Organocatalytic double arylation of 3-isothiocyanato oxindoles: Stereocontrolled synthesis of complex spirooxindoles

Article abstract of DOI:10.1016/j.tet.2018.11.016

Quinones, precursors of aromatic structures, were firstly employed as the electrophiles for the organocatalytic Michael addition/cyclization cascade reaction with versatile 3-isothiocyanato oxindoles. Chiral bifunctional organocatalyst was appropriate for this enantioselective transformation to afford a variety of novel spirooxindoles, possessing a spirocyclic stereocenter adjacent to the aromatic ring, via asymmetric double arylation. These synthesized spirooxindoles are very difficult to access by the reported methods and were obtained in excellent chemical yields with excellent enantioselectivities.

Full text of DOI:10.1016/j.tet.2018.11.016

Accepted Manuscript
Organocatalytic double arylation of 3-isothiocyanato oxindoles: Stereocontrolled
synthesis of complex spirooxindoles
Lin-Lin Zhang, Bing-Chao Da, Shao-Hua Xiang, Shuai Zhu, Zi-Yun Yuan, Zhen Guo,
Bin Tan
PII:
S0040-4020(18)31356-5
https://doi.org/10.1016/j.tet.2018.11.016
TET 29927
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 September 2018
Revised Date: 6 November 2018
Accepted Date: 9 November 2018
Please cite this article as: Zhang L-L, Da B-C, Xiang S-H, Zhu S, Yuan Z-Y, Guo Z, Tan B,
Organocatalytic double arylation of 3-isothiocyanato oxindoles: Stereocontrolled synthesis of complex
spirooxindoles, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.11.016.
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Organocatalytic double arylation of 3-
isothiocyanato oxindoles: stereocontrolled
synthesis of complex spirooxindoles
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a,b
b
c,∗
b
b
a,∗
b,∗
Lin-Lin Zhang , Bing-Chao Da , Shao-Hua Xiang , Shuai Zhu , Zi-Yun Yuan , Zhen Guo and Bin Tan
a
College of Material Science & Engineering, Taiyuan University of Technology, Shanxi 030024, China
b
Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China
c
Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen
518055, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Organocatalytic double arylation of 3-isothiocyanato oxindoles: stereocontrolled
synthesis of complex spirooxindoles
a,b
b
c,∗
b
b
a,∗
Lin-Lin Zhang , Bing-Chao Da , Shao-Hua Xiang , Shuai Zhu , Zi-Yun Yuan , Zhen Guo and Bin
Tan
b,∗
a
College of Material Science & Engineering, Taiyuan University of Technology, Shanxi 030024, China
Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China
b
c
Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518055, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Quinones, precursors of aromatic structures, were firstly employed as the electrophiles for the
organocatalytic Michael addition/cyclization cascade reaction with versatile 3-isothiocyanato
oxindoles. Chiral bifunctional organocatalyst was appropriate for this enantioselective
transformation to afford a variety of novel spirooxindoles, possessing a spirocyclic stereocenter
adjacent to the aromatic ring, via asymmetric double arylation. These synthesized spirooxindoles
are very difficult to access by the reported methods and were obtained in excellent chemical
yields with excellent enantioselectivities.
Available online
Keywords:
Organocatalytic
Quinones
2
009 Elsevier Ltd. All rights reserved.
3
-Isothiocyanato oxindoles
Pyrrolidonyl spirooxindoles
Stereocontrol
—
——
∗
∗
∗
Corresponding author. e-mail: xiangsh@sustc.edu.cn
Corresponding author. e-mail: guozhen@tyut.edu.cn
Corresponding author. e-mail: tanb@sustc.edu.cn

2
Tetrahedron
1
. Introduction
(Figure 2b). The major challenge for this scenario would be the
ACCEPTED MANUSCRIPT
selection of appropriate bifunctional catalyst and reasonable
conditions to inhibit the side reactions derived from the multiple
Spirooxindoles are privileged structures which constitute the
1
core backbones of a large family of bioactive natural products
and a substantial of pharmaceutically active molecules. With the
recent advance of organocatalysis, plentiful methods have been
developed for the enantioselective construction of the pivotal
spiro quaternary centers. Among these structurally diversified
spirooxindole scaffolds, 3,3′- and 3,2′-pyrrolidinyl spirooxindoles
featured with the unique spiro ring fusion at the C-3 position of
the oxindoles core with a nitrogen contained five-membered-ring
16
reactive sites of quinones. To extent the diversity of the
2
pyrrolidinyl spirooxindoles and offer more alternative targets for
the biological activity test, herein, we would like to present our
initial results about the cascade Michael addition/cyclization of
3
3
-isothiocyanato oxindoles and quinones with organocatalysts.
received considerable attentions due to their significantly
4
medicinal relevance (Figure 1). Despite
a
variety of
transformations have been elegantly established in the past few
5,6
decades, the pursuit of highly enantioenriched spirooxindoles
remains long-lasting synthetic challenge. Meanwhile,
a
systematic and in-depth investigations disclosed that the related
biological activities were greatly influenced by the three-
dimensional architecture of the rigid spirocyclic structures. As a
consequence, the exploration of facile and efficient protocols to
construct novel spirooxindole frameworks is of great importance
for the discovery of new leading compounds and drug molecules.
Figure 2. Pioneering work with 3-isothiocyanato oxindole and
our strategy for the construction of novel spirooxindole scaffolds.
2
. Results and Discussion
Initially, the reaction of 3-isothiocyanato oxindole 1a and 1,4-
naphthoquinone 2a was performed in CH Cl at room temperate
2
2
with chiral bifunctional thiourea C1 (10 mol%) as the catalyst.
Gratifyingly, the desired product 3a was obtained in 93% yield
with 81% enantiomeric excess (ee) after 15 minutes (Table 1,
entry 1). Then a series of thioureas were screened to evaluate the
effect of the catalyst. Firstly, the utilization of catalyst C2 with a
similar structure to C1 resulted in quantitative yield and 85% ee
(
Table 1, entry 2). Interestingly, bifunctional thiourea C3 with a
primary amine was unable to control the stereoselectivity for this
reaction (Table 1, entry 3). Besides, bisthiourea catalyst C4 gave
rise to significant erosion of enantioselectivity and yield,
indicating the bifunctional catalyst which could activate oxindole
and quinone simultaneously is essential to give a satisfactory
reaction result (Table 1, entry 4). Next, the installation of axial
chirality to the bifunctional thiourea (C5) led to only 79% ee
Figure 1. Representative bioactive molecules containing
pyrrolidinyl spirooxindole framework.
The adoption of oxindoles and especially, isatin derivatives as
the starting materials greatly stimulated the rapid improvement of7
asymmetric construction of spirocyclic quaternary stereocenters.
