Protecting group-directed diastereodivergent synthesis of chiral tetrahydronaphthalene-fused spirooxindoles via bifunctional tertiary amine catalysis

Article abstract of DOI:10.1021/acs.joc.9b01501

A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids bearing a quaternary carbon center at the β-position of THN has been developed. The diastereodivergent direct catalytic Michael-aldol reaction between 3-ylideneoxindole and 2-methylbenzaldehyde was accomplished by using bifunctional tertiary amine. Simply changing the protecting group on the substrate in the organocatalytic cascade reaction led to inverted diastereoselectivity in good yields with a high ee value. To explain the diastereodivergence of the organocatalytic Michael-aldol cascade, we also proposed plausible transition-state models for [4 + 2] annulation based on the observed stereochemistry of the products.

Full text of DOI:10.1021/acs.joc.9b01501

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Article
Protecting Group-directed Diastereodivergent
Synthesis of Chiral Tetrahydronaphthalene-fused
Spirooxindoles via Bifunctional Tertiary Amine Catalysis
Biao Wang, Xiao-Hui Wang, Wei Huang, Jin Zhou, Hong-Ping Zhu, Cheng Peng, and Bo Han
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01501 • Publication Date (Web): 26 Jul 2019
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Protecting Group-directed Diastereodivergent Synthesis of
Chiral Tetrahydronaphthalene-fused Spirooxindoles via
Bifunctional Tertiary Amine Catalysis
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Biao Wang,†‡ Xiao-Hui Wang,§‡ Wei Huang,† Jin Zhou,† Hong-Ping Zhu,† Cheng
Peng,†* and Bo Han†*
†
Key laboratory of Characteristic Chinese Resource in Southwest China, School of Pharmacy,
Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. E-mail:
pengcheng@cdutcm.edu.cn; hanbo@cdutcm.edu.cn.
§ Department of Pharmacy, Naval Authorities Clinic, Beijing 100841, China.
ABSTRACT: A collection of chiral spirocyclic THN-oxindole hybrids bearing a
quaternary carbon center at the β-position of THN have been developed. The
diastereodivergent direct catalytic Michael-aldol reaction between 3-ylideneoxindole
and 2-methylbenzaldehyde was accomplished by using bifunctional tertiary amine.
Simply by changing the protecting group on the substrate in the organocatalytic cascade
reaction led to inverted diastereoselectivity in good yields with high ee value. To
explain the diastereodivergence of the organocatalytic Michael-aldol cascade, we also
proposed plausible transition-state models for the [4+2] annulation based on the
observed stereochemistry of the products.
INTRODUCTION
Both tetrahydronaphthalene (THN) and spirooxindole are privileged frameworks that
can be found frequently in a vast number of natural products and pharmaceuticals with
antitumor activity (Figure 1a).1, 2 As a combination of privileged frameworks is a useful
way for systematically enhancing molecular diversity and thus discovering novel
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chemical entities in drug discovery,3 the easy construction of THN incorporated
spirooxindoles with a simple starting material is significant for natural product-like
molecule synthesis, drug discovery and biomedical research.
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Figure 1. (a) Example bioactive compounds with the privileged skeleton. (b) Asymmetric
construction of the C3-spirooxindole bearing various chemically complex rings.
It has been demonstrated that the stereochemistry in spirocyclic oxindoles has a
significant effect on their binding affinities to drug targets,4 so the asymmetric synthesis
of the optically pure C3-spirooxindole molecules has become a hot topic in medicinal
chemistry.5 Many methods have been established for enantio-selective synthesis of C3-
spirooxindoles fused with various chemically complex rings from three to seven
members (Figure 1b).6 For the synthetic methodologies of the designed architectures,
few attempts for the incorporation of the pharmacologically important THN with
spirooxindoles have been reported in the past few decades.7
Although the Smith’s groups firstly reported the asymmetric synthesis of THN-fused
spirooxindole bearing a quaternary carbon center at the α-position of THN,7a and the
Connon’s group documented the enantio- and diastereoselective synthesis of
spirooxindole analogues bearing a quaternary carbon center at the β-position of THN,7b
to the best of our knowledge, the protocols for the asymmetric construction of chiral
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spirooxindole-THN hybrids are still underdeveloped.8 From the retrosynthetic analysis,
the desired structure can be from 3-ylideneoxindole and 2-methylbenzaldehyde by
performing a tandem Michael-aldol reaction, and the chiral bifunctional H-Bonding
catalyst may afford the asymmetric version of the final products (Scheme 1).
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Scheme 1. Synthetic design of the THN-fused C3-spirooxindole scaffold bearing a hydrogen bond
acceptor on the hydronaphthalene moiety.
Despite great progress made on asymmetric synthesis, it remains a great challenge
for researchers to realize both enantio- and diastereocontrol for a complex molecule
bearing multiple stereogenic centers. To date, different approaches have been developed
to tune the diastereoselectivity efficiently in asymmetric catalysis,9 such as using
different chiral catalysts,10 central metals,11 ligands,12 the additives,13 or utilizing the
dual catalytic systems.14 However, it is rare for just changing the protecting group (PG)
of the substrate to inverse the diastereoselectivity,15 and it is still a promising field for
both asymmetric catalysis and medicinal chemistry. We wondered whether the different
PG could modulate the diastereoselectivity of the final products via distinct transition
state. If successful, we can evaluate how the stereochemistry of the all-carbon-based
chiral C3-spirooxindole scaffold influence the bioactivity.
RESULTS AND DICUSSION
We commenced our research by screening the reaction between Boc-protected 3-
ylideneoxindole 1a-Boc and nitro-substituted 2-methylbenzaldehyde 2a (Table 1),
promoted by a range of bifunctional hydrogen-bonding catalysts or chiral tertiary amine
catalysts (C1-C9). We planned to convert the intermediate product to its analogue 3a-
Boc and isomer 4a-Boc in order to protect the hydroxyl group and thereby ensure
solubility in CDCl3 for clear NMR spectra.
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Table 1. Optimization of reaction conditions.a
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entry
1
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Cat.
C1
C2
C3
C4
C5
C6
C7
C8
C9
C7
C7
C7
C7
C7
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
product (major)
yield (%)b
47
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65
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66
73
63
45
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84
80
65
drc
eed
24%
8%
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
65:35
73:27
75:25
71:29
78:22
55:45
80:20
70:30
81:19
60:40
55:45
50:50
88:12
90:10
7%
72%
78%
82%
96%
92%
95%
92%
65%
71%
99%
99%
9
10
11
12
13e
14f
MeCN
CH2Cl2
CH2Cl2
a Unless noted otherwise, reactions were performed with 1a-Boc (47.6 mg, 0.15 mmol), 2a (37.8
mg, 0.18 mmol) and Cat. (0.03 mmol) in anhydrous solvent (4 mL) at 0 oC for 24 h under N2; b
c
1
Yield of isolated major isomer. Calculated based on H NMR analysis of the crude reaction
mixture. d Determined by chiral HPLC analysis of major isomer. Reaction was performed at -
10 oC for 48h. f Reaction was performed at -20 oC for 48h.
e
To our satisfaction, using Takemoto's bifunctional chiral thiourea catalyst C7 gave
high diastereo- and enantioselectivities (Table 1, entry 7). Then we explored more
reaction parameters in order to improve yield. The choice of solvent affected the
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reaction, the yield and dr were sharply declined (entries 10-12). Reducing the reaction
temperature to -10 oC and -20 oC, and extending the reaction time led to a high dr and
ee (entries 13 and 14) but lower yield (entry 14). The optimal conditions were found to
be reaction in anhydrous CH2Cl2 at -10 oC for 48 hours (entry 13).
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Next, we investigated the N-protected group of the 3-ylideneoxindole, such as Cbz,
COOEt, and Ac, affording the corresponding compounds in weak yield (Table 2, entries
2-4). The dr and ee value were obviously changed. Thus, the Boc-protected substrate
was preferable for the cascade reaction.
Table 2. Scope for the protecting group of 1.a
entry
1
PG
1a
product (major) yield (%)b drc (3a:4a)
eed
Boc
Cbz
COOEt
Ac
1a-Boc
1a-Cbz
1a-COOEt
1a-Ac
3a-Boc
3a-Cbz
3a-COOEt
3a-Ac
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70
75
78
51
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10
88:12
90:10
75:25
68:32
6:94
99%
99%
99%
69%
89%
67%
57%
51%
2
3
4
5e
6e
7e
8e
Bn
1a-Bn
4a-Bn
Me
1a-Me
1a-Allyl
1a-CPh3
4a-Me
7:93
Allyl
CPh3
4a-Allyl
4a-CPh3
5:95
<5:95
a Unless noted otherwise, reactions were performed with 1a (0.15 mmol), 2a (37.8 mg, 0.18
mmol) and C7 (12.4 mg, 0.03 mmol) in anhydrous CH2Cl2 (4 mL) at -10 oC for 24 hours under
N2. b Yield of isolated major isomer. c Calculated based on 1H NMR analysis of the crude reaction
e
mixture. d Determined by chiral HPLC analysis of major isomer. Reaction was performed at -
10 oC for 7 days.
