Silica gel-promoted synthesis of multisubstituted spiroindolenines from tryptamines and γ-chloro-α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tet.2020.131765

Here we report a one-pot synthesis of multisubstituted spiroindolenines from a series of tryptamine derivatives with γ-chloro-α,β-unsaturated ketones. The reaction sequence consists of base-induced condensation and silica gel-promoted intramolecular Michael addition. The target molecules are afforded in up to 90% yield with up to >20:1 diastereoselectivity.

Full text of DOI:10.1016/j.tet.2020.131765

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Silica gel-promoted synthesis of multisubstituted spiroindolenines
from tryptamines and g-chloro-a,b-unsaturated ketones
Qiang-Qiang Liu, Chao Zheng**, Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai, 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Here we report a one-pot synthesis of multisubstituted spiroindolenines from a series of tryptamine
Received 1 October 2020
Received in revised form
8 November 2020
Accepted 9 November 2020
Available online xxx
derivatives with
g-chloro-a,b-unsaturated ketones. The reaction sequence consists of base-induced
condensation and silica gel-promoted intramolecular Michael addition. The target molecules are affor-
ded in up to 90% yield with up to >20:1 diastereoselectivity.
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
g
-Chloro-a,b-unsaturated ketone
Dearomatization
Silica gel
Spiroindolenine
Tryptamine
1. Introduction
were found quite reactive under even weak acidic conditions. They
were spontaneously transformed into the target molecules 4 dur-
Spiroindolenine is a privileged molecular scaffold that is widely
embedded in biologically active natural products and pharmaceu-
tical agents (Fig. 1) [1]. Therefore, extensive efforts have been
devoted in the selective synthesis of multisubstituted spi-
roindolenines [2]. Among the known synthetic strategies towards
the spiroindolenine structures, the intramolecular dearomatization
of indole derivatives has attracted broad interests [3,4]. The
nucleophilic attack of the C3 position of the indole ring to an
appropriately tethered electrophile provides the target spirocyclic
molecules with high efficiency and selectivity. In 2017, our group
reported an Ir-catalyzed asymmetric allylic dearomatization of
bis(indol-3-yl) allylic carbonates by applying a desymmetrization
strategy (Scheme 1a) [5]. The reaction afforded six-membered-ring
spiroindolenines bearing three contiguous stereogenic centers in
excellent yields, diastereo- and enantioselectivities. In order to
broaden the scope of the desymmetrization strategy, we envi-
ing the purification by silica gel column chromatography. This
discovery prompted us to develop a silica gel-promoted one-pot
synthesis of multisubstituted spiroindolenines 4 from tryptamine
derivatives 2 and g-chloro-a,b-unsaturated ketones [7]. Herein, we
report the results from this study.
2. Results and discussion
Our study commenced with the evaluation of the model reac-
tion between N-benzyl-2,2-di(1H-indol-3-yl)ethan-1-amine 2a
and (E)-5-chloropent-3-en-2-one 3a. The condensation of 2a with
3a occurred smoothly in the presence of KI and K2CO3 in acetone at
room temperature. The crude residue containing 1aa (obtained
after a simple work-up, see the Experimental section for details)
was next subjected to the silica gel-promoted Michael addition
reaction (Table 1). It was found that the reaction proceeded well in
CH2Cl2, CHCl3 or toluene, but was less efficient in Et2O, THF or
dioxane (entries 1e6). The mesh size and resource of the silica gel
did not influence the reaction outcome significantly. The target
sioned that dearomatization of bis(indol-3-yl)
a,b-unsaturated
ketones 1 might be achieved via an intramolecular Michael reaction
by a Brønsted acid (Scheme 2) [6]. To our surprise, compounds 1
molecule was typically afforded as
a mixture of two di-
astereoisomers (4aa and 4aa′) in about 70% combined yield with
5:1 dr using CH2Cl2 as the solvent (entries 1, 7e9). Further variation
of other reaction parameters suggested the optimal conditions of
* Corresponding author.
** Corresponding author.
E-mail address: slyou@sioc.ac.cn (S.-L. You).
https://doi.org/10.1016/j.tet.2020.131765
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: Q.-Q. Liu, C. Zheng and S.-L. You, Silica gel-promoted synthesis of multisubstituted spiroindolenines from tryptamines
and -chloro- -unsaturated ketones, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131765
g
a,b

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
Table 1
Optimization of reactions Conditionsa.
Fig. 1. Representative natural products and bioactive molecules containing spi-
roindolenine structures.
entry
silica gelb
solvent
time (h)
yield (%)c
drd
1
2
3
4
5
6
7
8
silica gel I
silica gel I
silica gel I
silica gel I
silica gel I
silica gel I
silica gel II
silica gel III
silica gel IV
silica gel II
silica gel II
silica gel II
silica gel II
CH2Cl2
CHCl3
Et2O
1
1
8
8
8
1
1
1
1
2
2
1
1
74
70
65
20
/
68
74
69
70
68
50
63
76
5:1
5:1
3:1
/
THF
dioxane
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
/
4:1
5:1
5:1
5:1
3:1
3:1
4:1
5:1
9
10e
11f
12g
13h
a
Reaction conditions for step 1: 2a (0.2 mmol), 3a (1.2 equiv), K2CO3 (2 equiv), KI
(1.2 equiv) in acetone (4 mL) at rt. Reaction conditions for step 2: Reaction residue of
step 1, silica gel (200 mg) in solvent (4 mL) at rt.
b
Silica gel I (300e400 mesh), silica gel II (100e200 mesh) and silica gel III
(200e300 mesh) were purchased from Jiangyou Silicone Co., Ltd. Silica gel IV
(230e400 mesh) was purchased from Silicycle Inc.
c
Combined yield of two diastereoisomers.
d
Determined by 1H NMR spectra of the crude reaction mixture.
e
Silica gel II (100 mg) was used.
Silica gel II (50 mg) was used.
In CH2Cl2 (2 mL).
In CH2Cl2 (8 mL).
f
g
Scheme 1. Synthesis of Spiroindolenines via Desymmetrization Strategy.
h
(52e85%), albeit with moderate diastereoselectivity (3:1e5:1 dr)
(Table 2). The relative configurations of 4aa and 4aa′ were deter-
mined by 2D NMR (See the SI for details), and those of other
products were assigned by analogy. In each diastereoisomer of the
products, both the alkyl ketone moiety and the unreacted indole
ring adopt the equatorial position of the piperidine ring. The rela-
tive configurations of the quaternary carbon at the ring junction are
different in 4 and 4’ (See the SI for details). Halogen atoms can be
tolerated on the alkyl chain of 3 and also the indole ring of 2,
leaving possible handles for further derivations of the products. The
reaction was readily scaled-up. Compounds 4aa and 4aa′ could be
obtained in 0.94 g (74% yield, 4:1 dr) from a 3 mmol-scale reaction
under the standard conditions.
The reaction protocol is also compatible with tryptamine de-
rivatives 5. Under slightly modified conditions for the second step
[in toluene at room temperature for 5 h with the silica gel I
(300e400 mesh, 100 mg)], one-pot syntheses of spiroindolenines 6
were accomplished from the reactions of 5 with g-chloro-a,b-un-
Scheme 2. Transformations of Product 6aa.
saturated ketones 3 (Table 3). Notably, in all the cases, the target
molecules were delivered in high yields (up to 90%) as a single
diastereoisomer (>20:1 dr). The relative configuration of 6aa was
established by X-ray crystallographic analysis.
the Michael addition as described in entry 13. The reaction was
performed on a 0.2 mmol scale in CH2Cl2 (0.025 M) at room tem-
Spiroindolenine 6aa was readily involved in a series of trans-
formations (Scheme 2). In the presence of BuOK as the base, an
perature for 1 h with silica gel II (100e200 mesh, 200 mg).
t
With the optimal conditions in hands, the scope of this reaction
intramolecular Mannich reaction of 6aa afforded tetracyclic spi-
roindoline 7 in 82% yield [8]. The methyl ketone and imine moieties
of 6aa were reduced in the presence of 10 equiv. of NaBH4, leading
to corresponding secondary alcohol 8 as a pair of diastereoisomers
(85% yield, 1.8:1 dr). In addition, the hydrogenation of 6aa by
was next explored. Various bis(indol-3-yl) derived amines 2 and
chloro- -unsaturated alkyl or aryl ketones 3 could participate the
reactions, delivering the desired indol-3-yl substituted six-
membered-ring spiroindolenines as pair of separable di-
astereoisomers (4 and 4′), in reasonable to good combined yields
g-
a,b
a
2

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
Table 2
Substrate scope for Bis(indol-3-yl) Derivativesa.
Pd(OH)2/C with the concomitant removal of the benzyl group
delivered spiroindoline 9 in 79% yield.
signals. Data for 1H NMR are recorded as follows: chemical shift (
ppm), multiplicity (s singlet, doublet, triplet,
d,
¼
d
¼
t
¼
m ¼ multiplet or unresolved, br ¼ broad singlet, coupling con-
stant(s) in Hz, integration). Data for 13C NMR are reported in terms
3. Conclusions
of chemical shift (d, ppm). For HRMS analyses of new compounds,
the species containing 35Cl or 79Br isotope(s) were measured.
In summary, we have developed a one-pot synthesis of multi-
substituted spiroindolenines from tryptamine derivatives and
g-
chloro- -unsaturated ketones, employing the intramolecular
a
,
b
4.2. General procedure for the preparation of 2
Michael addition promoted by silica gel as the key step. The reac-
tion features readily available starting materials, mild reaction
conditions and operational simplicity. The synthetic utility of the
products has been demonstrated by several useful transformations.
The synthesis of 2a, 2b, 2c, 2d, 2e was accomplished via the
following route according to reported procedures [5].
To a stirred solution of 2,2-di(1H-indol-3-yl)ethan-1-amine
derivative (2.0 mmol) was added PhCHO (2.4 mmol) in MeOH
(20 mL), and the mixture was stirred for 12 h at room temperature.
Then the reaction mixture was cooled to 0 ꢀC, and NaBH4 (10 mmol)
was added in portions. After the reaction was complete (monitored
by TLC), the solvent was removed by rotary evaporation. Then the
residue was purified by silica gel column chromatography (PE/
EtOAc ¼ 3/2) to afford the desired product 2.
4. Experimental section
4.1. General
Unless stated, all reactions were carried out in flame-dried
glassware under a dry argon atmosphere. All solvents were puri-
fied and dried according to standard methods prior to use. 1H and
13C NMR spectra were recorded on a Varian instrument (300 MHz
and 75 MHz, 400 MHz and 100 MHz respectively) and internally
referenced to tetramethylsilane signal or residual protio solvent
4.2.1. N-benzyl-2,2-di(1H-indol-3-yl)ethan-1-amine (2a) beige
solid, m.p. ¼ 73.2e75.8 ꢀC, 694.4 mg, 95% yield (2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
7.98 (s, 2H), 7.59 (d, J ¼ 8.0 Hz, 2H),
3

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
Table 3
Substrate scope for tryptamine Derivatives.
7.36e7.18 (m, 7H), 7.15 (t, J ¼ 7.4 Hz, 2H), 7.03 (t, J ¼ 7.6 Hz, 2H), 6.94
(d, J ¼ 1.2 Hz, 2H), 4.81 (t, J ¼ 7.0 Hz, 1H), 3.84 (s, 2H), 3.40 (d,
J ¼ 7.2 Hz, 1H), 3.87 (s, 2H), 3.33 (d, J ¼ 7.2 Hz, 2H). 13C NMR
(101 MHz, CDCl3)
d 135.2, 128.9, 128.8, 128.5, 128.0, 125.1, 124.1,
J ¼ 7.2 Hz, 2H), 1.61 (s, 1H). 13C NMR (101 MHz, CDCl3)
d
140.3, 136.5,
121.6, 114.9, 112.9, 112.8, 110.0, 52.1, 50.3, 33.0. IR (thin film): nmax
(cmꢁ1) ¼ 3441, 2823, 1452, 1325, 1214, 1091, 862, 834, 789, 765;
HRMS (ESI) calcd for C25H22Br2N3 [MþH]þ: 552.0175, Found:
552.0172.
128.3, 128.1, 126.9, 126.8, 122.0, 121.9, 119.5, 119.2, 117.9, 111.1, 53.8,
53.4, 34.5. IR (thin film): nmax (cmꢁ1) ¼ 3411, 3053,1454,1338,1264,
1094, 1011, 733, 699; HRMS (ESI) calcd for C25H24N3 [MþH]þ:
366.1965, Found: 366.1961.
4.2.4. N-benzyl-2,2-bis(5-methyl-1ꢀH-indol-3-yl)ethan-1-amine
(2d) beige solid, m.p. ¼ 70.2e72.4 C, 763.4 mg, 97% yield (2 mmol
scale)
4.2.2. N-benzyl-2,2-bis(5-fluoro-1H-indol-3-yl)ethan-1-amine (2b)
beige solid, m.p. ¼ 65.3e68.5 ꢀC, 714.7 mg, 89% yield (2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
8.13 (s, 2H), 7.30e7.18 (m, 7H), 7.12
1H NMR (400 MHz, CDCl3)
d 7.91 (s, 2H), 7.37 (s, 2H), 7.29e7.14
(dd, J ¼ 10.0, 2.4 Hz, 2H), 7.04 (d, J ¼ 2.4 Hz, 2H), 6.88 (td, J ¼ 8.8,
(m, 7H), 6.97 (dd, J ¼ 8.0, 1.6 Hz, 2H), 6.82 (d, J ¼ 2.4 Hz, 2H), 4.75 (t,
2.4 Hz, 2H), 4.64 (t, J ¼ 7.2 Hz, 1H), 3.84 (s, 2H), 3.36 (d, J ¼ 7.2 Hz,
J ¼ 7.2 Hz, 1H), 3.84 (s, 2H), 3.35 (d, J ¼ 7.2 Hz, 2H), 2.38 (s, 6H), 1.96
2H). 13C NMR (101 MHz, CDCl3)
d
157.4 (d, J ¼ 235.4 Hz), 139.6, 133.1,
(s, 1H). 13C NMR (101 MHz, CDCl3)
d 140.0, 134.9, 128.3, 128.3, 128.2,
128.3 (d, J ¼ 27.4 Hz), 127.1, 127.0, 127.0, 123.8, 117.3 (d, J ¼ 4.7 Hz),
127.1, 126.8, 123.5, 122.3, 119.1, 117.2, 110.8, 53.5, 53.1, 34.3, 21.5. IR
(thin film): nmax (cmꢁ1) ¼ 3408, 3028, 2832, 1453, 1264, 1094, 794,
732, 699; HRMS (ESI) calcd for C27H28N3 [MþH]þ: 394.2278, Found:
394.2274.
