Enantioselective Halocyclization of Indole Derivatives: Using 1,3-Dihalohydantoins with Anionic Chiral Co(III) Complexes

Article abstract of DOI:10.1055/a-1310-5213

Highly enantioselective halocyclization reactions of indole derivatives, including tryptophols and tryptamines, have been accomplished by means of anionic chiral Co(III) complexes and 1,3-dihalohydantoins (as little as 0.50 equiv). 3-Halo-fused indolines

Full text of DOI:10.1055/a-1310-5213

Submission Date:
Accepted Date:
Publication Date:
2020-10-19
2020-11-13
2020-11-13
Accepted Manuscript
Synlett
Enantioselective Halocyclization of Indole Derivatives: Using 1,3-Dihalohydan-
toins with Anionic Chiral Co(III) Complexes
Ting-Ting Sun, Kun Liu, Shun-Xin Zhang, Chun-Ru Wang, Chuan-Zhi Yao, Jie Yu.
Affiliations below.
DOI: 10.1055/a-1310-5213
Please cite this article as: Sun T-T, Liu K, Zhang S-X et al. Enantioselective Halocyclization of Indole Derivatives: Using 1,3-Dihalohydan-
toins with Anionic Chiral Co(III) Complexes. Synlett 2020. doi: 10.1055/a-1310-5213
Conflict of Interest: The authors declare that they have no conflict of interest.
This study was supported by National Natural Science Foundation of China (http://dx.doi.org/10.13039/501100001809), 21672002,
Anhui Provincial Natural Science Funds for Distinguished Young Scholar, 1908085J07
Abstract:
The highly enantioselective halocyclization reactions of indole derivatives, including tryptophols and tryptamines, have been
accomplished by means of anionic chiral Co(III) complexes and 1,3-dihalohydantoins (as little as 0.50 equiv). 3-Halo fused
indolines were obtained in excellent yields (up to 98%) and enantioselectivities (up to 98% ee), employing the chiral anion pha-
se-transfer catalysis strategy.
Corresponding Author:
Jie Yu, Anhui Agricultural University, Depart. of Applied Chemistry, Hefei, China, jieyu@ahau.edu.cn
Affiliations:
Ting-Ting Sun, Anhui Agricultural University, Dept. of Applied Chemistry, Hefei, China
Kun Liu, Anhui Agricultural University, applied chemistry, Hefei, China
Shun-Xin Zhang, Anhui Agricultural University, Dept. of Applied Chemistry, Hefei, China
[
…]
Jie Yu, Anhui Agricultural University, Depart. of Applied Chemistry, Hefei, China
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Synlett
Letter / Cluster / New Tools
Enantioselective Halocyclization of Indole Derivatives: Using 1,3-
Dihalohydantoins with Anionic Chiral Co(III) Complexes
◊
a
Ting-Ting Sun
◊
a
Kun Liu
Shun-Xin Zhang
◊
a
a
Chun-Ru Wang
a
Chuan-Zhi Yao
a
Jie Yu *
a
Department of Applied Chemistry, Anhui Agricultural
University, Hefei, 230036, China
jieyu@ahau.edu.cn
◊
These authors contributed equally to this work.
Received:
Accepted:
Published online:
DOI:
iodofunctionalization 7c,7d with high stereoselectivities. It turned
out that Brønsted acids of anionic chiral Co(III) complexes can
function like chiral-anion-mediated catalysts8,9 to undergo
exchange reactions with NBS or NIS, leading to the formation of
the halogen cation-anionic chiral Co(III) complex species
Abstract The highly enantioselective halocyclization reactions of indole
derivatives, including tryptophols and tryptamines, have been accomplished
by means of anionic chiral Co(III) complexes and 1,3-dihalohydantoins (as little
as 0.50 equiv). 3-Halo fused indolines were obtained in excellent yields (up to
+
-
7
{
X [Co*] } (Scheme 1B). Therefore, we speculated that the
9
8%) and enantioselectivities (up to 98% ee), employing the chiral anion
anionic chiral Co(III) complexes which are highly soluble in
nonpolar media could also act as solid-liquid biphasic transfer
catalysts to shuttle the less-soluble DXDMHs (especially the
DIDMH) across the solvent interface to control the
stereochemistry. The uncatalyzed reaction may be slower than
the phase-transfer catalyzed process, as the insoluble parent
achiral halogenating agent should be much less reactive with
phase-transfer catalysis strategy.
Key words anion phase-transfer catalysis, chiral Co(III) complex, Brønsted acid,
indole derivatives, halocyclization
Asymmetric electrophilic halogenations of olefins are the most
fundamental transformations for building up various kinds of
enantioenriched heterocyclic molecules, enabled by either
organocatalysts or chiral metal-complexes.1,2 Tremendous
efforts have been made on the asymmetric halofunctionalization
that mostly relies on the easy handling N-halo reagents, such as
N-haloamides, N-haloimides (especially N-halosuccinimides),
and 1,3-dihalo-5,5-dimethylhydantoins (DXDMHs, X = I, Br, I).3
Among these reagents, N-halosuccinimides (NXS) are the most
studied group of N-halo compounds, which can be utilized for the
highly stereoselective reactions under mild conditions. 3a-3d
Besides, the commercially available DXDMHs, which possess the
same selectivity as NXS and equal or better halogenating ability,
are also frequently used.3g The traditional activation mode of
+
-
respect to the in situ generated soluble chiral X [Co*] species.
Moreover, the exchange reaction between chiral Co(III)
1
3
complexes and DXDMHs with two N ,N -halo groups could make
DXDMHs more economical in comparison to NXS (Scheme 1C).
3
DXDMHs is believed to form enhanced electrophilic N -halogen
species, which were generated through protonation or
coordination of the C-2 carbonyl moiety by chiral Brønsted or
Lewis acid catalysts or the interaction between the halogenating
reagents with nucleophilic Lewis bases (Scheme 1A).1d,3g,4-6
Despite these elegant achievements, the study of the activation
manner of DXDMHs remains limited, and the asymmetric
Scheme 1 Asymmetric halogenation with anionic chiral Co(III) complexes.
The asymmetric halocyclizations of indole derivatives,
including tryptamines and tryptophols, could provide convenient
access to enatioenriched halo-substituted fused indolines, pivotal
intermediates in the synthesis of natural alkaloids and other
biological active molecules.10,11 In 2011, Gouverneur reported an
elegant asymmetric fluorocyclization of indole derivatives with a
chiral amine Lewis base catalyst.11a Then Ma, Xie and Lai made a
milestone contribution on the enantioselective bromocyclization
of tryptamines and tryptophols catalyzed by chiral phosphoric
acid.11b-d Recently, You and coworkers established the
asymmetric fluorocyclization of indole derivatives with chiral
phosphoric acid.11f-g Despite these progresses, the development
5
6
versions using the more reactive DBDMH or DIDMH have been
less recognized due to the rapid background reactions. Thus, the
exploration of novel chiral catalyst systems with DXDMHs
1
3
bearing two N ,N -X bonds in an atom-economical manner is still
desirable to offer new opportunities for the development of
enantioselective halogenations.
In our previous works on asymmetric halofunctionalization,7
we have developed the chiral Co(III) complexes as bifunctional
phase-transfer catalysts (Scheme 1, Λ-(S,S)-1) for either
7a,7b
intramolecular bromocyclization
or intermolecular
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of enantioselective iodo- and chloro-functionalization of indole
derivatives and the exploration of the novel activation mode of N-
halo reagents are still highly desirable. Herein, we present the
enantioselective halocyclization of indole derivatives with
anionic chiral Co(III) complexes, employing DXDMHs (as little as
Table 2 Substrate scope of enantioselective iodocyclization.a
0.50 equiv, X = I, Br, Cl) as the halogenating reagents. Chiral
Co(III)-complex-templated Brønsted acid enabled the synthesis
of the 3-halo fused indoline products with up to 98% yield and
with 98% ee.
Our studies commenced with the iodocyclization of N-Boc
protected tryptophol 2a, a substrate which allows the creation of
a
stereogenic iodinated quaternary carbon center. The
iodocyclization reactions of 2a with various iodinating reagents,
such as DIDMH, NIS and N-iodosaccharin (NISC), were initially
tested in the presence of 10 mol% of Brønsted acid of anionic
chiral Co(III) complexes Λ-1a (Table 1, entries 1-3). As
anticipated, the more reactive DIDMH turned out to be the best
iodine source for this iodocyclization by premixing Λ-1a with
iodinating reagent and following slow addition of tryptophol 2a
(
entries 1-3). Other reaction parameters were then evaluated,
including Chiral Co(III)-complex-templated Brønsted acids and
sodium salts (Λ-1b-1f) and solvents, which were found to be less
efficient (entries 4-10). Increasing the solvent volume enabled a
slightly improved enantioselectivity (entry 11 vs entry 1). To our
delight, the utilization of CCl
reaction in 98% yield, furnishing 3-iodofuroindoline 3a with 95%
ee (entry 12). Employing toluene as a co-solvent in CCl at lower
4
rendered the iodocyclization
4
temperature led to a little decline in stereoselectivity (entry 13).
It is noteworthy that the addition of DIDMH in one portion to the
mixture of Λ-1 and 2a proved detrimental (entry 14).
a
Table 1 Optimization of the iodocyclization conditions of 2a.a
Unless otherwise noted, reactions were carried out by slow addition (over 20
minutes) of 2 (0.10 mmol) in CCl (1.0 mL) to a mixture of DIDMH (0.10 mmol), Λ-1a
4
(
0.01 mmol) and 4 Å MS (100 mg) in CCl
4
(4.0 mL) at -20 °C under an air atmosphere
in the absence of light for 72 h. Isolated yield. c Determined by HPLC analysis.
b
d
Values in parentheses are yields and ee when DIDMH (0.05 mmol for tryptophols
e
and 0.06 mmol for tryptamines) was employed. CCl
4
/toluene (5:1, 5.0 mL) was used
f
g
I+ reagent
b
c
as solvent at -30 °C. CCl
4
/toluene (20:1, 5.0 mL) was used at -30 °C. DIDMH (0.12
entry
Λ-1
1a
1a
1a
1b
1c
1d
1e
1f
1a
1a
1a
1a
solvent
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
T [°C]
-30
-30
-30
-30
-30
-30
-30
-30
-30
-30
-30
-20
Yield (%)
ee (%)
4
mmol) and CCl (2.0 mL) was used at -20 °C.
1
2
3
4
5
6
7
8
9
DIDMH
NIS
NISC
79
93
90
84
5
70
54
50
75
70
90
98
79
62
67
70
3
Under the optimized reaction conditions, the substrate scope
of the asymmetric iodocyclization with respect to the substituted
tryptophols and tryptamines 2 was explored (Table 2).12 The
tryptophols 2a-2c with electron-withdrawing protecting groups
DIDMH
DIDMH
DIDMH
DIDMH
DIDMH
DIDMH
DIDMH
DIDMH
DIDMH
3
(
Boc, Ts and Alloc) could be converted to the corresponding
39
68
50
61
86
95
iodocyclization products with good yields and
CHCl
3
enantioselectivities (up to 95% ee). The substituent on the indole
moiety of N-Boc-protected tryptophols 2d-2m was then
evaluated. In general, the electronic feature of all the substrates
did not exert significant effect on the enantioselectivities. Either
electron-donating or electron-withdrawing substituents at the
different positions of the indole moiety were nicely tolerated to
afford the 3-iodofuroindolines 3d-3m in good to excellent yields
(up to 97%) and enantioselectivities (up to 96% ee).13 The
absolute configuration of 3b was assigned by X-ray
crystallographic diffraction of its enantiopure sample.14
Furthermore, the di-Boc-protected tryptamine 2n could also
undergo the asymmetric iodocyclization,13 providing the product
10
MTBE
PhMe
1
1
1d
2d
CCl
/PhMe
20:1)
CCl
4
CCl
(
4
1
3d
4e
1a
1a
DIDMH
DIDMH
-30
-20
83
86
88
81
1
4
a
Unless otherwise noted, reactions were carried out by slow addition (over 20
minutes) of 2a (0.10 mmol) in solvent (0.50 mL) to a mixture of I+ reagent (0.10
mmol), Λ-1 (0.01 mmol) and 4 Å MS (100 mg) in solvent (0.50 mL) under an air
atmosphere in the absence of light for 48 h. Isolated yield. c Determined by HPLC
b
d
analysis. The reaction was carried out by slow addition of 2a in solvent (1.0 mL) to
the reaction mixture in solvent (4.0 mL) for 72 h. Solid DIDMH was added in one
portion to the reaction mixture of 2a with 1a in CCl (5.0 mL).
4
e
3
2
n with good enantioselectivity. 5-substitutied tryptamines 2o-
p with electron-donating groups could participate in the
reaction in good enantioselectivities (up to 89% ee) but with
moderate yield. In particularly, excellent yield and good
enantioselectivity were observed in the case of 7-methyl-
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substituted product 3q. We have also evaluated the
iodocyclization when half of DIDMH was employed for a selection
of tryptophols and tryptamines (Table 2, values in parentheses).
Interestingly, even with 0.50 equiv of DIDMH, 3-
iodofuroindolines 3a, 3c, 3d and 3j were obtained with a slight
also be applied for the bromocyclization of tryptamines,
providing the products 4n-4p in up to 97% yield and 82% ee.
Moreover, 3-bromofuroindolines 4a, 4c, 4e-4h, 4k and 4l were
returned in up to 97% ee with 0.50 equiv of DBDMH (Table 4,
values in parentheses). In each case both the yields and
enantioselectivities nearly match those realized with 1.0 equiv of
1
decrease enantioselectivities. It is indicated that both the N - and
3
1
3
N -iodo groups indeed participate in the anionic chiral Co(III)
DBDMH, which suggested that both N - and N -bromo groups of
DBDMH could also be involved in the phase-transfer catalytic
bromocyclization.
complex-mediate phase-transfer procedure.
Chiral Co(III)-complex-templated Brønsted acid (Λ-1a) was
also identified to be a general catalyst for the asymmetric
bromocyclization. At the outset of our investigation, different
bromine sources including NBS, DBDMH, N-bromophthalimide
Table 4 Substrate scope of enantioselective bromocyclization.a
(
NBP) and N-bromoacetamide (NBA) were studied, and the NBS
delivered the best outcome (95% ee) (Table 3, entries 1-4).
Further screening of other catalysts Λ-1a-1f didn’t give better
results (entries 5-9), and lower reaction efficiency was observed
when the bromocyclization was performed in CCl
4
with NBS
(
entry 10). It is noticed that a good enantioselectivity was
obtained by premixing Λ-1a with NBS (entry 11), while lowering
the temperature resulted in a higher enantiomeric excess of 95%
(
entry 12). As anticipated, the bromocyclization by premixing Λ-
1
4
a with DBDMH could also proceed smoothly to give the product
a in good enantioselectivity (entry 13). Excitingly, the use of
CCl /toluene co-solvents enabled the reaction in excellent yield
4
with 96% ee (entry 14).
Table 3 Optimization of the bromocyclization conditions of 2a.a
+
b
c
entry
Λ-1
1a
1a
1a
1a
1b
1c
1d
1e
1f
Br reagent
solvent
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
T [°C]