8
On the other hand, isothiocyanates have been widely used in
(
Table 1, entry 5). Notably, the cinchona alkaloid derived catalyst
C6 promoted this reaction effectively to afford product 3a in
6% yield with 91% ee (Table 1, entry 6). Other analogues (C7-
organocatalytic asymmetric cyclization to synthesize optically
pure spirooxindoles with a synthetically useful thiolactone motif
9
8a
since its first disclosure by Wang’s group. Subsequently, the
creative merging of oxindoles and isothiocyanates was attained to
generate 3-isothiocyanato oxindoles as efficient nucleophiles for
the direct aldol/cyclization with simple and inactive ketones by
C9) were surveyed to further improve the reaction course but in
futile (Table 1, entries 7-9). Subsequent screening of various
solvents illustrated that CH Cl was superior to the other tested
2
2
solvents (Table 1, entries 10-15). Because of the instability of
compound 1a, similar reaction outcomes were obtained when
excess 1a (1.5 equiv) was used, while obvious reduction of
chemical yield was detected with 1.0 equivalent of 1a (Table 1,
entries 16-17). Further optimization found that the temperature
brought about negligible effect on the reaction course and 5
mol% of catalyst loading could uphold the stereoselectivity
effectively without loss of chemical yield (Table 1, entries 18-
9
10
Yuan’s group in 2011 (Figure 2a). After that, aldehydes as well
11
as a wide range of Michael acceptors were demonstrated to be
applicable substrates for the asymmetric [3+2] cyclization
reactions with 3-isothiocyanato oxindoles, delivering diversified
spirooxindole structures. Nonetheless, asymmetric installation of
a spirocyclic quaternary stereocenter adjacent to aryl substituent,
to the best of our knowledge, was rarely reported to-date.
Meanwhile, conventionally asymmetric substitution reaction of
inert arene to introduce stereogenic elements nearby an aromatic
2
1). Then we concluded the optimal reaction conditions as
follows: 1.2 equivalent of 1a, 1.0 equivalent of 2a, 5 mol% of C6
12
ring remains challenging. In this context, an ingenious solution
and CH Cl as the solvent at room temperature for 15 min (Table
13
2
2
was offered by Gong’s group with quinone as a precursor of
aromatic structure and the chiral isoindoline was achieved in
1
, entry 20).
excellent
enantioselectivity
via
organocatalytic
re-
With the optimized conditions in hand, we started to explore
14
aromatization. Inspired by this pioneering work and our
ongoing efforts on this field, we envisaged that quinone
derivatives should be competent reactants with 3-isothiocyanato
the generality of this reaction. Firstly, several 3-isothiocyanato
oxindoles with different substituents or substituted positions were
synthesized and subjected to the standard conditions with 2a. As
shown in Table 2, the reaction with C-5 methyl substituted
15
oxindoles to access
a
new class of spirocyclic
thiopyrrolidineoxindoles via asymmetric double-arylation

3
substrate 1b underwent smoothly to furnish th
A
e
C
de
C
sir
E
ed
P
p
TED
ct MANUSCRIPT
ro
du
3
b in 98% yield with 92% ee. The 3-isothiocyanato oxindole
a
Table 1. Optimization of the reaction conditions.
providing the respective products 3h (87% ee) and 3w (88% ee)
with better enantiocontrol, at the expense of lower yields.
a
Table 2. Substrate scope for the double arylation reactions.
Temp
yield
(%)
ee
c
entry catalyst
X
solvent
Y
b
(
°C)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
(%)
81
85
0
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C5
C6
C7
C8
C9
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
10
10
10
10
10
10
10
10
10
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
93
99
50
47
92
96
96
98
98
82
96
75
78
75
67
97
79
96
95
36
79
-91
-90
81
80
1
0
1
2
3
4
5
6
7
8
9
0
1
10 ClCH
2
CH
CHCl
2
Cl 1.2
3
1.2
-90
-90
-80
-79
-40
-4
-91
-90
-91
-91
-91
-23
1
1
1
1
1
1
1
1
1
2
2
10
10
10
10
10
10
10
10
10
5
toluene
THF
MeCN
1.2
1.2
1.2
1.2
1.5
1.0
1.2
1.2
CH
3
OH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
Cl
Cl
Cl
2
2
2
2
-30
rt
rt
Cl
Cl
2
1.2
1.2
96 (96)
80
1
2
a
Reactions were carried out with 1a, 1,4-naphthoquinone 2a (0.05 mmol) and
chiral thiourea catalyst in 0.5 mL of solvent for 15 min.
The yields were determined by H NMR analysis using CH Br as the
2 2
b
1
internal standard. An isolated yield is given in parentheses.
c
The ee values were determined by chiral HPLC analysis.
with electron-donating methoxy group on C5 or C6 position was
also suitable substrate to afford the corresponding product 3c or
3
d in excellent yield and enantioselectivity, while the oxindole
substrate possessing a fluoro substituent gave rise to slightly
lower enantiomeric excess (3e). The di-substituted substrate was
also well tolerated, and the spirooxindole 3f was yielded with
similar outcome as compared to the model reaction. Replacement
of the protecting group of oxindole from methyl to n-propyl or
benzyl provided the product 3g or 3h in excellent yield, albeit
lower stereoselectivity. Next, di-substituted 1,4-naphthoquinone
a
Reactions were carried out with 1 (0.24 mmol), 2 (0.20 mmol) and C6 (5
2 2
mol%) in 2 mL CH Cl at rt for 15 min, unless otherwise specified. Isolated
2
b was employed as the reactant for this reaction. From the
yields were given and the ee values were determined by chiral HPLC
analysis.
The reaction was conducted in the presence of 10 mol% CPA and the
results we can see, all the examined 3-isothiocyanato oxindole
nucleophiles could react with 2b effectively to give compounds
3
b
structure of the CPA is shown in Table 2.
i-3o in good to excellent yields (80-96%) with extremely good
enantioselectivities (92-98%). Aside from 1,4-naphthoquinones,
anthracene-1,4-dione (2c) was also applicable substrate for this
transformation, affording 3p-3v in 66-97% yields with 88-95%
enantioselectivities. Quinone 2d could deliver the product 3w in
To further verify the utility of current protocol, a gram-scale
reaction of 1a and 2a was then carried out under the optimal
conditions. The spirooxindole 3a was obtained in 95% yield with
9
3% ee (Figure 3a). Negligible deterioration of yield and slightly
9
0% yield, however, the stereocontrol for this transformation was
higher enantiomeric excess were observed as compared to the
small-scale synthesis. Furthermore, the plausible transition state
for the stereocontrol was depicted in Figure 3b. In the proposed
structure, the bifunctional chiral thiourea could activate both the
unsatisfactory (66% ee) under this set of conditions. Furthermore,
17
chiral phosphoric acid (CPA), another well-known bifunctional
catalyst, also exhibited the potential for catalyzing this reaction,

4
Tetrahedron
le MANUSCRIPT
3
-isothiocyanato oxindole and the quino
A
neCCviaEP
m
TED
ul
tip
hydrogen bonding. Meanwhile, the chiral backbone of the
catalyst offers an ideal environment for the introduction of the
chirality. Finally, the absolute configuration of compound 3a was
determined by X-ray single crystal analysis after
recrystallization (Figure 4), and those of other products in Table
4
. Experimental section
4
.1 General Information
Chemicals were purchased from commercial sources and used
18
2
were assigned by analogy.
as received without further purification unless mentioned
otherwise. Analytical thin layer chromatography (TLC) was
performed on precoated silica gel 60 GF254 plates. Flash column
chromatography was performed using Tsingdao silica gel.
