The application of Morita-Baylis-Hillman reaction: Synthetic studies on perophoramidine

Article abstract of DOI:10.1016/j.tet.2017.05.067

A new concise methodology was developed for the synthesis of the two vicinal quaternary centers of the natural product perophoramidine. Key steps involved the Morita–Baylis–Hillman reaction, reductive cyclization and allylic alkylation. Moreover, most con

Full text of DOI:10.1016/j.tet.2017.05.067

Accepted Manuscript
The application of Morita-Baylis-Hillman reaction: Synthetic studies on
perophoramidine
Lin Wu, Qian-Ru Zhang, Ji-Rong Huang, Yang Li, Fu Su, Lin Dong
PII:
S0040-4020(17)30568-9
10.1016/j.tet.2017.05.067
TET 28733
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 April 2017
Revised Date: 17 May 2017
Accepted Date: 19 May 2017
Please cite this article as: Wu L, Zhang Q-R, Huang J-R, Li Y, Su F, Dong L, The application of Morita-
Baylis-Hillman reaction: Synthetic studies on perophoramidine, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.05.067.
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ACCEPTED MANUSCRIPT
2
Graphical Abstract
A new concise methodology was developed
for the synthesis of the two vicinal
quaternary centers of the natural product
perophoramidine. Key steps involved the
Morita-Baylis-Hillman reaction, reductive
cyclization and allylic alkylation. Moreover,
most conditions are simple and convenient
with good yields.
The application of Morita-Baylis-Hillman
reaction: synthetic studies on perophoramidine
Lin Wu,a Qian-Ru Zhang,a Ji-Rong Huang,a
Yang Li,a Fu Su,a,* and Lin Donga,*
aKey Laboratory of Drug-Targeting and Drug Delivery
System of the Education Ministry, West China School of
Pharmacy, Sichuan University, Chengdu 610041,China

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
The application of Morita-Baylis-Hillman reaction: synthetic studies on
perophoramidine
Lin Wu,a Qian-Ru Zhang,a Ji-Rong Huang,a Yang Li,a Fu Su,a,* and Lin Donga,*
a Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu
610041,China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new concise methodology was developed for the synthesis of the two vicinal quaternary
centers of the natural product perophoramidine. Key steps involved the
Morita–Baylis–Hillman reaction, reductive cyclization and allylic alkylation. Moreover, most
conditions are simple and convenient with good yields.
Available online
Keywords:
Vicinal quaternary centers
MBH
Reductive cyclization
Allylic alkylation
total synthesis of (+)-perophoramidine.5 Recently, Wang
achieved the total synthesis of (+)-perophoramidine using a
1. Introduction
nickel(II)-catalyzed asymmetric alkylation reaction.6 Trost
utilized a molyndenum-catalyzed asymmetric allylic alkylation to
crate (-)-perophoramidine.7
In 2002, Ireland and co-workers reported the isolation of
perophoramidine from the Philippine ascidian organism
Perophoranamei, and this architecturally intriguing natural
product possesses cytotoxicity toward HCT116 colon carcinoma
cells (IC50 = 60 µM).1 With use of multidimensional NMR
techniques, the striking molecular structure of perophoramidine
is characterized by its complex densely functionalized hexacyclic
system with two crucial vicinal all-carbon quaternary
stereocenters, the skeletal connectivity of which is related to the
Penicillium derived communesin alkaloids (Figure 1).2
Recently, Morita–Baylis–Hillman (MBH) reaction has
emerged as a very versatile tool to deliver multifunctional
compounds.9 Toward a unique synthetic strategy distinct from the
reported strategies, we envisioned our efforts towards the
synthesis of perophoramidine core structure via a key MBH
reaction as the starting response, which might construct the
pivotal quaternary center at the first step.
Me
H
H
N
O
N
N
B
N
A
O
N3
OR
Cl
D
N
C
F
E
N
H
N
N
Br
N
H
O
H
NH2
Cl
A
B
Perophoramine
H
N
O
O
NC
NC
COOMe
O
COOMe
O
OH
Figure 1. Structures of Perophoramidine and Communesins
N
H
N
N
H
O
By virtue of the appealing biological activities and
challenging structures, perophoramidine has attracted an attention
of synthetic organic chemists in recent years.3-8 The first total
synthesis of (±)-perophoramidine was reported by Funk, which
employed hetero Diels–Alder reaction as a key step.3 Rainier
H
E
D
C
O
HO
MBH
COOMe
O
O
N
H
N
developed
a new spiro cyclization reaction to generate
H
(±)-dehaloperophoramidine.4 Subsequently, the asymmetric
F
biomimetic Diels–Alder reaction has been used by Qin to first
Figure 2. Retrosynthetic synthesis of Perophoramidine
Corresponding author. Tel.: +86-28-85503538; e-mail: dongl@scu.edu.cn

2
As depicted in Figure 2, we expected that the target
perophoramidine could be synthesized from the azide compound
A via formation of the A ring. The compound A could be
generated from spiro lactam intermediate C via arylation reaction
and condensation. Reductive cyclization of aldehyde compound
D could deliver the lactam compound C. The requisite aldehyde
Table 1.
