Palladium(II)-Catalyzed Formal [3 + 2] Cycloaddition of Aziridines with 3-Substituted Indoles: Synthesis of Enantioenriched Pyrroloindolines

Article abstract of DOI:10.1021/acs.joc.5b01931

A Pd-catalyzed enantiospecific formal [3 + 2] cycloaddition between chiral aziridines and indoles has been developed. With this method, chiral pyrroloindolines in enantiomerically pure forms were constructed in high yields and diastereoselectivities under mild conditions.

Full text of DOI:10.1021/acs.joc.5b01931

Article
pubs.acs.org/joc
Palladium(II)-Catalyzed Formal [3 + 2] Cycloaddition of Aziridines
with 3‑Substituted Indoles: Synthesis of Enantioenriched
Pyrroloindolines
You-ming Huang, Chang-wu Zheng, Lu Pan, Qiao-wen Jin, and Gang Zhao*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai, 200032, China
S
* Supporting Information
ABSTRACT: A Pd-catalyzed enantiospecific formal [3 + 2]
cycloaddition between chiral aziridines and indoles has been
developed. With this method, chiral pyrroloindolines in
enantiomerically pure forms were constructed in high yields
and diastereoselectivities under mild conditions.
the Rh-catalyzed [3 + 2]-annulation of C3-substituted indoles
with 4-aryl-1-sulfonyl-1,2,3-triazoles to provided chiral didehy-
dropyrroloindolines9 (Scheme 1, route d). In 2000, Nakagawa’s
group reported the [3 + 2] cycloaddition of the unsubstituted
aziridine with N-methyl-3-methylindoles promoted by stoichi-
metric amount of Sc(OTf)3 with TMSCl as the additive.10
Wang and co-workers studied the cycloaddition between
mesoaziridines and C3-alkylindoles mediated by magnesium
catalyst.11 Using their methods, pyrroloindolines with no
substitution or with alkyl-substituted groups in the pyrrole
rings were constructed smoothly (Scheme 1, route e).
However, the syntheses of pyrroloindolines with aryl-
substituted groups are not sufficiently investigated; herein, we
would like to present our contributions to the construction of
these backbones via a [3 + 2] cycloaddition reaction between
C3-substituted indoles and achiral or chiral 2-arylaziridines
catalyzed by the simple Pd(II) salts.12
INTRODUCTION
■
Aziridines have been extensively utilized as one of the most
useful three membered ring functionalities in the reactions with
a variety of carbon and heteroatom nucleophiles for the
construction of various amino acids, chiral ligands, nitrogen-
containing heterocycles, and alkaloids.1,2 During the past few
years, with the easily accessible enantiopure aziridines, a couple
of stereoselective ring-opening reactions have been reported to
provide nonracemic products directly. Ghorai and co-workers3
have reported extensive work on the Lewis acid catalyzed SN2-
type ring-opening of enantiopure N-activated aziridines to
provide the corresponding products with partial loss of
enantiopurity in almost all cases. Recently, Takeda and co-
workers developed a Pd-catalyzed enantiospecific cross-
coupling of chiral 2-arylaziridines with arylboronic acids for
the construction of 2-arylphenethylamines in an enantiopure
form using N-heterocyclic carbene (NHC) ligands to promote
the coupling.4 In this context, an efficient method for
regioselective and stereospecific ring-opening of chiral
aziridines is still in great demand.
Pyrroloindoline backbones are present in an array of
fascinating natural products with interesting biological activities
such as (−)-physostigmine,5a (−)-debromoflustramine E,5b
(−)-gliocladin C,5c (+)-folicanthine,5d (−)-bionectin A,5e and
(+)-nocardioazine B5f (Figure 1). Considerable efforts have
been devoted to developing elegant strategies for the
construction of hexahydropyrrolo[2,3-b]indoles, which, to the
best of our knowledge, can be accessed through four general
strategies concerning the enantioselective synthesis.
RESULTS AND DISCUSSION
■
Our initial investigation was commenced with the reaction
between C3-methylindole 1a and aziridine 2a (as a racemic
mixture) catalyzed by various Lewis acids in toluene (Table 1).
When the commonly used Zn(OTf)2, Mg(OTf)2, and Cu-
(OAc)2 were employed as the catalysts, no products were
observed (Table 1, entries 1−3). Fortunately, the alternative
Cu(OTf)2 and Sc(OTf)3 did provide the desired products,
although the yields and diastereoselectivities were low (Table 1,
entries 4, 5). The Pd(II) complexes, which are more popular in
transition metal catalysis, have also been applied as Lewis acids
to promote a variety of reactions.13 Using PdCl2 as the catalyst,
the reaction indeed happened with the yield and diaster-
eoselectivity largely improved. Thus, various Pd(II) catalysts
were then examined and Pd(PhCN)2Cl2 was found to give the
best results (69% yield and 6:1 dr, Table 1, entry 7). In the
The first strategy is started with tryptophan or tryptamine
derivatives by using biomimetic methods6 (Scheme 1, route a).
The second strategy by using 2-oxoindoles as the starting
materials undergoes alkylation and a series of functional group
interconversions and cyclization7 (Scheme 1, route b). The
third pathway is developed by Michael-type Friedel−Crafts
alkylations of indoles with N-acylated α,β-dehydroamino esters8
(Scheme 1, route c). Recently, Davies and co-workers reported
Received: August 19, 2015
© XXXX American Chemical Society
A
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Article
Figure 1. Representative natural products containing the pyrroloindolines.
Scheme 1. Retrosynthetic Approaches
following studies, solvents such as MeCN, DCM, THF, or
DMF were screened; however, the yields and diastereoselectiv-
ities were not improved. The study of the effect of temperature
on the diastereoselectivity was also made; the lower reaction
temperature gave the better diastereoselectivity (see Supporting
Information, page S2). Finally, when the ratio of 2a:1a was
increased to 2:1, the corresponding product could be obtained
in 81% yield and 10:1 dr (Table 1, entries 12). In addition to
the Pd(II) catalyst, another transition metal PtCl2 was also
evaluated, and the reaction underwent smoothly; however, only
5:1 dr was observed (Table 1, entry 13).
Under the optimized conditions, the reaction scope was
examined (Table 2). The reaction worked well with a series of
indoles. Using the methyl group instead of benzyl group to
protect the nitrogen of indole, the yield and diastereoselectivity
were preserved (3b). Indoles with various types of substituents
on the phenyl rings provided the products with good to
excellent yield, and moderate to good dr (3c−3g), regardless of
their electronic nature or positions. In addition, the reactions of
cyclopenta- and cyclohexa-fused indoles also proceeded
smoothly, giving tetracyclic indolines 3h and 3i containing
two quaternary bridging carbons in high yields with excellent
diastereoselectivities. What is more, indole C3 substituents
other than methyl group are also compatible in the reaction,
albeit with moderate yields and stereoselectivities (3j−3l). As
for the aziridines, the electronic nature of substituents on the 2-
aryl group did not affect the reactivity significantly (3m−3q).