Furthermore, applying these optimized conditions to the other N-protected substrates
1a, like the N-Bn, N-Me, N-Allyl, and N-CPh3, led to inverted diastereoselectivity,
generating the reversed products (entries 5-8). The results showed that the Bn-protected
compound 4a-Bn was the best in 51% yield with 91:9 dr and 89% ee (entry 5 vs 6-8).
Hence, the optimal reaction conditions were established: (i) for the Boc-protected
substrates, 20 mol % of C7 and 4Å MS (25 mg) in anhydrous CH2Cl2 at -10 oC for 48
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h under N2; (ii) for the Bn-protected substrates, 20 mol % of C7 and 4Å MS (25 mg) in
anhydrous CH2Cl2 at -10 oC for 7 days under N2.
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With these optimal conditions in hand, we investigated the scope of the reaction using
Boc-protected substrate 1-Boc for the preparation of 3 and Bn-protected substrate 1-Bn
for the synthesis of 4 (Scheme 2 and 3). These two sets of compounds are
diastereoisomers with different protecting groups. The electronic properties and
position of R1 substituents on the oxoindole moiety slightly affected the reaction, except
in the case of 4-Br 3-ylideneoxindole. In the case of Boc-protected substrates, target
products were obtained in high yield with good stereoselectivities; in the case of Bn-
protected substrates, moderate yield and good stereoselectivities were observed. Apart
from ester group, we also examined different benzoyl group for R2 variation. The
reaction worked well for substrates carrying benzoyl groups at the R2 position, except
the product 4l in which the major isomer and minor isomer could not be isolated by
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column chromatography and
reverse-phase chromatography.
However,
monosubstituted 2b and 2c showed poor nucleophilicity: the target chiral compounds
3q-3r and 4q-4r were not obtained under optimal reaction conditions, and only racemic
products were obtained when the strong base DBU was used and the temperature was
below 40 oC. In order to verify the practical utility of the methodology, we demonstrated
the large-scale reaction of 3-ylideneoxidole (1a-Boc, 2.0 mmol) and 2-
methylbenzaldehyde 2a (2.4 mmol) under optimal reaction conditions. The desired
product 3a was obtained in 76% yield with 98% ee (Scheme 4a). We also performed
the large-scale reaction of 3-ylideneoxidole (1a-Bn, 2.0 mmol) and 2-
methylbenzaldehyde 2a (2.4 mmol) under optimal reaction conditions, smoothly
affording the desired product 4a in 47% yield with 85% ee (Scheme 4b).
The absolute configurations of compound 3d and 4d (the TMS-protected group of
4d was removed) were determined by X-ray crystallographic analysis.16 These results
were used to tentatively infer the absolute configuration of the other chiral products 3
and 4.
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Scheme 2. Substrate scope of the annulation reaction. Yield was calculated from the isolated major
isomer 3. The dr was determined by 1H NMR of the crude reaction mixture. The ee was determined
by chiral HPLC.
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Scheme 3. Substrate scope of the annulation reaction. Yield was calculated from the isolated major
isomer 4. The dr was determined by 1H NMR of the crude reaction mixture. The ee was determined
by chiral HPLC.
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Scheme 4. The large-scale experiment for the synthesis of 3a and 4a.
We hypothesized about plausible transition states that could explain the high
diastereo- and enantioselectivities observed. These transition states and the associated
catalytic modes are consistent with the mechanistic models proposed by Takemoto and
others.17 In our proposal, two hydrogen bonds form between the nitro group of substrate
2a and the two N-H groups of the thiourea catalyst (Scheme 5A).17b, c The protonated
tertiary amine group may form another two hydrogen-bonding interactions with the two
carbonyls of the Boc-protected 3-ylideneoxindole 1a-Boc.17a The first Michael addition
of carbanion to substrate 2a occurs via attack from the Si face of the electron-deficient
olefin. A subsequent intramolecular aldol reaction takes place between the Si face of
the C3-position on the oxindole and the Re face of the aldehyde group. This affords the
major isomer 3a with a (1'R,3R,3'S)-configuration.
We further predict that substrate 2a can be activated and fixed through two hydrogen
bonds with the thiourea catalyst (Scheme 5B). In the presence of the Bn group on the
3-ylideneoxindole, reaction stereochemistry inverts as follows. The protonated tertiary
amine group form the hydrogen-bonds with the C2 carbonyl and ethyl ester groups on
substrate 1a-Bn. While the first Michael addition of carbanion to substrate 2a occurs
via attack from the Si face of the electron-deficient olefin as in the preceding case,
subsequent carbon-carbon bond formation takes place from the Re face of the C3-
position on the oxindole and the Si face of the aldehyde group. This affords the major
isomer 4a with a (1'S,3S,3'S)-configuration.
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Scheme 5. Proposed transition states to explain the observed stereochemistry.
CONCLUSION
We have used organocatalytic [4+2] annulation to prepare, in good yield, a collection
of chiral spirocyclic THN-oxindole hybrids bearing multiple stereocenters and various
functional groups. Simply by changing the protecting group of the substrate in the
Michael-aldol cascade reaction, we accomplished controlled-diastereodivergence,
generating the reversed products with high stereoselectivities. The proposed transition
state indicated that the protecting group was a significant role in the diastereoselectivity
switching.
EXPERIMENTAL SECTION
General information
1
Nuclear Magnetic Resonance (NMR) data were obtained for H at 400 MHz or 600
MHz, and for 13C at 100 MHz or 150 MHz. Chemical shifts were reported in parts per
million (ppm) with tetramethylsilane resonance as the internal standard in CDCl3
solution. Data are reported as follows: chemical shift [multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br s = broad singlet), coupling constant(s)
(Hz), integration]. ESI high resolution mass spectra (HRMS) were recorded using
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electrospray ionization on a Waters SYNAPT G2 (Q-TOF) instrument. The
enantiomeric ratio was determined by High Performance Liquid Chromatography
(HPLC) analysis on chiral column in comparison with authentic racemates, using the
Daicel Chiralpak AD/OD/IE (250 x 4.6 mm). UV detection was monitored at 254 nm.
Optical rotation data were examined in CH2Cl2 solution at 25 °C and λ = 589 nm.
Column chromatography was performed on a silica gel (200-300 mesh) using an eluent
of ethyl acetate and petroleum ether. TLC was performed on glass backed silica plates;
products were visualized using UV light. Melting points were determined on a Mel-
Temp apparatus.
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General procedure for the synthesis of the N-Boc-3-ylideneoxindoles (1-Boc).
The Wittig olefination was carried out by mixing the corresponding isatin (3.4 mmol)
with the appropriate Wittig reagent (1.05 equiv.) in toluene (20 mL). The reaction was
stirred at 90 oC for 0.5 h. Then the reaction was cooling and filtrated during a silica pad.
The crude mixture was dissolved in MeCN (25 mL), and Boc2O (1.2 equiv.) and DMAP
(0.2 equiv.) were added. The mixture was stirred at ambient temperature until the
reaction was completed based on TLC. The solvent was removed under reduced
pressure and the mixture was purified by flash chromatography to yield the respective
products, which was was further analyzed by 1H NMR, 13C{1H} NMR, and HRMS.
Reported compounds N-Boc-3-ylideneoxindoles 1a, 1b, 1d, 1k,18e 1c, 1i,18b 1g,18d
1h, 1j,18c and 1m, 1o, 1p,18a were prepared according to the literature.18 The new
substrates 1e-Boc, 1f-Boc, 1l-Boc, and 1n-Boc were obtained according to the literature
procedure with functional group modifications,18e and the detailed data was listed below.
tert-butyl (E)-6-chloro-3-(2-ethoxy-2-oxoethylidene)-2-oxoindoline-1-carboxylate (1e-
o
1
Boc). Light green solid, 813.5 mg, 68% yield, m.p. 63-65 C. H NMR (600 MHz,
CDCl3): δ (ppm) 8.67 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 9.0,
1.8 Hz, 1H), 6.91 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.65 (s, 9H), 1.38 (t, J = 7.2 Hz,
13
3H); C{1H} NMR (150 MHz, CDCl3): δ (ppm) 165.4, 165.3, 148.6, 142.6, 138.7,
135.5, 129.4, 124.8, 123.5, 118.5, 115.7, 85.3, 61.5, 28.0, 14.1; HRMS (ESI-TOF) m/z:
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[M + Na] calcd for C17H18ClNO5Na 374.0771; found 374.0772.
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tert-butyl (E)-4-bromo-3-(2-ethoxy-2-oxoethylidene)-2-oxoindoline-1-carboxylate (1f-
Boc). White solid, 892.3 mg, 66% yield, m.p. 78-80 oC. 1H NMR (600 MHz, CDCl3):
δ (ppm) 7.89 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.22 (t, J = 8.4
Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.63 (s, 9H), 1.39 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
(150 MHz, CDCl3): δ (ppm)166.1, 162.5, 148.6, 141.9, 131.4, 129.7, 129.2, 128.3,
119.1, 118.5, 114.3, 85.1, 61.9, 28.0, 14.0; HRMS (ESI-TOF) m/z: [M + Na] calcd for
C17H18BrNO5Na 418.0266; found 418.0263.
