R. W.; Bennet, A. J.; McClung, R. E. D.;
Aarts, G. H. M.; Klobukowski, M.; McDonald, R.; Santarsiero, B.
D. J. Am. Chem. Soc. 1994, 116, 2448. (b) Neverov, A.; Brown, R. S.
J. Org. Chem. 1996, 61, 962. (c) Brown, R. S. Acc. Chem. Res. 1997,
30, 131. (d) Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem.
Soc. 2010, 132, 1232.
ylquinuclidin-2-yl]methyl}
(Cat 5)
Thiophene-2,5-dicarboxylate
White solid; yield: 576 mg (66%); mp 147–150 °C; []D19.4 +24.9
(c 0.33, CHCl3). IR (plate): 1722, 1715, 1620, 1596, 1530, 1507,
1462, 1448, 1362, 1320, 1241 cm–1. 1H NMR (400 MHz, CDCl3):
 = 8.69 (d, J = 4.49 Hz, 2 H), 8.00 (d, J = 9.15 Hz, 2 H), 7.79 (s, 2
H), 7.41–7.35 (m, 6 H), 6.67 (d, J = 1.48 Hz, 2 H), 4.17–4.08 (m, 4
H), 3.43–3.38 (m, 2 H), 3.06 (q, J = 12.64 Hz, 2 H), 2.69–2.64 (m,
2 H), 2.36 (d, J = 12.96 Hz, 2 H), 1.87–1.71 (m, 12 H), 1.66–1.62
(m, 2 H), 1.58–1.49 (m, 6 H), 1.45–1.40 (m, 2 H), 1.37–1.25 (m, 4
H), 0.98 (t, J = 7.35 Hz, 6 H), 0.83 (t, J = 7.25 Hz, 6 H). 13C NMR
(100 MHz, CDCl3):  = 160.3, 157.7, 147.2, 144.6, 142.8, 138.8,
133.7, 131.8, 126.7, 122.4, 118.3, 101.8, 75.7, 68.1, 59.0, 58.5,
42.8, 37.3, 31.2, 28.5, 27.7, 25.3, 23.6, 19.3, 13.8, 12.0. HRMS
(ESI): m/z [M + H]+ calcd for C52H64N4O6S: 873.4618; found:
873.4619.
Halolactones 2 and 3
To a solution of alkenoic acid (1.0 equiv, 0.1 mmol) and catalyst
cat 5 (0.05 equiv, 0.005 mmol, 4.6 mg) in a mixture of CHCl3 (2
mL) and hexane (4 mL) at –78 °C in the dark under N2 was added
N-bromosuccinimide (NBS) (1.2 equiv, 0.12 mmol, 21 mg) or N-
iodosuccinimide (NIS). The resulting mixture was stirred at
–78 °C and the reaction progress monitored by TLC. After com-
pletion, the reaction was quenched with saturated Na2SO3 (2
mL) at –78 °C and then warmed to room temperature. The solu-
tion was diluted with H2O (3 mL) and extracted with CH2Cl2
(3 × 5 mL). The combined extracts were washed with brine (5
mL), dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography using hex-
ane/EtOAc to yield the corresponding halolactone.
(R)-5-(Bromomethyl)-5-phenyldihydrofuran-2(3H)-one (2a)
Colorless oil; yield: 24.7 mg (97%); []D
20 5
. –13.95 (c 0.66,
CHCl3); 83% ee. 1H NMR (400 MHz, CDCl3):  = 7.40–7.32 (m, 5
H), 3.72 (d, J = 11.31 Hz, 1 H), 3.67 (d, J = 11.31 Hz, 1 H), 2.85–
2.74 (m, 2 H), 2.58–2.47 (m, 2 H). 13C NMR (100 MHz, CDCl3):
 = 175.5, 140.7, 128.8, 128.6, 124.9, 86.4, 41.0, 32.3, 29.0. HPLC
(Daicel ChiralPak IC-3, i-PrOH/hexane = 25:75, 0.6 mL/min, 214
nm): t1 = 21.8 (minor), t2 = 25.0 (major).
(19) Catalyst Preparation
To a stirred solution of 2,5-thiophenedicarbonyl dichloride (1.0
equiv, 1.0 mmol, 209 mg) in CH2Cl2 (20 mL) at 0 °C were added
dropwise the alkyl derivative of the cinchona alkaloid (2.1
equiv, 2.1 mmol) and Et3N (4.0 equiv, 4.0 mmol) in CH2Cl2 (15
mL) using a dropping funnel. After the addition was complete,
the mixture was stirred for 6 h at 0 °C to room temperature.
After completion of the reaction, saturated NaHCO3 solution (20
mL) was added to the mixture. The resulting solution was
extracted with CH2Cl2 (3 × 20 mL) and the combined organic
layer washed with brine (20 mL), dried over Na2SO4 and concen-
trated on a rotary evaporator under vacuum. The resulting solid
was purified by column chromatography with CH2Cl2/MeOH
(10:1).
3-(Bromomethyl)-4,5-dihydrobenzo[c]oxepin-1(3H)-one
(3a)
White semi-solid; yield: 20.7 mg (81%); []D
26 1
. –3.5 (c 0.2,
CHCl3); racemic. 1H NMR (400 MHz, CDCl3):  = 7.70 (dd, J = 7.5,
0.7 Hz, 1 H), 7.47 (td, J = 7.5, 1.1 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 1 H),
7.20 (d, J = 7.5 Hz, 1 H), 4.30–4.17 (m, 1 H), 3.55 (dd, J = 10.8, 6.1
Hz, 1 H), 3.47 (dd, J = 10.8, 5.4 Hz, 1 H), 3.05–2.95 (m, 1 H),
2.83–2.75 (m, 1 H), 2.20–2.10 (m, 2 H). 13C NMR (100 MHz,
CDCl3):  = 170.4, 137.7, 133.0, 131.2, 130.3, 128.8, 127.6, 77.1,
32.8, 32.6, 29.4. HPLC (Daicel ChiralPak IC-3, i-PrOH/hexane =
25:85, 0.6 mL/min, 214 nm): t1 = 25.0 (minor), t2 = 29.1 (major).
2-{(1S)-(6-Butoxyquinolin-4-yl)[(2S)-5-ethylquinuclidin-2-
yl]methyl} 5-{(1S)-(6-Butoxyquinolin-4-yl)[(2S,4S,5R)-5-eth-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F