However, the o-Br-substituted 2-aryl aziridine gave the
corresponding product (3r) with decreased diastereoselectivity
compared to the p-Br-substituted 2-aryl aziridine, probably
because of the steric effect of bromine at the ortho position of
the phenyl ring. In addition, reactions with aziridines protected
by different sulfonyl groups also proceed smoothly (3s−3u).
Further exploration was also conducted to construct chiral
hexahydropyrrolo[2,3-b]indole backbones. For this purpose,
enantiomerically pure aziridines were employed as the
substrates. To our great delight, the ring-opening reaction
between chiral aziridines and indoles with various substituents
B
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Article
a
selectivity (Scheme 4c). These results were probably because of
the difference of Lewis acidity between Sc(III) and Pd(II).
Kinetic experiments conducted showed that the reaction with
electron-rich substrates, with electron-rich substituents on
either the sulfonamides or the 2-aromatic rings, has a large
initial reaction rate, as the electron-rich substrate is more liable
to coordinate with palladium; thus the reaction is faster (Figure
2).
Based on the above results, a plausible mechanism is
proposed. The Pd catalyst coordinated to the aziridine,14
generating a highly reactive species, which undergoes
nucleophilic attack by indoles in an SN2 fashion to provide
stereoinverted iminium ion, followed by cyclization to obtain
the desired product (Scheme 5).
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
yield [%]
dr
1
Zn(OTf)2
Mg(OTf)2
Cu(OAc)2
Cu(OTf)2
Sc(OTf)2
NR
NR
NR
40
d
2
d
d
3
4
1:1
1:1
6:1
6:1
9:1
5:1
5:1
d
5
24
6
PdCl2
65
7
Pd(PhCN)2Cl2
Pd(OAc)2
Pd(O2CCF3)2
Pd(NO3)2
Pd(PPh3)2Cl2
Pd(PhCN)2Cl2
PtCl2
69
8
43
CONCLUSIONS
9
24
■
10
11
53
In summary, we have developed a Pd-catalyzed formal [3 + 2]
cycloaddition of achiral and chiral aziridines with indoles. The
reaction allows for preparation of chiral hexahydropyrrolo[2,3-
b]indoles in enantiomerically pure forms. Further studies will
concentrate on a detailed mechanism as well as extending the
synthetic utility of this strategy.
NR
81
e
12
10:1
5:1
e
13
82
a
Reaction conditions: 1a (0.1 mol), 2a (0.1 mol), catalyst (10 mol %),
b
toluene (1.0 mL). Yield of the isolated product after column
c
d
chromatography. Determined by 1H NMR analysis. Not determined.
e
1a (0.1 mol), 2a (0.2 mol).
EXPERIMENTAL SECTION
■
The melting points recorded are uncorrected. Nuclear magnetic
resonance spectra were recorded at 400 MHz. All chemical shifts (δ)
are given in ppm. Data are reported as follows: chemical shift,
integration, multiplicity (s = single, d = doublet, t = triplet, q = quartet,
br = broad, m = multiplet), and coupling constants (Hz). Ee values
were determined by chiral HPLC analysis using Chiral ID-3, Chiral
OD-H, or Chiral AD-H connected with Chiral PC-2. The mobile
phase was a binary mixture, n-hexane/i-PrOH. Optical rotations (α)
were measured on a polarimeter with a sodium lamp in the given
solvent at the indicated concentration (c, g/100 mL) and temperature
(°C). High resolution mass spectra were recorded under TOF
conditions. All solvents were used after redistillation according to
standard procedures. All reactions were carried out employing oven-
dried glassware. 3-Substituted indoles 1 were prepared according to
procedures reported previously.15 Aziridines 2 were synthesized using
reported procedures.16 Compound 4 is commercially available.
2-(4-Chlorophenyl)-1-tosylaziridine (2b): 1H NMR (400 MHz,
CDCl3) δ = 2.34 (d, J = 4.0 Hz, 1H), 2.44 (s, 3H), 2.98 (d, J = 7.2 Hz,
1H), 3.74 (dd, J = 4.0 Hz, J = 7.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H),
7.25−7.27 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H).
on the phenyl rings afforded the corresponding pyrroloindo-
lines in enantiomerically pure form with good yields and
diastereoselectivities (Table 3). The absolute configuration of
(S,S,S)-3c was unambiguously determined by single-crystal X-
ray analysis (see Supporting Information), confirming the
complete stereoinversion at the C-2 of aziridine. Other chiral
products can therefore be assigned by analogy.
In the following studies, stereochemical outcomes of the
reactions were probed with electron-rich 1,3,5-trimethoxyben-
zene 4 and (R)-2a or (S)-2a (Schemes 2a and 2b). As
predicted, both of the products could be attained as a single
enantiomer. This represents great progress compared to the
same initial study performed by Ghorai (Scheme 2c).3
Therefore, we tried to explore the mechanism difference
between Pd(II) and Sc(OTf)3.
A variety of control experiments were first performed to
verify the Pd(II) catalyst acting as the Lewis acid. Under strictly
oxygen-free conditions, the reaction could go smoothly; while
the reaction of C3-methylindole 1a and benzyl-substituted
aziridine was examined and no product was observed under the
same conditions14 (Scheme 3a). Using Pd(0) catalysts such as
Pd(PPh3)4 or Pd2(dba)3, no desired product was observed and
the two substrates were recovered quantitatively (Scheme 3b).
Furthermore, when the Pd(PPh3)2Cl2 or PdCl2 coupled with
phosphines or amines ligands were used as the catalysts, the
reaction did not proceed probably due to the addition of
ligands decreasing the Lewis acidity of palladium by resonance
of unpaired electrons to the empty orbit of metal palladium
(Scheme 3c).
Three more reactions of enantiopure aziridine in toluene
with Sc(OTf)3 or Pd(PhCN)2Cl2 were investigated, and results
are shown in Scheme 4. It can be seen that the ee of (R)-2a was
dropped to 39% with Sc(OTf)3 after 10 min (Scheme 4a),
while the racemization was not observed with Pd(PhCN)2Cl2
as the catalyst (Scheme 4b). Furthermore, in agreement with
the above results, Sc(OTf)3-catalyzed [3 + 2] cycloaddition of
indole 1a with chiral aziridine (S)-2a provided low stereo-
1
2-(4-Bromophenyl)-1-tosylaziridine (2c): H NMR (400 MHz,
CDCl3) δ = 2.34 (d, J = 4.4 Hz, 1H), 2.44 (s, 3H), 2.98 (d, J = 7.2 Hz,
1H), 3.72 (dd, J = 4.4 Hz, J = 7.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H),
7.34 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz,
2H).
1
2-(2-Bromophenyl)-1-tosylaziridine (2g): H NMR (400 MHz,
CDCl3) δ = 2.27 (d, J = 4.4 Hz, 1H), 2.45 (s, 3H), 3.03 (d, J = 7.2 Hz,
1H), 3.99 (dd, J = 4.4 Hz, J = 7.2 Hz, 1H), 7.12−7.22 (m, 3H), 7.36
(d, J = 7.6 Hz, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H).