Visualization on TLC was achieved by use of UV light (254 nm).
a
O
S
OH
NCS
C6 (5 mol%)
HN
O
+
N
CH2Cl2, rt
1
13
OOH
O
95% yield, 93% ee
1.377 g
N
H and C NMR spectra were recorded on Bruker 400 MHz
spectrometer in acetone-d or DMSO-d with tetramethylsilane
1
a (816 mg)
2a
3a
6
6
(
TMS) as internal standard. The chemical shifts are expressed in
O
1
b
ppm and coupling constants are given in Hz. Data for H NMR
are recorded as follows: chemical shift (δ, ppm), multiplicity (s =
singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br =
NCS
1
3
N
broad), coupling constant (Hz), integration. Data for C NMR
are reported in terms of chemical shift (δ, ppm). The
enantiomeric excess values were determined by chiral HPLC
with an Agilent instrument and a Daicel CHIRALPAK column.
The chiral HPLC methods were calibrated with the
corresponding racemic mixtures. The racemic products used to
determine the ee values were obtained without catalyst. High
resolution mass spectroscopy (HRMS) analyses were performed
at a Bruker Daltonics. Inc mass instrument (ESI). Absolute
configuration of a product was determined by X-ray analysis.
O
Me
Et
O
S
H
H
H
N
H
N
N
Ar
H
MeO
N
Figure 3. Gram-scale reaction and proposed bifunctional
activation transition state.
4
.2 General procedure for the synthesis of chiral spirooxindole 3
-Isothiocyanato oxindoles 1 (0.24 mmol, 1.2 equiv) and
3
catalyst C6 (6.0 mg, 5 mol%) were dissolved in CH Cl (2.0 mL)
2
2
at room temperature. Quinones 2 (0.2 mmol, 1.0 equiv) were
added over 10 minutes. Then the resulting solution was stirred at
the same temperature until TLC indicated that the reaction was
finished. The reaction mixture was concentrated under reduced
pressure and purified by flash chromatography with PE/EA (4/1)
to afford the products 3.
4
[
.2.1
benzo[f]isoindole-1,3'-indolin]-2'-one (3a)
Yellow solid, 70 mg, 96% yield, 91% ee. Mp 184-186 °C. H
NMR (400 MHz, Acetone-d ): δ 11.86 (s, 1H), 9.97 (s, 1H), 8.43
(R)-4,9-Dihydroxy-1'-methyl-3-thioxo-2,3-dihydrospiro
1
6
(d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.13 (brs, 1H), 7.71-
7
2
.59 (m, 2H), 7.42 (td, J = 7.6, 1.2 Hz, 1H), 7.13 (d, J = 8.8 Hz,
H), 7.05 (t, J = 7.2 Hz, 1H), 3.31 (s, 3H). C NMR (100 MHz,
13
Acetone-d ): δ 194.63, 171.16, 149.87, 144.96, 138.71, 130.32,
6
Figure 4. The X-ray structure of compound 3a.
1
1
29.82, 128.47, 126.10, 125.96, 125.47, 123.97, 123.48, 123.20,
23.01, 121.59, 116.16, 108.86, 72.49, 26.25. HRMS (ESI) calcd
3
. Conclusion
for [M+H] C H O N S, m/z: 363.0798, found: 363.0788.
2
0
15
3
2
-
1
IR(KBr): v 3265, 1647, 1600, 1564, 1517, 1446, 1375, 1234 cm .
In conclusion, we have developed an efficient organocatalytic
25
[
α]D = +143.40, (c = 0.50, acetone). HPLC analysis: Chiralpak
OD3 (hexane/i-PrOH = 85/15, flow rate = 1.0 mL/min, λ = 254
nm), t (minor) = 9.6 min; t (major) = 15.5 min.
enantioselective Michael addition/cyclization cascade reaction
for the construction of highly enantioenriched spirooxindoles.
Quinone derivatives were firstly utilized as the electrophiles and
nucleophiles for this type of reactions with versatile 3-
isothiocyanato oxindole substrates. A wide spectrum of novel
spirooxindoles possessing a spirocyclic stereocenter adjacent to
the aromatic ring which are not easily accessible by the reported
methods were synthesized in excellent yields with excellent
enantioselectivities via asymmetric double-arylation. As the
spirooxindole scaffolds are frequently occurred in medicinally
relevant molecules and the biological activities were significantly
influenced by the rigid configuration, the extension of the
complexity and diversity of the spirooxindole library may
provide more alternative targets for the downstream biological
activity studies.
R
R
4
[
.2.2 (R)-4,9-Dihydroxy-1',5'-dimethyl-3-thioxo-2,3-dihydrospiro
benzo[f]isoindole-1,3'-indolin]-2'-one (3b)
Yellow solid, 74 mg, 98% yield, 92% ee. Mp 202-204 °C. H
NMR (400 MHz, Acetone-d ): δ 11.85 (s, 1H), 9.96 (s, 1H), 8.42
1
6
(d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.11 (brs, 1H), 7.71-
7
6
.61 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H),
.94 (s, 1H), 3.28 (s, 3H), 2.24 (s, 3H). C NMR (100 MHz,
13
Acetone-d ): δ 194.52, 171.04, 149.85, 142.60, 138.67, 132.55,
6
1
1
30.48, 129.84, 128.42, 126.07, 125.91, 125.44, 124.60, 123.46,
23.35, 121.60, 116.18, 108.61, 72.61, 26.24, 19.97. HRMS
(
ESI) calcd for [M+H] C H O N S, m/z: 377.0954, found:
21 17 3 2
3
1
77.0947. IR(KBr): v 3261, 1645, 1602, 1560, 1508, 1446, 1375,
-1 25
242 cm . [α] = +133.40, (c = 0.50, acetone). HPLC analysis:
D

5
Chiralpak OD3 (hexane/i-PrOH = 85/15, flow r
A
ate
C
=
C
1
E
.0
P
m
T
L/
E
m
D
in, MA85
N SC
/1
U
5,
flo
w
R
ra
I
te = 1.0 mL/min, λ = 214 nm), t (minor) = 7.3
R
P
T
λ = 254 nm), t (minor) = 10.2 min; t (major) = 16.5 min.
min; t (major) = 14.2 min.