ACCEPTED MANUSCRIPT
The exploration of arylation reaction to form 8a
compound
D
could be obtained from the isatin via
Morita-Baylis-Hillman reaction.
2. Results and discussion
Entry
Aryl halide
Base
Ligand Solvent Result
1
2
3
4
2-iodoaniline
2-iodoaniline
KHMDS
LiHMDS
KHMDS
LiHMDS
-
THF
THF
Messb
Messb
dppf
-
1-bromo-2-iodobenzene
1-bromo-2-iodobenzene
MeCN Messb
MeCN Messb
dppf
a
All reaction conditions unless otherwise specified: 0.1 mmol of 7, 0.15
mmol of aryl halide, 0.3 mmol of base, 5 mol % of Pd(dba)2, 0.2 mmol of
ZnCl2, 1 mL of solvent, reflux, 36 h, under argon atmosphere.
bAryl halide was homocoupling and 7 was decomposed.
With 7 in hand, we next examined the construction of the D
ring. To achieve this goal, we settled upon various arylation
reactions to establish the second quaternary carbon center.11
Unfortunately, the approaches using 2-iodoaniline or
1-bromo-2-iodobenzene as the source of aromatic groups were all
failed (Table 1).
In view of above result, we decided to change the target and
keep on studying the analogue of perophoramidine skeleton.
Therefore, we then speculated to build the second quaternary
center via allylation reactions (Scheme 3). To our surprise, only
benzoyl chloride as a protecting agent could protect the amide,
giving the Bz protection of the lactam 9 together with
O-protection product 9’ in good yield.11 Allylation of Bz
protection product 9 gave a single alkylation product 10 and less
amount of 10’. The desired oxidation product 11 was performed
through ozonation sequence from alkenyl compound 10.
Scheme 1. Synthesis of cyano compound 3 via MBH reaction
Firstly, we set out to investigate whether the key intermediate
quaternary carbon compound 3 could be built via MBH reaction
(Scheme 1). It was found that MBH reaction as a means could
really proceed well to afford the tertiary alcohol 1 from
commercially available isatin, which then followed by Boc
protection and nucleophilic elimination reaction providing
product 2. Subsequently, 2 went through decarboxylation to give
the desired quaternary center intermediate 3. It is worth noting
that the nitrogen in isatin had to be protected first with methyl
group, otherwise key intermediate 3 can’t be obtained.
Scheme 2. Synthesis of the spiro-fused oxoindolin 7
As we expected, 1,4-addition of 3 worked smoothly with vinyl
Grignard reagent under the established reaction conditions,
generating terminal alkenyl 4 in 80% yield. After oxidation of
alkenyl group by O3 and then reduction in the presence of
NaBH4, the resultant alcohol underwent intramolecular ester
exchange to yield lactone compound 6, which was subjected to
reduction and subsequent amine ester exchange to deliver
important spiro-fused oxoindolin 7, whose structure was
established by X-ray analysis (Scheme 2).10
Scheme 3. Synthesis of the spiro compound 11

3
Table 2.
ACCEPTED MANUSCRIPT
The exploration of aromatization reaction to form 8a
Bz
O
Bz
Bz
O
O
N
N
N
OH
OH
OH
OH
conditions
or
O
NHR
N
O
O
O
N
N
N
11
12
13
Entry
Amine
Acid
Base
Reductive agent
Desiccant
Temp.
Solvent
Result
/°C
1
2
3
4
5
6
7
8
H2NMe
BnNH2
BnNH2
BnNH2
NH3
H2N-Boc
BnNH2
NH4OAc
BnNH2
H2N-OH
H2N-OH
H2N-OH
H2N-OH
H2N-OH
H2N-OH
H2N-OH
TsOH
Ti(OiPr)4
NaBH(OAc)3
TsOH
AcOH
TsOH
-
-
-
-
-
-
-
-
-
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaCNBH3
NaBH3CN
Al2Te3
-
0-30
30
Toluene
THF
CH2Cl2
Toluene
THF
THF
AcOH
THF/H2O
THF
THF
THF
MeOH
EtOH/H2O (1:1)
THF/H2O (1:1)
EtOH
Decomposed
Decomposed
Decomposed
Decomposed
Decomposed
Decomposed
Decomposed
Trace
Trace
Decomposed
Trace
Trace
Trace
MgSO4
-
-
MgSO4
-
-
-
0-30
0-120
0-75
0-110
30-70
50
100
0-75
30
30
30
30
80
Et3N
-
E3N
NaOH
NaOH (40% aq)
NaHCO3
Na2CO3
AcONa
9
AcOH
Pd/H2
LAH
-
10
11
12
13
14
15
16
-
-
-
-
-
-
-
MgSO4
-
-
-
-
-
-
-
-
-
-
-
-
Trace
Trace
Trace
Py
30
THF/H2O (3:2)
a All reaction conditions unless otherwise specified: 0.1 mmol of 11, 0.15 mmol of amine, 0.15 mmol of acid, 0.2 mmol of base, 0.5-0.7 mmol of reductive agent,
0.12 mmol of desiccant, 1 mL of solvent, 12 h.