111.8 (d, J ¼ 9.8 Hz), 110.4 (d, J ¼ 26.6 Hz), 104.4 (d, J ¼ 23.7 Hz),
53.57, 52.46, 34.48. 19F NMR (376 MHz, CDCl3)
d
ꢁ124.58 to ꢁ124.52
(m, 1F). IR (thin film): nmax (cmꢁ1) ¼ 3464, 1484, 1453, 1344, 1264,
1167,1095, 936, 852, 797, 732, 700; HRMS (ESI) calcd for C25H22F2N3
[MþH]þ: 402.1776, Found: 402.1773.
4.2.5. N-benzyl-2,2-bis(6-methyl-1H-indol-3-yl)ethan-1-amine
ꢀ
(2e) beige solid, m.p. ¼ 82.2e84.8 C, 771.3 mg, 98% yield (2 mmol
4.2.3. N-benzyl-2,2-bis(5-bromo-1H-indol-3-yl)ethan-1-amine
(2c) white solid, m.p. ¼ 159.8e161.2 ꢀC, 941.9 mg, 90% yield (2 mmol
scale)
scale)
1H NMR (400 MHz, CDCl3)
d
8.27 (s, 2H), 7.26 (d, J ¼ 8.4 Hz, 2H),
7.20 (s, 5H), 6.99 (s, 2H), 6.73 (d, J ¼ 8.0, 2H), 6.70 (d, J ¼ 1.6 Hz, 2H),
4.84 (t, J ¼ 7.4 Hz, 1H), 3.71 (s, 2H), 3.27 (d, J ¼ 7.6 Hz, 2H), 2.29 (s,
1H NMR (400 MHz, CDCl3)
d
8.46 (m, 2H), 7.50 (s, 2H), 7.27e7.24
(m, 5H), 7.17 (d, J ¼ 1.2 Hz, 4H), 6.94 (d, J ¼ 2.0 Hz, 2H), 4.76 (t,
6H). 13C NMR (101 MHz, CDCl3)
d 137.0, 134.4, 131.7, 129.2, 128.7,
4

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
128.1, 124.3, 122.2, 121.0, 118.8, 115.2, 111.4, 51.8, 50.5, 32.9, 21.5. IR
(thin film): nmax (cmꢁ1) ¼ 3407, 2829, 1452, 1337, 1263, 1091, 1027,
799, 732, 699; HRMS (ESI) calcd for C27H28N3 [MþH]þ: 394.2278,
Found: 394.2274.
purified by silica gel chromatography (n-hexane/DCM ¼ 2/1) to
afford the pure product.
4.4.1. (E)-1-([1,10-biphenyl]-4-yl)-4-chlorobut-2-en-1-one (3i)
white solid, m.p. ¼ 112.4e114.1 ꢀC, 231.0 mg, 45% yield (2 mmol
scale, 3 steps)
4.3. General procedure for the preparation of 3ae3g
1H NMR (400 MHz, CDCl3)
d
8.05 (d, J ¼ 8.4 Hz, 2H), 7.71 (d,
The synthesis of 3ae3g was accomplished via the following
route according to reported procedures [9].
J ¼ 8.0 Hz, 2H), 7.64 (d, J ¼ 7.2 Hz, 2H), 7.48 (t, J ¼ 7.4 Hz, 2H),
7.44e7.38 (m, 1H), 7.21e7.25 (m, 1H), 7.10 (dt, J ¼ 15.2, 5.6 Hz, 1H),
To a stirred solution of acid chloride (2.0 mmol) and allyl chlo-
ride (4.0 mmol) in dichloromethane (4 mL) was added aluminum
chloride (2.4 mmol) in portions over 10 min. The mixture was
stirred for 2 h at 0 ꢀC and for 1 h at room temperature and then
poured onto crushed ice. The organic layer was separated, dried
with Na2SO4, filtered and triethylamine (4 mL) was added. The
mixture was refluxed for 2 h, cooled to room temperature. The
solvents were removed under reduced pressure, Then the residue
was purified by silica gel column chromatography (PE/EtOAc ¼ 50/
1) to afford the desired product.
4.32 (d, J ¼ 5.6, 2H). 13C NMR (101 MHz, CDCl3)
d 189.2, 145.9, 141.4,
139.7, 135.9, 129.3, 129.0, 128.3, 127.5, 127.3, 127.3, 43.3. nmax
(cmꢁ1) ¼ 1667, 1616, 1598, 1402, 1337, 1293, 1258, 1228, 1207, 1003,
732, 697; HRMS (ESI) calcd for C16H13ClNaO [MþNa]þ: 279.0547,
Found: 279.0553.
4.4.2. (E)-4-chloro-1-(3,4-dichlorophenyl)but-2-en-1-one (3j)
white solid, m.p. ¼ 44.6e46.5 ꢀC, 234.0 mg, 47% yield (2 mmol scale,
3 steps)
1H NMR (400 MHz, CDCl3)
d
7.98 (d, J ¼ 2.0 Hz, 1H), 7.74 (dd,
J ¼ 8.4, 2.0 Hz, 1H), 7.53 (d, J ¼ 8.4 Hz, 1H), 7.10e7.04 (m, 2H),
4.3.1. (E)-4-chloro-1-cyclopentylbut-2-en-1-one (3d) brown liquid,
4.29e4.25 (m, 2H). 13C NMR (101 MHz, CDCl3)
d 187.2, 142.7, 137.7,
193.3 mg, 56% yield (2 mmol scale, 2 steps)
136.7, 133.3, 130.8, 130.5, 127.5, 126.4, 43.0. nmax (cmꢁ1) ¼ 3067,
1673, 1626, 1582, 1556, 1417, 1387, 1292, 1274, 1209, 1029, 972, 732,
675; HRMS (ESI) calcd for C10H8Cl3O [MþH]þ: 248.9635, Found:
248.9635.
1H NMR (400 MHz, CDCl3)
d
6.85 (dt, J ¼ 15.5, 6.1 Hz, 1H), 6.41
(dt, J ¼ 15.5, 1.6 Hz, 1H), 4.20 (dd, J ¼ 6.2, 1.5 Hz, 2H), 3.17e3.02 (m,
1H), 1.91e1.73 (m, 4H), 1.56e1.73 (m, 4H). 13C NMR (101 MHz,
CDCl3)
d 201.6, 139.1, 130.8, 49.6, 43.0, 28.9, 26.0. nmax
(cmꢁ1) ¼ 2953, 2868,1695,1670,1632,1449,1359,1288,1252,1200,
1110, 975, 713, 661; HRMS (ESI) calcd for C9H14ClO [MþH]þ:
173.0728, Found: 173.0735.
4.5. General procedure for the preparation of 4 and 4’
To a stirred solution of tryptamine derivative (0.2 mmol) and
g-
chloro- -unsaturated ketone (0.24 mmol) in acetone (4 mL) was
a,b
4.3.2. (E)-1,7-dichlorohept-2-en-4-one (3f) brown liquid, 223.2 mg,
62% yield (2 mmol scale, 2 steps)
added K2CO3 (0.4 mmol, 55 mg) and KI (0.24 mmol, 40 mg) at room
temperature. After the reaction was complete (monitored by TLC),
the crude reaction mixture was filtrated with Celite and washed
with DCM, the solvent was removed under reduced pressure. Then
the residue was re-dissolved in DCM and washed with water. The
organic layer was dried over Na2SO4, and concentrated.
To a stirred solution of this residue in DCM (8 mL) was added
silica gel (100e200 mesh, 200 mg). The reaction mixture was
stirred at room temperature. After completion, the residue was
filtrated and concentrated. The residue was purified by flash col-
umn chromatography (hexanes/EtOAc ¼ 2/1 to 1/2) to afford the
product.
1H NMR (400 MHz, CDCl3)
d
6.87 (dt, J ¼ 15.6, 6.0 Hz, 1H), 6.37
(dt, J ¼ 15.6, 1.6 Hz, 1H), 4.21 (dd, J ¼ 6.0, 1.6 Hz, 2H), 3.61 (t,
J ¼ 6.4 Hz, 2H), 2.80 (t, J ¼ 7.0 Hz, 2H), 2.11 (m, 2H). 13C NMR
(101 MHz, CDCl3)
d 198.2, 139.7, 131.3, 44.3, 42.8, 37.3, 26.2. nmax
(cmꢁ1) ¼ 2961, 1699, 1676, 1635, 1439, 1410, 1372, 1323, 1293, 1210,
1103, 974, 708, 648; HRMS (ESI) calcd for C7H11Cl2O [MþH]þ:
181.0181, Found: 181.0182.
4.3.3. (E)-1,8-dichlorooct-2-en-4-one (3g) brown liquid, 253.5 mg,
65% yield (2 mmol scale, 2 steps)
1H NMR (400 MHz, CDCl3)
d
6.84 (dt, J ¼ 15.5, 6.1 Hz, 1H), 6.36
(dt, J ¼ 15.6, 1.6 Hz, 1H), 4.20 (dd, J ¼ 6.0, 1.6 Hz, 2H), 3.56 (t,
4.5.1. 1-((3R,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-3,40-
piperidin]-50-yl)propan-2-one (4aa) beige solid,
J ¼ 6.0 Hz, 2H), 2.63 (t, J ¼ 6.8 Hz, 2H), 1.87e1.72 (m, 4H). 13C NMR
(101 MHz, CDCl3)
d
198.8, 139.4, 131.2, 44.5, 42.8, 39.7, 31.7, 20.9.
m.p. ¼ 112.4e114.8 ꢀC, 56.4 mg, 63% yield (0.2 mmol scale)
nmax (cmꢁ1) ¼ 2956, 1699, 1676, 1635, 1444, 1409, 1370, 1289, 1254,
1104, 975, 723, 705, 648; HRMS (ESI) calcd for C8H13Cl2O [MþH]þ:
195.0338, Found: 195.0339.
1H NMR (400 MHz, CDCl3)
d
7.88 (s, 1H), 7.82 (d, J ¼ 7.6 Hz, 1H),
7.65 (s, 1H), 7.60e7.53 (m, 1H), 7.48 (d, J ¼ 7.6 Hz, 1H), 7.44e7.37 (m,
3H), 7.36e7.22 (m, 4H), 7.14e7.02 (m, 3H), 5.64 (s, 1H), 4.13 (dd,
J ¼ 12.0, 3.0 Hz, 1H), 3.83 (AB, JAB ¼ 13.2 Hz, 1H), 3.73 (AB,
JBA ¼ 13.2 Hz, 1H), 3.35e3.25 (m, 1H), 3.06 (td, J ¼ 12.0, 4.0 Hz, 2H),
2.82 (t, J ¼ 12.0 Hz,1H), 2.57 (t, J ¼ 11.6 Hz, 1H), 1.87 (s, 3H), 1.66 (dd,
J ¼ 18.2, 8.2 Hz, 1H), 1.53 (dd, J ¼ 18.2, 3.4 Hz, 1H). 13C NMR
4.4. General procedure for the preparation of 3he3j
The synthesis of 3h, 3i, 3j was accomplished via the following
route according to reported procedures [10].
(101 MHz, CDCl3)
d 206.7, 178.6, 157.8, 138.6, 137.6, 134.7, 129.0,
A solution of aryl-substituted 2-bromoethanone (2.0 mmol) and
PPh3 (2.2 mmol) in THF (6 mL) was refluxed for 4 h. Upon cooling,
volatiles were removed, the solid was re-dissolved in DCM and
extracted with aq. NaOH (20% w/w in H2O), washed with water,
dried over MgSO4, filtered and evaporated to dryness. The crude
product was purified by silica gel chromatography (EtOAc/n-
hexane ¼ 2/1) to afford the pure product.
128.5, 128.3, 127.2, 127.0, 125.4, 125.2, 121.9, 121.7, 120.5, 119.4, 117.8,
112.5, 110.9, 65.2, 62.6, 55.3, 54.2, 42.5, 37.2, 34.5, 30.3. IR (thin
film): nmax (cmꢁ1) ¼ 3056, 2923, 2810, 1712, 1355, 1264, 1159, 1099,
1026, 1014, 738, 701; HRMS (ESI) calcd for C30H30N3O [MþH]þ:
448.2383, Found: 448.2390.
4.5.2. 1-((3S,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-3,40-
piperidin]-50-yl)propan-2-one (4aa0) beige solid,
A solution of aldehyde (2.0 mmol) and the Wittig reagent
(2.2 mmol) in toluene (4 mL) was refluxed for 24 h. The mixture
was cooled and extracted with EtOAc, washed with H2O, dried over
MgSO4, filtered and evaporated to dryness. The crude product was
m.p. ¼ 101.2e103.5 ꢀC, 11.6 mg, 13% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d 8.66 (s, 1H), 8.13 (s, 1H), 7.43e7.34
(m, 4H), 7.34e7.27 (m, 3H), 7.27e7.20 (m, 1H), 7.14e7.01 (m, 3H),
5

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
6.96 (td, J ¼ 6.8, 0.8 Hz, 1H), 6.90e6.80 (m, 1H), 4.01 (dd, J ¼ 12.4,
3.6 Hz, 1H), 3.80 (AB, JAB ¼ 13.2 Hz, 1H), 3.66 (AB, JBA ¼ 13.2 Hz, 1H),
3.24e3.12 (m, 3H), 2.73 (t, J ¼ 12.0 Hz, 1H), 2.38 (t, J ¼ 11.4 Hz, 1H),
1.93 (dd, J ¼ 17.2, 9.2 Hz, 1H), 1.73 (s, 3H), 1.46 (dd, J ¼ 17.6, 3.2 Hz,
7.42e7.36 (m, 4H), 7.35e7.28 (m, 3H), 7.26e7.22 (m, 1H), 7.14e7.04
(m, 3H), 6.98 (m, J ¼ 7.2 Hz, 1H), 6.92 (t, J ¼ 7.2, 1H), 6.65 (d,
J ¼ 2.4 Hz, 1H), 4.01 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.81 (AB, JAB ¼ 13.2 Hz,
1H), 3.65 (AB, JBA ¼ 13.2 Hz, 1H), 3.22e3.14 (m, 3H), 2.73 (t,
J ¼ 12.2 Hz, 1H), 2.40 (t, J ¼ 11.8 Hz, 1H), 2.03e1.80 (m, 3H), 1.44 (dd,
1H). 13C NMR (101 MHz, CDCl3)
d 206.6, 174.3, 155.0, 140.6, 137.6,
134.9, 129.0, 128.3, 128.1, 127.2, 126.7, 126.5, 122.0, 121.5, 120.7,
120.5, 118.8, 118.4, 112.9, 110.7, 65.6, 62.8, 58.6, 57.9, 41.6, 40.1, 38.3,
30.0. nmax (cmꢁ1) ¼ 3056, 2922, 2807, 1714, 1548, 1494, 1456, 1340,
1264, 1163, 908, 731, 699; HRMS (ESI) calcd for C30H30N3O [MþH]þ:
448.2383, Found: 448.2381.