R
R
R
4
.2.3
(R)-4,9-Dihydroxy-5'-methoxy-1'-methyl-3-thioxo-2,3-
4.2.7
(R)-4,9-Dihydroxy-1'-propyl-3-thioxo-2,3-dihydrospiro
dihydrospiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3c)
Yellow solid, 77 mg, 98% yield, 90% ee. Mp 215-217 °C. H
[benzo[f]isoindole-1,3'-indolin]-2'-one (3g)
Yellow solid, 77 mg, 99% yield, 86% ee. Mp 194-196 °C. H
1
1
NMR (400 MHz, Acetone-d ): δ 11.85 (s, 1H), 9.98 (s, 1H), 8.42
NMR (400 MHz, Acetone-d ): δ 11.84 (s, 1H), 10.07 (s, 1H),
6
6
(
7
1
d, J = 8.0 Hz, 1H) 8.17 (d, J = 8.0 Hz, 1H), 8.11 (brs, 1H), 7.70-
8.39 (d, J = 8.8 Hz, 1H), 8.17 (brs, 1H), 8.14 (d, J = 8.4 Hz, 1H),
7.66-7.57 (m, 2H), 7.37 (td, J = 8.0, 1.6 Hz, 1H), 7.14 (d, J = 8.0
Hz, 1H), 7.08 (dd, J = 7.2, 1.6 Hz, 1H), 7.00 (td, J = 7.6, 1.2 Hz,
1H), 3.84-3.69 (m, 2H), 1.81-1.71 (m, 2H), 0.99 (t, J = 7.2 Hz,
.60 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 8.8, 2.8 Hz,
13
H), 6.82 (d, J = 2.4 Hz, 1H), 3.68 (s, 3H), 3.27 (s, 3H).
C
NMR (100 MHz, Acetone-d ): δ 194.63, 170.95, 156.54, 149.85,
6
13
1
1
2
3
1
0
8
38.74, 138.23, 129.85, 128.44, 126.59, 126.10, 125.96, 123.47,
23.28, 121.64, 116.22, 115.00, 110.82, 109.40, 72.85, 55.24,
6.34. HRMS (ESI) calcd for [M+H] C H O N S, m/z:
3H). C NMR (100 MHz, Acetone-d ): δ 194.55, 171.21, 149.78,
6
144.48, 138.85, 130.27, 129.71, 128.44, 126.09, 125.95, 125.59,
124.12, 123.51, 123.18, 122.81, 121.60, 116.26, 109.19, 72.56,
42.01, 20.68, 10.85. HRMS (ESI): calcd for [M+H]
C H O N S, m/z: 391.1111, found: 391.1107. IR(KBr): v 3371,
21
17
4
2
93.0904, found: 393.0894. IR(KBr): v 3279, 2839, 1622, 1602,
-
1
25
D
561, 1506, 1458, 1448, 1379, 1233 cm . [α] = +120.06, (c =
22 19
3
2
-
1
25
D
.50, acetone). HPLC analysis: Chiralpak OD3 (hexane/i-PrOH =
1645, 1602, 1558, 1508, 1448, 1375, 1242 cm . [α] = +168.10,
5/15, flow rate = 1.0 mL/min, λ = 254 nm), t (minor) = 11.6
(c = 0.50, acetone). HPLC analysis: Chiralpak OD3 (hexane/i-
R
min; t (major) = 23.5 min.
PrOH = 85/15, flow rate = 1.0 mL/min, λ = 214 nm), t (minor) =
R
R
6
.6 min; t (major) = 18.7 min.
R
4
.2.4
(R)-4,9-Dihydroxy-6'-methoxy-1'-methyl-3-thioxo-2,3-
dihydrospiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3d)
Yellow solid, 76 mg, 97% yield, 93% ee. Mp 189-191 °C. H
4.2.8
(R)-1'-Benzyl-4,9-dihydroxy-3-thioxo-2,3-dihydrospiro
1
[benzo[f]isoindole-1,3'-indolin]-2'-one (3h)
Yellow solid, 81 mg, 93% yield, 74% ee. Mp 212-214 °C. H
1
NMR (400 MHz, Acetone-d ): δ 11.83 (s, 1H), 9.89 (s, 1H),
6
8
.44-8.33 (m, 1H), 8.19-8.10 (m, 1H), 8.03 (brs, 1H), 7.66-7.56
NMR (400 MHz, Acetone-d ): δ 11.87 (s, 1H), 10.19 (s, 1H),
6
(
(
(
1
1
2
3
1
0
8
m, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.55
dd, J = 8.0, 2.4 Hz, 1H), 3.83 (s, 3H), 3.27 (s, 3H). C NMR
8.45 (d, J = 8.0 Hz, 1H), 8.36 (brs, 1H), 8.21 (d, J = 8.4 Hz, 1H),
7.73-7.62 (m, 2H), 7.58-7.53 (m, 2H), 7.40-7.28 (m, 4H), 7.14 (d,
J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.0 Hz,
13
100 MHz, Acetone-d ): δ 194.33, 171.77, 162.10, 149.83,
6
13
46.32, 138.64, 129.88, 128.40, 126.06, 125.89, 124.90, 123.45,
23.38, 121.59, 116.73, 116.15, 107.09, 96.67, 72.36, 55.16,
6.31. HRMS (ESI) calcd for [M+H] C H O N S, m/z:
1H), 5.15 (d, J = 16.0 Hz, 1H), 5.02 (d, J = 16.0 Hz, 1H).
C
NMR (100 MHz, Acetone d ): δ 194.66, 171.54, 149.87, 144.06,
6
138.87, 135.93, 130.11, 129.69, 128.61, 128.49, 127.44, 127.35,
126.18, 126.00, 125.65, 124.15, 123.55, 123.10, 121.60, 116.26,
109.82, 72.55, 43.93. HRMS (ESI) calcd for [M+H]
C H O N S, m/z: 439.1111, found: 439.1101. IR(KBr): v 3363,
21
17
4
2
93.0904, found: 393.0895. IR(KBr): v 3366, 2839, 1647, 1602,
-
1
25
D
566, 1506, 1458, 1448, 1379, 1230 cm . [α] = +124.21, (c =
.50, acetone). HPLC analysis: Chiralpak OD3 (hexane/i-PrOH =
2
6
19
3
2
-
1
25
D
5/15, flow rate = 1.0 mL/min, λ = 254 nm), t (minor) = 12.9
1647, 1610, 1560, 1498, 1437, 1448, 1375, 1240 cm . [α]
=
R
min; t (major) = 28.3 min.
+208.28, (c = 0.50, acetone). HPLC analysis: Chiralpak OD3
R
(
hexane/i-PrOH = 85/15, flow rate = 1.0 mL/min, λ = 254 nm), tR
4
.2.5 (R)-6'-Fluoro-4,9-dihydroxy-1'-methyl-3-thioxo-2,3-dihydro
(minor) = 8.4 min; t (major) = 12.1 min.