At this stage, we tried to convert the aldehyde group into an
amine, and further synthesizing the D ring.11 However, after a lot
of experiments, we couldn’t get the desired aminated product 12
(Table 2). Unfortunately, these conditions were also no working
to obtain hydroxylamine product 13.
Entry Substrate Reductive agent Lewis acid Solvent Temp.
Result
/°C
1
2
3
4
5
6
15
15
15
16
16
16
LAH
AlH3-Me2NEt
NaBH4
-
THF 25-75 Decomposed
THF 0-75 Decomposed
-
CoCl2
MeOH 0-75 Decomposed
THF 25-75 Decomposed
LAH
-
-
AlH3-Me2NEt
NaBH4
THF
0-75 Decomposed
CoCl2
MeOH 0-75 Decomposed
Scheme 4 Synthesis of amide compounds 15 and 16
a All reaction conditions unless otherwise specified: 0.1 mmol of 15 or 16,
0.5-1 mmol of reductive agent, 0.12 mmol of Lewis acid, 1 mL of solvent, 12
h.
After that, we wanted to convert the aldehyde group to the
amide and then to synthesize the D ring by using the Zhou’s
conditions.12 In this instance, on exposure to potassium carbonate
and NIS, aldehyde 11 underwent oxidation to furnish
esterification product 14, which could be involved in the similar
amine ester exchange process to lead the amide products 15 and
16 (Scheme 4). Worthy of note, however, is the failure of amide
15 or 16 to form ring-closed product 17 under the conditions on
Table 3, probably due to the carbonyl groups of triamides 15 and
16 don’t have enough reactive.
3. Conclusions
In summary, we have developed an efficient approach to
construct system with two quaternary centers of the
perophoramidine core skeleton via Morita-Baylis-Hillman (MBH)
reaction as the key step. Further application of this process is
under investigation.
4. Experimental section
4.1. General
Table 3.
Studies on construction of the D ringa

4
Solvents and reagents were purified by standard methods.
Thin-layer chromatography was performed on EM 250 Kieselgel
60 F254 silica gel plates. The spots were visualized by staining
with KMnO4 or under a UV lamp. 1H and 13C NMR spectra were
recorded with a spectrometer operating at 400 or 600 MHz for
proton and carbon nuclei, respectively. High-resolution mass
spectra (HRMS) was obtained using positive electrospray
ionization by the TOF method.
chromatography eluting with petroleum and ethyl acetate (5:1)
1
ACCEPTED MANUSCRIPT
to afford compound 3 (6.5 g, 85 %) as a light red solid. H NMR
(600 MHz, CDCl3): δ 7.31-7.28 (m, 1H), 7.20-7.17 (m, 1H),
7.02-7.00 (m, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.54 (s, 1H), 6.02 (s,
1H), 3.52 (s, 3H), 3.23 (s, 3H), 3.09-3.06 (m, 1H), 2.78-2.76 (m,
1H) ppm; 13C NMR (100 MHz, CDCl3): δ 175.3, 164.8, 144.0,
137.3, 129.8, 128.7, 128.2, 123.3, 123.1, 115.8, 108.9, 52.4, 51.5,
26.8, 24.8 ppm. ESI HRMS calcd for C15H14N2O3+H 271.1004,
found 271.1011.
4.2.
(R)-methyl2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)
acrylate (1)
4.5
methyl2-(3-(cyanomethyl)-1-methyl-2-oxoindolin-3-yl)
pent-4-enoate (4)
Isatin (10 g, 68.0 mmol) was dissolved in DMF (100 mL) and
cooled to 0 °C in an ice bath. Sodium hydride (60% wt, 3.3 g,
81.6 mmol) was added and the solution was stirred for 10
minutes before addition of methyl iodide (4.7 mL, 74.83 mmol).