J ¼ 17.4, 3.0 Hz, 1H), 1.37e1.22 (m, 2H), 0.70 (t, J ¼ 7.4 Hz, 3H). 13
C
NMR (101 MHz, CDCl3)
d 208.9, 174.2, 155.1, 140.6, 137.6, 134.9,
129.0,128.3,128.1,127.2,126.8,126.5,122.1,121.6,120.7,120.5,118.9,
118.5, 113.1, 110.7, 65.7, 62.8, 58.6, 58.0, 44.8, 40.7, 40.1, 38.3, 17.0,
13.5. nmax (cmꢁ1) ¼ 3055, 2962, 2877, 2807, 1709, 1619, 1548, 1455,
1341, 1263, 1098, 1066, 1011, 734, 700; HRMS (ESI) calcd for
4.5.3. 1-((3R,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-3,40-
piperidin]-50-yl)butan-2-one (4 ab) beige solid,
C
32H34N3O [MþH]þ: 476.2696, Found: 476.2694.
m.p. ¼ 84.3e86.6 ꢀC, 60.7 mg, 62% yield (0.2 mmol scale)
4.5.7. 2-((3R,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-3,40-
piperidin]-50-yl)-1-cyclopentylethan-1-one (4ad) beige solid,
m.p. ¼ 98.8e101.4 ꢀC, 58.0 mg, 58% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
7.87 (s, 1H), 7.81 (d, J ¼ 7.2 Hz, 1H),
7.74 (s, 1H), 7.58e7.53 (m, 1H), 7.45 (d, J ¼ 7.6 Hz, 1H), 7.42e7.36 (m,
3H), 7.35e7.22 (m, 4H), 7.10e7.03 (m, 3H), 5.63 (d, J ¼ 2.0 Hz, 1H),
4.12 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.83 (AB, JAB ¼ 13.2 Hz, 1H), 3.72 (AB,
JBA ¼ 13.2 Hz, 1H), 3.35e3.25 (m, 1H), 3.08e3.01 (m, 2H), 2.82 (t,
J ¼ 12.0 Hz, 1H), 2.58 (t, J ¼ 11.4 Hz, 1H), 2.08 (q, J ¼ 3.2 Hz, 2H), 1.63
(dd, J ¼ 17.6, 8.0 Hz, 1H), 1.51 (dd, J ¼ 17.6, 4.0 Hz, 1H), 0.88 (t,
1H NMR (400 MHz, CDCl3)
d
7.88 (s, 1H), 7.82 (d, J ¼ 7.6 Hz, 1H),
7.71 (s, 1H), 7.57e7.54 (m, 1H), 7.47e7.42 (m, 1H), 7.41e7.36 (m, 3H),
7.35e7.21 (m, 4H), 7.10e7.03 (m, 3H), 5.63 (d, J ¼ 2.4 Hz, 1H), 4.12
(dd, J ¼ 12.0, 3.6 Hz, 1H), 3.83 (AB, JAB ¼ 13.2 Hz, 1H), 3.71 (AB,
JBA ¼ 13.2 Hz, 1H), 3.36e3.27 (m, 1H), 3.03 (dt, J ¼ 12.0, 3.2 Hz, 2H),
2.82 (t, J ¼ 12.0 Hz, 1H), 2.59 (t, J ¼ 11.6 Hz, 1H), 2.54e2.44 (m, 1H),
1.68 (dd, J ¼ 17.6, 8.0 Hz, 1H), 1.62e1.39 (m, 9H). 13C NMR (101 MHz,
J ¼ 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 209.5, 178.6, 157.8,
138.6,137.5,134.7,129.0,128.5,128.3,127.2,127.0,125.4,125.1,121.8,
121.6, 120.5,119.3, 117.8, 112.5, 110.9, 65.3, 62.6, 55.3, 54.3, 41.3, 37.2,
36.2, 34.7, 7.6. nmax (cmꢁ1) ¼ 2920, 1708, 1561, 1455, 1341, 1099, 693,
917, 738, 699; HRMS (ESI) calcd for C31H32N3O [MþH]þ: 462.2540,
Found: 462.2549.
CDCl3)
d 211.3, 178.6, 157.9, 138.6, 137.6, 134.7, 129.0, 128.4, 128.3,
127.2, 127.0, 125.4, 125.1, 121.8, 121.6, 120.5, 119.3, 117.8, 112.5, 110.8,
65.3, 62.7, 55.3, 54.4, 51.4, 41.0, 37.3, 34.6, 28.9, 28.6, 25.8. nmax
(cmꢁ1) ¼ 2963, 2927, 2873, 2807, 1706, 1563, 1454, 1373, 1340, 1097,
1047, 738, 699; HRMS (ESI) calcd for C34H36N3O [MþH]þ: 502.2853,
Found: 502.2859.
4.5.4. 1-((3S,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-3,40-
piperidin]-50-yl)butan-2-one (4 ab0) beige solid,
m.p. ¼ 78.5e80.8 ꢀC, 11.8 mg, 12% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d 8.66 (s, 1H), 7.90 (s, 1H), 7.42e7.35
4.5.8. 2-((3S,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-3,40-
piperidin]-50-yl)-1-cyclopentylethan-1-one (4ad0) beige solid,
m.p. ¼ 79.4e82.4 ꢀC, 15 mg, 15% yield (0.2 mmol scale)
(m, 4H), 7.35e7.28 (m, 3H), 7.26e7.22 (m, 1H), 7.14e7.04 (m, 3H),
7.01e6.95 (m, 1H), 6.95e6.89 (m, 1H), 6.65 (d, J ¼ 2.8 Hz, 1H), 4.01
(dd, J ¼ 12.0, 3.6 Hz, 1H), 3.81 (AB, JAB ¼ 13.2 Hz, 1H), 3.65 (AB,
JBA ¼ 13.2 Hz, 1H), 3.23e3.16 (m, 3H), 2.74 (t, J ¼ 12.0 Hz, 1H),
2.45e2.36 (m, 1H), 2.08e1.95 (m, 1H), 1.94e1.83 (m, 2H), 1.45 (dd,
J ¼ 17.2, 3.2 Hz, 1H), 0.78 (t, J ¼ 7.4 Hz, 3H). 13C NMR (101 MHz,
1H NMR (400 MHz, CDCl3)
d 8.67 (s, 1H), 8.07 (s, 1H), 7.42e7.35
(m, 4H), 7.34e7.27 (m, 3H), 7.26e7.21 (m, 1H), 7.13e7.02 (m, 3H),
6.97 (t, J ¼ 7.0 Hz, 1H), 6.91 (t, J ¼ 7.8 Hz, 1H), 4.01 (dd, J ¼ 12.2,
3.4 Hz, 1H), 3.81 (AB, JAB ¼ 12.8 Hz, 1H), 3.64 (AB, JBA ¼ 13.2 Hz, 1H),
3.23e3.16 (m, 3H), 2.72 (t, J ¼ 12.0 Hz, 1H), 2.46e2.33 (m, 2H), 1.93
(dd, J ¼ 17.4, 8.6 Hz, 1H), 1.63e1.18 (m, 9H). 13C NMR (101 MHz,
CDCl3)
d 209.4, 174.3, 155.0, 140.6, 137.5, 134.9, 129.0, 128.4, 128.1,
127.2, 126.8, 126.5, 122.1, 121.6, 120.7, 120.5, 118.9, 118.5, 113.1, 110.7,
65.7, 62.8, 58.5, 58.0, 40.4, 40.1, 38.4, 36.1, 7.5. nmax (cmꢁ1) ¼ 3052,
2925, 1712, 1548, 1494, 1456, 1373, 1342, 1264, 731, 700; HRMS (ESI)
calcd for C31H32N3O [MþH]þ: 462.2540, Found: 462.2536.
CDCl3)
d 210.9, 174.3, 155.0, 140.6, 137.6, 134.9, 129.0, 128.3, 128.0,
127.2, 126.8, 126.5, 122.1, 121.5, 120.7, 120.5, 118.8, 118.5, 113.0, 110.7,
65.7, 62.8, 58.5, 58.1, 51.3, 40.1, 39.9, 38.1, 28.8, 28.1, 25.8, 25.8. nmax
(cmꢁ1) ¼ 3056, 2949, 2868, 2805, 1705, 1548, 1494, 1455, 1370,
1342, 1263, 1097, 1012, 734, 699; HRMS (ESI) calcd for C34H36N3O
[MþH]þ: 502.2853, Found: 502.2852.
4.5.5. 1-((3R,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-3,40-
piperidin]-50-yl)pentan-2-one (4ac) beige solid,
m.p. ¼ 95.6e97.8 ꢀC, 57.0 mg, 60% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
7.88 (s, 1H), 7.82 (d, J ¼ 7.2 Hz, 1H),
7.67 (s, 1H), 7.58e7.54 (m, 1H), 7.47 (d, J ¼ 7.6 Hz, 1H), 7.43e7.37 (m,
3H), 7.36e7.21 (m, 4H), 7.12e7.02 (m, 3H), 5.64 (d, J ¼ 2.4 Hz, 1H),
4.13 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.83 (AB, JAB ¼ 13.2 Hz, 1H), 3.73 (AB,
JBA ¼ 13.2 Hz, 1H), 3.35e3.26 (m, 1H), 3.08e3.01 (m, 2H), 2.82 (t,
J ¼ 12.0 Hz,1H), 2.58 (t, J ¼ 11.8 Hz,1H), 2.06 (t, J ¼ 7.4, 2H), 1.63 (dd,
J ¼ 17.8, 8.2 Hz, 1H), 1.51 (dd, J ¼ 17.8, 4.2 Hz, 1H), 1.46e1.37 (m, 2H),
4.5.9. 1-((3R,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-3,40-
piperidin]-50-yl)butan-2-one (4ae) beige solid, m.p. ¼ 72.6e74.4 ꢀC,
53.0 mg, 53% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
7.87 (s, 1H), 7.81 (d, J ¼ 7.2 Hz, 1H),
7.68 (s, 1H), 7.57e7.54 (m, 1H), 7.45 (d, J ¼ 7.6 Hz, 1H), 7.42e7.35 (m,
3H), 7.35e7.21 (m, 4H), 7.11e7.03 (m, 3H), 5.63 (d, J ¼ 2.4 Hz, 1H),
4.13 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.82 (AB, JAB ¼ 13.2 Hz, 1H), 3.72 (AB,
JBA ¼ 13.2 Hz, 1H), 3.33e3.25 (m, 1H), 3.06e3.01 (m, 2H), 2.82 (t,
J ¼ 12.0 Hz, 1H), 2.57 (t, J ¼ 11.6 Hz,1H), 2.09e2.02 (m, 2H), 1.62 (dd,
J ¼ 18.0, 8.0 Hz, 1H), 1.50 (dd, J ¼ 17.6, 4.0 Hz, 1H), 1.42e1.33 (m, 2H),
1.26e1.15 (m, 2H), 1.15e1.05 (m, 2H), 0.82 (t, J ¼ 7.2 Hz, 3H). 13C
0.77 (t, J ¼ 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 209.0, 178.6,
157.9,138.6,137.6,134.7,129.0,128.5,128.3,127.2,127.0,125.4,125.1,
121.9, 121.7, 120.5, 119.4, 117.8, 112.5, 110.9, 65.3, 62.6, 55.3, 54.2,
45.0, 41.7, 37.2, 34.6, 17.0, 13.5. nmax (cmꢁ1) ¼ 2959, 2923, 2874,
2807, 1706, 1562, 1455, 1373, 1339, 738, 699; HRMS (ESI) calcd for
C
32H34N3O [MþH]þ: 476.2696, Found: 476.2706.
NMR (101 MHz, CDCl3) d 209.2, 178.6, 157.9, 138.6, 137.6, 134.7,
129.0,128.5,128.3,127.2,127.0,125.4,125.1,121.8,121.7,120.5,119.4,
117.8, 112.5, 110.9, 65.3, 62.6, 55.3, 54.3, 43.1, 41.7, 37.2, 34.6, 31.2,
23.2, 22.3, 13.8. nmax (cmꢁ1) ¼ 2953, 2927, 2870, 1707, 1455, 1372,
1339, 1099, 738, 699; HRMS (ESI) calcd for C34H38N3O [MþH]þ:
504.3009, Found: 504.3016.