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-30
-30
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
NBS
DBDMH
NBP
93
77
74
22
78
77
72
85
52
81
84
87
97
85
78
81
76
84
11
9
85
11
75
91
95
86
NBA
NBS
NBS
NBS
NBS
NBS
NBS
NBS
10
1a
1a
1a
1a
CCl
4
a
Unless otherwise noted, reactions were carried out by slow addition of the solution
1
1
1
1d
2d
3d
PhMe
PhMe
PhMe
of 2 (0.10 mmol) to a mixture of DBDMH (0.10 mmol), Λ-1a (0.01 mmol) and 4 Å MS
NBS
(
100.0 mg) at -30 °C under an air atmosphere in the absence of light for 48 h.
DBDMH
/toluene (20:1, 5.0 mL) was used as solvent. b Isolated yield. c Determined by
CCl
4
d
CCl
4
/PhMe
HPLC analysis. Values in parentheses are yields and ee when 0.50 equiv of DBDMH
was employed. CCl /toluene (5:1, 5.0 mL) was used as solvent. Solid DBDMH was
4
1
4e
1a
DBDMH
-30
95
96
e
f
(20:1)
added in one portion to the reaction mixture.
a
+
Unless otherwise noted, reactions were carried out by addition of solid Br source
The asymmetric chlorocyclization reaction of tryptophols 2
with DCDMH in the presence of Brønsted acid (Λ-1a) was also
successful,13 delivering the corresponding products in moderate
yield with up to 42% ee (Scheme 2).
(
0.10 mmol) to a mixture of 2a (0.1 mmol), Λ-1 (0.01 mmol) and 4 Å MS (100 mg) in
b
solvent (1.0 mL) under an air atmosphere in the absence of light for 24 h. Isolated
yield. Determined by HPLC analysis. A solution of 2a (0.5 mL) was slowly added to
the mixture (0.5 mL) for 48 h. A solution of 2a (1.0 mL) was slowly added to the
mixture (4.0 mL) for 48 h.
c
d
e
To evaluate the efficiency of the chiral anion phase-transfer
catalytic procedure, the enantiomeric excesses of the 3-
bromofuroindolines 4 of the bromocyclizations were also carried
out in the presence of DBDMH (Table 4).15 All tryptophols bearing
carbamate or sulfonate N-protecting groups worked well under
these conditions, leading to the formation of the products 4a-4c
in up to 96% ee. The absolute configuration of 4b was also
assigned by X-ray crystallographic diffraction.14 The electronic
nature of tryptophols 2 has little influence on the reactivity, as
products 4d-4m were obtained in 78-97% yield with good to
excellent enantioselectivities (82-98% ee). This protocol could
Scheme 2 Asymmetric chlorocyclization reaction with DCDMH.
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Interestingly, the enantioselective halocyclization using with
.50 equiv of DIDMH and DBDMH could be scaled up, even the
chiral halogenating reagent 8 is soluble in the nonpolar solvent
0
(such as CCl and PhMe), thus could render the enantioselective
4
presence of 2 mol% of Λ-1a was sufficient to render a 3 mmol-
scale bromocyclization to give 4a in 87% yield and 89% ee
halofunctionalization with indole derivatives 2 to afford the
products via the transition states TS-I and regenerate the catalyst
Λ-1. As illustrated in TS-I and TS-II, the halocyclization could
favorably occur on the Re face in TS-I, as the Si face might be
disfavored due to the steric repulsion between the indole ring
and the tert-butyl of the Schiff base (TS-II).
(
Scheme 3A). To demonstrate the synthetic utility of the
halocyclization, silver(I)-mediated both the iodide 3a and
bromide 4a with acetate16 could afford the 3-acetoxyfuro-
indoline 6, the core skeleton of (+)-madindoline A,10c in 92% and
9
3% ee, respectively (Scheme 3B). Subsequently, a few control
experiments were performed to get insight into the mechanism
Scheme 3C). 3-iodofuroindolines 3a could be obtained in 44%
In summary, we have developed efficient phase-transfer
catalytic halocyclization reactions of indole derivatives
(including tryptophols and tryptamines), using DXDMHs that
contained two activated halo groups (as little as 0.50 equiv) as
atom-economical halogen sources. The employment of Brønsted
acid of anionic chiral Co(III) complexes allows the stereoselective
formation of 3-halo indolines in excellent yields (up to 98%) with
good to excellent enantioselectivities (up to 98% ee). The process
could also undergo on a large scale even in the presence of 2 mol%
catalyst and 0.50 equiv of DXDMHs. Further development of
these chiral anion phase-transfer catalysts and application of the
halogenation reactions are underway.
(
yield with nearly maintained enantioselectivity (93% ee) even
when 0.30 equiv. of DIDMH was employed. Moreover, the less
active 1-ITMH and 3-ITMH were used as iodinating reagents, in
which N - or N -iodo was replaced by a methyl group, affording
the product 3a in high yield but with reduced enantioselectivities.
It appeared that the rate of the formation of chiral iodinating
species from 1-ITMH or 3-ITMH might be slower than that of
DIDMH, leading to a comparable competition between the
catalytic and noncatalytic reaction.
1
3
Funding Information
We are grateful for financial support from NSFC (Grant 21672002), Anhui
Provincial Natural Science Funds for Distinguished Young Scholar
(
1908085J07), Shennong Scholar Program of Anhui Angricultural
University and National Undergraduate Training Program for Innovation
and Entrepreneurship (202010364039).
Supporting Information
YES (this text will be updated with links prior to publication)
Primary Data
NO (this text will be deleted prior to publication)
References and Notes
(
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2
1
Scheme 3 Synthetic versatility of the catalytic system and preliminary
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(
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5
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According to these experimental data, we propose a catalytic
7
cycle based on our previous works (Scheme 4). The Brønsted
1
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Soc. 2011, 133, 9164. (i) Denmark, S. E.; Burk, M. T. Org. Lett. 2012,
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exchange reaction with DXDMHs to give the covalent ‘CO X
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2
1
(
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(b) Xie, W.; Jiang, G.; Liu, H.; Hu, J.; Pan, X.; Zhang, H.; Wan, X.; Lai,
Y.; Ma, D. Angew. Chem. Int. Ed. 2013, 52, 12924. (c) Liu, H.; Jiang,
G.; Pan, X.; Wan, X.; Lai, Y.; Ma, D.; Xie, W. Org. Lett. 2014, 16, 1908.
(d) Feng, X.; Jiang, G.; Xia, Z.; Hu, J.; Wan, X.; Gao, J.-M.; Lai, Y.; Xie,
W. Org. Lett. 2015, 17, 4428. (e) Cai, Q.; Yin, Q.; You, S.-L. Asian J.
Org. Chem. 2014, 3, 408. (f) Liang, X.-W.; Liu, C.; Zhang, W.; You, S.-
L. Chem. Commun. 2017, 53, 5531. (g) Liang, X.-W.; Cai, Y.; You, S.-
L. Chin. J. Chem. 2018, 36, 925.
4
(
4) For selected examples of asymmetric halogenation involving
DCDMH, see: (a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.;
Borhan, B. J. Am. Chem. Soc. 2010, 132, 3298. (b) Jaganathan, A.;
Garzan, A.; Whitehead, D. C.; Staples, R. J.; Borhan, B. Angew. Chem.
Int. Ed. 2011, 50, 2593. (c) Zhang, W.; Liu, N.; Schienebeck, C. M.;
Decloux, K.; Zheng, S.; Werness, J. B.; Tang, W. Chem.-Eur. J. 2012,
(12) General experimental procedures for
a representative
iodocyclization to 3a
A 10-mL oven-dried vial was charged with DIDMH (0.10 mmol or
0.05 mmol), catalyst Λ-1a (7.2 mg, 0.01 mmol), activated 4 Å
1
8, 7296. (d) Jaganathan, A.; Staples, R. J.; Borhan, B. J. Am. Chem.
Soc. 2013, 135, 14806. (e) Yin, Q.; You, S.-L. Org. Lett. 2013, 15,
266. (f) Yin, Q.; You, S.-L. Org. Lett. 2014, 16, 1810. (g) Yin, Q.; You,
4
molecular sieves (100.0 mg) and CCl (4.0 ml) at room temperature
in the absence of light. The mixture was cooled to -20 ºC and stirred
for 30 min. A precooled solution of the tryptophol 2a (0.10 mmol)
4
S.-L. Org. Lett. 2014, 16, 2426. (h) Soltanzadeh, B.; Jaganathan, A.;
Staples, R. J.; Borhan, B. Angew. Chem. Int. Ed. 2015, 54, 9517. (i)
Yin, Q.; Wang, S.-G.; Liang, X.-W.; Gao, D.-W.; Zheng, J.; You, S.-L.
Chem. Sci. 2015, 6, 4179. (j) Cai, Q.; Luo, J.; Zhao, X. Angew. Chem.
Int. Ed. 2019, 58, 1315. (k) Wedek, V.; Van Lommel, R.; Daniliuc, C.
G.; De Proft, F.; Hennecke, U. Angew. Chem. Int. Ed. 2019, 58, 9239.
5) For selected examples of asymmetric halogenation involving
DBDMH, see: (a) Murai, K.; Matsushita, T.; Nakamura, A.;
Fukushima, S.; Shimura, M.; Fujioka, H. Angew. Chem. Int. Ed. 2010,
4
in CCl (1.0 ml) was added dropwise to the mixture over 20 min
and the reaction was stirred vigorously until the reaction was
complete (monitored by TLC). The reaction was then quenched
3
with pre-cooled NEt (-20 ºC, 1.0 mmol) and saturated aqueous
Na (0.50 mL). The mixture was purified by flash column
2 2 3
S O
chromatography (silica gel, petrol ether/EtOAc = 10/1) to give the
enantioenriched product 3a. yield: for 1.0 equiv DIDMH, 37.9 mg
(98%); for 0.5 equiv DIDMH, 32.5 mg (84%); (Flash column
chromatography eluent, petroleum ether/ethyl acetate = 10/1);
(
20
= -82.6 (c 0.38 CH
3
OH); 1H-NMR (600 MHz,
49, 9174. (b) Murai, K.; Nakamura, A.; Matsushita, T.; Shimura, M.;
colorless oil; [α]
D
Fujioka, H. Chem.-Eur. J. 2012, 18, 8448. (c) Zhou, L.; Tay, D. W.;
Chen, J.; Leung, G. Y. C.; Yeung, Y.-Y. Chem. Commun. 2013, 49, 4412.
CDCl ) δ 7.79 (s, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H),
7.05 (t, J = 7.4 Hz, 1H), 6.45 – 6.17 (m, 1H), 3.85 – 3.76 (m, 1H), 3.45
– 3.32 (m, 1H), 2.99 – 2.86 (m, 2H), 1.61 (s, 9H); 13C-NMR (151 MHz,
3
(d) Li, Z.; Shi, Y. Org. Lett. 2015, 17, 5752. (e) Pan, H.; Huang, H.; Liu,
W.; Tian, H.; Shi, Y. Org. Lett. 2016, 18, 896. (f) Guo, S.; Cong, F.; Guo,
R.; Wang, L.; Tang, P. Nat. Chem. 2017, 9, 546. (g) Lu, Y.; Nakatsuji,
H.; Okumura, Y.; Yao, L.; Ishihara, K. J. Am. Chem. Soc. 2018, 140,
3
CDCl ) δ 151.92, 129.93, 125.17, 123.84, 115.02, 110.12, 103.32,
82.23, 67.81, 67.32, 47.91, 28.46; HRMS (ESI) calculated for
+
C H18INNaO
15
3
[M+Na] : 410.0229, found 410.0223; Enantiomeric
6
039. (h) Wang, Y.-F.; Shao, J.-J.; Wang, B.; Chu, M.-M.; Qi, S.-S.; Du,
excess: for 1.0 equiv DIDMH, 95%; for 0.5 equiv DIDMH, 92%;
determined by HPLC (Daicel Chirapak IE, hexane / isopropanol =
90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 9.20 min,
X.-H.; Xu, D.-Q. Adv. Synth. Catal. 2018, 360, 2285.
(
(
6) For an example of asymmetric halogenation involving DIDMH, see:
Cai, Y.; Liu, X.; Li, J.; Chen, W.; Wang, W.; Lin, L.; Feng, X. Chem.-Eur.
J. 2011, 17, 14916.
tmin = 8.43 min.
(13) See the Supporting Information for details.
7) (a) Jiang, H.-J.; Liu, K.; Yu, J.; Zhang, L.; Gong, L.-Z. Angew. Chem. Int.
Ed. 2017, 56, 11931. (b) Liu, K.; Jiang, H.-J.; Li, N.; Wang, J.; Zhang,
Z.-Z.; Yu, J. J. Org. Chem. 2018, 83, 6815. (c) Li, N.; Yu, H.; Wang, R.;
Shen, J.; Wu, W.-Q.; Liu, K.; Sun, T.-T.; Zhang, Z.-Z.; Yao, C.-Z.; Yu, J.
Tetrahedron Lett. 2018, 59, 3605. (d) Wang, R.; Wu, W.-Q.; Li, N.;
Shen, J.; Liu, K.; Yu, J. Synlett 2019, 30, 1077.
(14) CCDC 1938720 (3b) and 1938617 (4b) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre.
(15) General experimental procedures for
a representative
bromocyclization to 4a
A 10-mL oven-dried vial was charged with DBDMH (0.10 mmol or
(
(
8) For selected reviews, see: (a) Lacour, J.; Hebbe-Viton, V. Chem. Soc.
Rev. 2003, 32, 373. (b) Lacour, J.; Moraleda, D. Chem. Commun.
0.05 mmol), catalyst Λ-1a (7.2 mg, 0.01 mmol), activated 4 Å
molecular sieves (100.0 mg) and PhMe/CCl (1:20, 4.0 mL) at room
4
temperature in the absence of light. The mixture was cooled to -30
ºC and stirred for 30 min. A precooled solution of the tryptophol
4
2a (0.10 mmol) in PhMe/CCl (1:20, 1.0 mL) was added dropwise
2
1
4
2
009, 7073. (c) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38,
187. (d) Wenzel, M.; Hiscock, J. R.; Gale, P. A. Chem. Soc. Rev. 2012,
1, 480. (e) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem.
012, 4, 603. (f) Mahlau, M.; List, B. Angew. Chem. Int. Ed. 2013, 52,
18. (g) Brak, K.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2013, 52, 534.
to the mixture over 20 min and the reaction was stirred vigorously
until the reaction was complete (monitored by TLC). The reaction
5
9) For selected examples on chiral anions catalysis, see: (a) Sigman,
M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (b) Sigman,
M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39,
was then quenched with pre-cooled NEt
3
(-30 ºC, 1.0 mmol) and
saturated aqueous Na (0.50 mL). The mixture was purified by
2 2 3
S O
flash column chromatography (silica gel, petrol ether/EtOAc =
10/1) to give the enantioenriched product 4a. yield: for 1.0 equiv
DBDMH, 32.3 mg (95%); for 0.5 equiv DBDMH, 28.6 mg (84%);
(Flash column chromatography eluent, petroleum ether/ethyl
1
2
279. (c) Llewellyn, D. B.; Adamson, D.; Arndtsen, B. A. Org. Lett.
000, 2, 4165. (d) Carter, C.; Fletcher, S.; Nelson, A. Tetrahedron:
Asymmetry 2003, 14, 1995. (e) Mayer, S.; List, B. Angew. Chem. Int.
Ed. 2006, 45, 4193. (f) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F.
D. Science 2007, 317, 496. (g) Hamilton, G. L.; Kanai, T.; Toste, F. D.
J. Am. Chem. Soc. 2008, 130, 14984. (h) Yu, J.; Jiang, H.-J.; Zhou, Y.;
Luo, S.-W.; Gong, L.-Z. Angew. Chem. Int. Ed. 2015, 54, 11209. (i)
Zhang, X.; Zhao, K.; Li, N.; Yu, J.; Gong, L.-Z.; Gu, Z. Angew. Chem. Int.
Ed. 2020, 59, 19899.
20
1
acetate = 10/1); colorless oil; [α]
D
3
= -137.1 (c 0.32 CH OH); H-
NMR (600 MHz, CDCl ) δ 7.84 (s, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.28
3
(t, J = 7.8 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.34 – 6.12 (m, 1H), 4.00
(t, J = 8.0 Hz, 1H), 3.53 – 3.45 (m, 1H), 2.94 – 2.86 (m, 1H), 2.80 (dd,
J = 12.3, 3.8 Hz, 1H), 1.60 (s, 9H); 13C-NMR (151 MHz, CDCl
3
) δ
151.86, 141.73, 131.86, 130.50, 124.87, 123.76, 115.00, 100.87,
82.28, 67.79, 61.77, 45.09, 28.43; Enantiomeric excess: for 1.0
equiv DBDMH, 96%; for 0.5 equiv DBDMH, 96%; determined by
HPLC (Daicel Chirapak IC, hexane / isopropanol = 70/30, flow rate
1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 4.41 min, tmin = 4.04 min.
(16) Xu, J.; Tong, R. Green Chem. 2017, 19, 2952.
(
(
10) For recent reviews, see: (a) Song, J.; Chen, D.-F.; Gong, L.-Z. Natl. Sci.
Rev. 2017, 4, 381. (b) Palmieri, A.; Petrini, M. Nat. Prod. Rep. 2019,
36, 490. (c) Zheng, C.; You, S.-L. Nat. Prod. Rep. 2019, 36, 1589.
11) For selected examples, see: (a) Lozano, O.; Blessley, G.; del Campo,
T. M.; Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.;
Borman, R.; Gouverneur, V. Angew. Chem. Int. Ed. 2011, 50, 8105.
Template for SYNLETT © Thieme Stuttgart · New York
2020-11-12
page 5 of 5