The resulting solution was stirred at this temperature for 20
minutes and quenched with water and extracted three times with
EtOAc. The combined organic layers were dried over sodium
sulfate and concentrated, and then red solid was obtained. To a
solution of the above red solid in methyl acrylate (100 mL) was
added triethylenediamine (4.4 g, 20.0 mmol). The solution was
stirred for 38 h at room temperature and then washed with water,
extracted with EtOAc twice and dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography eluting with petroleum and
ethyl acetate (2:1) to give the titled compound 1 (14.8 g, 88%) as
a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.29-7.25 (m, 1H),
7.11 (d, J = 8 Hz, 1H), 6.99-6.96 (m, 1H), 6.81 (d, J = 8 Hz, 1H),
6.48 (d, J = 20 Hz, 2H), 4.70 (s, 1H), 3.54 (s, 3H), 3.17 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 176.5, 165.1, 144.5, 139.2,
130.1, 129.6, 127.9, 123.7, 123.0, 108.6, 76.2, 52.0, 26.4 ppm.
ESI HRMS calcd for C13H14NO4+H 248.0923, found 248.0912.
To a solution of 3 (8 g, 29.6 mmol) in dry THF (100 mL) at -78
°C under argon atmosphere, vinyl magnesium bromide solution
(1 M in THF, 32.6 mL, 32.6 mmol) was added in a dropwise
manner over 10 minutes. After 1.5 h, the reaction mixture was
quenched with a saturated aqueous NH4Cl solution and the
aqueous layer was extracted with EtOAc twice, dried over
sodium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography eluting
with petroleum and ethyl acetate (7:1) to afford compound 4 (7.1
1
g, 80%) as a light yellow solid. H NMR (600 MHz, CDCl3): δ
7.39-7.36 (m, 1H), 7.30-7.29 (m, 1H), 7.14-7.11 (m, 1H),
6.91-6.90 (m, 1H), 5.68-5.61 (m, 1H), 4.98-4.95 (m, 2H), 3.66 (s,
3H), 3.32-3.29 (m, 1H), 3.23 (s, 3H), 2.92-2.86 (m, 1H),
2.88-2.86 (m, 1H), 2.42-2.33 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3): δ 175.1, 171.5, 143.5, 134.3, 129.9, 128.0, 123.5, 123.4,
117.6, 116.2, 108.9, 51.9, 49.7, 49.5, 30.7, 26.6, 23.1 ppm. ESI
HRMS calcd for C17H18N2O3+H 299.1317, found 299.1391.
4.6 methyl2-(3-(cyanomethyl)-1-methyl-2-oxoindolin-3-yl)-4-
oxobutanoate (5)
A solution of 4 (10.0 g, 33.6 mmol) in CH2Cl2 (60 mL) and
MeOH (40 mL) was cooled to −78 °C. Ozone was then bubbled
through the solution for 1.5 h when it became yellow and the
flow of ozone was stopped. To the above solution was added
dimethyl sulfide (2.9 mL, 40.3 mmol) at −78 °C. After being
stirred at this temperature for 15 minutes, the reaction mixture
was warmed to room temperature, stirred for an additional 12 h,
and concentrated under reduced pressure. The residue was
purified by silica gel chromatography eluting with petroleum and
4.3
Methyl2-((S)-3-((R)-1-cyano-2-ethoxy-2-oxoethyl)-1-
methyl-2-oxoindolin-3-yl) acrylate (2)
To a solution of 1 (10 g, 40.5 mmol) and di-t-Butyl decarbonate
(10.6 g, 48.6 mmol) in CH2Cl2 (100 mL), 4-dimethylamino
pyridine (98.8 mg, 0.8 mmol) was added. The solution was
stirred for 9 h at -10 °C and then washed with water, extracted
with CH2Cl2 twice and dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography eluting with petroleum
andethyl acetate (6:1) to afford a yellow solid. To a solution of
the above solid in methylbenzene (100 mL), ethyl cyanacetate
(4.6 mL, 42.7 mmol) and triethylenediamine (783 mg, 3.56
mmol) were added at room temperature. After 1 h, the reaction
mixture was washed with water, extracted with EtOAc twice and
dried over sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography eluting with petroleum and ethyl acetate (5:1) to
1
ethyl acetate (2:1) to give 5 (8.3 g, 82%) as a yellow solid. H
NMR (600 MHz, CDCl3): δ 9.57 (s, 1H), 7.40-7.38 (m, 1H),
7.35-7.34 (m, 1H), 7.15-7.13 (m, 1H), 6.94-6.92 (m, 1H), 3.73 (s,
3H), 3.57-3.56 (m, 1H), 3.26-3.24 (m, 4H), 2.89-2.80 (m, 2H),
2.28-2.25 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 198.3,
174.5, 170.4, 143.3, 130.2, 127.7, 123.7, 123.5, 116.1, 109.2,
52.6, 49.3, 42.9, 40.7, 26.6, 24.3 ppm. ESI HRMS calcd for
C16H16N2O4+H 301.1110, found 301.1188.