4.5.6. 1-((3S,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-3,40-
piperidin]-50-yl)pentan-2-one (4ac0) beige solid,
m.p. ¼ 70.7e73.6 ꢀC, 19.0 mg, 20% yield (0.2 mmol scale)
1H NMR (400 MHz, Chloroform-d)
d 8.67 (s, 1H), 7.92 (s, 1H),
6

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
4.5.10. 1-((3S,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-
3,40-piperidin]-50-yl)butan-2-one (4ae0) beige solid,
(cmꢁ1) ¼ 2928, 2808, 1708, 1456, 1339, 1216, 1098, 909, 736, 699;
HRMS (ESI) calcd for C33H35ClN3O [MþH]þ: 524.2463, Found:
524.2475.
m.p. ¼ 75.2e77.8 ꢀC, 17.0 mg, 17% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d 8.67 (s, 1H), 7.88 (s, 1H), 7.42e7.35
(m, 4H), 7.35e7.27 (m, 3H), 7.26e7.22 (m, 1H), 7.15e7.03 (m, 3H),
6.98 (t, J ¼ 7.0 Hz, 1H), 6.92 (t, J ¼ 7.0 Hz, 1H), 6.65 (d, J ¼ 2.4 Hz, 1H),
4.01 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.81 (AB, JAB ¼ 13.2 Hz, 1H), 3.66 (AB,
JBA ¼ 13.2 Hz,1H), 3.22e3.14 (m, 3H), 2.73 (t, J ¼ 12.2 Hz,1H), 2.40 (t,
J ¼ 11.4 Hz, 1H), 2.02e1.94 (m, 1H), 1.91e1.82 (m, 2H), 1.44 (dd,
J ¼ 17.2, 3.2 Hz, 1H), 1.33e1.11 (m, 4H), 1.07e0.98 (m, 2H), 0.80 (t,
4.5.14. 1-((3S,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-
3,40-piperidin]-50-yl)-3-chloropropan-2-one (4 ag0) brown sticky
oil, 18.9 mg, 18% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d 8.67 (s, 1H), 7.99 (s, 1H), 7.42e7.35
(m, 4H), 7.35e7.28 (m, 3H), 7.27e7.21 (m, 1H), 7.14e7.03 (m, 3H),
6.98 (t, J ¼ 7.0 Hz, 1H), 6.92 (t, J ¼ 7.4 Hz, 1H), 6.64 (d, J ¼ 2.4 Hz, 1H),
4.01 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.79 (AB, JAB ¼ 13.2 Hz, 1H), 3.67 (AB,
JBA ¼ 13.2 Hz, 1H), 3.38 (t, J ¼ 6.4 Hz, 2H), 3.24e3.13 (m, 3H), 2.74 (t,
J ¼ 12.2 Hz, 1H), 2.41 (t, J ¼ 12.4 Hz, 1H), 2.08e1.96 (m, 1H),
1.91e1.86 (m, 2H), 1.56e1.35 (m, 5H). 13C NMR (101 MHz, CDCl3)
J ¼ 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 209.1, 174.3,155.1, 140.6,
137.6,134.9,129.0,128.3,128.1,127.2,126.8,126.5,122.1,121.6,120.7,
120.5, 118.9, 118.5, 113.1, 110.7, 65.7, 62.8, 58.6, 58.0, 43.0, 40.7, 40.1,
38.3, 31.1, 23.2, 22.3, 13.8. nmax (cmꢁ1) ¼ 3058, 3029, 2953, 2928,
1710, 1548, 1494, 1456, 1371, 1342, 1261, 1098, 1067, 1014, 737, 700;
d
208.1, 174.2, 155.0, 140.5, 137.6, 134.9, 129.0, 128.4, 128.1, 127.2,
HRMS (ESI) calcd for
504.3008.
C
34H38N3O [MþH]þ: 504.3009, Found:
126.8, 126.5, 122.2, 121.6, 120.7, 120.6, 118.9, 118.5, 113.0, 110.7, 65.7,
62.8, 58.6, 58.0, 44.5, 41.9, 40.8, 40.1, 38.3, 31.6, 20.7. nmax
(cmꢁ1) ¼ 3048, 2886, 2806, 2766, 1710, 1548, 1493, 1455, 1371, 1341,
1264, 733, 700; HRMS (ESI) calcd for C33H35ClN3O [MþH]þ:
524.2463, Found: 524.2460.
4.5.11. 1-((3R,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-
3,40-piperidin]-50-yl)-3-chloropropan-2-one (4af) beige solid,
m.p. ¼ 70.7e72.8 ꢀC, 51.0 mg, 50% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
7.87 (s, 1H), 7.82 (d, J ¼ 7.2 Hz, 1H),
4.5.15. 2-((3R,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-
3,40-piperidin]-50-yl)-1-phenylethan-1-one (4ah) beige solid,
m.p. ¼ 93.1e95.2 ꢀC, 48.9 mg, 48% yield (0.2 mmol scale)
7.62 (s, 1H), 7.58e7.48 (m, 1H), 7.47 (d, J ¼ 7.6 Hz, 1H), 7.43e7.38 (m,
3H), 7.36e7.23 (m, 4H), 7.15e7.03 (m, 3H), 5.65 (d, J ¼ 2.4 Hz, 1H),
4.13 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.82 (AB, JAB ¼ 13.2 Hz, 1H), 3.74 (AB,
JBA ¼ 13.2 Hz, 1H), 3.50e3.38 (m, 2H), 3.35e3.26 (m, 1H), 3.07e3.01
(m, 2H), 2.83 (t, J ¼ 12.2 Hz, 1H), 2.59 (t, J ¼ 11.8 Hz, 1H), 2.28e2.22
(m, 2H), 1.94e1.83 (m, 2H), 1.66 (dd, J ¼ 17.6, 8.0 Hz, 1H), 1.54 (dd,
1H NMR (400 MHz, CDCl3)
d
7.96 (s, 1H), 7.87 (d, J ¼ 7.6 Hz, 1H),
7.68 (s, 1H), 7.64e7.60 (m, 2H), 7.59e7.54 (m, 1H), 7.50e7.44 (m,
2H), 7.44e7.28 (m, 8H), 7.26e7.22 (m, 1H), 7.13e7.03 (m, 3H), 5.67
(d, J ¼ 2.4 Hz, 1H), 4.16 (dd, J ¼ 12.2, 3.8 Hz, 1H), 3.86 (AB,
JAB ¼ 13.6 Hz, 1H), 3.72 (AB, JBA ¼ 13.2 Hz, 1H), 3.49e3.42 (m, 1H),
3.18 (dd, J ¼ 11.8, 4.2 Hz, 1H), 3.05 (dd, J ¼ 11.6, 3.6 Hz, 1H), 2.85 (t,
J ¼ 12.0 Hz, 1H), 2.68 (t, J ¼ 11.6 Hz, 1H), 2.16e2.12 (m, 2H). 13C NMR
J ¼ 18.0, 4.4 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d 207.7, 178.6, 157.8,
138.5, 137.5, 134.7, 129.0, 128.6, 128.3, 127.3, 127.0, 125.4, 125.2,
121.9, 121.7, 120.5, 119.4, 117.8, 112.5, 110.9, 65.3, 62.7, 55.4, 54.2,
44.3, 41.9, 39.8, 37.2, 34.8, 26.0. nmax (cmꢁ1) ¼ 3337, 2972, 2924,
2887, 1713, 1454, 1377, 1087, 1046, 879, 741, 700; HRMS (ESI) calcd
for C32H33ClN3O [MþH]þ: 510.2307, Found: 510.2314.
(101 MHz, CDCl3)
d 198.4, 178.5, 157.9, 138.7, 137.5, 136.6, 134.7,
133.1, 129.1, 128.6, 128.5, 128.4, 127.9, 127.2, 127.1, 125.5, 125.3, 121.9,
121.8, 120.6, 119.4, 117.9, 112.6, 110.9, 65.5, 62.7, 55.3, 54.4, 37.6, 37.4,
35.2. nmax (cmꢁ1) ¼ 2964, 1679, 1447, 1261, 1094, 1048, 1021, 799,
740, 689; HRMS (ESI) calcd for C35H32N3O [MþH]þ: 510.2540,
Found: 510.2547.
4.5.12. 1-((3S,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-
3,40-piperidin]-50-yl)-3-chloropropan-2-one (4af0) beige solid,
m.p. ¼ 87.5e90.2 ꢀC, 16.0 mg, 16% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
8.68 (s, 1H), 7.93 (s, 1H), 7.42e7.36
4.5.16. 2-((3S,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-
3,40-piperidin]-50-yl)-1-phenylethan-1-one (4ah0) beige solid,
m.p. ¼ 146.2e148.7 ꢀC, 16.3 mg, 16% yield (0.2 mmol scale)
(m, 4H), 7.36e7.29 (m, 3H), 7.28e7.22 (m, 1H), 7.15e7.04 (m, 3H),
6.99 (t, J ¼ 7.0 Hz, 1H), 6.93 (t, 7.0 Hz, 1H), 6.65 (d, J ¼ 2.4 Hz, 1H),
4.02 (dd, J ¼ 12.2, 3.4 Hz, 1H), 3.80 (AB, JAB ¼ 13.2 Hz, 1H), 3.68 (AB,
JBA ¼ 13.2 Hz, 1H), 3.40e3.28 (m, 2H), 3.20e3.15 (m, 3H), 2.75 (t,
J ¼ 12.0 Hz, 1H), 2.42 (t, J ¼ 12.4 Hz, 1H), 2.23e2.15 (m, 1H),
2.06e1.85 (m, 2H), 1.80e1.68 (m, 2H), 1.49 (dd, J ¼ 17.0, 3.8 Hz, 1H).
1H NMR (400 MHz, CDCl3)
d 8.75 (s, 1H), 7.88 (s, 1H), 7.65e7.55
(m, 2H), 7.51e7.43 (m, 2H), 7.38 (d, J ¼ 7.2 Hz, 3H), 7.35e7.27 (m,
5H), 7.27e7.21 (m, 1H), 7.15e7.02 (m, 3H), 6.98 (t, J ¼ 7.0 Hz, 3H),
6.92 (t, J ¼ 7.0 Hz, 3H), 6.68 (d, J ¼ 2.0 Hz, 1H), 4.05 (dd, J ¼ 12.2,
3.4 Hz, 1H), 3.85 (AB, JAB ¼ 13.2 Hz, 1H), 3.64 (AB, JBA ¼ 13.2 Hz, 1H),
3.41e3.28 (m, 2H), 3.20 (dd, J ¼ 12.0, 3.2 Hz,1H), 2.75 (t, J ¼ 12.0 Hz,
1H), 2.54e2.40 (m, 2H), 2.03 (dd, J ¼ 17.0, 2.4 Hz, 1H). 13C NMR
13C NMR (101 MHz, CDCl3)
d 207.5, 174.2, 155.1, 140.5, 137.5, 134.9,
129.0, 128.4, 128.2, 127.2, 126.8, 126.5, 122.2, 121.6, 120.7, 120.6,
118.9, 118.5, 113.0, 110.7, 65.7, 62.8, 58.6, 57.9, 44.2, 41.0, 40.1, 39.6,
38.4, 26.0. nmax (cmꢁ1) ¼ 3421, 3055, 2891, 2805, 2767, 1712, 1548,
1494, 1456, 1372, 1340, 1364, 735, 700; HRMS (ESI) calcd for
(101 MHz, CDCl3) d 198.1,174.3,155.1,140.6,137.5,136.4,134.9,133.1,
129.0, 128.4, 128.3, 128.2, 127.93, 127.2, 126.8, 126.5, 121.9, 121.6,
120.8, 120.6, 118.9, 118.5, 113.1, 110.7, 65.7, 62.8, 58.4, 58.1, 40.2, 38.8,
36.5. nmax (cmꢁ1) ¼ 3055, 2889, 2807, 2765, 1681, 1596, 1455, 1340,
1264, 1097, 1071, 1001, 733, 699; HRMS (ESI) calcd for C35H32N3O
[MþH]þ: 510.2540, Found: 510.2537.
C
32H33ClN3O [MþH]þ: 510.2307, Found: 510.2305.
4.5.13. 1-((3R,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-
3,40-piperidin]-50-yl)-3-chloropropan-2-one (4 ag) brown sticky oil,
56.6 mg, 54% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
7.87 (s, 1H), 7.82 (d, J ¼ 7.2 Hz, 1H),
4.5.17. 1-([1,10-biphenyl]-4-yl)-2-((3R,30S,50R)-10-benzyl-3’-(1H-
indol-3-yl)spiro[indole-3,40-piperidin]-50-yl)ethan-1-one (4ai)
beige solid, m.p. ¼ 83.2e85.3 ꢀC, 58.6 mg, 50% yield (0.2 mmol
scale)
7.68 (s, 1H), 7.58e7.54 (m, 1H), 7.46 (d, J ¼ 7.6 Hz, 1H), 7.42e7.37 (m,
3H), 7.35e7.22 (m, 4H), 7.11e7.04 (m, 3H), 5.64 (d, J ¼ 2.0 Hz, 1H),
4.12 (dd, J ¼ 11.8, 3.4 Hz, 1H), 3.81 (AB, JAB ¼ 13.2 Hz, 1H), 3.73 (AB,
JBA ¼ 13.2 Hz, 1H), 3.43 (t, J ¼ 6.2 Hz, 2H), 3.34e3.21 (m, 1H),
3.06e3.00 (m, 2H), 2.83 (t, J ¼ 12.0 Hz, 1H), 2.58 (t, J ¼ 11.6 Hz, 1H),
2.09 (t, J ¼ 7.0 Hz, 2H), 1.67e1.47 (m, 6H). 13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
d
7.98 (s, 1H), 7.88 (d, J ¼ 7.6 Hz, 1H),
7.72e7.66 (m, 2H), 7.63 (s, 1H), 7.60e7.52 (m, 5H), 7.50e7.37 (m,
7H), 7.32 (t, J ¼ 7.4 Hz, 3H), 7.26e7.20 (m, 1H), 7.15e7.03 (m, 3H),
5.67 (d, J ¼ 2.4 Hz, 1H), 4.18 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.87 (AB,
JAB ¼ 13.2 Hz, 1H), 3.73 (AB, JBA ¼ 13.2 Hz, 1H), 3.52e3.40 (m, 1H),
3.20 (dd, J ¼ 12.0, 4.0 Hz, 1H), 3.06 (dd, J ¼ 12.0, 3.6 Hz, 1H), 2.86 (t,
d
208.3, 178.6, 157.8, 138.5, 137.6, 134.7, 129.0, 128.5, 128.3, 127.2,
127.0, 125.5, 125.2, 121.9, 121.7, 120.5, 119.4, 117.8, 112.5, 110.9, 65.3,
62.6, 55.4, 54.2, 44.5, 42.0, 41.7, 37.2, 34.7, 31.6, 20.7. nmax
7

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
J ¼ 12.0 Hz, 1H), 2.71 (t, J ¼ 11.6 Hz, 1H), 2.16 (d, J ¼ 6.0 Hz, 2H). 13
C
4.5.21. 1-((3R,30S,50R)-10-benzyl-5-fluoro-3’-(5-fluoro-1H-indol-3-
yl)spiro[indole-3,40-piperidin]-50-yl)propan-2-one (4ba) beige solid,
m.p. ¼ 86.2e88.9 ꢀC, 60.9 mg, 63% yield (0.2 mmol scale)
NMR (101 MHz, CDCl3) d 197.9, 178.5, 157.9, 145.7, 139.7, 138.6, 137.5,
135.3, 134.7, 129.0, 128.9, 128.6, 128.5, 128.3, 128.2, 127.2, 127.1,
127.0, 125.5, 125.3, 121.9, 121.8, 120.6, 119.4, 117.9, 112.6, 110.9, 65.5,
62.7, 55.2, 54.4, 37.6, 37.3, 35.3. nmax (cmꢁ1) ¼ 3052, 3032, 2923,
2808, 2361, 2339, 1677, 1602, 1453, 1263, 1097, 989, 731, 698; HRMS
(ESI) calcd for C41H36N3O [MþH]þ: 586.2853, Found: 586.2861.