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tert-butyl (E)-3-(2-(2-fluorophenyl)-2-oxoethylidene)-2-oxoindoline-1-carboxylate (1l-
Boc). Orange solid, 398.2 mg, 32% yield m.p. 49-50 oC. 1H NMR (600 MHz, CDCl3):
δ (ppm) 8.54 (d, J = 7.8 Hz, 1H), 7.95−7.92 (m, 2H), 7.77 (d, J = 4.2 Hz, 1H), 7.61−7.57
(m, 1H), 7.47−7.44 (m, 1H), 7.31−7.27 (m, 1H), 7.21−7.16 (m, 2H), 1.67 (s, 9H);
13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 188.6, 166.3, 161.8 (d, JCF = 256.4 Hz),
148.9, 142.0, 135.4 (d, JCF = 9.3 Hz), 134.8 (d, JCF = 2.0 Hz), 133.2, 131.0 (d, JCF = 2.0
Hz), 129.1 (d, JCF = 6.3 Hz), 127.2, 126.6 (d, JCF = 11.7 Hz), 124.7 (d, JCF = 3.6 Hz),
124.6, 120.4, 116.5 (d, JCF = 22.8 Hz), 115.0, 84.7, 28.1; HRMS (ESI-TOF) m/z: [M +
Na] calcd for C21H18FNO4Na 390.1118; found 390.1116.
tert-butyl
(E)-3-(2-(3,4-dichlorophenyl)-2-oxoethylidene)-2-oxoindoline-1-
o
carboxylate (1n-Boc). Yellow solid. 472.3 mg, 32% yield, m.p. 120-122 C. 1H NMR
(600 MHz, CDCl3): δ (ppm) 8.43 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.94 (d,
J = 8.4 Hz, 1H), 7.90 (dd, J = 8.4, 1.8 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H),
7.46 (t, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 1.67 (s, 9H); 13C{1H} NMR (150 MHz,
CDCl3): δ (ppm) 188.4, 166.0, 148.7, 142.2, 138.6, 137.1, 136.2, 133.8, 133.5, 131.1,
130.6, 127.7, 127.4, 125.2, 124.7, 120.1, 115.2, 84.9, 28.08; HRMS (ESI-TOF) m/z: [M
+ Na] calcd for C21H17Cl2NO4Na 440.0432; found 440.0431.
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General procedure for the asymmetric synthesis of 3.
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The reaction was carried out with 3-ylideneoxidole 1-Boc (0.3 mmol), 2-
methylbenzaldehyde 2 (0.36 mmol) and C7 (49.6 mg, 0.06 mmol) with 4Å in anhydrous
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CH2Cl2 (4.0 mL) at -10 C for 48 hours under N2. The reaction mixture was direct
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purified by flash chromatography on a silica gel to afford the intermediate.
The protection hydroxyl group of the intermediate gave the corresponding easily
separable THN-fused spirooxindole derivative 3. To a solution of intermediate in
CH2Cl2 (4 mL) was added TMSCl (25.9 μL, 0.3 mmol) and imidazole (45.8 mg, 0.6
mmol). The mixture was stirred at 0 oC until the reaction was completed based on TLC.
The reaction was quenched with aqueous NaHCO3 (aq) and CH2Cl2. The organic layer
was dried by Na2SO4 and concentrated. The residue was purified by chromatography
on silica gel to give the major isomer product 3 which were dried under vacuum and
further analyzed by 1H NMR, 13C{1H} NMR, HRMS and HPLC.
1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3a). White solid,
144.5 mg, 80% yield, 88:12 dr, 99% ee by HPLC on Chiralpak OD column (30% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 7.75 min, tmajor = 10.31 min, [α]D
= +62.64 (c 1.00, CH2Cl2), m.p. 158-160 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.75
(s, 1H), 8.51 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6
Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 5.01 (s, 1H), 3.93 (dd, J = 12.8 Hz, 1H), 3.76−3.63
(m, 2H), 3.24 (q, J = 12.4 Hz, 2H), 1.64 (s, 9H), 0.73 (t, J = 7.2 Hz, 3H), -0.16 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 174.8, 170.3, 149.1, 148.4, 146.8, 143.6,
141.6, 137.6, 129.9, 128.8, 124.8, 124.0, 123.1, 119.0, 115.5, 85.0, 75.8, 61.4, 55.9,
47.2, 28.3, 25.7, 13.5, -0.3; HRMS (ESI-TOF) m/z: [M + Na] calcd for
C28H33N3O10SiNa 622.1833; found 622.1832.
1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-5-fluoro-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3b). White
solid, 145.8 mg, 79% yield, 84:16 dr, 99% ee by HPLC on Chiralpak IE column (30%
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2-propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 7.11 min, tminor = 8.08 min, [α]D
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= -14.55 (c 1.00, CH2Cl2), m.p. 140-142 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.82
(s, 1H), 8.28 (s, 1H), 7.88 (dd, J = 9.2, 4.8 Hz, 1H), 7.07 (td, J = 8.8, 2.8 Hz, 1H), 6.78
(dd, J = 8.0, 2.8 Hz, 1H), 4.83 (s, 1H), 4.03−3.97 (m, 2H), 3.79 (dd, J = 17.2, 5.6 Hz,
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1H), 3.72−3.60 (m, 2H), 1.60 (s, 9H), 1.06 (t, J = 7.2 Hz, 3H), 0.03 (s, 9H); C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 172.8, 170.1, 158.9 (d, JCF = 242.1 Hz), 148.3, 148.0,
145.3, 140.5, 137.6, 135.5 (d, JCF = 2.5 Hz), 129.1 (d, JCF = 8.2 Hz), 126.8, 119.2, 115.6
(d, JCF = 7.9 Hz), 115.1 (d, JCF = 22.5 Hz), 112.0 (d, JCF = 25.0 Hz), 84.4, 72.2, 61.1,
52.1, 42.8, 27.5, 26.0, 13.1, -0.3; 19F NMR (565 MHz, CDCl3): δ (ppm) -117.12; HRMS
(ESI-TOF) m/z: [M + Na] calcd for C28H32FN3O10SiNa 640.1739; found 640.1738.
1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-7-fluoro-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3c). White
solid, 140.1 mg, 76% yield, 83:17 dr, 91% ee by HPLC on Chiralpak OD column (30%
2-propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 5.92 min, tmajor = 10.80 min,
[α]D25 = +15.40 (c 1.00, CH2Cl2), m.p. 83-85 oC. 1H NMR (400 MHz, CDCl3): δ (ppm)
8.81 (s, 1H), 8.29 (s, 1H), 7.16−7.06 (m, 2H), 6.77 (dd, J = 7.2, 0.8 Hz, 1H), 4.89 (s,
1H), 4.08−3.95 (m, 2H), 3.80 (dd, J = 16.0, 4.0 Hz, 1H), 3.70−3.59 (m, 2H), 1.59 (s,
9H), 1.05 (t, J = 7.2 Hz, 3H), 0.03 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
173.4, 170.5, 148.5, 148.4 (d, JCF = 249.4 Hz), 147.2, 145.9, 141.3, 138.7 (d, JCF = 1.8
Hz), 138.1, 131.3 (d, JCF = 1.9 Hz), 127.0, 125.0 (d, JCF = 6.8 Hz), 120.6 (d, JCF = 3.6
Hz), 119.7, 117.6 (d, JCF = 20.4 Hz), 85.4, 72.7, 61.8, 53.5, 43.8, 27.7, 26.4, 13.6, 0.3;
19F NMR (565 MHz, CDCl3): δ (ppm) -118.59; HRMS (ESI-TOF) m/z: [M + Na] calcd
for C28H32FN3O10SiNa 640.1739; found 640.1738.
1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-5-chloro-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3d). White
solid, 154.7 mg, 81% yield, 91:9 dr, >99% ee by HPLC on Chiralpak IE column (30%
2-propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 7.33 min, [α]D25 = -25.85 (c 1.00,
CH2Cl2), m.p. 141-143 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.75 (s, 1H), 8.54 (s,
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1H), 7.87 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.8, 2.4 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H),
5.08 (s, 1H), 4.01−3.92 (m, 3H), 3.60 (dd, J = 18.8, 6.0 Hz, 1H), 3.44 (dd, J = 12.0, 6.4
Hz, 1H), 1.59 (s, 9H), 1.01 (t, J = 7.2 Hz, 3H), -0.08 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 171.7, 169.6, 148.7, 148.0, 146.4, 142.1, 140.3, 136.6, 130.1, 129.8,
129.4, 125.9, 122.2, 119.1, 116.8, 84.7, 76.2, 61.7, 52.5, 46.1, 28.0, 26.8, 13.5, -0.3;
HRMS (ESI-TOF) m/z: [M + Na] calcd for C28H32ClN3O10SiNa 656.1443; found
656.1440.