4.7 2-(1-methyl-2-oxo-3-(2-oxotetrahydrofuran-3-yl) indolin
-3-yl) acetonitrile (6)
1
afford compound 2 (11.6 g, 84 %) as a light red solid. H NMR
(600 MHz, CDCl3): δ 7.53 (d, J = 7.2 Hz, 1H), 7.32-7.30 (m,
1H), 7.07-7.04 (m, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H),
5.57 (s, 1H), 5.35 (s, 1H), 3.97-3.92 (m, 2H), 3.72 (s, 3H), 3.16
(s, 3H), 0.99-0.97 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
173.2, 166.0, 163.2, 144.0, 136.4, 130.1, 129.1, 126.6, 124.9,
123.2, 114.8, 108.9, 62.9, 55.3, 52.5, 42.6, 26.8, 13.6 ppm. ESI
HRMS calcd for C18H18N2O5+H 342.1216, found 343.1310.
To a solution of 5 (9 g, 30.0 mmol) in MeOH (100 mL) at 0 °C
was added sodium borohydride (8.0 g, 210.0 mmol) over 20
minutes. After being stirred for 5 h at room temperature, the
reaction mixture was diluted with EtOAc, quenched with a
saturated NH4Cl solution in an ice bath. The aqueous layer was
extracted with EtOAc twice. The combined organic layers were
washed with a saturated NaCl solution, dried over sodium
sulfate, and concentrated under reduced pressure. The residue
was purified by silica gel chromatography eluting with petroleum
and ethyl acetate (2:1) to give 6 (6.9 g, 80%) as a white solid. 1H
NMR (600 MHz, CDCl3): δ 7.44-7.43 (m, 1H), 7.35-7.33 (m,
1H), 7.10-7.08 (m, 1H), 6.88-6.87 (m, 1H), 4.23-4.19 (m, 1H),
4.12-4.08 (m, 1H), 3.33-3.30 (m, 1H), 3.27-3.24 (m, 1H), 3.21 (s,
3H), 2.79-2.76 (m, 1H), 2.27-2.21 (m, 1H), 1.94-1.87 (m, 1H)
4.4
acrylate (3)
methyl2-(3-(cyanomethyl)-1-methyl-2-oxoindolin-3-yl)
A solution of 2 (9 g, 26.3 mmol) in dimethyl sulfoxide (90 mL)
and water (9 mL) was heated to 125 °C for 30 h. Then the
mixture was extracted with EtOAc twice, washed with water
twice, dried over sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column

5
ppm; 13C NMR (100 MHz, CDCl3): δ 174.9, 174.2, 143.7, 130.1,
127.5, 123.6 (d, J = 14.8 Hz, 1H), 116.2, 109.2, 65.9, 48.7, 43.6,
26.7, 25.1, 24.0 ppm. ESI HRMS calcd for C15H14N2O3+H
271.1004, found 271.0744.
4.10 3'-allyl-1'-benzoyl-3'-(2-hydroxyethyl)-1-methylspiro
[indoline-3,4'-piperidine]-2,2'-dione (10)
ACCEPTED MANUSCRIPT
To a solution of 9 (3.0 g, 7.8 mmol), Potassium tert-butoxidein
(1.4 g, 12.0 mmol) and 18-Crown-6 (1.1 g, 4.0 mmol) in THF (40
mL) at 50 °C was added allyl bromide (1.0 mL, 11.7 mmol) in a
dropwise manner over 5 minutes. The reaction mixture was
stirred overnight and extracted with EtOAc twice, dried over
sodium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography eluting
with petroleum and ethyl acetate (1:1) to afford compound 10
4.8 3'-(2-hydroxyethyl)-1-methylspiro[indoline-3,4'-
piperidine]-2,2'- dione (7)
To a solution of 6 (8.1 g, 30.0 mmol) and Cobaltous chloride
(55% wt, 10.7 g, 45 mmol) in MeOH (100 mL) at 0 °C was
added sodium borohydride (1.7 g, 45. 0 mmol) over 20 minutes.
After being stirred for 10 h at 60 °C, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography eluting with CH2Cl2 and MeOH (20:1)
1
(1.8 g, 55 %) as a white solid. H NMR (400 MHz, CDCl3): δ
8.06-8.04 (m, 2H), 7.55-7.51 (m, 1H), 7.45-7.41 (m, 2H),
7.36-7.33 (m, 1H), 7.10-7.06 (m, 2H), 6.93-6.91 (m, 1H),
5.97-5.87 (m, 1H), 5.31-5.28 (m, 2H), 4.38-4.36 (m, 2H),
4.25-4.20 (m, 1H), 4.12-4.06 (m, 1H), 3.56-3.52 (m, 2H), 3.25 (s,
3H), 3.17-3.15 (m, 1H), 2.50-2.42 (m, 1H), 2.00-1.92 (m, 1H),
1.75-1.71 (m, 1H), 1.09-1.02 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3): δ 177.8, 170.5, 166.4, 143.5, 132.7, 132.3, 129.7, 128.9,
128.8, 128.2, 124.1, 122.9, 118.6, 108.7, 64.2, 51.0, 49.8, 43.5,
42.5, 31.2, 27.5, 26.5 ppm. ESI HRMS calcd for C25H26N2O4+H
419.1893, found 419.1981.