1-((4-Methoxyphenyl)sulfonyl)-2-phenylaziridine (2h): 1H
NMR (400 MHz, CDCl3) δ = 2.38 (d, J = 4.8 Hz, 1H), 2.96 (d, J
= 7.6 Hz, 1H), 3.75 (dd, J = 4.8 Hz, J = 7.6 Hz, 1H), 3.87 (s, 3H), 6.98
(d, J = 8.8 Hz, 2H), 7.21−7.23 (m, 2H), 7.26−7.30 (m, 3H), 7.92 (d, J
= 8.8 Hz, 2H).
1-((4-Bromophenyl)sulfonyl)-2-phenylaziridine (2i): 1H NMR
(400 MHz, CDCl3) δ = 2.43 (d, J = 4.4 Hz, 1H), 3.02 (d, J = 7.2 Hz,
1H), 3.81 (dd, J = 4.4 Hz, J = 7.2 Hz, 1H), 7.21−7.23 (m, 2H), 7.30−
7.31 (m, 3H), 7.68 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H).
1-((4-Nitrophenyl)sulfonyl)-2-phenylaziridine (2j): 1H NMR
(400 MHz, CDCl3) δ = 2.49 (d, J = 4.8 Hz, 1H), 3.10 (d, J = 7.2 Hz,
1H), 3.88 (dd, J = 4.8 Hz, J = 7.2 Hz, 1H), 7.19−7.21 (m, 2H), 7.29−
7.31 (m, 3H), 8.17 (d, J = 8.4 Hz, 2H), 8.36 (d, J = 8.4 Hz, 2H).
C
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Article
a
Table 2. Reaction Scope
a
b
Reaction conditions: 1a (0.1 mol), 2a (0.2 mol), Pd(PhCN)2Cl2 (10 mol %), toluene (1.0 mL). Yield of the isolated product after column
c
1
chromatography. Determined by H NMR analysis.
a
Table 3. Construction of Chiral Hexahydropyrrolo[2,3-b]indoles
b
c
d
entry
R
2
products
yield [%]
dr
ee [%]
>99/99
1
2
H
H
(S)-2a
(R)-2a
(S)-2a
(S)-2a
(S)-2a
(S)-2a
(S)-2a
(S)-2h
(S)-2i
(S)-2j
(S,S,S)-3a
81
83
67
75
63
65
62
75
73
70
9/1
9/1
5/1
8/1
9/1
8/1
6/1
7/1
7/1
6/1
(R,R,R)-3a
(S,S,S)-3b
(S,S,S)-3c
(S,S,S)-3e
(S,S,S)-3f
(S,S,S)-3g
(S,S,S)-3s
(S,S,S)-3t
(S,S,S)-3u
>−99/−99
>99/99
>99/99
>99/99
>99/99
>99/99
>99/99
>99/99
>99/99
3
H, N-Me
4-Br
6-Br
5-F
4
5
6
7
5-OMe
H
8
9
H
10
H
a
b
Reaction conditions: 1a (0.1 mol), 2a (0.2 mol), Pd(PhCN)2Cl2 (10 mol %), toluene (1.0 mL). Yield of the isolated product after column
c
d
1
chromatography. Determined by H NMR analysis. Ee % of 3/3′ determined by chiral HPLC analysis.
General Procedure for the [3 + 2] Cycloaddition. To a mixture
of 3-substituted indole 1 (0.1 mmol, 1.0 equiv) and Pd(PhCN)2Cl2
(0.01 mmol, 0.1 equiv) in toluene (1.0 mL) was added aziridine 2 (0.2
mmol, 2.0 equiv) at room temperature. The reaction was monitored
D
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concentrated to afford the corresponding product 3 after flash column
chromatography (hexanes/ethyl acetate = 10/1−5/1).
(3S,3aS,8aS)-8-Benzyl-3a-methyl-3-phenyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3a): 40 mg, yield
81%; white solid; mp = 98−100 °C; [α]2D6 = −52.9 (c = 0.9 in CHCl3);
1H NMR (400 MHz, CDCl3) δ = 1.24 (s, 3H), 2.44 (s, 3H), 2.76 (dd,
Scheme 2. Stereochemical Study with the Reaction of 1,3,5-
Trimethoxybenzene
J = 6.4 Hz, J = 12.8 Hz, 1H), 3.50 (t, J = 12.8 Hz, 1H), 3.87−3.92 (m,
1H), 4.70 (AB, J = 16.0 Hz, 2H), 5.48 (s, 1H), 5.56 (d, J = 7.2 Hz,
1H), 6.27 (t, J = 7.2 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 7.2
Hz, 2H), 6.94 (t, J = 7.6 Hz, 1H), 7.21−7.34 (m, 10H), 7.73 (d, J = 8.0
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 21.6, 26.4, 48.1, 51.2,
55.4, 56.9, 89.9, 105.4, 116.5, 125.7, 127.0, 127.3, 127.4, 127.6, 128.0,
128.4, 128.5, 128.91, 128.93, 135.8, 137.2, 138.7, 143.8, 150.2 ppm; IR
(neat) ν 1603, 1494, 1455, 1349, 1162, 1088, 1036, 960 cm−1; ESI-MS
(m/z) 495 (M + H+); MALDI/DHB calcd for C31H31N2O2S+
495.2101, found 495.2113; dr = 10/1. HPLC-separation conditions:
Chiralcel AD-H/PC-2, 25 °C, 254 nm, 90/10 hexane/i-PrOH, 1.0
mL/min; trans diastereoisomer, t = 23.8 min, >99% ee; cis
diastereoisomer, t = 22.4 min, >99% ee.
(3R,3aR,8aR)-8-Benzyl-3a-methyl-3-phenyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3a): 41 mg, yield
83%; [α]2D5 = +29.3 (c = 0.7 in CHCl3); 1H NMR (400 MHz, CDCl3)
δ = 1.24 (s, 3H), 2.44 (s, 3H), 2.76 (dd, J = 6.4 Hz, J = 12.8 Hz, 1H),
3.50 (t, J = 12.8 Hz, 1H), 3.87−3.92 (m, 1H), 4.70 (AB, J = 16.0 Hz,
2H), 5.48 (s, 1H), 5.56 (d, J = 7.2 Hz, 1H), 6.27 (t, J = 7.2 Hz, 1H),
6.32 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 7.2 Hz, 2H), 6.94 (t, J = 7.6 Hz,
1H), 7.21−7.34 (m, 10H), 7.73 (d, J = 8.0 Hz, 2H); ESI-MS (m/z)
495 (M + H+); trans diastereoisomer, t = 20.7 min, >99% ee; cis
diastereoisomer, t = 25.7 min, >99% ee.