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1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-6-chloro-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3e). White
solid, 148.6 mg, 78% yield, 87:13 dr, >99% ee by HPLC on Chiralpak OD column (30%
2-propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 7.13 min, [α]D25 = -58.19 (c 1.00,
CH2Cl2), m.p. 130-132 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.80 (s, 1H), 8.42 (s,
1H), 7.99 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.88 (d, J = 8.0 Hz, 1H), 5.23 (s, 1H),
3.93−3.82 (m, 3H), 3.78 (t, J = 8.4 Hz, 1H), 3.61 (dd, J = 19.2, 8.0 Hz, 1H), 1.67 (s,
9H), 0.97 (t, J = 7.2 Hz, 3H), 0.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
175.8, 169.2, 148.4, 148.3, 146.3, 143.0, 142.0, 135.8, 134.9, 124.4, 123.9, 123.8, 122.9,
118.9, 115.3, 84.9, 74.8, 61.5, 54.6, 44.1, 27.8, 25.0, 13.2, -0.3; HRMS (ESI-TOF) m/z:
[M + Na] calcd for C28H32ClN3O10SiNa 656.1443; found 656.1445.
1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-4-bromo-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3f). White
solid, 166.2 mg, 81% yield, >95:5 dr, 37% ee by HPLC on Chiralpak OD column (30%
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2-propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 5.70 min, tminor = 7.39 min, [α]D
= +28.80 (c 1.00, CH2Cl2), m.p. 161-163 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.74
(s, 1H), 8.52 (s, 1H), 7.93 (dd, J = 8.4, 1.2 Hz, 1H), 7.38 (dd, J = 8.4, 0.8 Hz, 1H), 7.29
(d, J = 8.4 Hz, 1H), 5.70 (s, 1H), 4.26 (dd, J = 8.8, 6.4 Hz, 1H), 4.05 (dd, J = 18.0, 8.8
Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.49 (dd, J = 17.6, 6.4 Hz, 1H), 1.58 (s, 9H), 1.01 (t,
J = 7.2 Hz, 3H), -0.07 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 171.7, 170.1,
148.4, 148.2, 146.2, 143.7, 142.7, 137.2, 130.8, 128.9, 126.4, 125.3, 118.6, 117.8, 114.4,
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84.8, 71.7, 61.5, 55.8, 43.1, 27.9, 25.9, 13.5, -0.3; HRMS (ESI-TOF) m/z: [M + Na]
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calcd for C28H32BrN3O10SiNa 700.0938; found 700.0941.
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1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-5-bromo-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3g). White
solid, 161.4 mg, 79% yield, 90:10 dr, 95% ee by HPLC on Chiralpak IE column (30%
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2-propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 7.65 min, tminor = 8.58 min, [α]D
= -38.84 (c 1.00, CH2Cl2), m.p. 123-125 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.76
(s, 1H), 8.54 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 8.8, 2.0 Hz, 1H), 7.34 (d, J
= 2.0 Hz, 1H), 5.07 (s, 1H), 4.01−3.93 (m, 3H), 3.60 (dd, J = 18.8, 6.0 Hz, 1H), 3.44
(dd, J = 12.0, 6.4 Hz, 1H), 1.59 (s, 9H), 1.01 (t, J = 7.2 Hz, 3H), -0.08 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 171.6, 169.6, 148.7, 148.1, 146.3, 142.1, 140.8,
136.8, 132.3, 130.5, 125.8, 125.0, 119.1, 117.2, 117.1, 84.8, 76.3, 61.7, 52.5, 46.1, 28.0,
26.8, 13.5, -0.3; HRMS (ESI-TOF) m/z: [M + Na] calcd for C28H32BrN3O10SiNa
700.0938; found 700.0939.
1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-6-bromo-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3h). White
solid, 158.3 mg, 78% yield, 85:15 dr, >99% ee by HPLC on Chiralpak OD column (30%
2-propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 7.23 min, [α]D25 = -30.75 (c 1.00,
CH2Cl2), m.p. 128-130 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.80 (s, 1H), 8.42 (s,
1H), 8.14 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 5.82 (d, J = 8.0 Hz, 1H), 5.22 (s, 1H),
3.93−3.83 (m, 3H), 3.78 (t, J = 8.4 Hz, 1H), 3.61 (dd, J = 19.2, 8.0 Hz, 1H), 1.67 (s,
9H), 0.97 (t, J = 7.2 Hz, 3H), 0.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
175.7, 169.1, 148.4, 148.3, 146.3, 143.0, 142.1, 135.8, 126.8, 124.4, 124.1, 123.4, 122.8,
118.9, 118.1, 84.9, 74.8, 61.5, 54.6, 44.0, 27.8, 25.0, 13.2, -0.3; HRMS (ESI-TOF) m/z:
[M + Na] calcd for C28H32BrN3O10SiNa 700.0938; found 700.0938.
1-(tert-butyl)
3'-ethyl
6-bromo-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (minor isomer of 3h).
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propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 6.13 min tmajor = 9.50 min, [α]D
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+23.20 (c 1.00, CH2Cl2), m.p. 101-103 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.81
(s, 1H), 8.28 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 6.84 (d, J = 8.0
Hz, 1H), 4.84 (s, 1H), 4.04−3.96 (m, 2H), 3.79 (dd, J = 16.8, 4.8 Hz, 1H), 3.68 – 3.57
(m, 2H), 1.61 (s, 9H), 1.07 (t, J = 7.2 Hz, 3H), 0.02 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 173.3, 170.6, 148.7, 148.5, 145.9, 141.3, 141.1, 138.0, 127.1, 126.9,
125.9, 123.1, 119.7, 118.4, 85.3, 72.8, 61.7, 52.6, 43.6, 28.0, 26.4, 13.7, 0.3; HRMS
(ESI-TOF) m/z: [M + Na] calcd for C28H32BrN3O10SiNa 700.0938; found 700.0937.
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1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-5,5',7'-trinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3i). White solid,
143.3 mg, 74% yield, 87:13 dr, 79% ee by HPLC on Chiralpak OD column (30% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 8.63 min, tmajor = 10.87 min, [α]D
= -13.05 (c 1.00, CH2Cl2), m.p. 109-111 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.79
(s, 1H), 8.54 (s, 1H), 8.35 (dd, J = 9.2, 2.4 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.12 (d, J
= 8.8 Hz, 1H), 5.18 (s, 1H), 4.02−3.93 (m, 3H), 3.68 (dd, J = 18.8, 6.0 Hz, 1H), 3.58
(dd, J = 11.6, 6.4 Hz, 1H), 1.61 (s, 9H), 1.04 (t, J = 7.2 Hz, 3H), -0.11 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 175.5, 169.0, 148.3, 146.4, 142.7, 140.2, 135.6,
131.9, 126.7, 126.1, 124.7, 119.1, 116.8, 116.1, 84.7, 74.9, 61.6, 54.6, 44.1, 27.8, 25.1,
13.2, -0.3; HRMS (ESI-TOF) m/z: [M + Na] calcd for C28H32N4O12SiNa 667.1684;
found 667.1685.
1-(tert-butyl) 3'-ethyl (1'R,3R,3'S)-5-methyl-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (3j). White solid,
135.1 mg, 73% yield, 84:16 dr, >99% ee by HPLC on Chiralpak OD column (30% 2-
propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 8.33 min, [α]D25 = -74.09 (c 1.00,
CH2Cl2), m.p. 146-148 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.80 (s, 1H), 8.44 (s,
1H), 7.77 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.74 (d, J = 1.2 Hz, 1H), 5.24
(s, 1H), 3.94 (dd, J = 19.2, 8.4 Hz, 1H), 3.85−3.74 (m, 3H), 3.59 (dd, J = 19.2, 8.0 Hz,
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1H), 2.07 (s, 3H), 1.66 (s, 9H), 0.91 (t, J = 7.2 Hz, 3H), 0.19 (s, 9H); C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 176.3, 169.3, 148.6, 148.3, 146.2, 143.4, 138.7, 136.1,
133.3, 129.4, 124.4, 124.3, 123.7, 118.7, 114.2, 84.1, 74.9, 61.3, 54.8, 44.1, 27.8, 25.0,
20.9, 13.1, -0.3; HRMS (ESI-TOF) m/z: [M + Na] calcd for C29H35N3O10SiNa 636.1989;
found 636.1987.
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1-(tert-butyl)
3'-ethyl
5-methyl-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1,3'-dicarboxylate (minor isomer of 3j).