1
to give 7 (7.3 g, 89%) as a white solid. H NMR (600 MHz,
CDCl3): δ 7.36-7.33 (m, 1H), 7.21-7.19 (m, 1H), 7.15-7.12 (m,
1H), 6.89-6.88 (m, 1H), 6.22 (s, 1H), 5.03-5.01 (m, 1H),
4.01-3.96 (m, 1H), 3.63-3.58 (m, 1H), 3.38-3.30 (m, 2H), 3.23 (s,
3H), 2.80-2.78 (m, 1H), 2.33-2.27 (m, 1H), 1.92-1.85 (m, 2H),
0.94-0.91 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 176.4,
174.2, 143.4, 131.3, 128.9, 123.2, 122.1, 108.4, 62.7, 50.6, 46.8,
37.9, 30.8, 29.1, 26.2 ppm. ESI HRMS calcd for C15H18N2O3+H
275.1317, found 275.1425.
4.123'-(2-(allyloxy)ethyl)-1'-benzoyl-1-methylspiro[indoline-3,
4'-piperidine]-2,2'-dione (10′)
4.91'-benzoyl-3'-(2-hydroxyethyl)-1-methylspiro[indoline-3,4'
-piperidine]-2,2'-dione (9)
1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 7.6 Hz, 2H),
7.57-7.53 (m, 1H), 7.44-7.40 (m, 2H), 7.28-7.24 (m, 1H), 7.05 (d,
J = 7.2 Hz, 1H), 6.86-6.82 (m, 2H), 5.94-5.84 (m, 1H), 5.35-5.31
(m, 1H), 5.25-5.23 (m, 1H), 4.46-4.41 (m, 1H), 4.38-4.33 (m,
1H), 4.20-4.15 (m, 1H), 4.08-4.03 (m, 1H), 3.93-3.86 (m, 1H),
3.30-3.22 (m, 4H), 2.92-2.91 (m, 1H), 2.35-2.28 (m, 1H),
2.21-2.13 (m, 1H), 1.91-1.88 (m, 1H), 1.18-1.11 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3): δ 176.6, 170.2, 166.0, 143.1, 132.7,
132.6, 131.5, 129.5, 128.6, 128.1, 122.9, 122.1, 117.3, 108.3,
64.7, 50.6, 50.0, 43.0, 42.7, 31.3, 27.0, 26.1 ppm. ESI HRMS
calcd for C25H26N2O4+H 419.1871, found 419.1906.
To
a
solution of lactam
7
(8.0 g, 29.2 mmol),
4-dimethylaminopyridine (356.2 mg, 2.9 mmol) and
triethylamine (5.3 mL, 38.0 mmol) in MeCN (100 mL) under
nitrogen was added benzoyl chloride (1.7 g, 45.0 mmol) over 10
minutes. And the resulting mixture solution was stirred at room
temperature for 1.5 h and then at 70 °C overnight. After
completion of the reaction, water (30 mL) was added in one
portion and the reaction mixture was stirred at 70 °C for 1 h to
hydrolyze excess Bz2O. The residue mixture was cooled to
temperature, and then diluted with saturated NaHCO3, extracted
with EtOAc twice, dried over sodium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography eluting with petroleum/ethyl acetate
4.112-(1'-benzoyl-3'-(2-hydroxyethyl)-1-methyl-2,2'-dioxospir
o[indoline-3,4'-piperidine]-3'-yl) acetaldehyde (11)
1
(1:2) to afford compound 9 (7.2 g, 65%) as a white solid. H
A solution of 10 (1.26 g, 3 mmol) in CH2Cl2 (15 mL) and MeOH
(10 ml) was cooled to −78 °C. Ozone was then bubbled through
the solution for 0.5 h, when the mixture became yellow and the
flow of ozone was stopped. To the above solution was added
dimethyl sulfide (0.3 mL, 4.1 mmol) at −78 °C. After being
stirred at this temperature for 10 minutes, the reaction mixture
was warmed to room temperature, stirred for an additional 12 h,
and concentrated under reduced pressure. The residue was
purified by silica gel chromatography eluting with petroleum and
NMR (400 MHz, CDCl3): δ 7.92-7.90 (m, 2H), 7.57-7.54 (m,
1H), 7.48-7.41 (m, 2H), 7.29-7.25 (m, 1H), 7.08-7.07 (m, 1H),
6.88-6.85 (m, 2H), 5.97 (s, 1H), 4.42-4.36 (m, 1H), 4.34-4.29 (m,
1H), 3.99-3.92 (m, 1H), 3.36-3.34 (m, 1H), 3.23 (s, 3H), 2.88 (s,
1H), 2.34-2.26 (m, 1H), 2.22-2.14 (m, 1H), 1.89 (d, J = 12 Hz,
1H), 1.19-1.15 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ
176.6, 172.7, 166.1, 143.2, 132.8, 131.5, 130.4, 129.6, 128.7,
128.2, 123.0, 122.2, 108.4, 64.6, 50.3, 42.6, 37.9, 31.4, 26.4, 26.2
ppm. ESI HRMS calcd for C22H22N2O4+H 379.1580, found
379.1666.