1H NMR (400 MHz, CDCl3)
d 7.86 (s, 1H), 7.82 (s, 1H), 7.53 (dd,
J ¼ 8.6, 2.2 Hz, 1H), 7.42e7.30 (m, 5H), 7.28e7.24 (m, 1H), 7.16 (dd,
J ¼ 9.6, 2.0 Hz, 1H), 7.08 (td, J ¼ 8.8, 2.0 Hz, 1H), 7.00 (dd, J ¼ 8.8,
4.4 Hz, 1H), 6.80 (td, J ¼ 9.2, 2.4 Hz, 1H), 5.86 (d, J ¼ 2.4 Hz, 1H), 3.99
(dd, J ¼ 12.0, 3.6 Hz, 1H), 3.82 (AB, JAB ¼ 13.2 Hz, 1H), 3.72 (AB,
JBA ¼ 13.2 Hz, 1H), 3.32e3.24 (m, 1H), 3.08 (dd, J ¼ 12.0, 4.0 Hz, 1H),
3.01 (dd, J ¼ 11.8, 3.8 Hz, 1H), 2.76 (t, J ¼ 12.0 Hz, 1H), 2.49 (t,
J ¼ 11.8 Hz, 1H), 1.89 (s, 3H), 1.70 (dd, J ¼ 18.2, 8.2 Hz, 1H), 1.53 (dd,
4.5.18. 1-([1,10-biphenyl]-4-yl)-2-((3S,30S,50R)-10-benzyl-3’-(1H-
indol-3-yl)spiro[indole-3,40-piperidin]-50-yl)ethan-1-one (4ai0)
beige solid, m.p. ¼ 113.1e114.8 ꢀC, 18.7 mg, 16% yield (0.2 mmol
scale)
J ¼ 18.2, 3.8 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d 206.3, 178.3 (d,
J ¼ 3.5 Hz), 160.5 (d, J ¼ 246.0 Hz), 157.8 (d, J ¼ 134.8 Hz), 153.7 (d,
J ¼ 2.3 Hz), 140.3 (d, J ¼ 8.5 Hz), 137.4, 131.2, 128.9, 128.4, 127.3,
122.3, 122.2, 122.1, 115.1 (d, J ¼ 23.5 Hz), 113.2 (d, J ¼ 25.3 Hz), 112.5
(d, J ¼ 4.9 Hz), 111.6 (d, J ¼ 9.7 Hz), 110.5 (d, J ¼ 26.5 Hz), 102.9 (d,
J ¼ 23.9 Hz), 66.0, 62.6, 54.9, 54.0, 42.5, 37.4, 34.4, 30.3. 19F NMR
1H NMR (400 MHz, CDCl3)
d 8.77 (s, 1H), 7.89 (s, 1H), 7.71e7.63
(m, 2H), 7.61e7.52 (m, 4H), 7.49e7.42 (m, 3H), 7.39 (dd, J ¼ 7.7,
1.5 Hz, 4H), 7.34e7.28 (m, 3H), 7.26e7.21 (m, 1H), 7.17e7.03 (m, 3H),
6.99 (t, J ¼ 8.0 Hz, 1H), 6.93 (t, J ¼ 8.0, 1H), 6.68 (d, J ¼ 2.4 Hz, 1H),
4.06 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.86 (AB, JAB ¼ 13.2 Hz, 1H), 3.65 (AB,
JBA ¼ 13.6 Hz, 1H), 3.43e3.30 (m, 2H), 3.21 (dd, J ¼ 11.8, 3.4 Hz, 1H),
2.76 (t, J ¼ 12.2 Hz,1H), 2.54e2.43 (m, 2H), 2.07 (dd, J ¼ 16.8, 2.0 Hz,
(376 MHz, CDCl3)
d
ꢁ115.8 to ꢁ115.7 (m, 1F), ꢁ124.3 to ꢁ124.1 (m,
1F). nmax (cmꢁ1) ¼ 2964, 2899, 1713, 1628, 1585, 1455, 1362, 1257,
1165, 794, 736, 700; HRMS (ESI) calcd for C30H28F2N3O [MþH]þ:
484.2195, Found: 484.2201.
1H). 13C NMR (101 MHz, CDCl3)
d 197.8, 174.3, 155.2, 145.7, 140.7,
139.7, 137.6, 135.1, 134.9, 129.0, 128.9, 128.5, 128.3, 128.2, 127.2,
127.0, 126.8, 126.5, 121.9, 121.6, 120.8, 120.7, 118.9, 118.5, 113.1, 110.7,
65.8, 62.9, 58.5, 58.1, 40.2, 38.9, 36.6. nmax (cmꢁ1) ¼ 3056, 3031,
2923, 2807, 1678, 1603, 1455, 1341, 1267, 1221, 1190, 1098, 998, 739,
699; HRMS (ESI) calcd for C41H36N3O [MþH]þ: 586.2853, Found:
586.2851.
4.5.22. 1-((3S,30S,50R)-10-benzyl-5-fluoro-3’-(5-fluoro-1H-indol-3-
yl)spiro[indole-3,40-piperidin]-50-yl)propan-2-one (4ba0) beige
solid, m.p. ¼ 113.4e115.6 ꢀC, 15.5 mg, 16% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d 8.61 (s, 1H), 8.07 (s, 1H), 7.42e7.37
(m, 2H), 7.36e7.30 (m, 2H), 7.27e7.20 (m, 2H), 7.12 (dd, J ¼ 7.6,
2.4 Hz, 1H), 7.03e6.97 (m, 2H), 6.83e6.72 (m, 2H), 6.69 (d,
J ¼ 2.0 Hz, 1H), 3.85 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.81 (AB, JAB ¼ 13.6 Hz,
1H), 3.65 (AB, JBA ¼ 13.2 Hz, 1H), 3.24 (dd, J ¼ 11.8, 3.0, 1H),
3.18e3.07 (m, 2H), 2.72 (t, J ¼ 12.2 Hz, 1H), 2.37 (t, J ¼ 11.6 Hz, 1H),
1.98 (dd, J ¼ 17.6, 9.6 Hz, 1H), 1.82 (s, 3H), 1.47 (dd, J ¼ 17.6, 2.8 Hz,
4.5.19. 2-((3R,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-
3,40-piperidin]-50-yl)-1-(3,4-dichlorophenyl)ethan-1-one (4aj)
beige solid, m.p. ¼ 89.5e92.3 ꢀC, 49.8 mg, 43% yield (0.2 mmol
scale)
1H). 13C NMR (101 MHz, CDCl3)
d
206.1, 173.9 (d, J ¼ 3.5 Hz),161.9 (d,
J ¼ 248.2 Hz), 157.5 (d, J ¼ 235.7 Hz), 151.0 (d, J ¼ 1.7 Hz), 142.9 (d,
J ¼ 8.7 Hz), 137.4, 131.4, 128.9, 128.4, 127.3, 127.0 (d, J ¼ 9.7 Hz),
122.7, 121.5 (d, J ¼ 9.0 Hz), 115.1 (d, J ¼ 24.0 Hz), 112.8 (d, J ¼ 4.8 Hz),
111.4 (d, J ¼ 9.7 Hz), 110.3 (d, J ¼ 26.5 Hz), 109.7 (d, J ¼ 24.7 Hz),
103.3 (d, J ¼ 24.0 Hz), 66.1 (d, J ¼ 2.1 Hz), 62.7, 58.1, 57.6, 41.5, 40.5,
1H NMR (400 MHz, CDCl3)
d
7.92 (s, 1H), 7.86 (d, J ¼ 7.2 Hz, 1H),
7.66 (s, 1H), 7.60e7.56 (m, 2H), 7.48e7.36 (m, 6H), 7.35e7.30 (m,
3H), 7.27e7.25 (m, 1H), 7.13e7.05 (m, 3H), 5.66 (d, J ¼ 2.4 Hz, 1H),
4.17 (dd, J ¼ 12.2, 3.8 Hz, 1H), 3.84 (AB, JAB ¼ 13.2 Hz, 1H), 3.75 (AB,
JBA ¼ 13.2 Hz, 1H), 3.49e3.48 (m, 1H), 3.14e3.05 (m, 2H), 2.87 (t,
J ¼ 11.8 Hz, 1H), 2.68 (t, J ¼ 11.8 Hz, 1H), 2.11e2.06 (m, 2H). 13C NMR
38.0, 30.1. 19F NMR (376 MHz, CDCl3)
d
ꢁ114.28 to ꢁ114.33 (m,
1F), ꢁ124.4 to ꢁ124.5 (m, 1F). nmax (cmꢁ1) ¼ 2917, 2856, 1713, 1631,
(101 MHz, CDCl3)
d 196.1, 178.4, 157.9, 138.4, 137.7, 136.2, 134.8,
1583, 1486, 1358, 1259, 1168, 791, 700, 668; HRMS (ESI) calcd for
C
30H28F2N3O [MþH]þ: 484.2195, Found: 484.2208.
133.2, 130.6, 129.9, 129.0, 128.7, 128.4, 127.3, 127.1, 126.9, 125.5,
125.4, 122.0, 121.9, 120.6, 119.5, 117.9, 112.5, 110.9, 65.5, 62.7, 55.4,
54.3, 37.6, 37.4, 35.3. nmax (cmꢁ1) ¼ 3059, 2924, 2810, 1685, 1583,
1557, 1456, 1387, 1265, 1216, 1029, 736, 700; HRMS (ESI) calcd for
4.5.23. 1-((3R,30S,50R)-10-benzyl-5-bromo-3’-(5-bromo-1H-indol-
3-yl)spiro[indole-3,40-piperidin]-50-yl)propan-2-one (4ca) beige
solid, m.p. ¼ 72.4e74.6 ꢀC, 77.5 mg, 64% yield (0.2 mmol scale)
C
35H30Cl2N3O [MþH]þ: 578.1760, Found: 578.1767.
1H NMR (400 MHz, CDCl3)
d 7.93 (s, 1H), 7.88 (s, 2H), 7.63 (d,
J ¼ 1.8 Hz, 1H), 7.53 (d, J ¼ 8.0 Hz, 1H), 7.43e7.32 (m, 4H), 7.30e7.24
(m, 2H), 7.12 (d, J ¼ 8.8 Hz, 1H), 6.93 (d, J ¼ 8.4 Hz, 1H), 5.81 (d,
J ¼ 2.0 Hz, 1H), 4.00 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.83 (AB, JAB ¼ 13.2 Hz,
1H), 3.74 (AB, JBA ¼ 13.6 Hz, 1H), 3.33e3.24 (m, 1H), 3.06 (dd,
J ¼ 12.0, 4.0 Hz, 1H), 3.00 (dd, J ¼ 12.0, 3.6 Hz, 1H), 2.78 (t,
J ¼ 12.2 Hz, 1H), 2.50 (t, J ¼ 11.6 Hz, 1H), 1.89 (s, 3H), 1.72 (dd,
J ¼ 18.0, 8.0 Hz, 1H), 1.52 (dd, J ¼ 18.4, 4.0 Hz, 1H). 13C NMR
4.5.20. 2-((3S,30S,50R)-10-benzyl-3’-(1H-indol-3-yl)spiro[indole-
3,40-piperidin]-50-yl)-1-(3,4-dichlorophenyl)ethan-1-one (4aj0)
beige solid, m.p. ¼ 128.0e130.2 ꢀC, 10.4 mg, 16% yield (0.2 mmol
scale)
1H NMR (400 MHz, CDCl3)
d 8.73 (s, 1H), 7.95e8.01 (m, 1H), 7.62
(s, 1H), 7.43 (d, J ¼ 7.6 Hz, 1H), 7.39e7.34 (m, 4H), 7.34e7.21 (m, 5H),
7.12 (t, J ¼ 7.4 Hz,1H), 7.08e7.02 (m, 2H), 6.98 (t, J ¼ 7.4 Hz,1H), 6.92
(t, J ¼ 7.4 Hz, 1H), 6.65 (s, 1H), 4.04 (dd, J ¼ 12.2, 3.0 Hz, 1H), 3.82
(AB, JAB ¼ 13.2 Hz, 1H), 3.66 (AB, JBA ¼ 13.2 Hz, 1H), 3.34e3.15 (m,
3H), 2.76 (t, J ¼ 12.2 Hz, 1H), 2.48 (t, J ¼ 12.4 Hz, 1H), 2.35 (dd,
J ¼ 16.6, 9.4 Hz, 1H), 2.00 (dd, J ¼ 16.6, 2.4 Hz, 1H). 13C NMR
(101 MHz, CDCl3)
d 206.2, 178.9, 156.6, 140.7, 137.3, 133.3, 131.7,
128.9, 128.6, 128.5, 128.4, 127.3, 124.9, 122.9, 121.9, 120.5, 119.2,
112.9, 112.4, 111.9, 66.0, 62.4, 54.9, 54.0, 42.5, 37.3, 34.4, 30.3. nmax
(cmꢁ1) ¼ 2964, 2899, 2807, 1712, 1557, 1442, 1363, 1260, 1149, 1025,
882, 795, 736, 699; HRMS (ESI) calcd for C30H28Br2N3O [MþH]þ:
604.0594, Found: 604.0595.
(101 MHz, CDCl3)
d 196.0, 174.1, 155.0, 140.4, 137.6, 137.4, 135.7,
134.9, 133.0, 130.5, 129.9, 129.0, 128.3, 127.2, 126.9, 126.7, 126.6,
122.0, 121.6, 120.8, 120.7, 118.9, 118.4, 110.7, 65.7, 62.8, 58.5, 57.9,
40.1, 39.0, 36.6. nmax (cmꢁ1) ¼ 3052, 2809, 1687, 1583, 1553, 1456,
1264, 1030, 1010, 908, 730, 700; HRMS (ESI) calcd for C35H30Cl2N3O
[MþH]þ: 578.1760, Found: 578.1763.