White solid, 11.3 mg, 6% yield, 99% ee by HPLC on Chiralpak OD column (30% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 5.53 tmajor = 7.32 min, [α]D
=
+67.99 (c 1.00, CH2Cl2), m.p. 125-126 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.75
(s, 1H), 8.51 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.08 (s, 1H),
5.00 (s, 1H), 3.93 (dd, J = 14.8, 2.0 Hz, 1H), 3.75−3.67 (m, 2H), 3.27−3.16 (m, 2H),
2.36 (s, 3H), 1.63 (s, 9H), 0.73 (t, J = 7.2 Hz, 3H), -0.17 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 175.0, 170.4, 149.2, 148.4, 146.9, 143.8, 139.2, 137.6, 134.6,
130.2, 128.8, 124.0, 123.7, 118.9, 115.4, 84.8, 75.8, 61.4, 56.0, 47.3, 28.4, 25.8, 21.3,
13.6, -0.3; HRMS (ESI-TOF) m/z: [M + Na] calcd for C29H35N3O10SiNa 636.1989;
found 636.1990.
tert-butyl
(1'R,3R,3'S)-3'-benzoyl-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1-carboxylate (3k). White solid, 143.6
mg, 76% yield, 88:12 dr, >99% ee by HPLC on Chiralpak AD column (30% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 4.99 min, tmajor = 10.46 min, [α]D
o
1
= +121.73 (c 1.00, CH2Cl2), m.p. 178-180 C. H NMR (400 MHz, CDCl3): δ (ppm)
8.84 (s, 1H), 8.37 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.43−7.35 (m, 3H), 7.23 (t, J = 7.6
Hz, 2H), 7.10 (t, J = 8.4 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 5.57 (d, J = 7.2 Hz, 1H), 5.36
(s, 1H), 4.74 (dd, J = 7.6, 5.6 Hz, 1H), 4.10 (dd, J = 17.6, 5.6 Hz, 1H), 3.36 (dd, J =
17.6, 7.6 Hz, 1H), 1.61 (s, 9H), 0.15 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
197.8, 176.9, 148.4, 148.0, 146.1, 143.7, 140.5, 137.7, 135.9, 133.0, 128.6, 128.2, 127.6,
124.4, 123.9, 123.8, 118.8, 114.0, 84.3, 74.6, 55.8, 48.1, 27.8, 25.1, -0.3; HRMS (ESI-
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tert-butyl (1'R,3R,3'S)-3'-(2-fluorobenzoyl)-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1-carboxylate (3l). White solid,
145.4 mg, 75% yield, 87:11 dr, 87% ee by HPLC on Chiralpak OD column (20% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 8.54 min, tminor = 12.27 min, [α]D
= +16.80 (c 1.00, CH2Cl2), m.p. 191-193 oC. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.74
(s, 1H), 8.58 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.56−7.53 (m, 2H), 7.32 (t, J = 8.4 Hz,
1H), 7.18−7.12 (m, 3H), 7.09 (t, J = 7.2 Hz, 1H), 5.23 (s, 1H), 4.54 (dd, J = 12.6, 6.0
Hz, 1H), 3.88 (dd, J = 19.2, 12.6 Hz, 1H), 3.62 (dd, J = 19.2, 6.0 Hz, 1H), 1.64 (s, 9H),
-0.12 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 195.4, 173.2, 160.5, 149.1,
147.2 (d, JCF = 253.7 Hz), 142.8, 142.1, 137.3, 135.7 (d, JCF = 10.2 Hz), 131.5, 129.3,
128.6, 126.2, 125.1, 124.2, 121.2, 119.0, 116.7 (d, JCF = 24.5 Hz), 115.8, 84.3, 52.3,
52.1, 28.1, 26.8, -0.2; 19F NMR (565 MHz, CDCl3): δ (ppm) -111.69; HRMS (ESI-TOF)
m/z: [M + Na] calcd for C32H32N3O9FSiNa 672.1790; found 672.1793.
tert-butyl (1'R,3R,3'S)-3'-(4-fluorobenzoyl)-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1-carboxylate (3m). White solid,
153.9 mg, 79% yield, 90:10 dr, >99% ee by HPLC on Chiralpak IE column (20% 2-
propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 17.04 min, [α]D25 = -57.69 (c 2.00,
CH2Cl2), m.p. 173-175 oC. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.74 (s, 1H), 8.59 (s,
1H), 7.88 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 9.0, 5.4 Hz, 2H), 7.32 (t, J = 8.4 Hz, 1H),
7.13 (dd, J = 7.2, 1.2 Hz, 1H), 7.12−7.09 (m, 3H), 5.25 (s, 1H), 4.52 (dd, J = 12.0, 6.0
Hz, 1H), 3.93 (dd, J = 18.6, 12.0 Hz, 1H), 3.57 (dd, J = 19.2, 6.0 Hz, 1H), 1.63 (s, 9H),
-0.11 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 195.3, 173.2, 166.3 (d, JCF
=
255.9 Hz), 149.0, 148.0, 146.4, 142.8, 142.1, 137.2, 131.4, 131.2 (d, JCF = 9.3 Hz),
129.5, 128.5, 126.1, 124.3, 120.8, 119.0, 116.3 (d, JCF = 22.2 Hz), 115.9, 84.3, 76.7,
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52.2, 47.7, 28.1, 27.8, -0.3; F NMR (565 MHz, CDCl3): δ (ppm) -102.55; HRMS
(ESI-TOF) m/z: [M + Na] calcd for C32H32N3O9FSiNa 672.1790; found 672.1792.
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tert-butyl (1'R,3R,3'S)-3'-(3,4-dichlorobenzoyl)-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)
oxy)-3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1-carboxylate (3n). White
solid, 157.9 mg, 75% yield, 88:12 dr, 89% ee by HPLC on Chiralpak OD column (20%
2-propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 11.90 min, tminor = 16.56 min,
[α]D25 = -50.69 (c 1.00, CH2Cl2), m.p. 183-185 oC. 1H NMR (600 MHz, CDCl3): δ (ppm)
8.76 (s, 1H), 8.58 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.59 (dd,
J = 8.4, 2.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36–7.32 (m, 1H), 7.16–7.11 (m, 2H),
5.24 (s, 1H), 4.45 (dd, J = 11.6, 5.8 Hz, 1H), 3.93 (dd, J = 18.6, 11.6 Hz, 1H), 3.54 (dd,
J = 18.6, 5.8 Hz, 1H), 1.61 (s, 9H), -0.12 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ
(ppm) 195.0, 173.1, 149.1, 148.2, 146.6, 142.9, 142.2, 139.2, 137.1, 134.6, 134.1, 131.4,
130.4, 129.8, 128.6, 127.5, 126.2, 124.6, 121.0, 119.2, 116.1, 84.61, 76.7, 52.5, 48.1,
28.3, 27.7, -0.1; HRMS (ESI-TOF) m/z: [M + Na] calcd for C32H31N3O9Cl2SiNa
722.1104; found 722.1102.
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tert-butyl (1'R,3R,3'S)-3'-(4-bromobenzoyl)-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1-carboxylate (3o). White solid,
169.8 mg, 80% yield, 92:8 dr, 96% ee by HPLC on Chiralpak IE column (30% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 14.23 min, tminor = 16.58 min, [α]D
= -78.14 (c 2.00, CH2Cl2), m.p. 204-206 oC. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.74
(s, 1H), 8.58 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4
Hz, 2H), 7.33 (t, J = 8.4 Hz, 1H), 7.13−7.09 (m, 2H), 5.24 (s, 1H), 4.50 (dd, J = 12.0,
6.0 Hz, 1H), 3.93 (dd, J = 18.6, 12.0 Hz, 1H), 3.56 (dd, J = 19.2, 6.0 Hz, 1H), 1.62 (s,
13
9H), -0.12 (s, 9H); C{1H} NMR (150 MHz, CDCl3): δ (ppm) 195.9, 173.1, 149.0,
148.0, 146.4, 142.8, 142.0, 137.1, 133.6, 132.4, 129.8, 129.6, 129.5, 128.5, 126.1, 124.3,
120.8, 119.0, 115.9, 84.3, 76.6, 52.2, 47.8, 28.1, 27.7, -0.3; HRMS (ESI-TOF) m/z: [M
+ Na] calcd for C32H32N3O9BrSiNa 732.0989; found 732.0991.
tert-butyl
(1'R,3R,3'S)-3'-(4-methoxybenzoyl)-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)
oxy)-3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalene]-1-carboxylate (3p). White
solid, 158.2 mg, 79% yield, 89:11 dr, >99% ee by HPLC on Chiralpak OD column (20%
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2-propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 8.33 min, [α]D = -171.87 (c
5
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8
o
1
2.00, CH2Cl2), m.p. 178-180 C. H NMR (600 MHz, CDCl3): δ (ppm) 8.73 (s, 1H),
8.59 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 9.0 Hz, 2H), 7.30 (t, J = 8.4 Hz, 1H),
7.12 (d, J = 6.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 5.25 (s, 1H),
4.52 (dd, J = 12.6, 6.0 Hz, 1H), 3.92 (dd, J = 19.2, 12.2 Hz, 1H), 3.86 (s, 3H), 3.58 (dd,
J = 19.2, 6.0 Hz, 1H), 1.63 (s, 9H), -0.12 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ
(ppm) 195.1, 173.4, 164.3, 149.1, 148.0, 146.3, 142.9, 142.1, 137.5, 130.8, 129.3, 128.8,
127.8, 126.1, 124.2, 120.8, 118.9, 115.9, 114.3, 84.1, 55.6, 52.1, 47.4, 28.1, 28.1, -0.2;
HRMS (ESI-TOF) m/z: [M + Na] calcd for C33H35N3O10SiNa 684.1989; found
684.1987.
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General procedure for the asymmetric synthesis of 4.
The reaction was carried out with 3-ylideneoxidole 1-Bn (0.3 mmol), 2-
methylbenzaldehyde 2 (0.36 mmol) and C7 (24.8 mg, 0.06 mmol) with 4Å in anhydrous
CH2Cl2 (4.0 mL) at -10 oC for 7days under N2. The reaction mixture was direct purified
by flash chromatography on a silica gel to afford the intermediate.