R
spiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3e)
1
Yellow solid, 74 mg, 97% yield, 89% ee. Mp 179-180 °C. H
4.2.9
(R)-4,9-Dihydroxy-1',6,7-trimethyl-3-thioxo-2,3-dihydro
NMR (400 MHz, Acetone-d ): δ 11.83 (s, 1H), 9.96 (s, 1H), 8.42
spiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3i)
Yellow solid, 68 mg, 87% yield, 92% ee. Mp 267-269 °C. H
6
1
(d, J = 8.4 Hz, 1H), 8.26-8.13 (m, 2H), 7.70-7.60 (m, 2H), 7.18
(
dd, J = 8.4, 5.6 Hz, 1H), 7.03 (dd, J = 9.6, 2.8 Hz, 1H), 6.84-
NMR (400 MHz, Acetone-d ): δ 11.70 (s, 1H), 9.85 (s, 1H), 8.07
6
13
6
1
1
1
1
.76 (m, 1H), 3.33 (s, 3H). C NMR (100 MHz, Acetone-d ): δ
(s, 1H), 7.85-7.80 (m, 2H), 7.39 (td, J = 7.6, 1.6 Hz, 1H), 7.12-
6
1
3
94.72, 171.66, 163.35 (d, J = 43.5 Hz), 149.94, 146.84 (d, J =
2.4 Hz), 138.73, 129.83, 128.55, 126.16, 126.05, 125.58 (d, J =
0.3 Hz), 123.52, 122.93, 121.61, 121.12 (d, J = 3.0 Hz), 116.01,
6.99 (m, 3H), 3.28 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H). C NMR
(100 MHz, Acetone-d ): δ 194.65, 171.65, 149.53, 144.85,
6
138.74, 138.20, 135.74, 130.22, 128.51, 125.78, 124.68, 123.88,
123.05, 123.02, 121.87, 121.24, 115.52, 108.85, 72.37, 26.26,
19.91, 19.35. HRMS (ESI) calcd for [M+H] C H O N S, m/z:
19
09.00 (d, J = 23.0 Hz), 97.69 (d, J = 28.4 Hz), 71.95, 26.49. F
NMR (376 MHz, Acetone-d ): δ -110.86. HRMS (ESI) calcd for
6
22 19
3
2
[
M+H] C H O N SF, m/z: 381.0704, found: 381.0700. IR(KBr):
391.1111, found: 391.1107. IR(KBr): v 3356, 1647, 1612, 1558,
20
14
3
2
-
1
25
-1 25
v 3375, 1635, 1602, 1560, 1504, 1452, 1379, 1240 cm . [α]
=
1508, 1448, 1375, 1238 cm . [α]
= +144.49, (c = 0.50,
D
D
+
132.42, (c = 0.50, acetone). HPLC analysis: Chiralpak OD3
acetone). HPLC analysis: Chiralpak OD3 (hexane/i-PrOH =
(hexane/i-PrOH = 85/15, flow rate = 1.0 mL/min, λ = 300 nm), tR
90/10, flow rate = 1.2 mL/min, λ = 254 nm), t (minor) = 14.5
R
(
minor) = 9.2 min; t (major) = 15.0 min.
min; t (major) = 22.5 min.
R
R
4
[
.2.6 (R)-4',11'-Dihydroxy-1-methyl-3'-thioxo-2',3'-dihydrospiro
indoline-3,1'-naphtho[2,3-f]isoindol]-2-one (3f)
Yellow solid, 76 mg, 97% yield, 90% ee. Mp 208-210 °C. H
NMR (400 MHz, Acetone-d ): δ 11.83 (s, 1H), 9.92 (s, 1H), 8.38
4.2.10
(R)-4,9-Dihydroxy-1',5',6,7-tetramethyl-3-thioxo-2,3-
dihydrospiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3j)
Yellow solid, 74 mg, 92% yield, 98% ee. Mp 259-261 °C. H
NMR (400 MHz, Acetone-d ): δ 11.71 (s, 1H), 9.81 (s, 1H), 8.10
1
1
6
6
(
dd, J = 8.4, 2.0 Hz, 1H), 8.20-8.00 (m, 2H), 7.67-7.57 (m, 2H),
.94 (s, 1H), 6.70 (s, 1H), 3.53 (s, 3H), 2.59 (s, 3H), 2.14 (s, 3H).
(s, 1H), 7.86 (s, 1H), 7.82 (brs, 1H), 7.20 (dd, J = 8.0, 0.8 Hz,
1H), 6.99 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 3.26 (s, 3H), 2.46 (s,
3H), 2.41 (s, 3H), 2.22 (s, 3H). C NMR (100 MHz, Acetone-d6):
6
13
13
C NMR (100 MHz, Acetone-d ): δ 194.36, 171.89, 149.79,
6
1
1
1
3
1
40.09, 138.62, 134.29, 132.47, 129.81, 128.42, 126.05, 126.03,
25.91, 123.59, 123.46, 122.44, 121.61, 120.21, 116.11, 72.32,
9.72, 18.04. HRMS (ESI) calcd for [M+H] C H O N S, m/z:
δ 194.55, 171.31, 149.52, 142.55, 138.67, 138.12, 135.70,
132.48, 130.36, 128.60, 125.74, 124.70, 124.53, 123.04, 122.18,
121.30, 115.56, 108.54, 72.46, 26.19, 19.95, 19.84, 19.29. HRMS
(ESI) calcd for [M+H] C H O N S, m/z: 405.1267, found:
22
19
3
2
91.1111, found: 391.1098. IR(KBr): v 3292, 1647, 1601, 1560,
23
21
3
2
-
1
25
D
495, 1437, 1369, 1240 cm . [α]
= +155.80, (c = 0.50,
405.1262. IR(KBr): v 3365, 1647, 1606, 1561, 1519, 1448, 1361,
-1 25
acetone). HPLC analysis: Chiralpak OD3 (hexane/i-PrOH =
1236 cm . [α] = +112.02, (c = 0.50, acetone). HPLC analysis:
D

6
Tetrahedron
Chiralpak OD3 (hexane/i-PrOH = 85/15,
A
flo
C
w
C
r
E
at
P
e
T
=
E
1
D
.0 MA(c
NU
=
0
S
.5
C
0,
R
ac
I
etone). HPLC analysis: Chiralpak IC (hexane/i-
P
T
mL/min, λ = 300 nm), t (minor) = 11.3 min; t (major) = 13.6
PrOH = 85/15, flow rate = 1.0 mL/min, λ = 254 nm), t (minor) =
R
R
R
min.
22.0 min; t (major) = 26.4 min.
R
4
2
.2.11 (R)-4,9-Dihydroxy-5'-methoxy-1',6,7-trimethyl-3-thioxo-
4.2.15
(R)-4,9-Dihydroxy-6,7-dimethyl-1'-propyl-3-thioxo-2,3-
,3-dihydrospiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3k)
dihydrospiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3o)
Yellow solid, 80 mg, 96% yield, 97% ee. Mp 231-232 °C. H
1
1
Yellow solid, 73 mg, 87% yield, 94% ee. Mp 242-244 °C. H
NMR (400 MHz, Acetone-d ): δ 11.67 (s, 1H), 9.78 (s, 1H), 8.03
NMR (400 MHz, Acetone-d ): δ 11.74 (s, 1H), 9.94 (s, 1H), 8.12
6
6
(
1
s, 1H), 7.77 (s, 1H), 7.66 (brs, 1H), 7.05-6.89 (m, 2H), 6.75 (s,
(s, 1H), 7.95-7.70 (m, 2H), 7.40 (td, J = 7.6, 1.6 Hz, 1H), 7.17 (d,
J = 8.0 Hz, 1H), 7.09 (dd, J = 7.2, 1.2 Hz, 1H), 7.03 (td, J = 7.6,
1.2 Hz, 1H), 3.90-3.73 (m, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 1.84-
13
H), 3.65 (s, 3H), 3.25 (s, 3H), 2.44 (s, 3H), 2.38 (s, 3H).