1
ethyl acetate (2:1) to give 11 (1.0 g, 82%) as a yellow solid. H
NMR (600 MHz, CDCl3): δ 9.73 (s, 1H), 8.06-8.04 (m, 2H),
7.68-7.67 (m, 1H), 7.54-7.52 (m, 1H), 7.44-7.42 (m, 2H),
7.38-7.36 (m, 1H), 7.19-7.17 (m, 1H), 6.94-6.92 (m, 1H),
4.81-4.78 (m, 1H), 4.34-4.32 (m, 2H), 3.98-3.95 (m, 1H),
3.79-3.76 (m, 1H), 3.51-3.50 (m, 1H), 3.26-3.21 (m, 4H),
2.56-2.51 (m, 1H), 1.98-1.93 (m, 1H), 1.79-1.77 (m, 1H),
1.10-1.05 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 196.3,
177.6, 171.6, 166.4, 143.4, 132.7, 130.4, 129.7, 128.9, 128.5,
128.3, 124.9, 123.3, 108.6, 64.0, 57.9, 51.3, 46.0, 42.0, 31.2,
27.5, 26.6 ppm. ESI HRMS calcd for C24H24N2O5+H 421.1719,
found 421.1696.
4.102-(1'-benzoyl-1-methyl-2,2'-dioxospiro[indoline-3,4'-piper
idin] -3'-yl)ethyl benzoate ( 9′)
1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 5.2 Hz, 2H), 7.77 (d,
J = 5.2 Hz, 2H), 7.59-7.57 (m, 1H), 7.51-7.49 (m, 1H), 7.46-7.42
(m, 4H), 7.33-7.30 (m, 1H), 7.15 (d, J = 4.8 Hz, 1H), 6.95-6.93
(m, 1H), 6.89 (d, J = 5.2 Hz, 1H), 4.42-4.37 (m, 1H), 4.25-4.21
(m, 2H), 3.94-3.90 (m, 1H), 3.25 (s, 3H), 3.13 (d, J = 6 Hz, 1H),
2.43-2.38 (m, 1H), 2.26-2.22 (m, 1H), 2.13-2.08 (m, 1H),
1.11-1.06 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 177.0,
173.5, 173.2, 166.1, 143.4, 135.8, 132.9, 131.6, 131.4, 130.1,
129.5, 129.0, 128.3, 128.2, 128.1, 123.2, 122.1, 108.6, 63.7, 50.9,
45.5, 40.9, 32.4, 26.3, 25.2 ppm. ESI HRMS calcd for
C25H26N2O4+H 483.1920, found 483.1932.
4.12methyl2-(1'-benzoyl-3'-(2-hydroxyethyl)-1-methyl-2,2'-di
oxospiro[indoline-3,4'-piperidin]-3'-yl) acetate (14)
To a solution of 11 (0.8 g, 1.9 mmol) in MeOH (25 mL) was
added N-Iodosuccinimide (1.1 g, 4.8 mmol) and K2CO3 (662 mg,
4.8 mmol). The reaction mixture was stirred at room temperature

6
for 2.5 h, at which TLC analysis indicated complete consumption
of starting material. The saturated Na2S2O3 solution was added to
destroy any remaining N-Iodosuccinimide or hypoiodite species.
The resultant mixture was extracted with EtOAc twice, dried
over sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
eluting with petroleum and ethyl acetate (1:1) to afford
1. (a) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion,
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1
compound 14 (684 mg, 80%) as a white solid. H NMR (400
MHz, CDCl3): δ 8.05-8.03 (m, 2H), 7.73-7.71 (m, 1H), 7.54-7.50
(m, 1H), 7.44-7.40 (m, 2H), 7.37-7.33 (m, 1H), 7.18-7.14 (m,
1H), 6.93-6.91 (m, 1H), 4.75-4.70 (m, 1H), 4.36-4.32 (m, 2H),
3.89-3.85 (m, 1H), 3.82 (s, 3H), 3.77-3.73 (m, 1H), 3.53-3.51 (m,
1H), 3.25 (s, 3H), 3.22-3.19 (m, 1H), 2.73-2.71 (m, 1H),
2.55-2.49 (m, 1H), 2.00-1.93 (m, 1H), 1.78-1.75 (m, 1H),
1.10-1.04 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 177.7,
171.7, 169.7, 166.4, 143.3, 132.7, 130.5, 129.7, 128.8, 128.6,
128.2, 125.0, 123.3, 108.6, 64.1, 52.3, 51.4, 49.3, 45.9, 42.1,
31.1, 29.6, 27.5, 26.5 ppm. ESI HRMS calcd for C25H26N2O6+H
451.1824, found 451.1915.