Scheme 3. Control Experiments
(3S,3aS,8aS)-3a,8-Dimethyl-3-phenyl-1-tosyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (3b): 28 mg, yield 67%; white
solid; mp = 110−112 °C; [α]2D6 = −10.9 (c = 0.35 in CHCl3); H
1
NMR (400 MHz, CDCl3) δ = 1.27 (s, 3H), 2.47 (s, 3H), 2.73 (dd, J =
6.8 Hz, J = 12.8 Hz, 1H), 3.03 (t, J = 12.8 Hz, 3H), 3.39 (t, J = 12.8
Hz, 1H), 3.72−3.82 (m, 1H), 5.36 (s, 1H), 5.57 (d, J = 7.2 Hz, 1H),
6.28 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 8.0 Hz,
2H), 7.01 (t, J = 7.6 Hz, 1H), 7.20−7.26 (m, 3H), 7.34−7.40 (m, 2H),
7.82 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 21.6, 26.0,
31.3, 51.2, 55.0, 56.7, 91.1, 105.0, 116.4, 125.5, 127.4, 127.5, 128.0,
128.4, 128.6, 128.9, 130.0, 135.8, 137.2, 143.8, 150.9 ppm; IR (neat) ν
1605, 1493, 1453, 1347, 1303, 1162, 1092, 1024, 1001, 957 cm−1; ESI-
MS (m/z) 441 (M + Na+); MALDI/DHB calcd for C25H26N2O2S+
418.1710, found 418.1712; dr = 5/1. HPLC-separation conditions:
Chiralcel AD-H/PC-2, 25 °C, 254 nm, 90/10 hexane/i-PrOH, 1.0
mL/min; trans diastereoisomer, t = 49.2 min, >99% ee; cis
diastereoisomer, t = 54.2 min, >99% ee.
(3S,3aS,8aS)-8-Benzyl-4-bromo-3a-methyl-3-phenyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3c): 43 mg, yield
75%; white solid; mp = 129−131 °C; [α]2D5 = +25.2 (c = 0.78 in
CHCl3); 1H NMR (400 MHz, CDCl3) δ = 1.42 (s, 3H), 2.43 (s, 3H),
3.19 (t, J = 8.0 Hz, 1H), 3.61 (dd, J = 8.0 Hz, J = 12.0 Hz, 1H), 3.96
(dd, J = 8.0 Hz, J = 12.0 Hz, 1H), 4.63 (AB, J = 16.8 Hz, 2H), 5.49 (s,
1H), 6.19 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.73 (t, J = 8.0
Hz, 1H), 6.97 (d, J = 7.6 Hz, 2H), 7.05 (t, J = 7.6 Hz, 2H), 7.12 (t, J =
7.2 Hz, 2H), 7.25−7.35 (m, 7H), 7.70 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ = 21.6, 25.1, 49.6, 54.7, 57.1, 59.1, 92.3, 105.5,
120.9, 122.3, 127.0, 127.2, 127.4, 127.6, 127.7, 128.6, 129.2, 129.7,
129.9, 130.0, 136.2, 138.1, 138.2, 144.1, 152.2 ppm; IR (neat) ν 1596,
1569, 1495, 1454, 1351, 1304, 1164, 1088, 1024, 963 cm−1; ESI-MS
(m/z) 573 (M + H+); MALDI/DHB calcd for C31H30N2O2SBr+
573.1206, found 573.1202; dr = 8/1. HPLC-separation conditions:
Chiralcel ID-3, 25 °C, 214 nm, 80/20 hexane/i-PrOH, 0.7 mL/min;
trans diastereoisomer, t = 8.8 min, >99% ee; cis diastereoisomer, t =
10.3 min, >99% ee.
Scheme 4. Racemization Studies and Sc(OTf)3-Catalyzed
Reaction of Chiral Aziridine
(3S,3aS,8aS)-8-Benzyl-5-bromo-3a-methyl-3-phenyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3d): 52 mg, yield
91%; white solid; mp = 143−145 °C; 1H NMR (400 MHz, CDCl3) δ
= 1.21 (s, 3H), 2.45 (s, 3H), 2.72 (dd, J = 7.0 Hz, J = 12.4 Hz, 1H),
3.47 (t, J = 12.4 Hz, 1H), 3.84 (dd, J = 7.0 Hz, J = 12.4 Hz, 1H), 4.66
(AB, J = 16.4 Hz, 2H), 5.47 (s, 1H), 5.53 (s, 1H), 6.17 (d, J = 8.4 Hz,
by TLC analysis. At the end of the reaction, the mixture was quenched
with H2O (5 mL) and extracted with ethyl acetate (3 × 5 mL). The
combined organic layer was dried over Na2SO4, filtered, and
E
DOI: 10.1021/acs.joc.5b01931
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 2. Impacts of sulfonamide and phenyl substituents on ring opening rate.
Scheme 5. A Plausible Mechanism
1H), 6.83 (d, J = 6.4 Hz, 2H), 7.02 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H),
7.25−7.34 (m, 10H), 7.73 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ = 21.6, 26.2, 48.1, 51.0, 55.3, 56.9, 89.8, 106.8, 107.9, 127.2,
127.4, 127.9, 128.1, 128.7, 128.8, 130.0, 130.7, 130.9, 135.2, 137.0,
138.1, 144.0, 149.0 ppm; IR (neat) ν 1703, 1599, 1490, 1453, 1345,
1304, 1257, 1160, 1093, 1050, 963 cm−1; ESI-MS (m/z) 573 (M +
H+); MALDI/DHB calcd for C31H30N2O2SBr+ 573.1206, found
573.1218; dr = 9/1.
(3S,3aS,8aS)-8-Benzyl-6-bromo-3a-methyl-3-phenyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3e): 36 mg, yield
63%; white solid; mp = 152−154 °C; [α]2D6 = −6.67 (c = 0.22 in
CHCl3); 1H NMR (400 MHz, CDCl3) δ = 1.21 (s, 3H), 2.45 (s, 3H),
2.75 (dd, J = 2.8 Hz, J = 12.8 Hz, 1H), 3.47 (t, J = 12.8 Hz, 1H), 3.83
(dd, J = 6.4 Hz, J = 12.8 Hz, 1H), 4.66 (AB, J = 16.4 Hz, 2H), 5.35 (d,
J = 7.6 Hz, 1H), 5.47 (s, 1H), 6.38 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 0.8
Hz, 1H), 6.83 (d, J = 6.8 Hz, 2H), 7.22−7.35 (m, 10H), 7.71 (d, J =
8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 21.6, 26.3, 47.8, 51.0,
55.2, 56.5, 89.8, 108.3, 119.3, 122.6, 126.9, 127.18, 127.2, 127.4, 127.7,
128.1, 128.7, 128.8, 130.0, 135.4, 137.0, 137.9, 144.0, 151.4 ppm; IR
(neat) ν 1598, 1494, 1453, 1349, 1259, 1162, 1089, 1053, 1035, 961,
899 cm−1; ESI-MS (m/z) 573 (M + H+); MALDI/DHB calcd for
C31H30N2O2SBr+ 573.1206, found 573.1224; dr = 9/1. HPLC-
separation conditions: Chiralcel ID-3, 25 °C, 214 nm, 80/20
hexane/i-PrOH, 0.7 mL/min; trans diastereoisomer, tmajor = 8.1 min,
tminor = 7.8 min, >99% ee; cis diastereoisomer, tmajor = 8.5 min, tminor
=
9.0 min, >99% ee.