The protection hydroxyl group of the intermediate gave the corresponding easily
separable THN-fused spirooxindole derivative 4. To a solution of intermediate in
CH2Cl2 (4 mL) was added TMSCl (25.9 μL, 0.3 mmol) and imidazole (45.8 mg, 0.6
mmol). The mixture was stirred at 0 oC until the reaction was completed based on TLC.
The reaction was quenched with aqueous NaHCO3 (aq) and CH2Cl2. The organic layer
was dried by Na2SO4 and concentrated. The residue was purified by chromatography
on silica gel to give the major isomer product 4 which were dried under vacuum and
further analyzed by 1H NMR, 13C{1H} NMR, HPLC and HRMS.
ethyl
(1'S,3S,3'S)-1-benzyl-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-dihydro-
1'H-spiro [indoline-3,2'-naphthalene]-3'-carboxylate (4a). White solid, 90.8 mg, 51%
yield, 91:9 dr, 89% ee by HPLC on Chiralpak OD column (25% 2-propanol/n-hexane,
1 mL/min), UV 254 nm, tminor = 10.40 min, tmajor = 16.35 min, [α]D25 = +55.09 (c 1.00,
CH2Cl2), m.p. 133-135 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.76 (s, 1H), 8.56 (s,
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1H), 7.38−7.22 (m, 7H), 7.05 (t, J = 7.2 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.17 (s, 1H),
4.88 (s, 2H), 3.96 (dd, J = 16.0, 4.0 Hz, 1H), 3.68 (q, J = 7.2 Hz, 2H), 3.33−3.20 (m,
2H), 0.60 (t, J = 7.2 Hz, 3H), -0.21 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
176.5, 170.9, 148.4, 146.8, 144.7, 144.3, 137.5, 135.8, 129.6, 129.6, 128.9, 128.1, 127.9,
123.8, 123.6, 122.9, 118.8, 109.5, 74.6, 61.3, 54.8, 46.8, 44.4, 25.7, 13.5, -0.3; HRMS
(ESI-TOF) m/z: [M + Na] calcd for C30H31N3O8SiNa 612.1778; found 612.1779.
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ethyl (1'S,3S,3'S)-1-benzyl-5-fluoro-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-3'-carboxylate (4b). White solid, 107.6
mg, 59% yield, 90:10 dr, 89% ee by HPLC on Chiralpak OD column (25% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 10.23 min, tmajor = 16.64 min, [α]D
= +84.39 (c 1.00, CH2Cl2), m.p. 105-107 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.77
(s, 1H), 8.55 (s, 1H), 7.34−7.28 (m, 5H), 7.04 (dd, J = 8.0, 2.8 Hz, 1H), 6.96 (td, J =
8.8, 2.4 Hz, 1H), 6.69 (q, J = 4.4 Hz, 1H), 5.17 (s, 1H), 4.87 (s, 2H), 3.98 (dd, J = 15.6,
3.2 Hz, 1H), 3.84−3.72 (m, 2H), 3.32−3.21 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H), -0.16 (s,
13
9H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 176.1, 170.7, 159.2 (d, JCF = 241.1
Hz), 148.4, 146.8, 143.8, 140.7, 137.2, 135.4, 131.1 (d, JCF = 7.4 Hz), 129.0, 128.1,
127.8, 123.9, 118.9, 115.7 (d, JCF = 23.2 Hz), 112.0 (d, JCF = 24.3 Hz), 110.0 (d, JCF
=
7.6 Hz), 74.4, 61.4, 55.1, 46.5, 44.5, 25.8, 13.6, -0.3; 19F NMR (565 MHz, CDCl3): δ
(ppm) -119.48; HRMS (ESI-TOF) m/z: [M + Na] calcd for C30H30N3O8FSiNa 630.1684;
found 630.1683.
ethyl (1'S,3S,3'S)-1-benzyl-7-fluoro-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-3'-carboxylate (4c). White solid, 100.7
mg, 55% yield, 89:11 dr, 73% ee by HPLC on Chiralpak AD column (30% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 7.00 min, tmajor = 14.37 min, [α]D
= +49.74 (c 1.00, CH2Cl2), m.p. 84-86 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.76
(s, 1H), 8.54 (s, 1H), 7.39 (d, J = 7.4 Hz, 2H), 7.32–7.25 (m, 3H), 7.08–6.99 (m, 3H),
5.12 (s, 1H), 5.02 (q, J = 15.2 Hz, 2H), 3.95 (dd, J = 15.2, 3.2 Hz, 1H), 3.75–3.59 (m,
13
2H), 3.30–3.18 (m, 2H), 0.61 (t, J = 7.2 Hz, 3H), -0.19 (s, 9H); C{1H} NMR (100
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MHz, CDCl3): δ (ppm) 176.2, 170.5, 148.3, 147.5 (d, JCF = 245.1 Hz), 146.7, 143.9,
137.3, 136.9, 132.7 (d, JCF = 3.6 Hz), 131.3 (d, JCF = 8.6 Hz), 128.6, 128.1 (d, JCF = 1.5
Hz), 127.9, 123.7, 123.5 (d, JCF = 6.4 Hz), 119.4 (d, JCF = 3.2 Hz), 118.7, 117.7 (d, JCF
= 19.6 Hz), 74.7, 61.2, 55.2, 46.8, 45.8, 25.7, 13.5, -0.4; 19F NMR (565 MHz, CDCl3):
δ (ppm) -133.04; HRMS (ESI-TOF) m/z: [M + Na] calcd for C30H30N3O8FSiNa
630.1684; found 630.1685.
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ethyl (1'S,3S,3'S)-1-benzyl-5-chloro-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-3'-carboxylate (4d). White solid, 107.2
mg, 58% yield, 94:6 dr, 86% ee by HPLC on Chiralpak OD column (10% 2-propanol/n-
hexane, 1 mL/min), UV 254 nm, tminor = 15.31 min, tmajor = 18.68 min, [α]D25 = +153.03
(c 1.00, CH2Cl2), m.p. 104-106 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.77 (s, 1H),
8.55 (s, 1H), 7.34−7.21 (m, 7H), 6.69 (d, J = 8.4 Hz, 1H), 5.18 (s, 1H), 4.86 (s, 2H),
3.98 (dd, J = 16.0, 4.0 Hz, 1H), 3.85−3.74 (m, 2H), 3.32−3.20 (m, 2H), 0.72 (t, J = 7.2
Hz, 3H), -0.16 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 175.9, 170.6, 148.3,
146.7, 143.7, 143.1, 137.2, 135.2, 131.3, 129.3, 129.0, 128.2, 128.2, 127.8, 124.1, 123.6,
119.0, 110.4, 74.3, 61.5, 54.8, 46.5, 44.5, 25.8, 13.6, -0.3; HRMS (ESI-TOF) m/z: [M
+ Na] calcd for C30H30N3O8ClSiNa 646.1388; found 646.1390.
ethyl (1'S,3S,3'S)-1-benzyl-6-chloro-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-3'-carboxylate (4e). White solid, 101.4
mg, 54% yield, 92:8 dr, 75% ee by HPLC on ChiralpakAD column (30% 2-propanol/n-
hexane, 1 mL/min), UV 254 nm, tminor = 9.18 min, tmajor = 11.66 min, [α]D25 = +59.34
(c 1.00, CH2Cl2), m.p. 106-108 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.77 (s, 1H),
8.54 (s, 1H), 7.3−7.29 (m, 5H), 7.16 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.0, 2.0 Hz, 1H),
6.77 (d, J = 1.6 Hz, 1H), 5.13 (s, 1H), 4.85 (s, 2H), 3.96 (dd, J = 16.0, 3.6 Hz, 1H), 3.74
(q, J = 7.2 Hz, 2H), 3.31−3.19 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H), -0.16 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 176.3, 170.6, 148.3, 146.7, 145.9, 143.8, 137.2,
135.4, 135.1, 129.0, 128.2, 127.9, 127.7, 124.4, 123.8, 122.4, 118.9, 109.9, 74.3, 61.4,
54.4, 46.5, 44.4, 25.7, 13.6, -0.3; HRMS (ESI-TOF) m/z: [M + Na] calcd for
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ethyl (1'S,3S,3'S)-1-benzyl-4-bromo-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-3'-carboxylate (4f). White solid, 110.3
mg, 55% yield, >95:5 dr, 85% ee by HPLC on Chiralpak AD column (30% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tmajor = 5.15 min, tminor = 23.35 min, [α]D
= -45.14 (c 1.00, CH2Cl2), m.p. 152-154 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.75
(s, 1H), 8.56 (s, 1H), 7.35−7.08 (m, 7H), 6.68 (d, J = 6.8 Hz, 1H), 5.80 (s, 1H), 5.12 (d,
J = 15.6 Hz, 1H), 4.56 (d, J = 16.0 Hz, 1H), 4.32 (dd, J = 10.0, 6.4 Hz, 1H), 4.13−4.10
(m, 1H), 3.99−3.90 (m, 2H), 3.54 (dd, J = 18.0, 6.4 Hz, 1H), 0.97 (t, J = 7.2 Hz, 3H), -
13
0.11 (s, 9H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 173.8, 170.4, 148.1, 146.8,
146.3, 143.0, 137.4, 135.1, 130.8, 128.7, 127.7, 127.4, 126.9, 126.8, 125.3, 118.7, 118.2,
108.5, 71.7, 61.3, 54.9, 43.9, 42.4, 26.2, 13.7, -0.3; HRMS (ESI-TOF) m/z: [M + Na]
calcd for C30H30N3O8BrSiNa 690.0883; found 690.0881.