Supporting Information for
Enantioselective Halocyclization of Indole Derivatives: Using 1,3-
Dihalohydantoins with Anionic Chiral Co(III) Complexes
Ting-Ting Sun, Kun Liu, Shun-Xin Zhang, Chun-Ru Wang, Chuan-Zhi Yao, and Jie Yu*
Department of Applied Chemistry, Anhui Agricultural University, Hefei, Anhui 230036, P. R. China
E-mail: jieyu@ahau.edu.cn
Table of Contents
1
. Introduction .......................................................................................................................................... 2
1
1
.1. General Data................................................................................................................................... 2
.2. Materials ......................................................................................................................................... 2
2
3
4
5
6
7
8
9
1
. Supplementary Tables ......................................................................................................................... 2
. General Procedure for Preparation of Substrates 2f and 2j ............................................................ 5
. Experimental Procedures of Iodocyclization and Characterization Data ...................................... 7
. Experimental Procedures of Bromocyclization and Characterization Data ................................ 14
. Experimental Procedures of Chlorocyclization and Characterization Data................................ 20
. Scale-up of the halocyclization process ............................................................................................ 22
. The Derivation of 3-Halofuranoindolines 3a and 4a....................................................................... 23
. General Procedure for Mechanistic Studies .................................................................................... 24
0. X-Ray diffraction Data .................................................................................................................... 25
1
1
0.1. X-ray single crystal data for 3b .................................................................................................. 25
0.2. X-ray single crystal data for 4b .................................................................................................. 26
1
1
1. References ......................................................................................................................................... 27
2. Selected NMR and HPLC................................................................................................................ 28
1
1
2.1. NMR of the substrates 2f and 2j................................................................................................. 28
2.2. NMR and HPLC of the products 3-6.......................................................................................... 30
1

1
. Introduction
1
.1. General Data
NMR spectra were recorded on Agilent-600 MHz spectrometer. Melting points were measured on a
digital melting point apparatus and the temperature was uncorrected. FT-ICRMS spectra were recorded
on P-SIMS-Gly of Bruker Daltonics Inc. HPLC analysis was performed on Waters-Breeze (2487 Dual λ
Absorbance Detector and 1525 Binary HPLC Pump, UV detection monitored at 254 nm). Chiralpak IA,
IC and IE columns were purchased from Daicel Chemical Industries, Ltd. The absolute configuration of
3
b and 4b was assigned by the X-ray analysis.
1
.2. Materials
Analytic grade solvents for the column chromatography and commercially available reagents were used
as received. CCl was dried over CaH and distilled prior to use. Toluene was dried over Na and
4
2
distilled prior to use. The catalysts (Λ-1a to Λ-1f) were synthesized according to the literature.[1]
Tryptophols 2a-2e, 2g-2i, 2k-2m and tryptamines 2n-2q were prepared according to following
procedure and the spectral data were in accordance with the literature.[2] 1-Iodo-3,5,5-
trimethylhydantoin (1-ITMH) and 3-iodo-1,5,5-trimethylhydantoin (3-ITMH) were generally
synthesized according to the procedure reported.[3]
2
. Supplementary Tables
Table S1 Asymmetric Iodocyclization of Tryptophols 2 under Different
Solvent and Temperature.a
(
10 mol%),
I
Λ
1a
OH -(S,S)-
DIDMH,
solvent, temperature,
O
R
R
N
PG
N H
4
Å MS
PG
2
3
CCl
4
/PhMe (20/1), -30 °Cb
CCl
4
, -20 °Cc
Entry
3
R
PG
yield (%)d
ee (%)e
88
yield (%)d ee (%)e
1
2
3
4
3a
3b
3c
3d
H
Boc
Ts
83
98
22
84
92
95
71
85
87
H
67f
88
H
Alloc 84
Boc 97
93
4-Me
90
2

5
6
7
8
9
1
3e
3f
4-Br
4-Cl
Boc
Boc
95
95
91
84
90
67
72
97
79
95
96
78
92
77
93
88
87
89
88
84
92
77
89
86
99
87
87
91
90
88
87
81
83
74
80
67
3g
3h
3i
5-OMe Boc
5-F
Boc
Boc
Boc
Boc
Boc
Boc
5-Br
5-Cl
6-Cl
7-Me
7-Cl
0
3j
11
3k
3l
1
1
2
3
3m
a
Unless otherwise noted, reactions were carried out by slow addition (over 20 minutes) of 2 (0.10 mmol) in
solvent (1.0 mL) to a mixture of DIDMH (0.10 mmol), Λ-1a (0.01 mmol) and 4 Å MS (100.0 mg) in solvent
b
(
4.0 mL) under an air atmosphere in the absence of light for 72 h. CCl
4
/toluene (20:1, 5.0 mL) was used at -
c
(2.0 mL) was used at -20 °C. d Isolated yield. Determined by HPLC analysis. CCl
e
f
3
0 °C. CCl
4
4
/toluene
(5:1, 5.0 mL) was used as solvent.
Table S2 Optimization of the Iodocyclization Conditions of Tryptamine 2n.a
(
10 mol%),
I
Λ
1
NHBoc
-(S,S)-
DIDMH,
NBoc
o
solvent, - 20 C,
Å MS
N
N H
Boc
4
Boc
2n
3n
Entry
1
solvent
PhMe
yield (%)b
ee (%)c
40
16
48
10
36
53
50
48
55
2
PhMe/n-hexane (1:1)
PhMe/n-hexane (1:3)
CCl4
60
3
62
4
70
5d
4
4
4
4
CCl
CCl
CCl
CCl
81
6d,e
7d,f
8d,g
76
76
77
a
Unless otherwise noted, reactions were carried out by addition of DIDMH (0.12 mmol) in one portion to a
mixture of 2n (0.10 mmol), Λ-1 (0.01 mmol) and 4 Å MS (100.0 mg) in solvent (2.0 mL) at -20 °C under an air
3

b
c
d
atmosphere in the absence of light for 48 h. Isolated yield. Determined by HPLC analysis. A solution of 2a
e
f
(
1.0 mL) was slowly added to the mixture (1.0 mL) for 48 h. DIDMH (0.10 mmol) was used. DIDMH (0.15
g
mmol) was used. DIDMH (0.30 mmol) was used.
Table S3 Optimization of the Chlorocyclization Conditions of 2a.a
O
Cl
N
O
(
10 mol%),
O
Cl
Λ
1
OH -(S,S)-
source,
+
N Cl
O
N Cl
Cl
O
Me
Me
DCDMH
N
S
o
solvent, - 20 C,
N
H
O
N
O
NCS
Cl
O
Boc
5a Boc
NCSC
2a
+
yield (%)b ee (%)c
Entry
Λ-1
Cl source
solvent
1
1a
1a
1a
1e
1a
1a
1a
1a
1a
NCS
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
N.R.
52
-
2
DCDMH
NCSC
42
-
3
N.R.
46
4
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
35
41
39
39
20
24
5d
6e
7
49
21
CCl
4
50
8
c-hexane
53
9f
PhMe
40
a
Unless otherwise noted, reactions were carried out by slow addition (over 20 minutes) of 2a (0.10 mmol) in
+
solvent (0.50 mL) to a mixture of Cl source (0.20 mmol), Λ-1 (0.01 mmol) in solvent (0.50 mL) under an air
atmosphere in the absence of light for 48 h. b Isolated yield. c Determined by HPLC analysis. d DCDMH (0.30
mmol) was used. e The reaction was carried out by addition of DCDMH (0.20 mmol) to a mixture of 2a (0.10
f
mmol) and Λ-1a (0.01 mmol) in toluene (1.0 mL) at -20 °C. LiCl (0.10 mmol) was used as additive.
4