(3S,3aS,8aS)-8-Benzyl-5-fluoro-3a-methyl-3-phenyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3f): 34 mg, yield
65%; white solid; mp = 127−129 °C; [α]2D6 = −22.2 (c = 0.42 in
CHCl3); 1H NMR (400 MHz, CDCl3) δ = 1.21 (s, 3H), 2.45 (s, 3H),
2.74 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 3.48 (t, J = 12.4 Hz, 1H), 3.84
(dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 4.67 (AB, J = 16.4 Hz, 2H), 5.47 (s,
1H), 5.54 (s, 1H), 6.17 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 6.8 Hz, 2H),
7.02 (d, J = 6.8 Hz, 1H), 7.25−7.37 (m, 10H), 7.73 (d, J = 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ = 21.6, 26.2, 48.1, 51.0, 55.3,
56.9, 89.8, 106.8, 108.0, 127.1, 127.2, 127.4, 127.9, 128.1, 128.6, 128.7
(JC−F = 207 Hz),128.8 130.0, 130.7, 130.9, 135.2, 137.0, 138.1, 144.0,
149.0 ppm; IR (neat) ν 1598, 1495, 1454, 1348, 1305, 1259, 1212,
1186, 1092, 1035, 960, 911 cm−1; IR (neat) ν 1598, 1492, 1454, 1416,
1349, 1290, 1162, 1089, 1052, 960 cm−1; IR (neat) ν 1699, 1598,
1490, 1454, 1416, 1349, 1262, 1205, 1170, 1090, 1051, 961, 913 cm−1;
MALDI/DHB (m/z) 513 (M + H+); MALDI/DHB calcd for
F
DOI: 10.1021/acs.joc.5b01931
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
C31H29N2O2SFNa+ 535.1825, found 535.1824; dr = 8/1. HPLC-
separation conditions: Chiralcel ID-3, 25 °C, 214 nm, 80/20 hexane/i-
PrOH, 0.7 mL/min; trans diastereoisomer, t = 26.4 min, >99% ee; cis
diastereoisomer, t = 23.0 min, >99% ee.
50%; white solid; mp = 58−60 °C; 1H NMR (400 MHz, CDCl3) δ =
1.65−1.70 (m, 1H), 2.02−2.07 (m, 1H), 2.43 (s, 3H), 2.77 (dd, J = 6.4
Hz, J = 12.8 Hz, 1H), 3.01−3.03 (m, 2H), 3.46 (t, J = 8.8 Hz, 1H),
3.80 (dd, J = 6.4 Hz, J = 12.8 Hz, 1H), 4.16 (s, 2H), 4.60 (AB, J = 16.4
Hz, 2H), 5.48 (d, J = 7.2 Hz, 1H), 5.86 (s, 1H), 6.25 (t, J = 7.2 Hz,
1H), 6.33 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 7.2 Hz, 2H), 6.96 (t, J = 7.6
Hz, 1H), 7.16−7.39 (m, 15H), 7.72 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ = 21.6, 39.0, 48.4, 50.2, 55.7, 59.4, 67.2, 87.4,
105.3, 116.3, 125.6, 126.1, 127.0, 127.4, 127.5, 127.6, 127.9, 128.4,
128.5, 128.6, 129.2, 129.9, 135.5, 137.2, 138.3, 143.8, 138.8, 151.0
ppm; IR (neat) ν 1602, 1494, 1454, 1349, 1270, 1162, 1095, 1030,
969, 912 cm−1; MALDI/DHB (m/z) 637 (M + Na+); MALDI/DHB
calcd for C39H38N2O3SNa+ 637.2495, found 637.2508; dr = 7/1.
8-Benzyl-3a-isopropyl-3-phenyl-1-tosyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (3l): 18 mg, yield 34%; white solid;
mp = 65−66 °C; 1H NMR (400 MHz, CDCl3) δ = 0.52 (d, J = 6.8 Hz,
3H), 0.87 (d, J = 6.8 Hz, 3H), 1.96−2.00 (m, 1H), 2.42 (s, 3H), 3.37−
3.58 (m, 2H), 3.77−3.81 (m, 1H), 4.70 (AB, J = 16.4 Hz, 2H), 5.56
(d, J = 7.2 Hz, 1H), 5.60 (s, 1H), 6.26−6.31 (m, 2H), 6.87 (d, J = 6.8
Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 6.8 Hz, 1H), 7.19−7.63
(m, 10H), 7.71 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ =
15.0, 15.6, 15.8, 16.2, 18.87, 18.94, 28.2, 30.7, 45.8, 47.2, 48.5, 51.4,
52.3, 62.2, 81.3, 84.9, 102.5, 104.6, 113.6, 114.9, 121.9, 123.7, 123.9,
124.2, 124.5, 124.71, 124.75, 124.8, 125.0, 125.2, 125.7, 125.8, 126.3,
126.6, 126.9, 127.2, 133.8, 134.6, 136.0, 136.8, 141.6, 148.5 ppm; IR
(neat) ν 1702, 1602, 1487, 1467, 1454, 1390, 1342, 1261, 1204, 1168,
1092, 1031, 919 cm−1; MALDI/DHB (m/z) 508 (M + H+); MALDI/
DHB calcd for C32H32N2O2S+ 508.2166, found 508.2172; dr = 2.5/1.
8-Benzyl-3-(4-chlorophenyl)-3a-methyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3m): 37 mg, yield
70%; white solid; mp = 146−148 °C; 1H NMR (400 MHz, CDCl3) δ
= 1.22 (s, 3H), 2.44 (s, 3H), 2.78 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H),
3.42 (t, J = 12.4 Hz, 1H), 3.81 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 4.68
(AB, J = 16.4 Hz, 2H), 5.49 (s, 1H), 5.64 (d, J = 7.2 Hz, 1H), 6.32 (t, J
= 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H),
7.19−7.34 (m, 9H), 7.72 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ = 21.6, 26.4, 48.2, 55.0, 56.9, 89.9, 105.6, 116.7, 125.6,
127.0, 127.3, 127.4, 130.0, 128.2, 128.6, 128.8, 129.9, 130.0, 133.4,
134.4, 137.1, 138.6, 143.9, 150.2 ppm; IR (neat) ν 1603, 1485, 1453,
1349, 1216, 1170, 1091, 1036, 1015, 960, 899 cm−1; ESI-MS (m/z)
529 (M + H+); MALDI/DHB calcd for C31H30N2O2SCl+ 529.1711,
found 529.1710; dr = 15/1.