4.5.24. 1-((3S,30S,50R)-10-benzyl-5-bromo-3’-(5-bromo-1H-indol-
3-yl)spiro[indole-3,40-piperidin]-50-yl)propan-2-one (4ca0) beige
solid, m.p. ¼ 143.3e146.0 ꢀC, 25.4 mg, 21% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3
d 8.57 (s, 1H), 7.91 (s, 1H), 7.61 (d,
8

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
J ¼ 1.6 Hz, 1H), 7.45 (d, J ¼ 1.2 Hz, 1H), 7.42e7.37 (m, 2H), 7.34 (t,
J ¼ 7.4 Hz, 2H), 7.27e7.24 (m, 2H), 7.14 (d, J ¼ 8.4 Hz, 1H), 7.08 (dd,
J ¼ 8.6, 1.8 Hz, 1H), 6.95 (d, J ¼ 8.4 Hz, 1H), 6.65 (d, J ¼ 2.4 Hz, 1H),
3.86 (dd, J ¼ 17.2, 3.6 Hz, 1H), 3.82 (AB, JAB ¼ 13.6 Hz, 1H), 3.64 (AB,
JBA ¼ 13.2 Hz, 1H), 3.30e3.21 (m, 1H), 3.19e3.05 (m, 2H), 2.71 (t,
J ¼ 12.0 Hz, 1H), 2.36 (t, J ¼ 11.6 Hz, 1H), 1.99 (dd, J ¼ 17.8, 9.8 Hz,
1H), 1.85 (s, 3H), 1.49 (dd, J ¼ 17.8, 2.6 Hz, 1H). 13C NMR (101 MHz,
4.5.28. 1-((3S,30S,50R)-10-benzyl-6-methyl-3’-(6-methyl-1H-indol-
3-yl)spiro[indole-3,40-piperidin]-50-yl)propan-2-one (4ea0) beige
solid, m.p. ¼ 88.5e90.7 ꢀC, 11.4 mg, 12% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d 8.63 (s, 1H), 7.75 (s, 1H), 7.40e7.20
(m, 7H), 7.13 (s, 1H), 6.92 (d, J ¼ 7.2 Hz, 1H), 6.83 (s, 1H), 6.77 (dd,
J ¼ 8.4, 0.8 Hz, 1H), 6.54 (d, J ¼ 2.4 Hz, 1H), 3.95 (dd, J ¼ 12.2, 3.8 Hz,
1H), 3.78 (AB, JAB ¼ 13.2 Hz, 1H), 3.64 (AB, JBA ¼ 13.2 Hz, 1H),
3.25e3.02 (m, 3H), 2.70 (t, J ¼ 12.0 Hz, 1H), 2.35 (t, J ¼ 11.6 Hz, 1H),
2.31 (s, 3H), 2.21 (s, 3H), 1.91 (dd, J ¼ 17.6, 9.6 Hz, 1H), 1.75 (s, 3H),
CDCl3)
d 206.1, 174.4, 154.0, 142.9, 137.6, 133.5, 131.5, 128.8, 128.4,
128.3, 127.3, 125.5, 124.8, 122.1, 121.9, 121.23, 120.9, 112.6, 112.4,
112.1, 66.1, 62.6, 57.9, 57.6, 41.5, 40.3, 37.8, 30.1. nmax (cmꢁ1) ¼ 2923,
2809, 2361, 1714, 1452, 1356, 1261, 1168, 1100, 883, 823, 795, 737,
701; HRMS (ESI) calcd for C30H28Br2N3O [MþH]þ: 604.0594, Found:
604.0594.
1.46 (dd, J ¼ 17.4, 3.0 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d 206.8,
174.5,155.5,138.0,137.7,135.5,131.3,129.0,128.4,127.4,127.2,124.8,
121.5, 121.3, 120.8, 120.1, 118.2, 113.1, 110.7, 65.2, 62.8, 58.8, 58.0,
41.7, 40.2, 38.7, 30.1, 21.5, 21.4. nmax (cmꢁ1) ¼ 2919, 2806, 1714, 1588,
1548, 1453, 1365, 1264, 1159, 1096, 799, 731, 699; HRMS (ESI) calcd
for C32H34N3O [MþH]þ: 476.2696, Found: 476.2695.
4.5.25. 1-((3R,30S,50R)-10-benzyl-5-methyl-3’-(5-methyl-1H-indol-
3-yl)spiro[indole-3,40-piperidin]-50-yl)propan-2-one (4da) beige
solid, m.p. ¼ 81.6e84.1 ꢀC, 57.1 mg, 60% yield (0.2 mmol scale)
4.6. General procedure for the preparation of 6
1H NMR (400 MHz, CDCl3)
d 7.80 (s, 1H), 7.52 (m, 2H), 7.43e7.30
To a stirred solution of tryptamine derivative (0.2 mmol) and 2
(0.24 mmol) in acetone (4 mL) was added K2CO3 (0.4 mmol, 55 mg)
and KI (0.24 mmol, 40 mg) at room temperature. The reaction
mixture was stirred overnight. After the reaction was complete
(monitored by TLC), the crude reaction mixture was filtrated with
Celite and washed with DCM. The solvent was removed under
reduced pressure. Then the residue was resolved in DCM and
washed with water. The organic layer was dried over Na2SO4, and
concentrated.
To a stirred solution of this residue was added silica gel
(300e400 mesh, 100 mg) in toluene (4 mL). The reaction mixture
was stirred overnight at room temperature. After completion, the
residue was filtered and concentrated. The residue was purified by
silica gel flash column chromatography (hexanes/EtOAc ¼ 2/1 to 1/
2) to afford the product.
(m, 6H), 7.29e7.24 (m,1H), 7.19 (d, J ¼ 8.0 Hz,1H), 7.00 (d, J ¼ 8.4 Hz,
1H), 6.89 (d, J ¼ 8.4, 1H), 5.59 (d, J ¼ 2.4 Hz, 1H), 4.07 (dd, J ¼ 12.0,
3.6 Hz, 1H), 3.86 (AB, JAB ¼ 13.6 Hz, 1H), 3.76 (AB, JBA ¼ 13.2 Hz, 1H),
3.29e3.22 (m, 1H), 3.08e2.98 (m, 2H), 2.81 (t, J ¼ 12.0 Hz, 1H), 2.58
(t, J ¼ 11.6 Hz, 1H), 2.45 (s, 3H), 2.42 (s, 3H), 1.89 (s, 3H), 1.66 (dd,
J ¼ 18.2, 8.2 Hz, 1H), 1.55 (dd, J ¼ 18.0, 4.0 Hz, 1H). 13C NMR
(101 MHz, CDCl3)
d 206.8, 177.7, 155.7, 138.8, 137.4, 134.9, 133.1,
129.1, 128.5, 128.3, 127.2, 126.4, 123.5, 121.1, 120.6, 117.6, 112.2, 110.5,
64.8, 62.5, 55.0, 53.9, 42.5, 37.4, 34.7, 30.3, 21.8, 21.5. nmax
(cmꢁ1) ¼ 2918, 2361, 1713, 1563, 1454, 1364, 1262, 1166, 1097, 1027,
796, 734, 700; HRMS (ESI) calcd for C32H34N3O [MþH]þ: 476.2696,
Found: 476.2703.
4.5.26. 1-((3S,30S,50R)-10-benzyl-5-methyl-3’-(5-methyl-1H-indol-
3-yl)spiro[indole-3,40-piperidin]-50-yl)propan-2-one (4da0) beige
solid, m.p. ¼ 88.0e91.6 ꢀC, 14.3 mg, 15% yield (0.2 mmol scale)
4.6.1. 1-((3S,30R)-10-benzylspiro[indole-3,40-piperidin]-30-yl)
propan-2-one (6aa) beige solid, m.p. ¼ 99.1e101.4 ꢀC, 59.2 mg, 89%
yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d 8.59 (s, 1H), 7.88 (s, 1H), 7.48e7.40
(m, 2H), 7.36 (t, J ¼ 7.4 Hz, 2H), 7.31e7.23 (m, 2H), 7.21 (d, J ¼ 7.6 Hz,
1H), 7.14 (s, 1H), 6.98 (d, J ¼ 8.0 Hz, 1H), 6.91 (d, J ¼ 7.6 Hz, 1H), 6.83
(d, J ¼ 8.4, 1H), 6.61 (d, J ¼ 2.4, 1H), 3.98 (dd, J ¼ 12.2, 3.4 Hz, 1H),
3.84 (AB, JAB ¼ 13.2 Hz, 1H), 3.67 (AB, JBA ¼ 13.2 Hz, 1H), 3.31e3.07
(m, 3H), 2.70 (t, J ¼ 12.0 Hz,1H), 2.43e2.35 (m, 3H), 2.33 (s, 3H),1.99
(dd, J ¼ 17.6, 9.6 Hz, 1H), 1.81 (s, 3H), 1.52 (dd, J ¼ 17.6, 2.8 Hz, 1H).
1H NMR (400 MHz, CDCl3)
d
7.91 (s, 1H), 7.65 (t, J ¼ 7.4 Hz, 2H),
7.45e7.32 (m, 5H), 7.31e7.19 (m, 2H), 3.75 (AB, JAB ¼ 13.2 Hz, 1H),
3.62 (AB, JBA ¼ 13.2 Hz, 1H), 3.06e2.83 (m, 3H), 2.56 (td, J ¼ 12.2,
2.6 Hz, 1H), 2.42e2.28 (m, 2H), 1.87 (s, 3H), 1.71 (dd, J ¼ 18.4, 7.9 Hz,
1H), 1.54 (dd, J ¼ 17.4, 3.6 Hz, 1H), 1.28 (dt, J ¼ 13.4, 2.7 Hz, 1H). 13
C
13C NMR (101 MHz, CDCl3)
d 206.8, 173.4, 153.1, 140.8, 137.8, 136.4,
NMR (101 MHz, CDCl3)
d 206.7, 179.1, 156.3, 140.2, 137.9, 128.9,
133.3,128.9,128.7, 128.3,127.9,127.2,127.1,123.1,122.9,120.7,120.0,
118.3, 112.7, 110.3, 65.1, 62.7, 58.4, 57.9, 41.6, 40.1, 38.4, 30.1, 21.5.
nmax (cmꢁ1) ¼ 3029, 2913, 2805, 2767, 1713, 1546, 1467, 1452, 1357,
1321, 1166, 1095, 820, 795, 734, 700; HRMS (ESI) calcd for
128.3, 127.1, 125.4, 124.7, 121.7, 62.9, 59.5, 54.8, 48.4, 42.5, 33.4, 30.3,
29.7. IR (thin film): nmax (cmꢁ1) ¼ 2929, 2906, 2828, 2813, 1712,
1560, 1468, 1451, 1417, 1370, 1356, 1331, 1318, 1178, 961, 776, 754,
710; HRMS (ESI) calcd for C22H25N2O [MþH]þ: 333.1961, Found:
333.1965.
C
32H34N3O [MþH]þ: 476.2696, Found: 476.2693.
4.5.27. 1-((3R,30S,50R)-10-benzyl-6-methyl-3’-(6-methyl-1H-indol-
3-yl)spiro[indole-3,40-piperidin]-50-yl)propan-2-one (4ea) beige
solid, m.p. ¼ 104.7e106.6 ꢀC, 58.0 mg, 61% yield (0.2 mmol scale)
4.6.2. 1-((3S,30R)-10-benzylspiro[indole-3,40-piperidin]-30-yl)butan-
2-one (6 ab) brown oil, 57.5 mg, 83% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
7.90 (s, 1H), 7.65 (t, J ¼ 7.0, 2H),
1H NMR (400 MHz, CDCl3)
d
7.84 (s, 1H), 7.64 (d, J ¼ 7.6 Hz, 1H),
7.43e7.31 (m, 5H), 7.30e7.19 (m, 2H), 3.76 (AB, JAB ¼ 13.2 Hz, 1H),
3.62 (AB, JBA ¼ 13.2 Hz, 1H), 3.08e2.83 (m, 3H), 2.56 (td, J ¼ 12.2,
2.6 Hz, 1H), 2.44e2.28 (m, 2H), 2.08 (q, J ¼ 7.3 Hz, 2H), 1.69 (dd,
J ¼ 17.2, 8.0 Hz,1H),1.53 (dd, J ¼ 17.6, 4.6 Hz,1H),1.27 (d, J ¼ 12.8 Hz,
7.45e7.42 (m, 2H), 7.40e7.37 (m, 2H), 7.35e7.29 (m, 3H), 7.26e7.22
(m, 1H), 7.07 (d, J ¼ 7.2 Hz, 1H), 6.93e6.88 (m, 2H), 5.59 (d,
J ¼ 2.0 Hz, 1H), 4.07 (dd, J ¼ 12.0, 3.6 Hz, 1H), 3.81 (AB, JAB ¼ 13.2 Hz,
1H), 3.72 (AB, JBA ¼ 13.2 Hz, 1H), 3.28e3.21 (m, 1H), 3.06e3.00 (m,
2H), 2.78 (t, J ¼ 12.0 Hz, 1H), 2.53 (t, J ¼ 11.6 Hz, 1H), 2.42 (s, 4H),
2.37 (s, 3H), 1.88 (s, 3H), 1.64 (dd, J ¼ 18.2, 8.2 Hz, 1H), 1.53 (dd,
1H), 0.88 (t, J ¼ 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 209.4, 179.1,
156.2, 140.2, 137.8, 128.9, 128.2, 127.1, 125.3, 124.7, 121.7, 62.9, 59.5,
54.9, 48.4, 41.3, 36.2, 33.5, 29.9, 7.5. nmax (cmꢁ1) ¼ 2910, 1710, 1559,
1455, 1374, 1114, 1079, 990, 961, 752, 711; HRMS (ESI) calcd for
J ¼ 18.0, 3.6 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d 206.8, 178.7, 158.2,
138.5, 137.6, 135.5, 135.1, 131.7, 129.0, 128.3, 127.2, 125.9, 125.0,
122.4, 121.2, 119.9, 117.5, 112.6, 110.9, 110.0, 64.9, 62.6, 55.5, 54.2,
42.5, 37.3, 34.6, 30.3, 21.5. nmax (cmꢁ1) ¼ 2914, 2806, 1711, 1620,
1560, 1452, 1339, 1157, 1099, 1050, 798, 748, 699, 664; HRMS (ESI)
calcd for C32H34N3O [MþH]þ: 476.2696, Found: 476.2706.
C
23H27N2O [MþH]þ: 347.2118, Found: 347.2124.
4.6.3. 1-((3S,30R)-10-benzylspiro[indole-3,40-piperidin]-30-yl)
pentan-2-one (6ac) brown oil, 57.0 mg, 79% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
7.90 (s, 1H), 7.65 (t, J ¼ 7.0 Hz, 2H),
9

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
7.42e7.33 (m, 5H), 7.30e7.21 (m, 2H), 3.75 (AB, JAB ¼ 13.2 Hz, 1H),
3.62 (AB, JBA ¼ 13.2 Hz, 1H), 3.04e2.86 (m, 3H), 2.56 (td, J ¼ 12.4,
2.8 Hz, 1H), 2.40e2.27 (m, 2H), 2.05 (t, J ¼ 7.4 Hz, 2H), 1.68 (dd,
J ¼ 17.8, 8.2 Hz, 1H), 1.52 (dd, J ¼ 17.6, 4.4 Hz, 1H), 1.45e1.36 (m, 2H),
1.29e1.26 (m,1H), 0.77 (t, J ¼ 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
1363, 736, 699; HRMS (ESI) calcd for C25H30ClN2O [MþH]þ:
409.2041, Found: 409.2049.