3
. General Procedure for Preparation of Substrates 2f and 2j
OH
OTBS
TBSCl, imidazole
DMF, 0°C - rt
(
Boc)
CH
2
O, DMAP
Cl
, rt
R
R
N
H
2
2
N
H
S1
S2
OTBS
OH
TBAF
R
R
2
f: R = 4-Cl
2
j: R = 5-Cl
N
THF, 0 ºC - rt
N
Boc
Boc
S3
To a solution of tryptophol S1 (5.0 mmol) and imidazole (11.0 mmol) in DMF (5.0 mL) was added tert-
butyldimethylsilyl chloride (5.5 mmol) at 0 ºC, the mixture was then allowed to warm to room
temperature and stirred for 4.5 h. After the reaction was completed, the reaction mixture was washed
with water (2 × 15.0 mL) and extracted with EtOAc (3 × 15.0 mL). The combined organic phases were
washed with brine (3 × 10.0 mL), dried over Na
2
SO , filtered and concentrated. The residue was
4
purified by flash chromatography (petrol ether/EtOAc = 5/1) to afford the intermediate S2.
To a solution of S2 (4.75 mmol) and 4-dimethylaminopyridine (0.48 mmol) in 15.0 mL CH
2
Cl was
2
added di-tert-butyl dicarbonate (7.125 mmol), the reaction was then stirred at room temperature for 2 h.
The reaction was quenched by adding aqueous saturated NH Cl (15.0 mL) and extracted with CH Cl (3
20.0 mL). The organic phases were washed with brine (3 × 20.0 mL), dried over Na SO , filtered and
4
2
2
×
2
4
concentrated. The crude product was purified by flash chromatography (petrol ether/EtOAc = 50/1) to
afford the intermediate S3.
To a solution of S3 in THF (20 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 6.6 mL)
at 0 ºC, then the ice bath was removed and the reaction was maintained room temperature for 5 h. The
reaction was washed with water (10.0 mL) and extracted with EtOAc (10.0 mL). The organic phase was
washed with brine (25.0 mL), dried over Na
2
SO , filtered and concentrated. The residue was purified by
4
flash chromatography (petrol ether/EtOAc = 4/1) gave the substrates 2f and 2j.
Tert-butyl 4-chloro-3-(2-hydroxyethyl)-1H-indole-1-carboxylate 2f: 2-(4-chloro-
Cl
1
OH 1H-indol-3-yl)ethanol was used; yield: 1.183 g (80% over 3 steps); H-NMR (600
MHz, CDCl
3
) δ 8.11 (s, 1H), 7.47 (s, 1H), 7.24 – 7.15 (m, 2H), 3.97 (t, J = 6.4 Hz, 2H),
N
Boc
2f
13
3
.21 (t, J = 6.4 Hz, 2H), 1.66 (s, 9H); C-NMR (151 MHz, CDCl
3
) δ 149.14, 137.29,
1
26.98, 126.30, 125.30, 124.91, 123.69, 116.81, 114.00, 84.09, 62.73, 29.84, 28.15; HRMS (ESI)
+
calculated for C15
H
18ClNNaO
3
[M+Na] : 318.0873, found. 318.0870.
5

Tert-butyl 5-chloro-3-(2-hydroxyethyl)-1H-indole-1-carboxylate 2j: 2-(5-chloro-1H-indol-3-
1
yl)ethanol was used; yield: 1.035 g (70% over 3 steps); H-NMR (600 MHz, CDCl
3
)
OH
Cl
δ 8.06 (s, 1H), 7.53 – 7.42 (m, 2H), 7.28 – 7.25 (m, 1H), 3.92 – 3.90 (m, 2H), 2.92 (t,
J = 6.3 Hz, 2H), 1.66 (s, 9H); 13C-NMR (151 MHz, CDCl
) δ 149.32, 134.00,
31.74, 128.25, 124.79, 124.57, 118.64, 116.63, 116.34, 83.95, 61.86, 28.29, 28.17;
N
Boc
j
3
2
1
+
HRMS (ESI) calculated for C15
H
18ClNNaO
3
[M+Na] : 318.0873, found. 318.0875.
6

4
. Experimental Procedures of Iodocyclization and Characterization Data
(10 mol%),
I
Λ-(S,S)-1a
YH
DIDMH,4 Å M.S.
Y
R
R
o
solvent, - 20 C
N
N H
PG
, Y = O or NBoc
PG
2
3
For 3a, 3g, 3i: A 10-mL oven-dried vial was charged with DIDMH (0.10 mmol or 0.05 mmol), catalyst
Λ-1a (7.2 mg, 0.01 mmol), activated 4 Å molecular sieves (100.0 mg) and CCl (4.0 ml) at room
temperature in the absence of light. The mixture was cooled to -20 ºC and stirred for 30 min. A
precooled solution of the tryptophol 2 (0.10 mmol) in CCl (1.0 ml) was added dropwise to the
mixture over 20 min and the reaction was stirred vigorously until the reaction was complete
monitored by TLC). The reaction was then quenched with pre-cooled NEt (-20 ºC, 1.0 mmol) and
saturated aqueous Na (0.50 mL). The mixture was purified by flash column chromatography
silica gel, petrol ether/EtOAc = 10/1) to give the enantioenriched indoline derivatives 3.
4
4
(
3
2
S
O
2 3
(
For 3b: A 10-mL oven-dried vial was charged with DIDMH (0.10 mmol), catalyst Λ-1a (7.2 mg, 0.01
mmol), activated 4 Å molecular sieves (100.0 mg) and PhMe/CCl (1:5, 4.0 mL) at room
temperature. The mixture was cooled to -30 ºC and stirred for 30 min. A precooled solution of the
tryptophol 2b (0.10 mmol) in PhMe/CCl (1:5, 1.0 mL) was added dropwise to the mixture over 20
min and the reaction was stirred vigorously until the reaction was complete (monitored by TLC).
The reaction was then quenched with pre-cooled NEt (-30 ºC, 1.0 mmol) and saturated aqueous
Na (0.50 mL). The mixture was purified by flash column chromatography (silica gel, petrol
4
4
3
2
S
2
O
3
ether/EtOAc = 5/1) to give the enantioenriched indoline derivative 3b.
For 3c-3f, 3h, 3j-3m: A 10-mL oven-dried vial was charged with DIDMH (0.10 mmol or 0.05 mmol),
catalyst Λ-1a (7.2 mg, 0.01 mmol), activated 4 Å molecular sieves (100.0 mg) and PhMe/CCl
4
(1:20,
4
.0 mL) at room temperature. The mixture was cooled to -30 ºC and stirred for 30 min. A precooled
solution of the tryptophol 2 (0.10 mmol) in PhMe/CCl (1:20, 1.0 mL) was added dropwise to the
4
mixture over 20 min and the reaction was stirred vigorously until the reaction was complete
monitored by TLC). The reaction was then quenched with pre-cooled NEt (-30 ºC, 1.0 mmol) and
saturated aqueous Na (0.50 mL). The mixture was purified by flash column chromatography
silica gel, petrol ether/EtOAc = 10/1) to give the enantioenriched indoline derivatives 3.
(
3
2
S
O
2 3
(
For 3n-3q: A 10-mL oven-dried vial was charged with DIDMH (0.12 mmol or 0.06 mmol), catalyst Λ-
a (7.2 mg, 0.01 mmol), activated 4 Å molecular sieves (100.0 mg) and CCl (1.0 ml) at room
temperature. The mixture was cooled to -20 ºC and stirred for 30 min. A precooled solution of the
tryptamine 2 (0.10 mmol) in CCl (1.0 ml) was added dropwise to the mixture over 20 min and the
1
4
4
7

reaction was stirred vigorously until the reaction was complete (monitored by TLC). The reaction
was then quenched with pre-cooled NEt (-20 ºC, 1.0 mmol) and saturated aqueous Na (0.50
mL). The mixture was purified by flash column chromatography (silica gel, petrol ether/EtOAc =
0/1) to give the enantioenriched indoline derivatives 3n-3q.
3
2
S
2
O
3
1
Tert-butyl (3aR,8aS)-3a-iodo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 3a: yield:
I
for 1.0 equiv DIDMH, 37.9 mg (98%); for 0.5 equiv DIDMH, 32.5 mg (84%); (Flash
O
2
0
column chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil; [α]
D
N
H
Boc
3a
1
=
-82.6 (c 0.38 CH
3
OH); H-NMR (600 MHz, CDCl
3
) δ 7.79 (s, 1H), 7.39 (d, J = 7.2 Hz,
1
3
1
H), 7.23 (t, J = 7.0 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.45 – 6.17 (m, 1H), 3.85 – 3.76 (m, 1H), 3.45 –
1
3
.32 (m, 1H), 2.99 – 2.86 (m, 2H), 1.61 (s, 9H); C-NMR (151 MHz, CDCl ) δ 151.92, 129.93, 125.17,
3
23.84, 115.02, 110.12, 103.32, 82.23, 67.81, 67.32, 47.91, 28.46; HRMS (ESI) calculated for
+
C
15
H
18INNaO
3
[M+Na] : 410.0229, found 410.0223; Enantiomeric excess: for 1.0 equiv DIDMH,
9
5%; for 0.5 equiv DIDMH, 92%; determined by HPLC (Daicel Chirapak IE, hexane / isopropanol =
0/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 9.20 min, tmin = 8.43 min.
9
(3aR,8aS)-3a-Iodo-8-tosyl-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]indole 3b: yield: 29.6 mg (67%);
I
(
Flash column chromatography eluent, petroleum ether/ethyl acetate = 5/1); white solid;
O
2
0
1
m.p. 162.8~164.2 °C; [α]
D
= -142.4 (c 0.30 CH
3
OH); H-NMR (600 MHz, CDCl ) δ
3
N
H
Ts
3b
7.80 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.30 – 7.27 (m,
1
1
H), 7.25 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 6.24 (s, 1H), 4.03 – 3.99 (m, 1H), 3.44 (ddd, J =
1
3
1.2, 9.3, 4.7 Hz, 1H), 2.87 – 2.81 (m, 1H), 2.73 (dd, J = 12.5, 3.9 Hz, 1H), 2.37 (s, 3H); C-NMR
(151 MHz, CDCl
3
) δ 144.51, 140.65, 135.61, 132.51, 130.73, 129.80, 127.51, 125.32, 124.90, 114.32,
+
1
03.34, 68.07, 61.48, 44.80, 21.67; HRMS (ESI) calculated for C17
H
16INNaO
3
S [M+Na] : 463.9793,
found 463.9788; Enantiomeric excess: 88%; determined by HPLC (Daicel Chirapak IC, hexane /
isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 47.95 min, tmin = 32.74 min.
Allyl (3aR,8aS)-3a-iodo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 3c: yield: for 1.0
I
equiv DIDMH, 31.4 mg (84%); for 0.5 equiv DIDMH, 26.7 mg (72%); (Flash column
O
20
chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil; [α]
D
= -
N
H
1
Alloc 104.4 (c 0.31 CH
c
OH); H-NMR (600 MHz, CDCl
) δ 7.81 (s, 1H), 7.41 (d, J = 7.5 Hz,
3
3
3
1
1
–
1
H), 7.26 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.38 (s, 1H), 6.04 (s, 1H), 5.44 (d, J = 17.1 Hz,
H), 5.31 (d, J = 9.9 Hz, 1H), 4.81 (s, 2H), 3.83 (t, J = 7.8 Hz, 1H), 3.41 (td, J = 10.0, 5.1 Hz, 1H), 2.99
1
3
2.87 (m, 2H); C-NMR (151 MHz, CDCl
3
) 152.33, 140.22, 132.15, 130.06, 125.18, 124.32, 118.48,
+
17.06, 103.24, 67.52, 66.71, 47.86; HRMS (ESI) calculated for C14
H
14INNaO
3
[M+Na] : 393.9916,
found 393.9919; Enantiomeric excess: for 1.0 equiv DIDMH, 93%; for 0.5 equiv DIDMH, 90%;
8