8-Benzyl-3-(4-bromophenyl)-3a-methyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3n): 40 mg, yield
70%; white solid; mp = 149−150 °C; 1H NMR (400 MHz, CDCl3) δ
= 1.22 (s, 3H), 2.44 (s, 3H), 2.76 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H),
3.42 (t, J = 12.4 Hz, 1H), 3.81 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 4.67
(AB, J = 16.4 Hz, 2H), 5.49 (s, 1H), 5.65 (d, J = 7.2 Hz, 1H), 6.32 (t, J
= 8.4 Hz, 2H), 6.71 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.96
(t, J = 8.0 Hz, 1H), 7.24−7.76 (m, 9H), 7.85 (d, J = 8.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ = 21.6, 26.4, 48.2, 51.2, 55.1, 56.8, 89.9,
105.6, 116.7, 121.5, 125.6, 127.0, 127.3, 127.4, 128.1, 128.57, 128.6,
130.0, 130.7, 131.1, 134.9, 137.1, 138.5, 143.9, 150.2 ppm; IR (neat) ν
1703, 1603, 1489, 1453, 1409, 1349, 1261, 1162, 1090, 1010, 961, 899
cm−1; ESI-MS (m/z) 573 (M + H+); MALDI/DHB calcd for
C31H30N2O2SBr+ 573.1206, found 573.1193; dr = 11/1.
8-Benzyl-3-(3-bromophenyl)-3a-methyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3o): 51 mg, yield
90%; white solid; mp = 151−153 °C; 1H NMR (400 MHz, CDCl3) δ
= 1.24 (s, 3H), 2.45 (s, 3H), 2.77 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H),
3.43 (t, J = 12.4 Hz, 1H), 3.82 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 4.68
(AB, J = 16.4 Hz, 2H), 5.49 (s, 1H), 5.64 (d, J = 7.2 Hz, 1H), 6.38 (t, J
= 7.6 Hz, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.91−6.96 (m, 2H), 7.04−
7.16 (m, 1H), 7.24−7.41 (m, 8H), 7.72 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ = 21.6, 26.4, 48.3, 51.2, 55.3, 57.0, 89.8, 105.7,
116.7, 122.1, 125.6, 127.0, 127.3, 127.4, 127.5, 128.0, 128.6, 128.7,
129.5, 130.0, 130.6, 132.0, 137.1, 138.4, 138.6, 144.0, 150.1 ppm; IR
(neat) ν 1702, 1602, 1567, 1493, 1453, 1402, 1348, 1260, 1203, 1170,
1089, 961, 904 cm−1; ESI-MS (m/z) 573 (M + H+); MALDI/DHB
calcd for C31H30N2O2SBr+ 573.1206, found 573.1202; dr = 7/1.
(3S,3aS,8aS)-8-Benzyl-5-methoxy-3a-methyl-3-phenyl-1-
tosyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3g): 32 mg,
yield 62%; white solid; mp = 61−63 °C; [α]2D6 = −22.7 (c = 0.67 in
CHCl3); 1H NMR (400 MHz, CDCl3) δ = 1.26 (s, 3H), 2.44 (s, 3H),
2.81 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 3.34 (s, 3H), 3.51 (t, J = 12.4
Hz 1H), 3.83 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 4.65 (dd, J = 16.4 Hz,
2H), 5.19 (dd, J = 2.0 Hz, 1H), 5.48 (s, 1H), 6.20 (d, J = 8.8 Hz, 1H),
6.51 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 6.88 (d, J = 6.0 Hz, 2H), 7.24−
7.31 (m, 10H), 7.74 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ = 21.6, 26.2, 49.2, 51.0, 55.3, 55.8, 57.0, 90.5, 106.1, 112.4,
114.2, 126.9, 127.3, 127.4, 127.6, 128.1, 128.9, 129.8, 129.9, 135.9,
137.2, 138.9, 143.7, 144.6, 151.6 ppm; IR (neat) ν 1597, 1495, 1454,
1429, 1347, 1262, 1219, 1160, 1093, 1038, 956, 909 cm−1; ESI-MS
(m/z) 525 (M + H+); MALDI/DHB calcd for C32H32N2O3SNa+
547.2026, found 547.2026; dr = 6/1. HPLC-separation conditions:
Chiralcel PC-2/AD-H, 25 °C, 254 nm, 90/10 hexane/i-PrOH, 1.0
mL/min; trans diastereoisomer, t = 38.6 min, >99% ee; cis
diastereoisomer, t = 22.5 min, >99% ee.
4-Benzyl-9-phenyl-11-tosyl-1,2,3,4-tetrahydro-3a,8b-
(epiminoethano)cyclopenta[b]indole (3h): 37 mg, yield 71%;
1
white solid; mp = 99−100 °C; H NMR (400 MHz, CDCl3) δ =
1.52−1.55 (m, 2H), 1.71−1.75 (m, 1H), 1.91−1.94 (m, 1H), 2.36 (s,
3H), 2.45−2.49 (m, 1H), 2.75−2.79 (m, 1H), 3.45−3.54 (m, 2H),
3.87 (t, J = 8.8 Hz, 1H), 4.48 (d, J = 16.8 Hz, 1H), 5.40 (d, J = 16.8
Hz, 1H), 6.15 (d, J = 8.0 Hz, 1H), 6.64 (t, J = 7.2 Hz, 1H), 6.83 (d, J =
7.2 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.15−7.27 (m, 4H), 7.32−7.40
(m, 4H), 7.32 (t, J = 7.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.52 (d, J =
8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 21.5, 26.7, 34.0, 38.0,
49.4, 51.5, 53.5, 70.5, 104.7, 107.0, 117.7, 122.5, 126.5, 126.8, 127.4,
127.7, 128.4, 128.5, 128.7, 129.4, 133.7, 137.1, 137.7, 139.7, 143.5,
150.5 ppm; IR (neat) ν 1703, 1603, 1486, 1464, 1453, 1384, 1324,
1217, 1160, 1088, 1032, 996, 932, 918 cm−1; ESI-MS (m/z) 521 (M +
H+); MALDI/DHB calcd for C33H33N2O2S+ 521.2257, found
521.2263; dr > 20/1.
9-Benzyl-12-phenyl-10-tosyl-6,7,8,9-tetrahydro-5H-8a,4b-
(epiminoethano)carbazole (3i): 33 mg, yield 62%; white solid; mp
= 186−188 °C; 1H NMR (400 MHz, CDCl3) δ = 1.00−1.05 (m, 1H),
1.16−1.21 (m, 1H), 1.41−1.48 (m, 3H), 1.61−1.68 (m, 1H), 2.34 (s,
3H), 3.23 (d, J = 14.8 Hz, 1H), 3.71−3.82 (m, 2H), 4.06 (t, J = 9.2 Hz,
1H), 4.14 (d, J = 16.8 Hz, 1H), 5.28 (d, J = 4.0 Hz, 1H), 6.19 (d, J =
7.6 Hz, 1H), 6.65−6.71 (m, 2H), 7.00−7.04 (m, 3H), 7.10 (d, J = 8.0
Hz, 2H), 7.22−7.35 (m, 7H), 7.67 (d, J = 8.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ = 20.7, 21.0, 21.4, 25.2, 28.9, 48.2, 50.4, 51.8, 58.4,
98.7, 108.4, 117.6, 122.2, 126.7, 127.2, 127.9, 128.3, 128.4, 128.8,
129.4, 131.1, 139.6, 143.3, 148.7 ppm; IR (neat) ν 1607, 1495, 1481,
1454, 1338, 1170, 1096, 1065, 1025, 991 cm−1; MALDI/DHB (m/z)
535 (M + H+); MALDI/DHB calcd for C34H35N2O2S+ 535.2414,
found 535.2419; dr > 20/1.