ethyl (1'S,3S,3'S)-1-benzyl-5-bromo-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-3'-carboxylate (4g). White solid, 120.1
mg, 60% yield, 93:7 dr, 85% ee by HPLC on Chiralpak OD column (10% 2-propanol/n-
hexane, 1 mL/min), UV 254 nm, tminor = 14.65 min, tmajor = 19.58 min, [α]D25 = +26.15
(c 1.00, CH2Cl2), m.p. 161-163 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.78 (s, 1H),
8.55 (s, 1H), 7.38–7.32 (m, 4H), 7.30–7.29 (m, 3H), 6.63 (d, J = 8.5 Hz, 1H), 5.17 (s,
1H), 4.85 (s, 2H), 3.97 (dd, J = 16.4, 4.0 Hz, 1H), 3.85–3.75 (m, 2H), 3.28 (dd, J = 16.4,
11.2 Hz, 1H), 3.20 (dd, J = 11.2, 4.0 Hz, 1H), 0.73 (t, J = 7.2 Hz, 3H), -0.16 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 175.8, 170.6, 148.3, 146.7, 143.7, 143.6,
137.2, 135.2, 132.2, 131.7, 129.0, 128.2, 127.7, 126.8, 123.8, 118.9, 115.2, 110.8, 74.3,
61.5, 54.7, 46.5, 44.4, 25.7, 13.6, -0.3; HRMS (ESI-TOF) m/z: [M + Na] calcd for
C30H30N3O8BrSiNa 690.0883; found 690.0880.
ethyl (1'S,3S,3'S)-1-benzyl-6-bromo-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-3'-carboxylate (4h). White solid, 118.5
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mg, 59% yield, 91:9 dr, 80% ee by HPLC on ChiralpakAD column (30% 2-propanol/n-
hexane, 1 mL/min), UV 254 nm, tminor = 10.69 min, tmajor = 13.53 min, [α]D25 = +45.44
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(c 1.00, CH2Cl2), m.p. 89-91 C. H NMR (400 MHz, CDCl3): δ (ppm) 8.77 (s, 1H),
8.53 (s, 1H), 7.35−7.28 (m, 5H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H),
6.92 (s, 1H), 5.13 (s, 1H), 4.85 (s, 2H), 3.95 (dd, J = 16.0, 3.6 Hz, 1H), 3.74 (q, J = 7.2
Hz, 2H), 3.31−3.19 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H), -0.16 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 176.2, 170.6, 146.7, 146.0, 143.7, 137.2, 135.1, 129.0, 128.5,
128.2, 127.7, 125.5, 124.7, 123.8, 123.1, 118.9, 112.6, 74.3, 61.4, 54.5, 46.4, 44.4, 25.7,
13.6, -0.3; HRMS (ESI-TOF) m/z: [M + Na] calcd for C30H30N3O8BrSiNa 690.0883;
found 690.0884.
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ethyl (1'S,3S,3'S)-1-benzyl-5,5',7'-trinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-dihydro-
1'H-spiro[indoline-3,2'-naphthalene]-3'-carboxylate (4i). White solid, 100.6 mg, 53%
yield, 90:10 dr, 92% ee by HPLC on Chiralpak AD column (30% 2-propanol/n-hexane,
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1 mL/min), UV 254 nm, tmajor = 7.75 min, tminor = 12.00 min, [α]D = -20.85 (c 1.00,
CH2Cl2), m.p. 111-113 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.89 (s, 1H), 8.44 (s,
1H), 8.10 (d, J = 8.8 Hz, 1H), 7.41−7.30 (m, 5H), 6.80 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H),
5.42 (d, J = 15.6 Hz, 1H), 5.31 (s, 1H), 4.68 (d, J = 16.0 Hz, 1H), 3.99 (dd, J = 18.4,
7.6 Hz, 1H), 3.89 (t, J = 7.6 Hz, 1H), 3.82−3.72 (m, 2H), 3.61 (dd, J = 18.4, 7.6 Hz,
1H), 0.80 (t, J = 7.2 Hz, 3H), 0.17 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
177.4, 169.1, 149.7, 148.3, 146.2, 142.7, 142.5, 136.0, 133.7, 128.6, 127.8, 127.1, 126.8,
125.6, 124.2, 119.2, 118.9, 108.3, 73.9, 61.3, 54.5, 44.4, 44.3, 25.2, 13.2, -0.2; HRMS
(ESI-TOF) m/z: [M + Na] calcd for C30H30N4O10SiNa 657.1629; found 657.1628.
ethyl (1'S,3S,3'S)-1-benzyl-5-methyl-5',7'-dinitro-2-oxo-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalene]-3'-carboxylate (4j). White solid, 86.5
mg, 47% yield, 89:11 dr, 77% ee by HPLC on Chiralpak OD column (10% 2-
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propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 12.81 min, tmajor = 16.61 min, [α]D
= +50.99 (c 1.00, CH2Cl2), m.p. 90-92 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.76
(s, 1H), 8.56 (s, 1H), 7.36−7.25 (m, 5H), 7.08 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.65 (d,
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J = 7.9 Hz, 1H), 5.16 (s, 1H), 4.86 (dd, J = 23.6, 15.6 Hz, 2H), 3.96 (dd, J = 16.0, 4.0
Hz, 1H), 3.75−3.66 (m, 2H), 3.32−3.18 (m, 2H), 2.31 (s, 3H), 0.62 (t, J = 7.2 Hz, 3H),
-0.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 176.4, 170.9, 148.4, 146.7,
144.4, 142.2, 137.5, 135.9, 132.5, 129.7, 129.7, 129.0, 128.0, 128.0, 124.4, 123.8, 118.8,
109.3, 74.6, 61.2, 54.8, 46.7, 44.4, 25.9, 21.3, 13.5, -0.3; HRMS (ESI-TOF) m/z: [M +
Na] calcd for C31H33N3O8SiNa 626.1935; found 626.1931.
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(1'S,3S,3'S)-3'-benzoyl-1-benzyl-5',7'-dinitro-1'-((trimethylsilyl)oxy)-3',4'-dihydro-
1'H-spiro[indoline-3,2'-naphthalen]-2-one (4k). White solid, 108.1 mg, 58% yield,
91:9 dr, 95% ee by HPLC on Chiralpak OD column (25% 2-propanol/n-hexane, 1
25
mL/min), UV 254 nm, tminor = 11.24 min, tmajor = 18.78 min, [α]D = +36.34 (c 1.00,
CH2Cl2), m.p. 146-148 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.81 (s, 1H), 8.59 (s,
1H), 7.38 (t, J = 7.2 Hz, 1H), 7.32−7.12 (m, 10H), 7.04−6.96 (m, 2H), 6.32 (d, J = 7.2
Hz, 1H), 5.17 (s, 1H), 5.03 (d, J = 15.2 Hz, 1H), 4.10−3.95 (m, 3H), 3.47 (dd, J = 16.8,
11.6 Hz, 1H), -0.27 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 199.3, 177.1,
148.7, 146.9, 144.6, 144.4, 138.4, 137.0, 135.7, 133.4, 129.5, 129.2, 128.7, 128.6, 128.3,
128.2, 128.1, 125.1, 123.9, 123.3, 119.1, 109.3, 75.2, 55.3, 49.2, 44.7, 26.0, -0.2; HRMS
(ESI-TOF) m/z: [M + Na] calcd for C34H31N3O7SiNa 644.1829; found 644.1832.
(1'S,3S,3'S)-1-benzyl-3'-(2-fluorobenzoyl)-5',7'-dinitro-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalen]-2-one (4l). White solid, 107.8 mg, 56%
yield, 86:14 dr, 99% ee by HPLC on Chiralpak OD column (30% 2-propanol/n-hexane,
1 mL/min), UV 254 nm, tminor = 7.98 min, tmajor = 19.94 min, [α]D25 = +261.51 (c 2.00,
CH2Cl2), m.p. 102-104 oC. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.80 (s, 1H), 8.57 (s,
1H), 7.33 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 7.4 Hz, 2H), 7.24 (d, J = 7.2 Hz, 2H), 7.18 (d,
J = 7.8 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.92 (t, J = 7.8 Hz,
1H), 6.82 (dd, J = 10.9, 8.3 Hz, 1H), 6.42 (d, J = 7.8 Hz, 1H), 5.24 (s, 1H), 4.97 (d, J =
15.6 Hz, 1H), 4.14−4.10 (m, 3H), 4.04 (dd, J = 16.8, 4.8 Hz, 1H), 3.43 (dd, J = 16.6,
10.6 Hz, 1H), -0.26 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 197.1, 176.3,
147.5 (d, JCF = 277.9 Hz), 144.3, 137.7, 135.5, 134.5 (d, JCF = 9.3 Hz), 130.5, 129.3,
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128.8 (d, JCF = 9.7 Hz), 128.5, 127.8, 124.6, 124.2, 123.9, 123.0, 122.3, 118.9, 116.3
(d, JCF = 22.8 Hz), 109.1, 74.6, 60.6, 54.4, 51.5, 44.3, -0.4; 19F NMR (565 MHz, CDCl3):
δ (ppm) -111.27; HRMS (ESI-TOF) m/z: [M + Na] calcd for C34H30N3O7FSiNa
662.1735; found 662.1732.