determined by HPLC (Daicel Chirapak IA, hexane / isopropanol = 70/30, flow rate 1.0 mL/min, T = 30
ºC, 254 nm): tmaj = 5.99 min, tmin = 4.90 min.
Me
I
Tert-butyl (3aR,8aS)-3a-iodo-4-methyl-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-
carboxylate 3d: yield: for 1.0 equiv DIDMH, 39.9 mg (97%); for 0.5 equiv DIDMH, 29.3
mg (73%); (Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1);
O
N
H
Boc
3
d
20
1
colorless oil; [α]
D
= -74.2 (c 0.39 CH
3
OH); H-NMR (600 MHz, CDCl
3
) δ 7.67 (s, 1H), 7.17 (t, J =
7
1
1
.8 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.38 (s, 1H), 3.81 (t, J = 6.6 Hz, 1H), 3.50 (s, 1H), 3.01 – 2.94 (m,
1
3
H), 2.91 – 2.84 (m, 1H), 2.42 (s, 3H), 1.61 (s, 9H); C-NMR (151 MHz, CDCl ) δ 148.47, 138.45,
3
34.74, 130.07, 126.06, 112.87, 104.29, 82.48, 66.80, 62.14, 45.37, 28.46, 19.17; HRMS (ESI)
+
calculated for C16
H
20INNaO
3
[M+Na] : 424.0386, found 424.0389; Enantiomeric excess: for 1.0 equiv
DIDMH, 90%; for 0.5 equiv DIDMH, 90%; determined by HPLC (Daicel Chirapak IC, hexane /
isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 4.63 min, tmin = 4.29 min.
Br
I
Tert-butyl (3aR,8aS)-4-bromo-3a-iodo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-
carboxylate 3e: yield: for 1.0 equiv DIDMH, 44.3 mg (95%); for 0.5 equiv DIDMH, 31.2
mg (67%); (Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1);
O
N
H
Boc
3e
2
0
1
colorless oil; [α]
D
= -83.0 (c 0.44 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.84 (s, 1H), 7.19 (d, J =
3
8
1
1
.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.37 (s, 1H), 3.82 (t, J = 7.3 Hz, 1H), 3.49 (s, 1H), 3.38 (d, J =
13
2.5 Hz, 1H), 2.86 – 2.75 (m, 1H), 1.59 (d, J = 15.7 Hz, 9H); C-NMR (151 MHz, CDCl ) δ 151.58,
3
42.44, 131.21, 127.94, 120.49, 114.28, 104.31, 82.79, 67.52, 66.98, 44.38, 28.40; HRMS (ESI)
+
calculated for C15
H
17BrINNaO
3
[M+Na] : 487.9334, found 487.9334; Enantiomeric excess: for 1.0
equiv DIDMH, 95%; for 0.5 equiv DIDMH, 84%; determined by HPLC (Daicel Chirapak IC, hexane /
isopropanol = 97/3, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 6.17 min, tmin = 5.55 min.
Cl
I
Tert-butyl (3aR,8aS)-4-chloro-3a-iodo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-
carboxylate 3f: yield: for 1.0 equiv DIDMH, 40.0 mg (95%); for 0.5 equiv DIDMH, 29.1
mg (69%); (Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1);
O
N
H
Boc
3f
20
1
colorless oil; [α]
D
= -83.2 (c 0.40 CH
3
OH); H-NMR (600 MHz, CDCl
3
) δ 7.78 (s, 1H), 7.21 (t, J =
8
1
1
.1 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.35 (s, 1H), 3.82 (t, J = 7.8 Hz, 1H), 3.48 (s, 1H), 3.32 (d, J =
1
3
2.4 Hz, 1H), 2.83 (dd, J = 20.0, 10.8 Hz, 1H), 1.61 (s, 9H); C-NMR (151 MHz, CDCl ) δ 151.62,
3
42.43, 131.42, 131.11, 124.65, 113.64, 104.25, 82.80, 67.49, 67.22, 44.43, 28.40; HRMS (ESI)
+
calculated for C15
H
17ClINNaO
3
[M+Na] : 443.9839, found 443.9839; Enantiomeric excess: for 1.0
equiv DIDMH, 96%; for 0.5 equiv DIDMH, 88%; determined by HPLC (Daicel Chirapak IC, hexane /
isopropanol = 97/3, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 5.79 min, tmin = 5.29 min.
9

Tert-butyl (3aR,8aS)-3a-iodo-5-methoxy-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate
I
3g: yield: 38.4 mg (92%); (Flash column chromatography eluent, petroleum
MeO
O
20
1
ether/ethyl acetate = 10/1); colorless oil; [α]
D
= -107.6 (c 0.38 CH
3
OH); H-NMR
N
H
Boc
(600 MHz, CDCl ) δ 7.69 (s, 1H), 6.90 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.25 (s, 1H),
3
3g
13
3
.80 (s, 4H), 3.41 (s, 1H), 2.96 – 2.89 (m, 1H), 2.89 – 2.83 (m, 1H), 1.60 (s, 9H); C-NMR (151 MHz,
CDCl
3
) δ 156.51, 151.98, 129.99, 115.88, 115.72, 110.34, 103.52, 81.89, 67.31, 57.28, 55.87, 47.78,
+
2
8.48; HRMS (ESI) calculated for C16
H
20INNaO
4
[M+Na] : 440.0335, found 440.0329; Enantiomeric
excess: 90%, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 70/30, flow rate 1.0
mL/min, T = 30 ºC, 254 nm): tmaj = 5.73 min, tmin = 5.16 min.
Tert-butyl (3aR,8aS)-5-fluoro-3a-iodo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 3h:
I
yield: for 1.0 equiv DIDMH, 34.0 mg (84%); for 0.5 equiv DIDMH, 25.9 mg (64%);
F
O
(Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless
N
H
Boc
20
1
oil; [α]
D
= -114.7 (c 0.34 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.76 (s, 1H), 7.13 –
3
3h
7
2
1
8
4
.02 (m, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.26 (s, 1H), 3.82 (t, J = 8.0 Hz, 1H), 3.45 – 3.37 (m, 1H), 2.95 –
1
3
.88 (m, 1H), 2.84 (dd, J = 12.5, 4.2 Hz, 1H), 1.60 (s, 9H); C-NMR (151 MHz, CDCl ) δ 160.13,
3
58.52, 151.80, 136.70, 116.73 (d, J = 23.4 Hz), 116.09 (d, J = 8.0 Hz), 111.94 (d, J = 24.7 Hz), 103.70,
+
2.47, 67.31, 47.69, 28.43; HRMS (ESI) calculated for C15
H
17FINNaO
3
[M+Na] : 428.0135, found
28.0134; Enantiomeric excess: for 1.0 equiv DIDMH, 92%; for 0.5 equiv DIDMH, 67%; determined
by HPLC (Daicel Chirapak IC, hexane / isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 ºC, 254 nm):
maj = 4.57 min, tmin = 4.31 min.
t
Tert-butyl (3aR,8aS)-5-bromo-3a-iodo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 3i:
I
yield: 41.5 mg (89%); (Flash column chromatography eluent, petroleum ether/ethyl
Br
O
acetate = 10/1); colorless oil; [α] 20
CDCl
.5 Hz, 1H), 3.44 – 3.36 (m, 1H), 2.95 – 2.88 (m, 1H), 2.87 – 2.82 (m, 1H), 1.60 (s, 9H); C-NMR
= -93.0 (c 0.41 CH
OH); H-NMR (600 MHz,
1
D
3
N
H
Boc
3
i
3
) δ 7.68 (s, 1H), 7.49 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H), 3.82 (t, J =
1
3
7
(151 MHz, CDCl
3
) δ 151.64, 132.84, 128.14, 123.83, 116.51, 115.94, 115.02, 103.59, 82.47, 67.35,
+
6
7.32, 47.71, 28.41; HRMS (ESI) calculated for C15
H
17BrINNaO
3
[M+Na] : 487.9334, found 487.9333;
Enantiomeric excess: 81%, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 80/20,
flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 6.83 min, tmin = 5.57 min.
I
Tert-butyl (3aR,8aS)-5-chloro-3a-iodo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-
-carboxylate 3j: yield: for 1.0 equiv DIDMH, 28.3 mg (67%); for 0.5 equiv DIDMH,
21.9 mg (52%); (Flash column chromatography eluent, petroleum ether/ethyl acetate =
Cl
O
8
N
H
Boc
3
j
2
0
1
1
0/1); colorless oil; [α]
D
= -141.8 (c 0.28 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.73 (s, 1H), 7.35
3
1
0

(s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.24 (s, 1H), 3.82 (t, J = 7.6 Hz, 1H), 3.46 – 3.33 (m, 1H), 2.98 – 2.88
1
3
(
m, 1H), 2.88 – 2.80 (m, 1H), 1.60 (s, 9H); C-NMR (151 MHz, CDCl
3
) δ 151.67, 139.17, 136.43,
1
29.97, 128.69, 125.22, 116.09, 103.65, 82.69, 67.34, 47.69, 28.41; HRMS (ESI) calculated for
+
C
15
H
17ClINNaO [M+Na] : 443.9839, found 443.9839; Enantiomeric excess: for 1.0 equiv DIDMH,
3
9
9
3%; for 0.5 equiv DIDMH, 88%; determined by HPLC (Daicel Chirapak IC, hexane / isopropanol =
7/3, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 6.52 min, tmin = 5.64 min.
Tert-butyl
(3aR,8aS)-6-chloro-3a-iodo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate
I
3
k: yield: 30.6 mg (72%); (Flash column chromatography eluent, petroleum
O
ether/ethyl acetate = 10/1); colorless oil; [α] 20
(600 MHz, CDCl
H), 6.26 (s, 1H), 3.81 (t, J = 7.5 Hz, 1H), 3.43 – 3.35 (m, 1H), 2.96 – 2.88 (m, 1H), 2.85 (dd, J = 12.4,
= -134.7 (c 0.32 CH
OH); H-NMR
1
D
3
N
H
Cl
Boc
3k
) δ 7.86 (s, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.03 (dd, J = 8.2, 1.8 Hz,
3
1
4
1
1
3
.1 Hz, 1H), 1.60 (s, 9H); C-NMR (151 MHz, CDCl ) δ 151.59, 141.63, 135.78, 133.23, 125.93,
3
23.95, 115.42, 103.84, 82.76, 67.85, 67.36, 47.83, 28.38; HRMS (ESI) calculated for
+
C
15
H
17ClINNaO
3
[M+Na] : 443.9839, found 443.9847; Enantiomeric excess: 88%, determined by
HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm):
maj = 4.83 min, tmin = 4.50 min.
t
Tert-butyl (3aR,8aS)-3a-iodo-7-methyl-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 3l:
I
yield: 38.9 mg (97%); (Flash column chromatography eluent, petroleum ether/ethyl
O
acetate = 10/1); colorless oil; [α] 20
CDCl
.36 – 3.31 (m, 1H), 2.91 – 2.87 (m, 2H), 2.31 (s, 3H), 1.59 (s, 9H); C-NMR (151 MHz, CDCl
= -120.6 (c 0.39 CH
OH); H-NMR (600 MHz,
1
D
3
N
H
Boc
Me
3
) δ 7.25 – 7.22 (m, 1H), 7.10 – 7.07 (m, 2H), 6.30 (s, 1H), 3.80 – 3.77 (m, 1H),
3
l
1
3
3
1
2
3
) δ
52.65, 139.46, 137.50, 132.35, 128.67, 125.82, 121.60, 105.57, 82.23, 67.58, 46.16, 36.62, 28.30,
+
0.04; HRMS (ESI) calculated for C16
H
20INNaO
3
[M+Na] : 424.0386, found 424.0380; Enantiomeric
excess: 87%, determined by HPLC (Daicel Chirapak IA, hexane / isopropanol = 97/3, flow rate 1.0
mL/min, T = 30 ºC, 254 nm): tmaj = 7.15 min, tmin = 6.79 min.
Tert-butyl
(3aR,8aS)-7-chloro-3a-iodo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate
I
3
m: yield: 33.3 mg (79%); (Flash column chromatography eluent, petroleum ether/ethyl
O
acetate = 10/1); colorless oil; [α] 20
CDCl
H), 6.27 (s, 1H), 3.84 – 3.79 (m, 1H), 3.37 (ddd, J = 10.2, 8.8, 5.5 Hz, 1H), 2.94 – 2.88 (m, 1H), 2.88 –
= -150.5 (c 0.33 CH
OH); H-NMR (600 MHz,
1
D
3
N
H
Boc
Cl
3
) δ 7.31 (dd, J = 7.6, 1.0 Hz, 1H), 7.28 (dd, J = 8.0, 1.0 Hz, 1H), 7.11 (t, J = 7.8 Hz,
3m
1
2
1
1
3
.83 (m, 1H), 1.59 (s, 9H); C-NMR (151 MHz, CDCl ) δ 151.84, 140.09, 138.13, 131.39, 126.57,
3
24.24, 122.67, 106.07, 82.94, 67.57, 45.96, 35.01, 28.17; HRMS (ESI) calculated for
+
C
15
H
17ClINNaO
3
[M+Na] : 443.9839, found 443.9839; Enantiomeric excess: 89%, determined by
1
1