8-Benzyl-3a-cyclohexyl-3-phenyl-1-tosyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (3j): 20 mg, yield 36%; white solid;
1
mp = 74−75 °C; H NMR (400 MHz, CDCl3) δ = 0.66−1.06 (m,
6H), 1.35−1.73 (m, 5H), 2.42 (s, 3H), 3.44−3.58 (m, 2H), 3.77−3.81
(m, 1H), 4.74 (AB, J = 16.8 Hz, 2H), 5.54 (d, J = 7.2 Hz, 1H), 5.60 (s,
1H), 6.23−6.31 (m, 2H), 6.84 (d, J = 6.8 Hz, 1H), 6.94 (t, J = 7.2 Hz,
1H), 7.02−7.33 (m, 1H), 7.19−7.33 (m, 10H), 7.71 (d, J = 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ = 21.4, 21.5, 25.6, 25.8, 26.1
26.2, 26.3, 26.5, 26.7, 27.7, 28.1, 28.2, 28.6, 29.7, 41.3, 43.5, 48.4, 48.6,
50.0, 53.8, 54.8, 64.7, 65.0, 68.0, 84.5, 87.3, 105.1, 107.2, 116.1, 117.3,
124.3, 126.3, 126.6, 126.8, 126.9, 127.1, 127.2, 127.3, 127.4, 127.6,
127.8, 128.1, 128.2, 128.3, 128.4, 128.9, 129.2, 129.5, 129.7, 130.9,
136.5, 137.2, 138.2, 138.5, 138.9, 143.0 149.7, 151.1 ppm; IR (neat) ν
1703, 1601, 1488, 1466, 1452, 1402, 1345, 1260, 1203, 1165, 1092,
1051, 928 cm−1; ESI-MS (m/z) 563 (M + H+); MALDI/DHB calcd
for C36H39N2O2S+ 563.2727, found 563.2738; dr = 2.5/1.
8-Benzyl-3a-(2-(benzyloxy)ethyl)-3-phenyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3k): 31 mg, yield
G
DOI: 10.1021/acs.joc.5b01931
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The Journal of Organic Chemistry
Article
8-Benzyl-3-(4-fluorophenyl)-3a-methyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3p): 40 mg, yield
78%; white solid; mp = 131−133 °C; 1H NMR (400 MHz, CDCl3) δ
= 1.22 (s, 3H), 1.45 (s, 3H), 2.79 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H),
3.42 (t, J = 12.4 Hz, 1H), 3.82 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 4.68
(AB, J = 16.4 Hz, 2H), 5.49 (s, 1H), 5.60 (d, J = 7.6 Hz, 1H), 6.28−
6.34 (m, 2H), 6.78−6.81 (m, 2H), 6.90−6.97 (m, 3H), 6.24−6.32 (m,
7H), 7.72 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 21.6,
26.4, 48.2, 51.4, 54.9, 56.8, 89.8, 105.6, 114.9 (JC−F = 21.4 Hz), 116.6,
125.6, 127.0, 127.3, 127.4, 128.3, 128.5, 128.6, 129.9, 130.4 (JC−F = 7.9
Hz), 131.6, 137.1, 138.6, 143.9, 150.2, 162.3 (JC−F = 245 Hz) ppm; IR
(neat) ν 1604, 1512, 1494, 1453, 1349, 1260, 1225, 1163, 1106, 1088,
1059, 1036, 960, 900 cm−1; MALDI/DHB (m/z) 513 (M + H+);
MALDI/DHB calcd for C31H30N2O2SF+ 513.2007, found 513.2006;
dr = 9/1.
8-Benzyl-3a-methyl-3-(p-tolyl)-1-tosyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (3q): 47 mg, yield 92%; white
solid; mp = 57−59 °C; 1H NMR (400 MHz, CDCl3) δ = 1.22 (s, 3H),
2.32 (s, 3H), 2.44 (s, 3H), 2.70 (dd, J = 6.8 Hz, J = 12.8 Hz, 1H), 3.46
(t, J = 12.8 Hz, 1H), 3.79 (dd, J = 6.8 Hz, J = 12.8 Hz, 1H), 4.71 (AB, J
= 16.4 Hz, 2H), 5.46 (s, 1H), 5.63 (d, J = 7.2 Hz, 1H), 6.27−6.32 (m,
2H), 6.73 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 7.6 Hz, 1H), 7.03−7.10 (m,
3H), 7.74 (d, J = 8.0 Hz, 2H), 7.23−7.34 (m, 6H), 7.72 (d, J = 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ = 21.1, 21.6, 26.4, 48.1, 51.3,
55.0, 56.8, 89.9, 105.4, 116.5, 125.8, 126.9, 127.3, 127.4, 128.3, 128.5,
128.7, 129.9, 132.6, 137.2, 138.7, 143.8, 150.2 ppm; IR (neat) ν 1603,
1516, 1494, 1454, 1402, 1348, 1260, 1217, 1185, 1163, 1091, 1036,
960, 900 cm−1; ESI-MS (m/z) 509 (M + H+); MALDI/DHB calcd for
C32H33N2O2S+ 509.2257, found 509.2262; dr = 12/1.
8-Benzyl-3-(2-bromophenyl)-3a-methyl-1-tosyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (3r): 38 mg, yield
67%; white solid; mp = 63−65 °C; 1H NMR (400 MHz, CDCl3) δ =
1.22 (s, 3H), 2.45 (s, 3H), 3.40−3.45 (m, 1.4H), 3.57−3.75 (m, 0.3H),
3.75−3.84 (m, 1H), 4.28−4.31 (m, 0.3H), 4.66−4.71 (m, 2H), 5.40 (s,
0.3H), 5.46 (s, 0.7H), 5.85 (d, J = 7.6 Hz, 0.7H), 6.30−6.35 (m,
1.4H), 6.43 (d, J = 8.0 Hz, 0.3H), 6.55 (dd, J = 2.0 Hz, J = 7.2 Hz,
0.7H), 6.72 (t, J = 7.2 Hz, 0.3H), 6.94−7.11 (m, 3H), 7.18−7.27 (m,
3H), 7.32−7.36 (m, 4H), 7.46−7.55 (m, 1.5H), 7.71 (d, J = 8.0 Hz,
0.6H), 7.78 (d, J = 8.0 Hz, 1.4H), 7.78 (d, J = 8.0 Hz, 0.2H); 13C
NMR (100 MHz, CDCl3) δ = 20.6, 21.6, 27.0, 48.2, 50.7, 52.6, 53.8,
57.8, 58.1, 89.5, 90.7, 105.6, 108.3, 116.4, 118.8, 122.9, 125.8, 125.9,
126.4, 127.0, 127.1, 127.2, 127.4, 127.7, 128.0, 128.4, 126.5, 128.6,
128.7, 128.8, 129.6, 130.2, 131.0, 133.0, 133.1, 135.4, 136.9, 138.5,
138.6, 144.0, 150.1 ppm; IR (neat) ν 1651, 1603, 1538, 1494, 1488,
1471, 1455, 1349, 1163, 1091, 1026, 958 cm−1; ESI-MS (m/z) 573 (M
+ H+); DART Positive calcd for C31H30N2O2BrS+ 573.1211, found
573.1196; dr = 2.5/1.