C
NMR (100 MHz, Acetone-d ): δ 194.68, 171.52, 156.58, 149.53,
6
13
1
1
2
38.72, 138.16, 138.11, 135.68, 128.42, 126.95, 124.63, 123.01,
21.81, 121.14, 115.52, 114.92, 110.77, 109.42, 72.69, 55.28,
6.42, 19.97, 19.37. HRMS (ESI) calcd for [M+H] C H O N S,
1.75 (m, 2H), 1.03 (t, J = 7.6 Hz, 3H). C NMR (100 MHz,
Acetone-d ): δ 194.61, 171.52, 149.51, 144.44, 138.69, 138.24,
6
135.70, 130.13, 128.45, 125.92, 124.72, 124.06, 123.09, 122.75,
121.97, 121.22, 115.63, 109.10, 72.40, 41.99, 20.67, 19.88,
19.34, 10.82. HRMS (ESI) calcd for [M+H] C H O N S, m/z:
23
21
4
2
m/z: 421.1217, found: 421.1207. IR(KBr): v 3368, 2835, 1654,
1
-
1
25
D
606, 1558, 1500, 1458, 1446, 1361, 1238 cm . [α] = +146.00,
24 23
3
2
(
c = 0.50, acetone). HPLC analysis: Chiralpak OD3 (hexane/i-
419.1424, found: 419.1414. IR(KBr): v 3388, 1654, 1610, 1559,
-1 25
PrOH = 85/15, flow rate = 0.8 mL/min, λ = 273 nm), t (minor) =
1
1521, 1449, 1362, 1238 cm . [α]
= +162.80, (c = 0.50,
acetone). HPLC analysis: Chiralpak OD3 (hexane/i-PrOH =
5/15, flow rate = 1.0 mL/min, λ = 254 nm), t (minor) = 9.1
R
D
5.1 min; t (major) = 24.3 min.
R
8
R
4
2
.2.12 (R)-4,9-Dihydroxy-6'-methoxy-1',6,7-trimethyl-3-thioxo-
min; t (major) = 13.2 min.
R
,3-dihydrospiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3l)
Yellow solid, 74 mg, 88% yield, 95% ee. Mp 208-210 °C. H
1
4.2.16 (R)-4',11'-Dihydroxy-1-methyl-3'-thioxo-2',3'-dihydrospiro
NMR (400 MHz, Acetone-d ): δ 11.70 (s, 1H), 9.76 (s, 1H), 8.07
[indoline-3,1'-naphtho[2,3-f]isoindol]-2-one (3p)
Yellow solid, 69 mg, 84% yield, 92% ee. Mp 298-299 °C. H
6
1
(s, 1H), 7.82 (s, 1H), 7.71 (brs, 1H), 6.97 (d, J = 8.0 Hz, 1H),
6
3
.73 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.0, 2.4 Hz, 1H), 3.83 (s,
H), 3.27 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H). C NMR (100 MHz,
NMR (400 MHz, Acetone-d ): δ 12.18 (s, 1H), 9.91 (s, 1H), 9.06
6
13
(s, 1H), 8.73 (s, 1H), 8.33-8.14 (m, 2H), 8.10-7.99 (m, 1H), 7.65-
7.57 (m, 2H), 7.47-7.41 (m, 1H), 7.20-7.13 (m, 2H), 7.10-7.03
Acetone-d ): δ 194.36, 172.16, 162.02, 149.50, 146.23, 138.65,
1
1
HRMS (ESI) calcd for [M+H] C H O N S, m/z: 421.1217,
found: 421.1210. IR(KBr): v 3356, 2839, 1653, 1604, 1508, 1458,
6
13
38.09, 135.65, 128.57, 124.81, 124.65, 123.03, 122.09, 121.21,
17.06, 115.51, 107.03, 96.64, 72.20, 55.13, 26.27, 19.88, 19.32.
(m, 1H), 3.33 (s, 3H). C NMR (100 MHz, Acetone-d ): δ
6
194.08, 171.48, 150.95, 144.93, 138.49, 132.83, 131.14, 130.29,
128.73, 128.33, 128.00, 127.27, 126.42, 125.98, 125.08, 124.04,
123.69, 123.00, 120.77, 120.54, 114.57, 108.83, 72.28, 26.22.
HRMS (ESI) calcd for [M+H] C H O N S, m/z: 413.0954,
23
21
4
2
-
1
25
D
1
448, 1363, 1227 cm . [α]
= +107.02, (c = 0.50, acetone).
24 17
3
2
HPLC analysis: Chiralpak OD3 (hexane/i-PrOH = 85/15, flow
rate = 1.0 mL/min, λ = 254 nm), t (minor) = 13.6 min; t (major)
found: 413.0957. IR(KBr): v 3421, 1655, 1610, 1560, 1508, 1449,
-1 25
1364, 1259 cm . [α]
D
= +149.62, (c = 0.50, acetone). HPLC
R
R
=
24.9 min.
analysis: Chiralpak IC (hexane/i-PrOH = 85/15, flow rate = 1.0
mL/min, λ = 320 nm), t (minor) = 13.6 min; t (major) = 19.7
min.
R
R
4
.2.13 (R)-6-Fluoro-4',11'-dihydroxy-1-methyl-3'-thioxo-2',3'-
dihydrospiro[indoline-3,1'-naphtho[2,3-f]isoindol]-2-one (3m)1
Yellow solid, 65 mg, 80% yield, 92% ee. Mp 252-253 °C. H
4.2.17 (R)-4',11'-Dihydroxy-1,5-dimethyl-3'-thioxo-2',3'-dihydro
NMR (400 MHz, Acetone-d ): δ 11.70 (s, 1H), 9.80 (s, 1H), 8.12
spiro[indoline-3,1'-naphtho[2,3-f]isoindol]-2-one (3q)
Yellow solid, 75 mg, 88% yield, 95% ee. Mp 281-283 °C. H
6
1
(s, 1H), 7.94-7.81 (m, 2H), 7.15 (dd, J = 8.0, 5.2 Hz, 1H), 7.01
(
3
1
dd, J = 9.2, 2.4 Hz, 1H), 6.83-6.76 (m, 1H), 3.32 (s, 3H), 2.47 (s,
NMR (400 MHz, DMSO-d ): δ 12.07 (s, 1H), 11.16 (s, 1H), 9.52
(s, 1H), 9.03 (s, 1H), 8.65 (s, 1H), 8.30-8.22 (m, 1H), 8.05-8.00
6
13
H), 2.43 (s, 3H). C NMR (100 MHz, Acetone-d ): δ 194.78,
6
71.87, 164.30 (d, J = 244.9 Hz), 149.63, 146.81 (d, J = 12.4
(m, 1H), 7.64-7.56 (m, 2H), 7.26-7.20 (m, 1H), 7.11 (d, J = 8.0
13
Hz), 138.48 (d, J = 62.9 Hz), 135.84, 128.62, 125.47 (d, J = 9.9
Hz, 1H), 6.94 (s, 1H), 3.37 (s, 3H), 2.20 (s, 3H). C NMR (100
Hz), 124.80, 123.10, 121.81, 121.43, 121.40, 121.30, 115.40,
MHz, DMSO-d ): δ 192.79, 171.94, 149.88, 142.56, 139.24,
6
1
1
08.74 (d, J = 23.8 Hz), 97.57 (d, J = 28.5 Hz), 71.80, 26.40,
132.78, 132.50, 131.03, 130.77, 129.21, 128.69, 127.93, 127.84,
126.95, 126.20, 125.01, 124.92, 123.71, 121.85, 120.18, 115.17,
109.40, 72.70, 27.30, 20.81. HRMS (ESI) calcd for [M+H]
C H O N S, m/z: 427.1111, found: 427.1117. IR(KBr): v 3277,
19
9.82, 19.29. F NMR (376 MHz, Acetone-d ): δ -111.14.