HPLC (Daicel Chirapak IA, hexane / isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 ºC, 254 nm):
maj = 4.99 min, tmin = 4.61 min.
t
Di-tert-butyl (3aR,8aR)-3a-iodo-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,8-dicarboxylate 3n:
I
yield: for 1.2 equiv DIDMH, 25.8 mg (53%); for 0.6 equiv DIDMH, 19.0 mg (39%);
NBoc
(Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless
N
H
Boc
20
1
3n
oil; [α]
D
= -143.5 (c 0.21 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.44 (s, 1H), 7.28
3
(d, J = 7.4 Hz, 1H), 7.20 – 7.15 (m, 1H), 7.05 – 6.97 (m, 1H), 6.38 (s, 1H), 3.49 – 3.40 (m, 1H), 2.87 –
1
3
2
1
2
.78 (m, 1H), 2.77 – 2.67 (m, 2H), 1.52 (s, 9H), 1.41 (s, 9H); C-NMR (151 MHz, CDCl ) δ 153.27,
3
52.30, 141.13, 135.83, 129.75, 124.28, 123.79, 117.84, 86.31, 82.14, 80.83, 64.26, 46.11, 37.14, 28.53,
+
8.40; HRMS (ESI) calculated for C20
H27IN
2
NaO
4
[M+Na] : 509.0913, found 509.0916;
Enantiomeric excess: for 1.2 equiv DIDMH, 81%; for 0.6 equiv DIDMH, 74%; determined by HPLC
(Daicel Chirapak IC, hexane / isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj
=
6
.52 min, tmin = 6.18 min.
I
Di-tert-butyl(3aR,8aR)-3a-iodo-5-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-
Me
NBoc
b]indole-1,8-dicarboxylate 3o: yield: 22.0 mg (44%); (Flash column
N
H
3o
Boc
chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil; [α]
D
20
=
1
-
156.7 (c 0.17 CH
3
OH); H-NMR (600 MHz, CDCl
3
) δ 7.37 (s, 1H), 7.14 (s, 1H), 7.04 (d, J = 8.1 Hz,
1
H), 6.44 (s, 1H), 3.50 (s, 1H), 2.94 – 2.85 (m, 1H), 2.83 – 2.71 (m, 2H), 2.31 (s, 3H), 1.58 (s, 9H), 1.48
) δ 153.29, 152.40, 138.90, 134.01, 131.19, 130.57, 124.01,
(
s, 9H); 13C-NMR (151 MHz, CDCl
3
117.65, 86.38, 81.92, 80.82, 63.58, 46.05, 37.59, 28.53, 28.40, 21.09; HRMS (ESI) calculated for
+
C
21
H29IN
2
NaO [M+Na] : 523.1070, found 523.1071; Enantiomeric excess: 89%, determined by
4
HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm):
t
maj = 6.35 min, tmin = 5.86 min.
I
Di-tert-butyl (3aR,8aR)-3a-iodo-5-methoxy-2,3,3a,8a-tetrahydropyrrolo[2,3-
MeO
NBoc
b]indole-1,8-dicarboxylate 3p: yield: 20.7 mg (40%); (Flash column
N
H
Boc
20
3p
chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil; [α]
D
1
=
=
-157.0 (c 0.16 CH
3
OH); H-NMR (600 MHz, CDCl
3
) δ 7.40 (s, 1H), 6.89 – 6.84 (m, 1H), 6.80 (dd, J
8.8, 2.2 Hz, 1H), 6.43 (s, 1H), 3.79 (s, 3H), 3.56 – 3.45 (m, 1H), 2.91 – 2.83 (m, 1H), 2.83 – 2.72 (m,
1
3
2
1
H), 1.58 (s, 9H), 1.48 (s, 9H); C-NMR (151 MHz, CDCl ) δ 156.83, 153.26, 152.50, 136.96, 134.77,
3
18.95, 115.65, 108.60, 86.50, 81.85, 80.85, 55.85, 45.98, 43.86, 28.53, 28.39; HRMS (ESI) calculated
+
for C21
H29IN
2
NaO
5
[M+Na] : 539.1019, found 539.1020; Enantiomeric excess: 85%, determined by
HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm):
maj = 6.58 min, tmin = 5.94 min.
t
1
2

I
Di-tert-butyl
(3aR,8aR)-3a-iodo-7-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-
NBoc
b]indole-1,8-dicarboxylate 3q: yield: for 1.2 equiv DIDMH, 47.5 mg (95%); for 0.6
N
H
Boc
q
Me
equiv DIDMH, 39.5 mg (79%); (Flash column chromatography eluent, petroleum
3
ether/ethyl acetate = 10/1); colorless oil; [α] 20
600 MHz, CDCl
) 1H NMR (400 MHz, CDCl
H), 3.41 – 3.30 (m, 1H), 2.89 (d, J = 7.5 Hz, 1H), 2.78 – 2.67 (m, 2H), 2.27 (s, 3H), 1.55 (s, 9H), 1.49
= -91.3 (c 0.35 CH
OH); H-NMR
1
D
3
(
3
3
) δ 7.17 (d, J = 6.5 Hz, 1H), 7.13 – 7.03 (m, 2H), 6.29 (s,
1
1
3
(
s, 9H); C-NMR (151 MHz, CDCl3) δ 153.59, 153.35, 140.62, 138.10, 131.78, 131.04, 126.21, 120.09,
8
8.22, 82.04, 80.66, 60.43, 45.58, 38.01, 28.69, 28.32, 19.30; HRMS (ESI) calculated for
+
C
21
H29IN
2
NaO
5
[M+Na] : 523.1070, found 523.1071; Enantiomeric excess: for 1.2 equiv DIDMH,
8
8%; for 0.6 equiv DIDMH, 78%; determined by HPLC (Daicel Chirapak IC, hexane / isopropanol =
0/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 6.73 min, tmin = 6.07 min.
9
1
3

5
. Experimental Procedures of Bromocyclization and Characterization Data
(10 mol%)
Br
,
Λ-(
S S
1a
)-
YH
DBDMH, CCl /PhMe
Y
4
R
R
o
-
30
N
C, 4 Å MS
N H
PG
, Y = O or NBoc
4
PG
2
For 4a, 4c-4m: A 10-mL oven-dried vial was charged with DBDMH (0.10 mmol or 0.05 mmol),
catalyst Λ-1a (7.2 mg, 0.01 mmol), activated 4 Å molecular sieves (100.0 mg) and PhMe/CCl (1:20,
.0 mL) at room temperature in the absence of light. The mixture was cooled to -30 ºC and stirred
4
4
for 30 min. A precooled solution of the tryptophol 2 (0.10 mmol) in PhMe/CCl (1:20, 1.0 mL) was
4
added dropwise to the mixture over 20 min and the reaction was stirred vigorously until the reaction
was complete (monitored by TLC). The reaction was then quenched with pre-cooled NEt (-30 ºC,
.0 mmol) and saturated aqueous Na (0.50 mL). The mixture was purified by flash column
3
1
2
S
2
O
3
chromatography (silica gel, petrol ether/EtOAc = 10/1) to give the enantioenriched indoline
derivatives 4.
For 4b: A 10-mL oven-dried vial was charged with DBDMH (0.10 mmol), catalyst Λ-1a (7.2 mg, 0.01
mmol), activated 4 Å molecular sieves (100.0 mg) and PhMe/CCl
temperature in the absence of light. The mixture was cooled to -30 ºC and stirred for 30 min. A
precooled solution of the tryptophol 2b (0.10 mmol) in PhMe/CCl (1:5, 1.0 mL) was added
dropwise to the mixture over 20 min and the reaction was stirred vigorously until the reaction was
complete (monitored by TLC). The reaction was then quenched with pre-cooled NEt (-30 ºC, 1.0
mmol) and saturated aqueous Na (0.50 mL). The mixture was purified by flash column
4
(1:5, 4.0 mL) at room
4
3
2
S
2
O
3
chromatography (silica gel, petrol ether/EtOAc = 5/1) to give the enantioenriched indoline
derivative 4b.
For 4n-4q: A 10-mL oven-dried vial was charged with the tryptamine 2 (0.10 mmol), catalyst Λ-1a (7.2
mg, 0.01 mmol), activated 4 Å molecular sieves (100.0 mg) and PhMe/CCl (1:20, 5.0 mL) at room
4
temperature in the absence of light. The mixture was cooled to -30 ºC and stirred for 30 min.
DBDMH (0.10 mmol) was added in one portion to the mixture and the reaction was stirred
vigorously until the reaction was complete (monitored by TLC). The reaction was then quenched
with pre-cooled NEt
3
(-30 ºC, 1.0 mmol) and saturated aqueous Na
2
S
2
O (0.50 mL). The mixture
3
was purified by flash column chromatography (silica gel, petrol ether/EtOAc = 10/1) to give the
enantioenriched indoline derivatives 4n-4q.
1
4

Tert-butyl (3aR,8aS)-3a-bromo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 4a: yield:
Br
for 1.0 equiv DBDMH, 32.3 mg (95%); for 0.5 equiv DBDMH, 28.6 mg (84%); (Flash
O
2
0
column chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil; [α]
D
N
H
Boc
1
4a
= -137.1 (c 0.32 CH
3
OH); H-NMR (600 MHz, CDCl
3
) δ 7.84 (s, 1H), 7.41 (d, J = 7.5 Hz,
1
–
H), 7.28 (t, J = 7.8 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.34 – 6.12 (m, 1H), 4.00 (t, J = 8.0 Hz, 1H), 3.53
13
3.45 (m, 1H), 2.94 – 2.86 (m, 1H), 2.80 (dd, J = 12.3, 3.8 Hz, 1H), 1.60 (s, 9H); C-NMR (151 MHz,
) δ 151.86, 141.73, 131.86, 130.50, 124.87, 123.76, 115.00, 100.87, 82.28, 67.79, 61.77, 45.09,
8.43; Enantiomeric excess: for 1.0 equiv DBDMH, 96%; for 0.5 equiv DBDMH, 96%; determined by
HPLC (Daicel Chirapak IC, hexane / isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 ºC, 254 nm):
maj = 4.41 min, tmin = 4.04 min.
CDCl
3
2
t
(3aR,8aS)-3a-Bromo-8-tosyl-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]indole 4b: yield: 37.4 mg (95%);
Br
(
Flash column chromatography eluent, petroleum ether/ethyl acetate = 5/1); white solid;
O
2
0
1
m.p. 180.4~181.1 °C; [α]
D
= -63.2 (c 0.36 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.80
3
N
H
Ts
4b
(d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.5 Hz,
1
H), 7.25 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 6.24 (s, 1H), 4.01 (t, J = 8.3 Hz, 1H), 3.44 (ddd,
1
3
J = 11.2, 9.3, 4.7 Hz, 1H), 2.87 – 2.81 (m, 1H), 2.73 (dd, J = 12.5, 3.9 Hz, 1H), 2.37 (s, 3H); C-NMR
151 MHz, CDCl ) δ 144.49, 140.65, 135.65, 132.53, 130.73, 129.80, 127.51, 125.32, 124.90, 114.32,
03.34, 68.07, 61.48, 44.80, 21.67; Enantiomeric excess: 89%, determined by HPLC (Daicel Chirapak
IC, hexane / isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 43.03 min, tmin
1.23 min.
(
3
1
=
3
Allyl (3aR,8aS)-3a-bromo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 4c: yield: for
Br
1
.0 equiv DBDMH, 30.8 mg (95%); for 0.5 equiv DBDMH, 30.1 mg (93%); (Flash column
O
chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil; [α] 20
= -183.9
D
N
H
Alloc
1
4c
(c 0.31 CH
3
OH); H-NMR (600 MHz, CDCl
3
) δ 7.86 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H),
7
5
7
1
.31 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.28 (s, 1H), 6.03 (s, 1H), 5.44 (d, J = 17.2 Hz, 1H),
.30 (d, J = 10.2 Hz, 1H), 4.81 (s, 2H), 4.02 (t, J = 8.2 Hz, 1H), 3.54 – 3.48 (m, 1H), 2.91 (td, J = 11.7,
1
3
.9 Hz, 1H), 2.82 (dd, J = 12.4, 4.3 Hz, 1H); C-NMR (151 MHz, CDCl
3
) δ 152.33, 141.46, 132.09,
31.84, 130.64, 124.89, 124.24, 118.47, 115.04, 100.77, 67.99, 66.71, 61.70, 45.04; Enantiomeric
excess: for 1.0 equiv DBDMH, 92%; for 0.5 equiv DBDMH, 90%; determined by HPLC (Daicel
Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 7.19 min,
t
min = 6.61 min.
Me
Br
Tert-butyl (3aR,8aS)-3a-bromo-4-methyl-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-
8-carboxylate 4d: yield: 32.2 mg (91%); (Flash column chromatography eluent,
O
N
H
Boc
4d
1
5

2
0
1
petroleum ether/ethyl acetate = 10/1); colorless oil; [α]
D
= -117.8 (c 0.32 CH OH); H-NMR (600
3
MHz, CDCl ) δ 7.71 (s, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.22 (s, 1H), 4.02 – 3.96
3
1
3
(
m, 1H), 3.65 – 3.55 (m, 1H), 2.92 – 2.82 (m, 2H), 2.49 (s, 3H), 1.60 (s, 9H); C-NMR (151 MHz,
CDCl ) 151.85, 141.90, 135.56, 130.60, 125.83, 112.78, 101.63, 82.30, 67.29, 62.90, 43.22, 28.43,
3
1
8.48; Enantiomeric excess: 92%, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol =
0/30, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 4.57 min, tmin = 4.17 min.
7
Tert-butyl (3aR,8aS)-3a,4-dibromo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 4e:
Br
Br
yield: for 1.0 equiv DBDMH, 37.3 mg (89%); for 0.5 equiv DBDMH, 33.5 mg (80%);
O
(
Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil;
N
H
Boc
2
0
1
[α]
D
= -93.0 (c 0.37 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.87 (s, 1H), 7.22 (d, J =
3
4
e
8
1
1
1
.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.20 (s, 1H), 4.04 – 3.97 (m, 1H), 3.63 – 3.54 (m, 1H), 3.27 (d, J =
13
2.6 Hz, 1H), 2.86 – 2.77 (m, 1H), 1.60 (s, 9H); C-NMR (151 MHz, CDCl ) δ 151.53, 143.69,
3
31.79, 127.83, 120.30, 114.26, 101.61, 82.77, 67.52, 62.19, 42.22, 28.39; Enantiomeric excess: for
.0 equiv DBDMH, 97%; for 0.5 equiv DBDMH, 96%; determined by HPLC (Daicel Chirapak IC,
hexane / isopropanol = 97/3, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 5.92 min, tmin = 5.15 min.
Tert-butyl (3aR,8aS)-3a-bromo-4-chloro-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate
Cl
Br
4f: yield: for 1.0 equiv DBDMH, 34.4 mg (92%); for 0.5 equiv DBDMH, 31.8 mg (85%);
O
(
Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil;
N
H
Boc
2
0
1
[α]
D
= -77.8 (c 0.34 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.81 (s, 1H), 7.24 (t, J =
3
4f
8
.1 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.19 (s, 1H), 4.01 (t, J = 7.3 Hz, 1H), 3.62 – 3.54 (m,
1
3
1
1
H), 3.22 (d, J = 11.9 Hz, 1H), 2.86 – 2.79 (m, 1H), 1.60 (s, 9H); C-NMR (151 MHz, CDCl ) δ
3
51.57, 143.41, 131.72, 124.53, 113.63, 101.56, 82.78, 67.74, 61.05, 42.18, 28.39; HRMS (ESI)
+
calculated for C15
H
17BrClNNaO
3
[M+Na] : 395.9978, found 395.9977. Enantiomeric excess: for 1.0
equiv DBDMH, 98%; for 0.5 equiv DBDMH, 97%; determined by HPLC (Daicel Chirapak IC, hexane /
isopropanol = 97/3, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 10.49 min, tmin = 9.62 min.
Br
Tert-butyl
(3aR,8aS)-3a-bromo-5-methoxy-2,3,3a,8a-tetrahydro-8H-furo[2,3-
MeO
O
b]indole-8-carboxylate 4g: yield: for 1.0 equiv DBDMH, 33.3 mg (90%); for 0.5
N
H
Boc
g
equiv DBDMH, 31.5 mg (85%); (Flash column chromatography eluent, petroleum
4
ether/ethyl acetate = 10/1); colorless oil; [α] 20
= -93.8 (c 0.33 CH
OH); H-NMR (600 MHz, CDCl
1
) δ
D
3
3
7
3
.74 (s, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.87 – 6.79 (m, 1H), 6.15 (s, 1H), 4.00 (t, J = 8.0 Hz, 1H), 3.80 (s,
1
3
H), 3.55 – 3.46 (m, 1H), 2.92 – 2.82 (m, 1H), 2.78 (dd, J = 12.4, 3.7 Hz, 1H), 1.59 (s, 9H); C-NMR
) δ 156.47, 151.89, 135.55, 132.77, 116.36, 115.86, 109.92, 101.07, 81.94, 67.73,
2.02, 55.85, 44.99, 28.44; Enantiomeric excess: for 1.0 equiv DBDMH, 97%; for 0.5 equiv DBDMH,
(151 MHz, CDCl
3
6
1
6