4.6.8. 2-((3S,30R)-10-benzylspiro[indole-3,40-piperidin]-30-yl)-1-
phenylethan-1-one (6ah) brown oil, 67.1 mg, 85% yield (0.2 mmol
scale)
d
209, 179.1, 156.2, 140.2, 137.8, 128.9, 128.2, 127.1, 125.3, 124.7, 121.7,
63.0, 59.5, 54.8, 48.43, 45.0, 41.7, 33.5, 29.7, 16.9, 13.5. nmax
(cmꢁ1) ¼ 2931, 2806, 1711, 1560, 1494, 1453, 1361, 1270, 1125, 1068,
1021, 962, 912, 735, 698; HRMS (ESI) calcd for C24H29N2O [MþH]þ:
361.2274, Found: 361.2284.
1H NMR (400 MHz, CDCl3)
d
7.98 (s, 1H), 7.69 (d, J ¼ 7.6 Hz, 1H),
7.67e7.59 (m, 3H), 7.48 (t, J ¼ 7.6 Hz, 1H), 7.44e7.30 (m, 7H),
7.30e7.22 (m, 2H), 3.78 (AB, JAB ¼ 13.2 Hz, 1H), 3.61 (AB,
JBA ¼ 13.2 Hz, 1H), 3.25e3.12 (m, 1H), 3.06 (dd, J ¼ 11.6, 4.0 Hz, 1H),
2.90 (dt, J ¼ 12.0, 4.0 Hz, 1H), 2.59 (td, J ¼ 12.4, 2.4 Hz, 1H), 2.49 (t,
J ¼ 11.4 Hz, 1H), 2.37 (td, J ¼ 13.2, 4.4 Hz, 1H), 2.29e2.07 (m, 2H),
4.6.4. 2-((3S,30R)-10-benzylspiro[indole-3,40-piperidin]-30-yl)-1-
cyclopentylethan-1-one (6ad) brown oil, 69.6 mg, 90% yield
(0.2 mmol scale)
1.38e1.23 (m, 1H). 13C NMR (101 MHz, CDCl3)
d 198.4, 179.0, 156.3,
1H NMR (400 MHz, CDCl3)
d
7.91 (s, 1H), 7.65 (d, J ¼ 8.0, 2H),
140.3, 137.8, 136.6, 133.1, 129.0, 128.4, 128.3, 128.3, 127.9, 127.1,
125.5, 124.8, 121.9, 63.0, 59.7, 55.1, 48.4, 37.6, 34.1, 29.9. nmax
(cmꢁ1) ¼ 2912, 2806, 1682, 1448, 1344, 1271, 1220, 990, 909, 730,
689; HRMS (ESI) calcd for C27H27N2O [MþH]þ: 395.2118, Found:
395.2125.
7.42e7.32 (m, 5H), 7.30e7.19 (m, 2H), 3.75 (AB, JAB ¼ 13.2 Hz, 1H),
3.62 (AB, JBA ¼ 13.2 Hz, 1H), 3.06e3.00 (m, 1H), 2.93e2.87 (m, 2H),
2.60e2.45 (m, 2H), 2.42e2.30 (m, 2H), 1.77e1.44 (m, 10H), 1.27 (m,
1H). 13C NMR (101 MHz, CDCl3)
d 211.1, 179.2, 156.3, 140.2, 137.9,
128.9,128.2,127.1,125.3,124.7, 121.6, 63.0, 59.6, 55.0, 51.3, 48.4, 41.1,
33.4, 29.8, 28.5, 25.7. nmax (cmꢁ1) ¼ 2946, 1706, 1560, 1451, 1368,
1025, 963, 747, 698, 655; HRMS (ESI) calcd for C26H31N2O [MþH]þ:
387.2431, Found: 387.2442.
4.6.9. 1-([1,10-biphenyl]-4-yl)-2-((3S,30R)-10-benzylspiro[indole-
3,40-piperidin]-30-yl)ethan-1-one (6ai) brown oil, 77.2 mg, 82%
yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d 8.00 (s, 1H), 7.74e7.63 (m, 4H),
4.6.5. 1-((3S,30R)-10-benzylspiro[indole-3,40-piperidin]-30-yl)butan-
7.59e7.53 (m, 4H), 7.48e7.31 (m, 8H), 7.30e7.24 (m, 2H), 3.79 (AB,
JAB ¼ 13.2 Hz, 1H), 3.62 (AB, JBA ¼ 13.2 Hz, 1H), 3.28e3.15 (m, 1H),
3.08 (dd, J ¼ 11.7, 4.1 Hz, 1H), 2.91 (dt, J ¼ 12.0, 3.6 Hz, 1H),
2.64e2.55 (m, 1H), 2.51 (t, J ¼ 11.4 Hz, 1H), 2.43e2.33 (m, 1H),
2.22e2.14 (m, 1H), 1.37e1.21 (m, 1H). 13C NMR (101 MHz, CDCl3)
2-one (6ae) brown oil, 60.0 mg, 80% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d 7.90 (s, 1H), 7.65 (t, 6.8 Hz, 2H),
7.42e7.33 (m, 5H), 7.29e7.21 (m, 2H), 3.75 (AB, JAB ¼ 13.2 Hz, 1H),
3.62 (AB, JBA ¼ 13.2 Hz, 1H), 3.04e2.87 (m, 3H), 2.56 (td, J ¼ 14.0,
2.0 Hz, 1H), 2.40e2.30 (m, 2H), 2.06 (t, J ¼ 7.4 Hz, 2H), 1.68 (dd,
J ¼ 17.6, 7.6 Hz, 1H), 1.52 (dd, J ¼ 17.6, 3.6 Hz, 1H), 1.41e1.33 (m, 2H),
1.29e1.17 (m, 3H), 1.14e1.06 (m, 2H), 0.83 (t, J ¼ 7.2 Hz, 3H). 13C
d
198.0, 179.1, 156.4, 145.7, 140.4, 139.8, 137.9, 135.4, 129.1, 128.9,
128.5, 128.4, 128.3, 128.2, 127.2, 127.2, 127.1, 125.6, 124.9, 121.9, 63.1,
59.8, 55.2, 48.5, 37.6, 34.3, 29.9. nmax (cmꢁ1) ¼ 3059, 2910, 2806,
1678, 1602, 1559, 1449, 1403, 1344, 991, 907, 727, 696; HRMS (ESI)
calcd for C33H31N2O [MþH]þ: 471.2431, Found: 471.2434.
NMR (101 MHz, CDCl3)
d 209.2, 179.2, 156.3, 140.3, 137.9, 128.9,
128.3, 127.1, 125.4, 124.8, 121.7, 63.0, 59.6 54.9, 48.5, 43.1, 41.7, 33.5,
31.1, 29.7, 23.2, 22.3, 13.8. nmax (cmꢁ1) ¼ 2927, 2806, 1711, 1560,
1453, 1362, 1269, 1109, 1073, 1025, 962, 912, 742, 698; HRMS (ESI)
calcd for C26H33N2O [MþH]þ: 389.2587, Found: 389.2579.
4.6.10. 2-((3S,30R)-10-benzylspiro[indole-3,40-piperidin]-30-yl)-1-
(3,4-dichlorophenyl)ethan-1-one (6aj) brown oil, 60.2 mg, 65% yield
(0.2 mmol scale)
4.6.6. 1-((3S,30R)-10-benzylspiro[indole-3,40-piperidin]-30-yl)-3-
chloropropan-2-one (6af) brown oil, 53.7 mg, 68% yield (0.2 mmol
scale)
1H NMR (400 MHz, CDCl3)
d 7.96 (s, 1H), 7.71e7.61 (m, 3H),
7.46e7.31 (m, 7H), 7.31e7.27 (m, 2H), 3.76 (AB, JAB ¼ 13.2 Hz, 1H),
3.64 (AB, JBA ¼ 13.2 Hz, 1H), 3.21e3.11 (m, 1H), 2.99 (dd, J ¼ 11.6,
4.4 Hz, 1H), 2.92 (d, J ¼ 11.6 Hz, 1H), 2.61 (t, J ¼ 12.0 Hz, 1H), 2.47 (t,
J ¼ 11.4 Hz, 1H), 2.42e2.31 (m, 1H), 2.22e2.03 (m, 2H), 1.38e1.29
1H NMR (400 MHz, CDCl3)
d
7.90 (s, 1H), 7.65 (t, J ¼ 8.0 Hz, 2H),
7.43e7.33 (m, 5H), 7.29e7.22 (m, 2H), 3.74 (AB, JAB ¼ 13.2 Hz, 1H),
3.63 (AB, JBA ¼ 13.2 Hz, 1H), 3.48e3.39 (m, 2H), 3.06e2.96 (m, 1H),
2.94e2.88 (m, 2H), 2.57 (td, J ¼ 12.0, 2.4 Hz, 1H), 2.42e2.30 (m, 2H),
2.27e2.23 (m, 2H), 1.91e1.84 (m, 2H), 1.72 (dd, J ¼ 17.4, 7.4 Hz, 1H),
1.57 (dd, J ¼ 17.8, 4.2 Hz, 1H), 1.34e1.23 (m, 1H). 13C NMR (101 MHz,
(m, 1H). 13C NMR (101 MHz, CDCl3)
d 196.2,179.0,156.2,140.0,137.8,
137.7,136.1,133.1,130.6,129.9,129.0,128.5,128.3,127.2,126.9,125.7,
124.8, 122.0, 63.0, 59.7, 54.9, 48.6, 37.6, 34.2, 29.8. nmax
(cmꢁ1) ¼ 2929, 2910, 2807, 2772, 1684, 1583, 1555, 1265, 1028, 736,
698; HRMS (ESI) calcd for C27H25Cl2N2O [MþH]þ:463.1338, Found:
463.1343.
CDCl3)
d 207.6, 179.1, 156.2, 140.0, 137.9, 128.9, 128.2, 127.1, 125.4,
124.7, 121.7, 62.9, 59.5, 54.7, 48.5, 44.2, 41.9, 39.7, 33.6, 29.7, 25.9.
nmax (cmꢁ1) ¼ 2913, 2807, 2767, 1712, 1560, 1494, 1451, 1361, 746,
699; HRMS (ESI) calcd for C24H28ClN2O [MþH]þ:395.1885, Found:
395.1892.
4.6.11. 1-((3S,30R)-10-benzyl-5-chlorospiro[indole-3,40-piperidin]-
30-yl)propan-2-one (6ba) brown oil, 63.8 mg, 87% yield (0.2 mmol
scale)
4.6.7. 1-((3S,30R)-10-benzylspiro[indole-3,40-piperidin]-30-yl)-3-
chloropropan-2-one (6 ag) brown oil, 62.2 mg, 76% yield (0.2 mmol
scale)
1H NMR (400 MHz, CDCl3)
d 7.90 (s, 1H), 7.62e7.55 (m, 2H),
1H NMR (400 MHz, CDCl3)
d
7.90 (s, 1H), 7.64 (t, J ¼ 7.4 Hz, 2H),
7.41e7.32 (m, 5H), 7.31e7.27 (m, 1H), 3.75 (AB, JAB ¼ 13.2 Hz, 1H),
3.63 (AB, JBA ¼ 13.2 Hz, 1H), 3.05e2.85 (m, 3H), 2.50 (td, J ¼ 12.4,
2.4 Hz, 1H), 2.37e2.26 (m, 2H), 1.89 (s, 3H), 1.80e1.70 (m, 1H), 1.53
(dd, J ¼ 18.0, 3.8 Hz, 1H), 1.33e1.25 (m, 1H). 13C NMR (101 MHz,
7.44e7.31 (m, 5H), 7.30e7.19 (m, 2H), 3.74 (AB, JAB ¼ 13.2 Hz, 1H),
3.63 (AB, JBA ¼ 13.2 Hz, 1H), 3.43 (t, J ¼ 6.4 Hz, 2H), 3.05e2.97 (m,
1H), 2.93e2.88 (m, 2H), 2.57 (td, J ¼ 12.0, 2.4 Hz, 1H), 2.43e2.28 (m,
2H), 2.09 (t, J ¼ 7.0 Hz, 2H), 1.77e1.46 (m, 6H), 1.34e1.24 (m, 1H). 13
C
CDCl3) d 206.3, 179.4, 154.7, 142.0, 137.7, 131.3, 128.9, 128.4, 128.3,
NMR (101 MHz, CDCl3)
d
208.2,179.1,156.2,140.1,137.8,129.0,128.3,
127.2, 125.1, 122.5, 62.8, 60.1, 54.7, 48.4, 42.5, 33.4, 30.3, 29.6. nmax
(cmꢁ1) ¼ 2914, 2807, 2767, 1715, 1557, 1443, 1413, 1355, 1147, 826,
734, 699; HRMS (ESI) calcd for C22H24ClN2O [MþH]þ: 367.1572,
Found: 367.1578.
128.3,127.2, 125.4,124.7, 121.7, 62.9, 59.5, 54.8, 48.5, 44.5, 42.0, 41.8,
33.6, 31.6, 29.7, 20.7.
nmax (cmꢁ1) ¼ 2936, 2911, 2806, 2766, 1710, 1560, 1494, 1452,
10

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
4.6.12. 1-((3S,30R)-10-benzyl-5-bromospiro[indole-3,40-piperidin]-
30-yl)propan-2-one (6ca) brown oil, 67.4 mg, 82% yield (0.2 mmol
scale)
reduced pressure, the residue was purified by silica gel column
chromatography (DCM/MeOH ¼ 20/1 to 10/1) to afford the target
product 7.