6
HRMS (ESI) calcd for [M+H] C H FO N S, m/z: 409.1017,
found: 409.1011. IR(KBr): v 3336, 1653, 1616, 1560, 1506, 1450,
1
22
18
3
2
25
19
3
2
-
1
25
D
-1
25
363, 1238, 1084 cm . [α]
= +118.26, (c = 0.50, acetone).
1647, 1609, 1561, 1521, 1456, 1369, 1221 cm . [α] = +151.26,
D
HPLC analysis: Chiralpak OD3 (hexane/i-PrOH = 85/15, flow
rate = 0.8 mL/min, λ = 254 nm), t (minor) = 12.2 min; t (major)
(c = 0.50, acetone). HPLC analysis: Chiralpak IC (hexane/i-
PrOH = 85/15, flow rate = 0.8 mL/min, λ = 240 nm), t (minor) =
R
R
R
=
16.8 min.
12.9 min; t (major) = 28.3 min.
R
4
.2.14 (R)-4,9-Dihydroxy-1',5',6,7,7'-pentamethyl-3-thioxo-2,3-
4.2.18 (R)-4',11'-Dihydroxy-5-methoxy-1-methyl-3'-thioxo-2',3'-
dihydrospiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3n)
Yellow solid, 75 mg, 90% yield, 92% ee. Mp 207-209 °C. H
dihydrospiro[indoline-3,1'-naphtho[2,3-f]isoindol]-2-one (3r)
Yellow solid, 75 mg, 85% yield, 88% ee. Mp 222-224 °C. H
1
1
NMR (400 MHz, Acetone-d ): δ 11.72 (s, 1H), 9.79 (s, 1H), 8.08
NMR (400 MHz, Acetone-d ): δ 12.16 (s, 1H), 9.91 (s, 1H), 9.05
6
6
(
s, 1H), 7.84 (s, 1H), 7.74 (brs, 1H), 6.96 (s, 1H), 6.70 (s, 1H),
.56 (s, 3H), 2.62 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).
(s, 1H), 8.73 (s, 1H), 8.28-8.15 (m, 2H), 8.07-8.01 (m, 1H), 7.62-
7.56 (m, 2H), 7.08-7.03 (m, 1H), 7.02-6.95 (m, 1H), 6.87-6.84
(m, 1H), 3.68 (s, 3H), 3.28 (s, 3H). C NMR (100 MHz,
3
13
13
C NMR (100 MHz, Acetone-d ): δ 194.40, 172.32, 149.47,
6
1
1
1
39.99, 138.68, 138.04, 135.63, 134.17, 132.44, 128.48, 126.40,
24.60, 123.01, 122.38, 122.28, 121.19, 120.14, 115.45, 72.15,
9.93, 19.69, 19.34, 18.02. HRMS (ESI) calcd for [M+H]
Acetone-d ): δ 194.10, 171.15, 156.55, 150.91, 138.50, 138.25,
6
132.82, 131.15, 128.72, 128.33, 128.08, 127.25, 127.08, 126.40,
125.11, 123.63, 120.80, 120.71, 115.02, 114.64, 110.84, 109.33,
72.63, 55.21, 26.26. HRMS (ESI) calcd for [M+H] C H O N S,
C H O N S, m/z: 419.1424, found: 419.1409. IR(KBr): v 3354,
1
24
23
3
2
25 19
4
2
-
1
25
654, 1605, 1561, 1521, 1449, 1358, 1238 cm . [α] = +152.56,
m/z: 443.1060, found: 443.1059. IR(KBr): v 3356, 2833, 1654,
D

7
-
1
A
25
1
(
606, 1558, 1521, 1460, 1437, 1363, 1225 cm
c = 0.50, acetone). HPLC analysis: Chiralpak OD3 (hexane/i-
PrOH = 85/15, flow rate = 0.8 mL/min, λ = 254 nm), t (minor) =
. [
C
α]CE
=
P
+
T
19
E
6.
D
38,MA12
N
4.
U
19
S
, 1
C
23
R
.6
I
9
P
, 1
T
22.75, 120.70, 120.63, 114.65, 109.11, 72.32,
D
41.98, 20.68, 10.81. HRMS (ESI) calcd for [M+H] C H O N S,
m/z: 441.1267, found: 441.1275. IR(KBr): v 3366, 1655, 1608,
1556, 1487, 1445, 1367, 1223 cm . [α] = +194.52, (c = 0.50,
26
21
3
2
R
-
1
25
D
1
9.1 min; t (major) = 34.4 min.
R
acetone). HPLC analysis: Chiralpak IF (hexane/i-PrOH = 85/15,
4
.2.19
(R)-4,9-Dihydroxy-1',5'-dimethyl-3-thioxo-2,3-dihydro
flow rate = 0.8 mL/min, λ = 254 nm), t (major) = 23.2 min; tR
R
spiro[benzo[f]isoindole-1,3'-indolin]-2'-one (3s)
1
(minor) = 29.1 min.
Yellow solid, 86 mg, 97% yield, 94% ee. Mp 246-247 °C. H
NMR (400 MHz, Acetone-d ): δ 12.16 (s, 1H), 9.85 (s, 1H), 9.00
4.2.23
(R)-4',7'-dihydroxy-1,5',6'-trimethyl-3'-thioxospiro
6
(
7
6
s, 1H), 8.69 (s, 1H), 8.22-8.12 (m, 2H), 8.05-7.96 (m, 1H), 7.58-
[indoline-3,1'-isoindolin]-2-one (3w)
Yellow solid, 61 mg, 90% yield, 66% ee. Mp 235-236 °C. H
1
.52 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H),
13
.55 (dd, J = 8.0, 2.4 Hz, 1H), 3.82 (s, 3H), 3.29 (s, 3H).