9
7%; determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 70/30, flow rate 1.0 mL/min, T
30 ºC, 254 nm): tmaj = 5.08 min, tmin = 4.57 min.
=
Tert-butyl (3aR,8aS)-3a-bromo-5-fluoro-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate
Br
4
h: yield: for 1.0 equiv DBDMH, 31.9 mg (89%); for 0.5 equiv DBDMH, 33.7 mg
F
O
(94%); (Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1);
N
H
Boc
20
1
colorless oil; [α]
D
= -150.1 (c 0.32 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.80 (s,
3
4h
1
3
H), 7.09 (dd, J = 7.7, 2.3 Hz, 1H), 6.98 (td, J = 8.7, 1.9 Hz, 1H), 6.18 (s, 1H), 4.01 (t, J = 8.0 Hz, 1H),
1
3
.55 – 3.45 (m, 1H), 2.94 – 2.84 (m, 1H), 2.75 (dd, J = 12.6, 3.6 Hz, 1H), 1.59 (s, 9H); C-NMR (151
) δ 160.12, 158.51, 151.77, 137.96, 117.33 (d, J = 23.2 Hz), 116.12 (d, J = 7.9 Hz), 111.69
d, J = 21.9 Hz) 101.26, 82.33, 67.74, 60.84, 44.97, 28.42; Enantiomeric excess: for 1.0 equiv
MHz, CDCl
3
(
DBDMH, 90%; for 0.5 equiv DBDMH, 94%; determined by HPLC (Daicel Chirapak IC, hexane /
isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 5.54 min, tmin = 5.10 min.
Tert-butyl (3aR,8aS)-3a,5-dibromo-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 4i:
Br
yield: 37.7 mg (90%); (Flash column chromatography eluent, petroleum ether/ethyl
Br
O
acetate = 10/1); colorless oil; [α] 20
CDCl
.0 Hz, 1H), 3.53 – 3.46 (m, 1H), 2.91 – 2.84 (m, 1H), 2.77 (dd, J = 12.5, 3.0 Hz, 1H), 1.59 (s, 9H);
13C-NMR (151 MHz, CDCl
) δ 151.58, 140.91, 133.40, 127.90, 116.53, 115.86, 101.10, 82.60, 67.77,
0.47, 44.95, 28.38; Enantiomeric excess: 93%, determined by HPLC (Daicel Chirapak IC, hexane /
= -34.0 (c 0.38 CH
OH); H-NMR (600 MHz,
1
D
3
N
H
Boc
4i
) δ 7.73 (s, 1H), 7.51 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 6.15 (s, 1H), 4.01 (t, J =
3
8
3
6
isopropanol = 97/3, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 6.25 min, tmin = 5.48 min.
Tert-butyl (3aR,8aS)-3a-bromo-5-chloro-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate
Br
4
j: yield: 31.1 mg (83%); (Flash column chromatography eluent, petroleum ether/ethyl
Cl
O
acetate = 10/1); colorless oil; [α] 20
CDCl
.0 Hz, 1H), 3.54 – 3.46 (m, 1H), 2.93 – 2.83 (m, 1H), 2.77 (dd, J = 12.5, 3.9 Hz, 1H), 1.59 (s, 9H);
= -67.0 (c 0.31 CH
OH); H-NMR (600 MHz,
1
D
3
N
H
Boc
j
4
3
) δ 7.78 (s, 1H), 7.37 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 4.02 (t, J =
8
13C-NMR (151 MHz, CDCl
) δ 151.66, 130.56, 128.67, 124.98, 116.12, 110.12, 101.18, 82.77, 67.80,
3
+
6
3
0.69, 44.97, 28.40; HRMS (ESI) calculated for C15
H
17BrClNNaO
3
[M+Na] : 395.9978, found
95.9977; Enantiomeric excess: 93%, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol
97/3, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 10.62 min, tmin = 9.52 min.
=
Tert-butyl (3aR,8aS)-3a-bromo-6-chloro-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate
Br
4
k: yield: for 1.0 equiv DBDMH, 35.6 mg (95%); for 0.5 equiv DBDMH, 35.6 mg
O
(95%); (Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1);
N
H
Cl
Boc
4k
1
7

2
0
1
colorless oil; [α]
D
= -156.5 (c 0.35 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.90 (s, 1H), 7.31 (d, J =
3
8
2
1
.1 Hz, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 6.17 (s, 1H), 4.01 (t, J = 8.1 Hz, 1H), 3.52 – 3.46 (m, 1H),
1
3
.92 – 2.85 (m, 1H), 2.76 (dd, J = 12.4, 4.3 Hz, 1H), 1.60 (s, 9H); C-NMR (151 MHz, CDCl
3
) δ
51.52, 142.77, 136.45, 130.39, 125.67, 123.89, 115.42, 101.36, 82.76, 67.82, 60.87, 45.02, 28.35;
Enantiomeric excess: for 1.0 equiv DBDMH, 89%; for 0.5 equiv DBDMH, 92%; determined by HPLC
Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj
.45 min, tmin = 5.04 min.
(
=
5
Tert-butyl (3aR,8aS)-3a-bromo-7-methyl-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate
Br
4
l: yield: for 1.0 equiv DBDMH, 30.8 mg (87%); for 0.5 equiv DBDMH, 28.3 mg (80%);
O
(Flash column chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil;
N
H
Boc
20
1
Me
[α]
D
= -174.5 (c 0.31 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.25 (d, J = 7.2 Hz, 1H),
3
4l
7
.16 – 7.08 (m, 2H), 6.18 (s, 1H), 3.98 – 3.94 (m, 1H), 3.42 (ddd, J = 10.4, 8.9, 5.1 Hz, 1H), 2.90 – 2.84
1
3
(
m, 1H), 2.81 – 2.76 (m, 1H), 2.32 (s, 3H), 1.57 (s, 9H); C-NMR (151 MHz, CDCl
34.63, 133.00, 128.49, 125.72, 121.61, 102.98, 82.27, 68.00, 61.67, 43.57, 28.30, 20.18;
Enantiomeric excess: for 1.0 equiv DBDMH, 92%; for 0.5 equiv DBDMH, 92%; determined by HPLC
Daicel Chirapak IC, hexane / isopropanol = 97/3, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 7.28
min, tmin = 6.25 min.
3
) δ 152.64, 140.59,
1
(
Br
Tert-butyl (3aR,8aS)-3a-bromo-7-chloro-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-
-carboxylate 4m: yield: 32.6 mg (87%); (Flash column chromatography eluent,
O
8
N
H
Boc
petroleum ether/ethyl acetate = 10/1); colorless oil; [α] 2
NMR (600 MHz, CDCl ) δ 7.33 (d, J = 7.8 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.16 (s, 1H),
.01 – 3.97 (m, 1H), 3.48 – 3.43 (m, 1H), 2.90 – 2.85 (m, 1H), 2.77 (ddd, J = 12.7, 4.9, 1.7 Hz, 1H),
0
= -150.3 (c 0.33 CH OH); H-
1
D
3
Cl
4
m
3
4
1
8
1
3
.58 (s, 9H); C-NMR (151 MHz, CDCl
3
) δ 151.84, 139.25, 137.18, 132.09, 126.48, 122.73, 103.41,
+
3.03, 67.96, 60.79, 43.44, 28.17; HRMS (ESI) calculated for C15
H
17ClINNaO
3
[M+Na] : 443.9839,
found 443.9834; Enantiomeric excess: 82%, determined by HPLC (Daicel Chirapak IC, hexane /
isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 5.69 min, tmin = 4.76 min.
Di-tert-butyl (3aR,8aR)-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,8-dicarboxylate 4n:
Br
yield: 42.6 mg (97%); (Flash column chromatography eluent, petroleum ether/ethyl
N
Boc acetate = 10/1); colorless oil; [α] 20
= -132.7 (c 0.27 CH
OH); H-NMR (600 MHz,
1
D
3
N
H
Boc
CDCl
3
) δ 7.65-7.51 (m, 1H), 7.40-7.34 (m, 1H), 7.31-7.27 (m, 1H), 7.09 (t, J = 7.3 Hz,
4n
1
H), 6.44 (s, 1H), 3.76-3.70 (m, 1H), 2.85-2.77 (m, 2H), 2.75-2.68 (m, 1H), 1.58 (s,
1
3
9
H), 1.49 (s, 9H); C-NMR (151 MHz, CDCl
3
) δ 153.52, 152.23, 142.19, 132.75, 130.37, 124.12,
1
23.85, 117.48, 84.01, 82.18, 80.83, 62.33, 46.26, 41.67, 28.48, 28.38; Enantiomeric excess: 82%,
1
8

determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30
ºC, 254 nm): tmaj = 5.27 min, tmin = 6.24 min.
Br
Di-tert-butyl (3aR,8aR)-3a-bromo-5-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-
Me
N
Boc b]indole-1,8-dicarboxylate 4o: yield: 42.6 mg (94%); (Flash column
N
H
Boc
o
20
chromatography eluent, petroleum ether/ethyl acetate = 10/1); colorless oil; [α]
D
4
1
=
-123.7 (c 0.37 CH
3
OH); H-NMR (600 MHz, CDCl
3
) δ 7.51-7.37 (m, 1H), 7.17-7.13 (m, 1H), 7.12-
7
.06 (m, 1H), 6.41 (s, 1H), 3.75-3.68 (m, 1H), 2.85-2.75 (m, 2H), 2.74-2.65 (m, 1H), 2.33 (s, 3H), 1.57
1
3
(
s, 9H), 1.48 (s, 9H); C-NMR (151 MHz, CDCl
17.32, 84.01, 81.90, 80.75, 62.50, 46.14, 28.42, 28.31, 20.97; Enantiomeric excess: 81%, determined
by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm):
maj = 5.50 min, tmin = 6.78 min.
3
) δ 153.49, 152.27, 139.89, 133.83, 131.12, 124.01,
1
t
Di-tert-butyl
(3aR,8aR)-3a-bromo-5-methoxy-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,8-
dicarboxylate 4p: yield: 40.4 mg (86%); (Flash column chromatography eluent,
Br
MeO
N
petroleum ether/ethyl acetate = 10/1); colorless oil; [α] 20
= -113.2 (c 0.36
Boc
D
N
H
Boc
p
1
CH
3
OH); H-NMR (600 MHz, CDCl
3
) δ 7.58-7.40 (m, 1H), 6.93-6.81 (m, 2H),
4
6
.44-6.30 (m, 1H), 3.81 (s, 3H), 3.76-3.68 (m, 1H), 2.88-2.80 (m, 1H), 2.78 – 2.67 (m, 1H), 2.66-2.55
1
3
(
m, 1H), 1.57 (s, 9H), 1.49 (s, 9H); C-NMR (151 MHz, CDCl
3
) δ 155.67, 152.43, 151.35, 134.75,
1
32.77, 115.25, 107.52, 83.11, 80.81, 79.77, 61.36, 54.76, 45.03, 30.22, 27.40, 27.29; Enantiomeric
excess: 78%, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0
mL/min, T = 30 ºC, 254 nm): tmaj = 5.98 min, tmin = 7.41 min.
Br
Di-tert-butyl
(3aR,8aR)-3a-bromo-7-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-
N
Boc
b]indole-1,8-dicarboxylate 4q: yield: 44.0 mg (97%); (Flash column chromatography
N
H
Boc
Me
20
eluent, petroleum ether/ethyl acetate = 10/1); colorless oil; [α]
OH); H-NMR (600 MHz, CDCl
.58-3.48 (m, 1H), 2.86-2.78 (m, 1H), 2.77-2.63 (m, 2H), 2.30 (s, 3H), 1.54 (s, 9H), 1.50 (s, 9H); C-
NMR (151 MHz, CDCl ) δ 153.73, 141.76, 135.24, 132.41, 131.06, 126.19, 120.30, 86.12, 82.04, 80.69,
2.24, 45.66, 28.68, 28.31, 19.33; Enantiomeric excess: 81%, determined by HPLC (Daicel Chirapak
IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 9.51 min, tmin
1.96 min.
D
= -96.8 (c 0.37
4q
1
CH
3
3
) δ 7.22-7.16 (m, 1H), 7.16-7.07 (m, 2H), 6.31-6.18 (m, 1H),
1
3
3
3
6
=
1
1
9