(3S,3aS,8aS)-8-Benzyl-1-((4-methoxyphenyl)sulfonyl)-3a-
methyl-3-phenyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole
(3s): 38 mg, yield 75%; white solid; mp = 69−70 °C; [α]2D6 = −39.5 (c
= 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3) δ = 1.26 (s, 3H), 2.88
(dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 3.49 (t, J = 12.4 Hz, 1H), 3.79−3.87
(m, 4H), 4.70 (AB, J = 16.4 Hz, 2H), 5.47 (s, 1H), 5.57 (d, J = 7.6 Hz,
1H), 6.27 (t, J = 7.6 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 7.2
Hz, 2H), 6.91−6.96 (m, 3H), 7.21−7.32 (m, 7H), 7.77 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ = 26.5, 48.2, 51.2, 55.5, 55.7,
56.9, 89.9, 105.4, 114.5, 116.5, 125.7, 127.0, 127.3, 127.6, 128.0, 128.4,
128.5, 128.9, 129.5, 131.8, 135.9, 138.7, 150.2, 163.2 ppm; IR (neat) ν
1597, 1495, 1455, 1348, 1260, 1159, 1095, 1027, 960 cm−1; ESI-MS
(m/z) 511 (M + H+); MALDI/DHB calcd for C31H31N2O3S+
511.2050, found 511.2056; dr = 7/1. HPLC-separation conditions:
Chiralcel AD-H/PC-2, 25 °C, 254 nm, 90/10 hexane/i-PrOH, 1.0
mL/min; trans diastereoisomer, t = 43.9 min, >99% ee; cis
diastereoisomer, t = 34.1 min, >99% ee.
1H), 6.28−6.35 (m, 2H), 6.87 (d, J = 6.8 Hz, 2H), 6.96 (t, J = 7.2 Hz,
1H), 7.24−7.29 (m, 7H), 7.60−7.68 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ = 26.5, 48.5, 51.1, 55.6, 57.0, 90.0, 105.6, 116.8, 125.8,
127.2, 127.7, 127.9, 128.1, 128.4, 128.6, 128.8, 128.9, 132.5, 135.5,
138.5, 139.3, 150.1 ppm; IR (neat) ν 1603, 1574, 1494, 1453, 1389,
1353, 1164, 1087, 1067, 1009, 960 cm−1; ESI-MS (m/z) 559 (M +
H+); MALDI/DHB calcd for C30H28N2O2SBr+ 559.1049, found
559.1062; dr = 7/1. HPLC-separation conditions: Chiralcel AD-H/
PC-2, 25 °C, 254 nm, 90/10 hexane/i-PrOH, 1.0 mL/min; trans
diastereoisomer, t = 19.0 min, >99% ee; cis diastereoisomer, t = 17.2
min, >99% ee.
(3S,3aS,8aS)-8-benzyl-3a-methyl-1-((4-nitrophenyl)-
sulfonyl)-3-phenyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]-
indole (3u): 37 mg, yield 70%; white solid; mp = 78−79 °C; [α]D26
=
1
−41.2 (c = 1.0 in CHCl3); H NMR (400 MHz, CDCl3) δ = 1.31 (s,
3H), 2.99 (dd, J = 6.4 Hz, J = 12.4 Hz, 1H), 3.52 (t, J = 12.4 Hz, 1H),
3.85−3.91 (m, 1H), 4.65 (s, 2H), 5.56 (s, 1H), 5.61 (d, J = 7.6 Hz,
1H), 6.30−6.35 (m, 2H), 6.88 (d, J = 6.8 Hz, 2H), 6.97 (t, J = 7.6 Hz,
2H), 7.23−7.29 (m, 7H), 7.94 (d, J = 8.4 Hz, 2H), 8.26 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ = 26.6, 49.2, 51.0, 56.0, 57.2,
90.3, 106.0, 117.3, 124.4, 125.8, 127.0, 127.2, 127.8, 128.1, 128.3,
128.6, 128.64, 128.9, 135.2, 138.2, 146.1 150.05, 105.08 ppm; IR
(neat) ν 1604, 1531, 1494, 1454, 1401, 1350, 1311, 1261, 1166, 1087,
1055, 1012, 960, 900 cm−1; ESI-MS (m/z) 526 (M + H+); MALDI/
DHB calcd for C30H28N3O4S+ 526.1795, found 526.1793; dr = 6/1.
HPLC-separation conditions: Chiralcel AD-H/PC-2, 25 °C, 254 nm,
90/10 hexane/i-PrOH, 1.0 mL/min; trans diastereoisomer, t = 99.9
min, >99% ee; cis diastereoisomer, t = 53.3 min, >99% ee.
4-Methyl-N-(2-phenyl-2-(2,4,6-trimethoxyphenyl)ethyl)-
benzenesulfonamide (5): 1H NMR (400 MHz, CDCl3) δ = 2.41 (s,
3H), 3.60 (s, 6H), 3.66−3.73 (m, 2H), 3.78 (s, 3H), 4.41 (t, J = 6.4
Hz, 1H), 4.66 (dd, J = 8.8, 7.2 Hz, 1H), 6.05 (s, 2H), 7.09−7.29 (m,
5H), 7.24 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H). HPLC-
separation conditions: Chiralcel OD-H, 25 °C, 254 nm, 90/10
hexane/i-PrOH, 1.0 mL/min; For (S)-5: t = 27.9 min, >99% ee, (R)-5:
t = 31.9 min, >99% ee.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01931.
■
S
3c (CIF)
1H and 13C NMR spectra and HPLC traces (PDF)
AUTHOR INFORMATION
Corresponding Author
*Fax: 0086-21-64166128. Tel: 0086-21-54925182. E-mail:
zhaog@sioc.ac.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Basic Research Program of
China (973 Program, 2010CB833200) and the National
Natural Science Foundation of China (Nos. 21272247,
21290184) is gratefully acknowledged.
REFERENCES
■
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DOI: 10.1021/acs.joc.5b01931
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