1H NMR (400 MHz, CDCl3)
d 7.88 (s, 1H), 7.77e7.73 (m, 1H),
7.57e7.50 (m, 2H), 7.41e7.32 (m, 4H), 7.31e7.25 (m, 1H), 3.76 (AB,
JAB ¼ 13.2 Hz, 1H), 3.63 (AB, JBA ¼ 13.2 Hz, 1H), 3.06e2.86 (m, 3H),
2.50 (td, J ¼ 12.0, 2.4 Hz, 1H), 2.33e2.27 (m, 2H), 1.89 (s, 3H), 1.76
(dd, J ¼ 17.6, 8.0 Hz, 1H), 1.53 (dd, J ¼ 17.6, 3.6 Hz, 1H), 1.33e1.21 (m,
4.7.1. (4aR,7aS,12bS)-3-benzyl-1,2,3,4,4a,5,7a,8-octahydropyrido
[3,4-d]carbazol-6(7H)-one (7) beige solid, m.p. ¼ 138.1e140.8 ꢀC,
54.5 mg, 82% yield (0.2 mmol scale)
1H NMR (400 MHz, CDCl3)
d
7.42e7.26 (m, 6H), 7.04 (t, J ¼ 7.6 Hz,
1H). 13C NMR (101 MHz, CDCl3)
d 206.3, 179.4, 155.2, 142.4, 137.7,
1H), 6.66 (t, J ¼ 7.6 Hz, 1H), 6.57 (d, J ¼ 7.6 Hz, 1H), 3.88 (dd, J ¼ 6.8,
2.0 Hz, 1H), 3.77e3.66 (m, 3H), 2.92e2.75 (m, 3H), 2.70e2.52 (m,
3H), 2.24e2.06 (m, 3H), 2.03e1.88 (m, 2H). 13C NMR (101 MHz,
131.4, 128.9, 128.3, 127.9, 127.2, 122.9, 119.4, 62.8, 60.1, 54.7, 48.3,
42.5, 33.3, 30.3, 29.5. nmax (cmꢁ1) ¼ 2912, 2807, 2768, 1715, 1556,
1441, 1355, 1260, 1148, 1057, 1027, 910, 824, 732, 701; HRMS (ESI)
calcd for C22H24BrN2O [MþH]þ: 411.1067, Found: 411.1062.
CDCl3)
d 209.1, 150.3, 129.3, 129.3, 128.5, 128.3, 127.2, 127.0, 118.0,
110.1, 65.8, 62.9, 54.3, 48.8, 47.5, 47.0, 40.8, 38.4, 37.7. nmax
(cmꢁ1) ¼ 2911, 2807, 1705, 1603, 1469, 1264, 1028, 733, 699; HRMS
(ESI) calcd for C22H25N2O [MþH]þ: 333.1961, Found: 333.1964.
4.6.13. 1-((3S,30R)-10-benzyl-5-methylspiro[indole-3,40-piperidin]-
30-yl)propan-2-one (6da) brown oil, 51.3 mg, 74% yield (0.2 mmol
scale)
4.8. Procedure for the preparation of 8
1H NMR (400 MHz, CDCl3)
d
7.80 (s, 1H), 7.51 (d, J ¼ 8.0 Hz, 1H),
7.40e7.30 (m, 5H), 7.29e7.25 (m, 1H), 7.18 (d, J ¼ 7.6, 1H), 3.75 (AB,
JAB ¼ 13.6 Hz, 1H), 3.63 (AB, JBA ¼ 13.2 Hz, 1H), 3.01e2.82 (m, 3H),
2.55 (td, J ¼ 12.0, 2.1 Hz, 1H), 2.39 (s, 3H), 2.36e2.21 (m, 2H), 1.86 (s,
3H), 1.75e1.65 (m, 1H), 1.54 (dd, J ¼ 17.6, 2.6 Hz, 1H), 1.28e1.21 (m,
To a stirred solution of 6aa (0.2 mmol) was added NaBH4
(2 mmol) under Ar in MeOH (2 mL) at room temperature. After the
reaction was completed (monitored by TLC), silica gel was added to
quench the reaction and filtered. After the solvent was removed
under reduced pressure, the residue was purified by silica gel col-
umn chromatography (DCM/MeOH ¼ 20/1 to 10/1) to afford the
target product 8.
1H). 13C NMR (101 MHz, CDCl3)
d 206.8, 178.1, 154.1, 140.4, 137.8,
135.2, 129.0, 128.8, 128.2, 127.1, 125.7, 121.2, 62.8, 59.3, 54.6, 48.3,
42.6, 33.5, 30.3, 29.8, 21.7. nmax (cmꢁ1) ¼ 2912, 2807, 2767, 1715,
1560, 1454, 1355, 1154, 966, 910, 822, 733, 699; HRMS (ESI) calcd for
C
23H27N2O [MþH]þ: 347.2118, Found: 347.2130.
4.8.1. 1-((3S,30R)-10-benzylspiro[indoline-3,40-piperidin]-30-yl)
propan-2-ol (8) beige solid, m.p. ¼ 55.6e57.3 ꢀC, 57.2 mg, 85% yield,
dr ¼ 1.8:1 (determined by HPLC) (0.2 mmol scale)
4.6.14. 1-((3S,30R)-10-benzyl-7-methylspiro[indole-3,40-piperidin]-
30-yl)propan-2-one (6ea) brown oil, 54.1 mg, 78% yield (0.2 mmol
scale)
1H NMR (400 MHz, CDCl3)
d
7.40e7.25 (m, 5H), 7.13 (d, J ¼ 7.2 Hz,
1H), 7.04 (t, J ¼ 7.6 Hz, 1H), 6.68 (td, J ¼ 7.2, 3.2 Hz, 1H), 6.62 (dd,
J ¼ 7.6, 4.0 Hz,1H), 4.02e3.42 (m, 6H), 3.27e3.22 (m,1H), 2.85e2.75
(m, 3H), 2.47e1.93 (m, 3H), 1.75e1.65 (m, 1H), 1.62e1.30 (m, 2H),
1H NMR (400 MHz, CDCl3)
d
7.88 (s, 1H), 7.46 (d, J ¼ 7.2 Hz, 1H),
7.39e7.29 (m, 4H), 7.28e7.23 (m, 1H), 7.21 (d, J ¼ 7.6, 1H), 7.12 (t,
J ¼ 7.6 Hz, 1H), 3.75 (AB, JAB ¼ 13.2 Hz, 1H), 3.61 (AB, JBA ¼ 13.2 Hz,
1H), 3.02e2.79 (m, 3H), 2.59 (s, 3H), 2.54 (dd, J ¼ 12.0, 2.4 Hz, 1H),
2.39e2.25 (m, 2H), 1.88 (s, 3H), 1.80e1.62 (m, 1H), 1.54 (d, J ¼ 17.2,
1.09 (t, J ¼ 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 151.8, 136.5,
129.54, 129.49, 128.4, 127.9, 127.8, 127.6, 127.5, 125.3, 125.3, 118.0,
118.0, 109.9, 109.8, 67.1, 64.8, 63.0, 59.6, 59.0, 55.1, 54.9, 49.5, 49.4,
47.2, 47.1, 39.5, 39.5, 38.4, 24.1, 23.8. nmax (cmꢁ1) ¼ 2962, 2925,1603,
1487, 1460, 1246, 1267, 1124, 1064, 1026, 733, 699; HRMS (ESI) calcd
for C22H29N2O [MþH]þ: 333.2274, Found: 333.2277.
1H), 1.28e1.18 (m, 1H). 13C NMR (101 MHz, CDCl3)
d 206.8, 177.9,
154.6, 140.1, 137.9, 131.3, 129.7, 128.9, 128.3, 127.1, 125.3, 122.2, 62.9,
59.5, 54.7, 48.3, 42.6, 33.4, 30.3, 29.8,16.9. nmax (cmꢁ1) ¼ 2912, 2807,
2767, 1714, 1562, 1452, 1358, 1265, 1157, 968, 912, 732, 699; HRMS
(ESI) calcd for C23H27N2O [MþH]þ: 347.2118, Found: 347.2120.
4.9. Procedure for the preparation of 9
4.6.15. 1-((3S,30R)-10-benzyl-5-methoxyspiro[indole-3,40-
piperidin]-30-yl)propan-2-one (6fa) brown oil, 58.7 mg, 81% yield
(0.2 mmol scale)
A solution of 6aa (0.2 mmol) in MeOH (2 mL) was added
Pd(OH)2/C (50 mg). Then the mixture was stirred under 1 atm H2 at
room temperature until TLC showed complete consumption of
starting material. After removal of Pd(OH)2/C, water was added and
the mixture was extracted with EtOAc (3 ꢂ 10 mL). The combined
organic layer was washed with brine, separated, dried over Na2SO4
and filtered. After the solvent was removed under reduced pres-
sure, the residue was purified by silica gel column chromatography
(DCM/MeOH ¼ 20/1 to 10/1) to afford the target product 9.
1H NMR (400 MHz, CDCl3)
d
7.76 (s, 1H), 7.56 (d, J ¼ 8.4 Hz, 1H),
7.41e7.31 (m, 4H), 7.30e7.26 (m, 1H), 7.16 (d, J ¼ 2.4 Hz, 1H), 6.91
(dd, J ¼ 8.4, 2.4 Hz,1H), 3.81 (s, 3H), 3.75 (AB, JAB ¼ 13.2 Hz,1H), 3.62
(AB, JBA ¼ 13.2 Hz, 1H), 3.04e2.82 (m, 3H), 2.55 (t, J ¼ 12.0 Hz, 1H),
2.40e2.25 (m, 2H), 1.89 (s, 3H), 1.73 (dd, J ¼ 17.6, 8.4 Hz, 1H), 1.57 (d,
J ¼ 18.0 Hz, 1H), 1.34e1.25 (m, 1H). 13C NMR (101 MHz, CDCl3)
d
206.7, 177.0, 157.5, 149.9, 141.8, 137.6, 129.0, 128.2, 127.1, 121.7,
112.5, 111.8, 62.9, 59.4, 55.6, 54.3, 48.0, 42.5, 33.7, 30.3, 29.7. nmax
(cmꢁ1) ¼ 2940, 2912, 2807, 2757, 1714, 1586, 1560, 1463, 1267, 1223,
4.9.1. 1-((3S,30R)-spiro[indoline-3,40-piperidin]-30-yl)propan-2-one
(9) sticky yellow oil, 38.1 mg, 78% yield (0.2 mmol scale)
1028, 732, 700; HRMS (ESI) calcd for
363.2067, Found: 363.2072.
C
23H27N2O2 [MþH]þ:
1H NMR (400 MHz, CDCl3)
d
7.28 (d, J ¼ 8.0 Hz, 1H), 7.09 (t,
J ¼ 7.6 Hz, 1H), 6.73 (t, J ¼ 7.6 Hz, 1H), 6.65 (dd, J ¼ 7.6, 1.1 Hz, 1H),
4.72 (s, 2H), 3.54 (d, J ¼ 9.2 Hz, 1H), 3.30e3.23 (m, 2H), 3.13e2.98
(m, 2H), 2.90 (dd, J ¼ 13.0, 8.6 Hz, 1H), 2.58 (dd, J ¼ 17.6, 3.2 Hz, 1H),
2.45e2.39 (m, 1H), 2.28 (dd, J ¼ 17.6, 9.2 Hz, 1H), 2.16e2.08 (m, 1H),
4.7. Procedure for the preparation of 7 [8]
To a stirred solution of 6aa (0.2 mmol) was added KOtBu
(0.2 mmol) under Ar in dry THF (3 mL) at ꢁ78 ꢀC. After the reaction
was completed (monitored by TLC), water was added to quench the
reaction and the mixture was extracted with DCM (3 ꢂ 10 mL). The
combined organic layer was washed with brine, separated, dried
over Na2SO4 and filtered. After the solvent was removed under
2.05 (s, 3H), 1.79e1.75 (m, 1H). 13C NMR (101 MHz, CDCl3)
d 207.6,
152.0, 132.0, 128.3, 125.3, 118.2, 109.9, 60.0, 46.6, 46.3, 42.4, 42.3,
37.7, 35.3, 30.5. nmax (cmꢁ1) ¼ 2921, 2850, 1706, 1604, 1487, 1462,
1356, 1263, 1171, 1155, 730, 699; HRMS (ESI) calcd for C15H21N2O
[MþH]þ: 245.1648, Found: 245.1653.
11

Q.-Q. Liu, C. Zheng and S.-L. You
Tetrahedron xxx (xxxx) xxx
54 (2018) 3625;
Declaration of competing interest
(k) J.T.R. Liddon, J.A. Rossi-Ashton, R.J.K. Taylor, W.P. Unsworth, Org. Lett. 20
(2018) 3349;
(l) M. Zhu, K. Zhou, X. Zhang, S.-L. You, Org. Lett. 20 (2018) 4379;
(m) J.-J. Suo, W. Liu, J. Du, C.-H. Ding, X.-L. Hou, Chem. Asian J. 13 (2018) 959;
(n) K. Liang, X. Tong, T. Li, B. Shi, H. Wang, P. Yan, C. Xia, J. Org. Chem. 83 (2018)
10948;
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
(o) P. Giacinto, A. Bottoni, A. Garelli, G.P. Miscione, M. Bandini, ChemCatChem
10 (2018) 2442;
(p) L. Peng, D. Xu, X. Yang, J. Tang, X. Feng, S.-L. Zhang, H. Yan, Angew. Chem.,
Int. Ed. 58 (2019) 216;
Acknowledgement
We thank MOST (2016YFA0202900), NSFC (21772219 and
21961132002), Science and Technology Commission of Shanghai
Municipality (18QA1404900 and 19590750400), Chinese Academy
of Sciences (XDB20000000 and QYZDYSSWSLH012), and Youth
Innovation Promotion Association of CAS (2017302) for financial
supports.
(q) H.-K. Liu, S.R. Wang, X.-Y. Song, L.-P. Zhao, L. Wang, Y.S. Tang, Angew. Chem.,
Int. Ed. 58 (2019) 4345;
(r) A.D. Marchese, F. Lind, A.E. Mahon, H. Yoon, M. Lautens, Angew. Chem., Int.
Ed. 58 (2019) 5095;
(s) Y.-Z. Cheng, Q.-R. Zhao, X. Zhang, S.-L. You, Angew. Chem., Int. Ed. 58 (2019)
18069;
ꢀ
(t) H.E. Ho, T.C. Stephens, T.J. Payne, P. O’Brien, R.J.K. Taylor, W.P. Unsworth, ACS
Catal 9 (2019) 504;
(u) Q. Yu, Y. Fu, J. Huang, J. Qin, H. Zuo, Y. Wu, F. Zhong, ACS Catal 9 (2019) 7285;
(v) P. Ranjan, G.M. Ojeda, U.K. Sharma, E.V. Van der Eycken, Chem. Eur. J. 25
(2019) 2442;
Appendix A. Supplementary data
(w) L. Ding, R.-D. Gao, S.-L. You, Chem. Eur. J. 25 (2019) 4330;
(x) Y. He, Z. Liu, D. Wu, Z. Li, K. Robeyns, L. Van Meervelt, E.V. Van der Eycken,
Org. Lett. 21 (2019) 4469;
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131765.
(y) H.-J. Zhang, Q. Gu, S.-L. You, Org. Lett. 21 (2019) 9420;
(z) R.-X. Liang, K. Wang, Q. Wu, W.-J. Sheng, Y.-X. Jia, Organometallics 38 (2019)
3927;
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