6
. Experimental Procedures of Chlorocyclization and Characterization Data
(10 mol%)
Λ-(S,S)-1a
Cl
OH
DCDMH,
O
R
o
R
toluene, - 20 C,
8 h
N
Boc
N H
5 Boc
4
2
A 10-mL oven-dried vial was charged with DCDMH (0.20 mmol), catalyst Λ-1a (7.2 mg, 0.01 mmol)
and PhMe (0.50 mL) at room temperature in the absence of light. The mixture was cooled to -20 ºC and
stirred for 30 min. A precooled solution of the tryptophols 2 (0.10 mmol) in PhMe (0.50 mL) was added
dropwise to the mixture over 20 min and the reaction was stirred vigorously until the reaction was
complete (monitored by TLC). The reaction was then quenched with pre-cooled NEt
mmol) and saturated aqueous Na (0.50 mL). The mixture was purified by flash column
chromatography (silica gel, petrol ether/EtOAc = 10/1) to give the enantioenriched indoline derivatives
3
(-20 ºC, 1.0
2
S
2
O
3
5
.
Tert-butyl (3aR,8aS)-3a-chloro-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 5a: yield:
Cl
1
5.4 mg (52%); (Flash column chromatography eluent, petroleum ether/ethyl acetate =
O
20
1
1
0/1); colorless oil; [α]
D
= -138.8 (c 0.15 CH
3
OH); H-NMR (600 MHz, CDCl ) δ 7.81
3
N
H
Boc
5a
(s, 1H), 7.43 – 7.35 (m, 1H), 7.33 – 7.26 (m, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.07 (s, 1H),
4
9
8
.12 – 4.05 (m, 1H), 3.59 – 3.51 (m, 1H), 2.83 – 2.75 (m, 1H), 2.72 – 2.64 (m, 1H), 1.60 (d, J = 4.5 Hz,
1
3
H); C-NMR (151 MHz, CDCl
3
) δ 151.63, 130.70, 128.64, 123.71, 116.12, 115.02, 110.11, 100.44,
+
0.95, 67.92, 59.69, 44.15, 28.44; HRMS (ESI) calculated for C15
H
18ClNNaO
3
[M+Na] : 318.0873,
found 318.0879; Enantiomeric excess: 42%, determined by HPLC (Daicel Chirapak IC, hexane /
isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 7.50 min, tmin = 6.81 min.
Tert-butyl (3aR,8aS)-3a-chloro-5-fluoro-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate
Cl
5
h: yield: 14.1 mg (45%); (Flash column chromatography eluent, petroleum ether/ethyl
F
O
acetate = 10/1); colorless oil; [α] 20
CDCl
t, J = 8.1 Hz, 1H), 3.56 (s, 1H), 2.82 – 2.74 (m, 1H), 2.66 (dd, J = 12.4, 3.5 Hz, 1H), 1.59 (s, 9H); C-
NMR (151 MHz, CDCl ) δ 160.12, 158.51, 151.78, 138.71, 117.44 (d, J = 23.2 Hz), 116.11 (d, J = 8.0
= -132.6 (c 0.14 CH
OH); H-NMR (600 MHz,
1
D
3
N
H
Boc
5h
3
) δ 7.82 (s, 1H), 7.14 – 7.05 (m, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.06 (s, 1H), 4.10
13
(
3
Hz), 110.11, 100.53, 93.45, 67.85, 60.32, 44.05, 28.41; HRMS (ESI) calculated for C15
H
17FClNNaO
3
+
[
M+Na] : 336.0779, found 336.0781; Enantiomeric excess: 41%, determined by HPLC (Daicel
Chirapak IC, hexane / isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 6.83 min,
min = 6.41 min.
t
2
0

Tert-butyl (3aR,8aS)-3a-chloro-7-methyl-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-
Cl
8
-carboxylate 5l: yield: 14.6 mg (47%); (Flash column chromatography eluent,
O
petroleum ether/ethyl acetate = 10/1); colorless oil; [α] 20
NMR (600 MHz, CDCl
.99 – 3.93 (m, 1H), 3.42 (ddd, J = 10.4, 8.9, 5.1 Hz, 1H), 2.91 – 2.83 (m, 1H), 2.81 – 2.76 (m, 1H),
= -162.3 (c 0.15 CH
OH); H-
1
N
H
Boc
D
3
Me
) δ 7.25 (d, J = 7.2 Hz, 1H), 7.19 – 7.06 (m, 2H), 6.18 (s, 1H),
5l
3
3
2
1
1
3
.32 (s, 3H), 1.57 (s, 9H); C-NMR (151 MHz, CDCl ) δ 152.64, 140.59, 134.63, 133.00, 128.49,
3
25.72, 121.61, 102.98, 82.27, 68.00, 61.67, 43.57, 28.30, 20.18; HRMS (ESI) calculated for
+
C
16
H
20ClNNaO
3
[M+Na] : 332.1029, found 332.1031; Enantiomeric excess: 30%, determined by
HPLC (Daicel Chirapak IC, hexane / isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 ºC, 254 nm):
maj = 7.00 min, tmin = 6.64 min.
t
2
1

7
. Scale-up of the halocyclization process
,
Λ-(S,S)-1
X
OH
reagent (0.50 equiv.)
3a, X = I, 1.0 mmol-scale,
mmol%
X+
5
-
O
Λ
1
, 88%, 85% ee
a, X = Br, 3.0 mmol-scale,
4
N
N H
2
mmol%
-
Λ 1
,
87%, 89% ee
2a Boc
Boc
For iodocyclization of 2a: A 50 mL oven-dried round-bottomed flask was charged with DIDMH (0.50
mmol), catalyst Λ-1a (36.0 mg, 0.05 mmol), activated 4 Å molecular sieves (500.0 mg) and CCl
7.0 ml) at room temperature in the absence of light. The mixture was cooled to -20 ºC and stirred for
0 min. A precooled solution of the tryptophol 2 (1.0 mmol, 261.3 mg) in CCl (3.0 ml) was added
dropwise to the mixture over 30 min and the reaction was stirred vigorously until the reaction was
complete (monitored by TLC, about 72 h). The reaction was then quenched with pre-cooled NEt (-
0 ºC, 5.0 mmol) and saturated aqueous Na (5.0 mL). The mixture was purified by flash
4
(
3
4
3
2
2
S
2
O
3
column chromatography (silica gel, petrol ether/EtOAc = 10/1) to give the enantioenriched indoline
derivative 3 (334.0 mg, 88% yield, 85% ee).
For bromocyclization of 2a: A 50 mL oven-dried round-bottomed flask was charged with DBDMH
(1.50 mmol), catalyst Λ-1a (43.2 mg, 0.06 mmol), activated 4 Å molecular sieves (1.00 g) and
PhMe/CCl
4
(1:20, 12.0 mL) at room temperature in the absence of light. The mixture was cooled to -
3
0 ºC and stirred for 30 min. A precooled solution of the tryptophol 2 (3.0 mmol, 784.0 mg) in
PhMe/CCl
4
(1:20, 3.0 mL) was added dropwise to the mixture over 30 min and the reaction was
stirred vigorously until the reaction was complete (monitored by TLC, about 36 h). The reaction was
then quenched with pre-cooled NEt (-30 ºC, 5.0 mmol) and saturated aqueous Na (5.0 mL).
3
2
S
2
O
3
The mixture was purified by flash column chromatography (silica gel, petrol ether/EtOAc = 10/1) to
give the enantioenriched indoline derivative 4 (885.0 mg, 87% yield, 89% ee).
2
2

8
. The Derivation of 3-Halofuranoindolines 3a and 4a
X
AcO
AgOAc, AcOH
40 ºC, 20min
O
O
N
H
N H
Boc
Boc
6
(
(
=
=
3
4
a X
I
for X = I, 80%, 92% ee,
for X = Br, 87%, 93% ee.
), 95% ee
a X Br
), 96% ee
To a solution of 3a (0.10 mmol) or 4a (0.10 mmol) in AcOH (1.0 mL) was added silver(I) acetate (0.11
mmol), and the reaction mixture was stirred at 40 ºC in the absence of light for 20 min. After the
mixture was cooled to room temperature, Et
2
O was added. The mixture was filtered and washed with
Et O. The organic volatile solvents were removed under reduced pressure, and the residue was purified
2
by column chromatography on silica gel to afford the product 6.
Tert-butyl (3aR,8aS)-3a-acetoxy-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate 6: yield:
2
7.8 mg (87%); (Flash column chromatography eluent, dichloromethane / methanol = 20/1); colorless
oil; [α] 20
= -164.1 (c 0.28 CH
OH); H-NMR (600 MHz, CDCl
1
) δ 7.86 (s, 1H), 7.51 (d, J = 6.8 Hz,
D
3
3
1
2
1
H), 7.35 – 7.27 (m, 1H), 7.08 – 6.96 (m, 1H), 6.09 (s, 1H), 4.09 (t, J = 7.5 Hz, 1H), 3.55 (s, 1H), 2.74 –
1
3
.67 (m, 1H), 2.66 – 2.58 (m, 1H), 2.03 (s, 3H), 1.59 (s, 9H); C-NMR (151 MHz, CDCl ) δ 169.81,
3
52.18, 141.27, 135.86, 130.73, 125.37, 123.16, 114.92, 96.76, 96.58, 82.89, 67.23, 39.74, 28.47, 21.43;
+
HRMS (ESI) calculated for C17
H
21NNaO
5
[M+Na] : 342.1317, found 342.1312; Enantiomeric excess:
9
3%, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T
=
30 ºC, 254 nm): tmaj = 8.01 min, tmin = 7.37 min.
2
3

9
. General Procedure for Mechanistic Studies
General Procedure for Asymmetric Halocyclization with Various N-halohydantoins
(
10 mol%),
I
Λ-(S,S)-1a
OH
source, 4 Å MS
+
I
O
o
CCl , - 20 C
N
4
N H
0.1 mmol scale
Boc
Boc
2a
3a
O
O
O
I
I
I
Me
Me
I
N
N
N
N
N
N
Me
Me
Me
O
O
O
Me
Me
Me
3-ITMH, 1 equiv,
.3 equiv: 44%, 93% ee 0.05 M: 88%, 82% ee 0.10 M: 88%, 62% ee
DIDMH, 0.02 M,
1-ITMH, 1 equiv,
0
For DIDMH: A 10-mL oven-dried vial was charged with DIDMH (0.03 mmol), Λ-1a (0.01 mmol),
activated 4 Å molecular sieves (100 mg) and CCl (4.0 ml) at room temperature. The mixture was
cooled to -20 ºC and stirred for 30 min. A precooled solution of the tryptophol 2a (0.10 mmol) in
CCl (1.0 ml) was added dropwise to the mixture over 20 min and the reaction was stirred
vigorously until the reaction was complete (monitored by TLC). The reaction was then quenched
with pre-cooled NEt (-20 ºC, 1.0 mmol) and saturated aqueous Na (0.5 mL). The mixture was
purified by flash column chromatography (silica gel, petrol ether/EtOAc = 10/1) to give the product
a.
4
4
3
2
S
2
O
3
3
For 3-ITMH: A 10-mL oven-dried vial was charged with 3-ITMH (0.10 mmol), Λ-1a (0.01 mmol),
activated 4 Å molecular sieves (100 mg) and CCl (1.0 mL) at room temperature. The mixture was
cooled to -20 ºC and stirred for 30 min. A precooled solution of the tryptophol 2a (0.10 mmol) in
CCl (1.0 ml) was added dropwise to the mixture over 20 min and the reaction was stirred
vigorously until the reaction was complete (monitored by TLC). The reaction was then quenched
with pre-cooled NEt (-20 ºC, 1.0 mmol) and saturated aqueous Na (0.5 mL). The mixture was
purified by flash column chromatography (silica gel, petrol ether/EtOAc = 10/1) to give the product
a.
4
4
3
2
S
2
O
3
3
For 1-ITMH: A 10-mL oven-dried vial was charged with 1-ITMH (0.10 mmol), Λ-1a (0.01 mmol),
activated 4 Å molecular sieves (100 mg) and CCl (0.5 mL) at room temperature. The mixture was
cooled to -20 ºC and stirred for 30 min. A precooled solution of the tryptophol 2a (0.10 mmol) in
CCl (0.5 mL) was added dropwise to the mixture over 20 min and the reaction was stirred
vigorously until the reaction was complete (monitored by TLC). The reaction was then quenched
with pre-cooled NEt (-20 ºC, 1.0 mmol) and saturated aqueous Na (0.5 mL). The mixture was
purified by flash column chromatography (silica gel, petrol ether/EtOAc = 10/1) to give the product
a.
4
4
3
2
S
2
O
3
3
2
4