C
NMR (400 MHz, Acetone-d ): δ 10.88 (s, 1H), 9.84 (s, 1H),
6
NMR (100 MHz, Acetone-d ): δ 193.79, 172.16, 162.08, 150.93,
7.43-7.38 (m, 1H), 7.22 (brs, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.06-
7.02 (m, 2H), 3.27 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H). C NMR
6
1
3
1
1
1
46.27, 138.40, 132.81, 131.09, 128.70, 128.33, 128.02, 127.24,
26.38, 125.04, 124.98, 123.66, 120.70, 120.66, 117.30, 114.57,
07.07, 96.67, 72.15, 55.15, 26.31. HRMS (ESI) calcd for
(100 MHz, Acetone-d ): δ 195.43, 170.76, 149.59, 144.95,
6
141.36, 133.11, 130.20, 128.79, 125.79, 124.92, 123.71, 122.90,
119.93, 108.81, 72.72, 26.23, 12.51, 10.89. HRMS (ESI) calcd
for [M+H] C H O N S, m/z: 341.0954, found: 341.0949.
[
M+H] C H O N S, m/z: 443.1060, found: 443.1066. IR(KBr):
25 19 4 2
v 3356, 2837, 1655, 1622, 1560, 1508, 1459, 1449, 1375, 1227
18
17
3
2
-
1
25
D
cm . [α]
= +157.42, (c = 0.50, acetone). HPLC analysis:
IR(KBr): v 3445, 1645, 1611, 1560, 1517, 1452, 1449, 1377,
-
1
25
D
Chiralpak OD3 (hexane/i-PrOH = 85/15, flow rate = 1.0 mL/min,
λ = 300 nm), t (minor) = 17.9 min; t (major) = 36.1 min.
1225 cm . [α] = +26.24, (c = 0.50, acetone). HPLC analysis:
Chiralpak OD3 (hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min,
λ = 254 nm), t (minor) = 7.3 min; t (major) = 9.4 min.
R
R
R
R
4
.2.20
(R)-6-Fluoro-4',11'-dihydroxy-1-methyl-3'-thioxo-2',3'-
dihydrospiro[indoline-3,1'-naphtho[2,3-f]isoindol]-2-one (3t) 1
Yellow solid, 58 mg, 66% yield, 92% ee. Mp 263-265 °C.
Acknowledgments
H
Financial support from the National Natural Science Foundation
of China (21772081), Shenzhen Special Funds for the
Development of Biomedicine, Internet, New Energy, and New
Material Industries (JCYJ20170412151701379) and Southern
University of Science and Technology (K01211007) is greatly
appreciated.
NMR (400 MHz, Acetone-d ): δ 12.13 (s, 1H), 9.86 (s, 1H), 9.04
6
(s, 1H), 8.72 (s, 1H), 8.34-8.16 (m, 2H), 8.07-7.99 (m, 1H), 7.62-
7
.55 (m, 2H), 7.24-7.18 (m, 1H), 7.05-6.99 (m, 1H), 6.82-6.76
13
(m, 1H), 3.33 (s, 3H). C NMR (100 MHz, Acetone-d ): δ
6
1
1
1
1
9
94.21, 171.92, 164.36 (d, J = 245.6 Hz), 151.05, 146.85 (d, J =
2.3 Hz), 138.50, 132.86, 131.18, 128.52 (d, J = 41.0 Hz),
27.99, 127.30, 126.45, 125.64 (d, J = 10.0 Hz), 125.11, 123.73,
21.67, 121.64, 120.78, 120.33, 114.41, 108.79 (d, J = 22.8 Hz),
Supplementary data
19
Experimental procedures, characterization data for all new
compounds.
7.62 (d, J = 28.5 Hz), 71.74, 26.43. F NMR (376 MHz,
-111.08. HRMS (ESI) calcd for [M+H]
C H FO N S, m/z: 431.0860, found: 431.0867. IR(KBr): v 3356,
Acetone-d6):
δ
2
4
16
3
2
References
-
1
25
D
1
654, 1616, 1559, 1506, 1449, 1375, 1261, 1217 cm . [α]
=
[
1] (a) Bindra, J. S. In: The Alkaloids (Ed.: Manske, R. H. F.), Academic
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+
158.91, (c = 0.50, acetone). HPLC analysis: Chiralpak OD-3
(hexane/i-PrOH = 85/15, flow rate = 0.8 mL/min, λ = 254 nm), tR
(
minor) = 14.7 min; t (major) = 19.6 min.
R
(c) Lin, H.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2003, 42, 36. (d)
4
.2.21
(R)-4',11'-Dihydroxy-1,5,7-trimethyl-3'-thioxo-2',3'-
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dihydrospiro[indoline-3,1'-naphtho[2,3-f]isoindol]-2-one (3u) 1
Yellow solid, 77 mg, 87% yield, 88% ee. Mp 251-253 °C. H
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Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.; Zou, B.;
Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.; Cohen, S.
B.; Spencer, K. R.; Gonzalez-Paez, G. E.; Lakshminarayana, S. B.; Goh,
A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.-P.; Brun, R.;
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6
(s, 1H), 8.71 (s, 1H), 8.25-8.15 (m, 2H), 8.05-7.97 (m, 1H), 7.62-
7
3
1
1
1
.52 (m, 2H), 6.95 (s, 1H), 6.78 (s, 1H), 3.57 (s, 3H), 2.61 (s,
H), 2.16 (s, 3H). C NMR (100 MHz, Acetone-d ): δ 193.84,
72.22, 150.92, 140.05, 138.32, 134.25, 132.81, 132.45, 131.10,
28.71, 128.34, 127.96, 127.25, 126.59, 126.37, 125.01, 123.64,
22.54, 120.91, 120.70, 120.16, 114.52, 72.10, 19.69, 18.02.
13
6
HRMS (ESI) calcd for [M+H] C H O N S, m/z: 441.1267,
found: 441.1270. IR(KBr): v 3356, 1655, 1605, 1560, 1506, 1445,
1
analysis: Chiralpak IC (hexane/i-PrOH = 85/15, flow rate = 1.0
mL/min, λ = 273 nm), t (minor) = 18.5 min; t (major) = 25.9
min.
26
21
3
2
-
1
25
D
362, 1231 cm . [α]
= +144.80, (c = 0.50, acetone). HPLC
R
R
[
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4
.2.22
(R)-4',11'-Dihydroxy-1-propyl-3'-thioxo-2',3'-dihydro
spiro[indoline-3,1'-naphtho[2,3-f]isoindol]-2-one (3v)
1
Yellow solid, 72 mg, 82% yield, 88% ee. Mp 237-239 °C. H
NMR (400 MHz, Acetone-d ): δ 12.19 (s, 1H), 10.00 (s, 1H),
6
9
7
2
.06 (s, 1H), 8.73 (s, 1H), 8.27-8.17 (m, 2H), 8.07-7.01 (m, 1H),
.62-7.55 (m, 2H), 7.41 (td, J = 7.6, 1.2 Hz, 1H), 7.21-7.14 (m,
H), 7.04 (td, J = 7.6, 0.8 Hz, 1H), 3.92-3.75 (m, 2H), 1.87-1.77
13
(m, 2H), 1.05 (t, J = 7.6 Hz, 3H). C NMR (100 MHz, Acetone-
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1
30.20, 128.71, 128.31, 127.93, 127.25, 126.40, 126.13, 125.10,
1
996, 49, 832. (c) Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino,

8
Tetrahedron
ACCEPTED MANUSCRIPT
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