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4.132-(3'-(2-hydroxyethyl)-1-methyl-2,2'-dioxospiro[indoline-
3,4'-piperidin]-3'-yl)-N-methylacetamide (15)
To a solution of 14 (135 mg, 0.3 mmol) in 5 mL MeOH was
added MeNH2 (2.5 mL, 30% in MeOH) at room temperature, and
the mixture was then stirred overnight. After evaporation, the
residue was directly applied to silica gel column chromatography
eluting with CH2Cl2 and MeOH (20:1) to afford compound 15
(72.4 mg, 70%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ
7.52-7.50 (m, 1H), 7.30-7.27 (m, 1H), 7.11-7.07 (m, 2H),
6.88-6.86 (m, 1H), 4.64 (s, 1H), 4.24-4.21 (m, 1H), 3.95-3.91 (m,
1H), 3.83-3.67 (m, 2H), 3.56-3.46 (m, 3H), 3.19 (s, 3H),
2.98-2.96 (m, 1H), 2.78-2.77 (m, 3H), 2.38-3.31 (m, 1H),
1.79-1.74 (m, 2H), 1.65-1.56 (m, 1H), 0.94-0.94 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3): δ 177.9, 172.9, 168.8, 143.1,
128.9, 128.4, 124.9, 123.4, 108.6, 67.9, 61.8, 51.5, 46.2, 45.3,
30.9, 30.0, 26.5, 26.2, 25.6 ppm. ESI HRMS calcd for
C18H23N3O4+H 346.1722, found 346.1706.
4.142-(1'-benzoyl-3'-(2-hydroxyethyl)-1-methyl-2,2'-dioxospir
o[indoline-3,4'-piperidin]-3'-yl) acetamide (16)
To a solution of 14 (100 mg, 0.22 mmol) in 5 mL MeOH was
added NH3 H2O (2 mL, 35% in H2O) at room temperature, and
the mixture was then stirred for 1.5 h. After evaporation, the
residue was directly applied to silica gel column chromatography
eluting with CH2Cl2 and MeOH (20:1) to afford compound 16
1
(72 mg, 75%) as a yellow solid. H NMR (600 MHz, CDCl3): δ
8.04-8.03 (m, 2H), 7.55-7.52 (m, 1H), 7.50-7.48 (m, 1H),
7.44-7.41 (m, 2H), 7.36-7.34 (m, 1H), 7.14-7.11 (m, 1H),
6.93-6.92 (m, 1H), 6.50 (s, 1H), 5.57 (s, 1H), 4.37-4.29 (m, 3H),
3.98-3.96 (m, 1H), 3.86-3.82 (m, 1H), 3.65-3.61 (m, 1H), 3.25 (s,
3H), 3.15-3.13 (m, 1H), 2.48-2.43 (m, 1H), 1.98-1.93 (m, 1H),
1.86-1.82 (m, 1H), 1.22-1.16 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3): δ 177.6, 175.1, 171.8, 170.8, 166.4, 143.2, 132.7, 130.3,
129.6, 128.9, 128.4, 128.2, 124.8, 123.2, 108.6, 64.0, 51.4, 51.1,
46.2, 42.4, 30.5, 27.6, 26.5ppm. ESI HRMS calcd for
C24H25N3O5+H 436.1828, found 436.1831.
Acknowledgements
We are grateful for the financial support from the NSFC
(2102106, 21572138).
Supplementary data
Supplementary data associated with this article can be found
in the online version.
References and notes

7
10. Crystallographic Data for 7: CCDC 1532495, C15H1 N2O3,
ACCEPTED MANUSCRIPT
8
M:274.31, Space group: P -1, Cell: a = 7.8109(7), b =
8.1431(9), c = 12.2697(13), alpha = 102.257(9), beta =
99.744(8), gamma = 111.689(9), Temperature: 293K, calcd:
1.336 g/cm-3.
11. For more details, see the Supporting Information.
12. Liu, X. L.; Zhang, W. H.; Yao, Zh.; Liu, X. W.; Peng, L. J.;
Zhao, Z.; Lu, Y.; Zhou, Y.; Yuan, W. C. Tetrahedron 2015,
71, 9483–9495.