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(1'S,3S,3'S)-1-benzyl-3'-(4-fluorobenzoyl)-5',7'-dinitro-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalen]-2-one (4m). White solid, 113.9 mg, 59%
yield, 90:10 dr, 98% ee by HPLC on Chiralpak OD column (30% 2-propanol/n-hexane,
1 mL/min), UV 254 nm, tminor = 6.49 min, tmajor = 18.86 min, [α]D25 = 209.32 (c 2.00,
CH2Cl2), m.p. 99-101 oC. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.86 (s, 1H), 8.39 (s,
1H), 7.40 (dd, J = 9.0, 5.4 Hz, 2H), 7.27 (dd, J = 6.6, 3.0 Hz, 3H), 7.15 (dd, J = 6.6, 2.4
Hz, 2H), 6.99 (t, J = 7.8 Hz, 1H), 6.77 (t, J = 9.0 Hz, 2H), 6.66 (t, J = 7.8 Hz, 1H), 6.45
(d, J = 7.8 Hz, 1H), 5.54 (d, J = 7.2 Hz, 1H), 5.39 (s, 1H), 4.78−4.74 (m, 2H), 4.70 (d,
J = 15.6 Hz, 1H), 4.10 (dd, J = 17.4, 4.8 Hz, 1H), 3.32 (dd, J = 17.4, 7.8 Hz, 1H), 0.12
(s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 196.6, 177.6, 165.7 (d, JCF = 254.3
Hz), 148.8, 146.3, 144.2, 143.9, 138.6, 135.0, 132.7, 130.8 (d, JCF = 9.0 Hz), 128.9,
128.8, 127.9, 127.6, 125.5, 125.1, 124.1, 122.6, 119.1, 115.6 (d, JCF = 21.8 Hz), 109.0,
73.9, 55.9, 47.1, 44.5, 25.8, 0.2; 19F NMR (565 MHz, CDCl3): δ (ppm) -104.12; HRMS
(ESI-TOF) m/z: [M + Na] calcd for C34H30N3O7FSiNa 662.1735; found 662.1730.
(1'S,3S,3'S)-1-benzyl-3'-(3,4-dichlorobenzoyl)-5',7'-dinitro-1'-((trimethylsilyl)oxy)-
3',4'-dihydro-1'H-spiro[indoline-3,2'-naphthalen]-2-one (4n). White solid, 114.3 mg,
56% yield, 93:7 dr, 97% ee by HPLC on Chiralpak OD column (30% 2-propanol/n-
hexane, 1 mL/min), UV 254 nm, tminor = 6.52 min, tmajor = 21.28 min, [α]D25 = +129.38
(c 2.00, CH2Cl2), m.p. 109-111 oC. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.82 (s, 1H),
8.58 (s, 1H), 7.34−7.29 (m, 4H), 7.28−7.26 (m, 2H), 7.14 (d, J = 7.8 Hz, 1H), 7.10 (dd,
J = 18.0, 8.4 Hz, 2H), 7.05−7.01 (m, 2H), 6.43 (d, J = 7.8 Hz, 1H), 5.11 (s, 1H), 5.08
(d, J = 15.0 Hz, 1H), 4.13 (d, J = 15.6 Hz, 1H), 3.98−3.94 (m, 2H), 3.45 (dd, J = 16.8,
13.2 Hz, 1H), -0.27 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 197.1, 176.9,
148.6, 147.0, 144.4, 144.3, 138.0, 137.9, 136.4, 135.5, 133.4, 130.6, 130.1, 129.8, 129.2,
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128.4, 128.3, 128.2, 127.0, 125.0, 123.8, 123.5, 119.2, 109.4, 75.2, 55.2, 49.5, 44.8,
25.7, -0.2; HRMS (ESI-TOF) m/z: [M + Na] calcd for C34H29N3O7Cl2SiNa 712.1050;
found 712.1049.
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(1'S,3S,3'S)-1-benzyl-3'-(4-bromobenzoyl)-5',7'-dinitro-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalen]-2-one (4o). White solid, 125.7 mg, 61%
yield, 92:8 dr, 93% ee by HPLC on Chiralpak OD column (30% 2-propanol/n-hexane,
1 mL/min), UV 254 nm, tminor = 6.86 min, tmajor = 23.91 min, [α]D25 = +207.72 (c 2.00,
CH2Cl2), m.p. 108-110 oC. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.81 (s, 1H), 8.58 (s,
1H), 7.32 (d, J = 6.6 Hz, 3H), 7.26−7.21 (m, 5H), 7.16 (d, J = 6.6 Hz, 1H), 7.08 (dd, J
= 15.6, 7.8 Hz, 3H), 7.00 (t, J = 7.2 Hz, 1H), 6.42 (d, J = 7.8 Hz, 1H), 5.12 (s, 1H), 4.96
(d, J = 15.0 Hz, 1H), 4.19 (d, J = 15.6 Hz, 1H), 4.01 (dd, J = 11.4, 3.6 Hz, 1H), 3.95 (d,
J = 16.8 Hz, 1H), 3.46 (dd, J = 15.6, 12.0 Hz, 1H), -0.27 (s, 9H); 13C{1H} NMR (150
MHz, CDCl3): δ (ppm) 198.2, 177.0, 148.6, 146.9, 144.4, 144.3, 138.2, 135.6, 135.5,
131.9, 129.6, 129.6, 129.2, 128.7, 128.4, 128.3, 128.2, 125.1, 123.8, 123.3, 119.1, 109.4,
75.2, 55.3, 49.1, 44.7, 25.8, -0.2; HRMS (ESI-TOF) m/z: [M + Na] calcd for
C34H30N3O7BrSiNa 722.0934; found 722.0932.
(1'S,3S,3'S)-1-benzyl-3'-(4-methoxybenzoyl)-5',7'-dinitro-1'-((trimethylsilyl)oxy)-3',4'-
dihydro-1'H-spiro[indoline-3,2'-naphthalen]-2-one (4p). White solid, 106.2 mg, 54%
yield, 91:9 dr, 96% ee by HPLC on Chiralpak OD column (30% 2-propanol/n-hexane,
1 mL/min), UV 254 nm, tminor = 7.77 min, tmajor = 16.34 min, [α]D25 = +138.38 (c 1.00,
CH2Cl2), m.p. 103-105 oC. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.86 (s, 1H), 8.41 (s,
1H), 7.48 (d, J = 9.0 Hz, 2H), 7.25 (dd, J = 6.6, 4.2 Hz, 3H), 7.10 (dd, J = 6.6, 2.4 Hz,
2H), 6.99 (dd, J = 8.4, 7.2 Hz, 1H), 6.68−6.66 (m, 3H), 6.44 (d, J = 7.8 Hz, 1H), 5.66
(d, J = 7.8 Hz, 1H), 5.41 (s, 1H), 4.86 (d, J = 15.6 Hz, 1H), 4.75 (dd, J = 7.2, 6.0 Hz,
1H), 4.66 (d, J = 15.6 Hz, 1H), 4.05 (dd, J = 18.0, 6.0 Hz, 1H), 3.78 (s, 3H), 3.35 (dd,
J = 17.4, 7.2 Hz, 1H), 0.13 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 196.1,
177.6, 163.7, 148.7, 146.2, 144.2, 143.8, 138.8, 135.1, 130.6, 129.1, 128.8, 128.5, 127.7,
127.4, 125.7, 125.0, 124.2, 122.5, 119.0, 113.7, 109.0, 74.1, 55.9, 55.6, 46.4, 44.4, 26.3,
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The Journal of Organic Chemistry
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at http://pubs.acs.org.
Crystal data for 3d and 4d (the TMS-protected group of 4d was removed).
1H and 13C NMR spectra and HPLC chromatograms for products 3 and 4.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: pengcheng@cdutcm.edu.cn.
*E-mail: hanbo@cdutcm.edu.cn.
ORCID
Cheng Peng: 0000-0003-3303-906X
Bo Han: 0000-0003-3200-4682
Author Contributions
‡ Biao Wang and Xiao-Hui Wang contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEGEMENTS
We are grateful for financial support from the National Natural Science Foundation of
China (81573588, 81630101, 81773889, and 21772131), the Science & Technology
Department of Sichuan Province (2017JZYD0001, 2017JQ0002, 2017JY0323).
REFERENCES
(1) (a) Han, N.-n.; Zhou, Q.; Huang, Q.; Liu, K.-j. Carnosic acid cooperates with
tamoxifen to induce apoptosis associated with Caspase-3 activation in breast cancer
cells in vitro and in vivo. Biomed. Pharmacother. 2017, 89, 827-837. (b) Zurlo, D.;
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