Organocatalytic Asymmetric Synthesis of Bridged Acetals with Spirooxindole Skeleton

Article abstract of DOI:10.1021/acs.joc.8b02156

The first highly diastereo- and enantioselective synthesis of bridged O,O-acetals embedded with spirooxindoles has been developed. Dioxindoles and 2-hydroxy cinnamaldehydes were employed as the reaction partners in this method. The desired products were obtained via diaryl prolinol TBS ether catalyzed Michael reaction followed by acetal formation with TFA.

Full text of DOI:10.1021/acs.joc.8b02156

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Note
Organocatalytic Asymmetric Synthesis of
Bridged Acetals with Spirooxindole Skeleton
Megha Balha, and Subhas Chandra Pan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02156 • Publication Date (Web): 29 Oct 2018
Downloaded from http://pubs.acs.org on October 30, 2018
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Organocatalytic Asymmetric Synthesis of Bridged Acetals with Spirooxindole
Skeleton
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Megha Balha and Subhas Chandra Pan*
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Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam,
781039
E-mail: span@iitg.ernet.in
O
R1
OH
1. catalyst (10 mol%)
CHO
O
PhCO2H (10 mol%)
acetonirile, rt, 8-20 h
R1
O
+
O
OH
N
N
R2
R2 = Ar, Alk
2. TFA, CH2Cl2
12 h
R2
R1 = 4-Me, 3-Cl etc.
up to 80% yield
up to 99% ee
22 examples
Ph
Ph
N
OTBS
H
ABSTRACT: The first highly diastereo- and enantioselective synthesis of bridged O,O-acetals
embedded with spirooxindoles has been developed. Dioxindoles and 2-hydroxy cinnamldehydes
were employed as the reaction partners in this method. The desired products were obtained via
diaryl prolinol TBS ether catalyzed Michael reaction followed by acetal formation with TFA.
Chiral O,O-acetals are important structural motifs present in a range of natural products and
pharmaceuticals and display a wide range of bioactivities.1 Thus considerable efforts have been
devoted in the recent times for the asymmetric synthesis of these compounds.2 Infact a number of
convenient approaches has been developed for the synthesis of mono cyclic acetals,3 fused acetals4
and spiroketals.5 For example, List and Čorić have elegantly developed asymmetric synthesis of
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spiroacetals using imidophosphoric acid as catalyst.5a In contrary, the asymmetric synthesis of
bridged O,O-acetals has been less developed though such skeleton is present in procyanidin A1,6
epicoccolide A,7 cholinesterease inhibitor8 and other bioactive compounds (Figure 1).9 Only
Jørgensen4a and Franzén10 recently reported organocatalytic synthesis of bridged acetals and Shi
and co-workers11 alternatively developed Pd-catalyzed synthesis of bridged [3,3,1]-ketals (Scheme
1). However, the structural variety and complexity of bridged acetals necessitate the development
of efficient synthesis of them having diverse scaffolds.
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O
O
Me
O
H
OH
OH
Me
HO
HO
OH
O
H
OH
OH
O
Epicoccolide A
O
HO
Me
O
RNH
O
O
OH
OH
HO
OH
O
O
Procyanidin A1
Cholinesterease inhibitor
OH
Figure 1. Representative bioactive bridged O,O-acetals
Spirocyclic oxindole frameworks have been frequently found in natural and unnatural compounds
and demonstrate varied and extensive biological activities.12 For this reason, extensive attention
has been given to access to the enantiopure spirocyclic oxindole containing skeletons during the
past decade. However, from the literature survey, it is evident that the most of the methods involve
the construction of spirooxindoles having monocyclic or fused scaffolds.13 Thus, the developement
of a facile method for the creation of multi rings embedded complex chiral spiro oxindoles is a
challenging task and only Chen, Wang and Feng demonstrated few examples.14
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During the initiation of the project, Bu and co-workers reported triflic acid catalyzed synthesis of
bridged ketals with spirooxindole motif15 but a catalytic asymmetric synthesis of spirooxindoles
having briged acetal structure is still not knowndespite high medical importance of bridged acetals
and spirooxindoles individually.
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Scheme 1. Catalytic asymmetric synthesis of bridged acetals.
(A) Previous reports: Synthesis of bridged acetals with carbocycle skeleton
1. chiral
O
O
sec amine
R
R
O
O
O
2. AcCl
Franzen etal10
HO
R
+
H
O
O
R
1. chiral
R
O
sec amine
H
H
2. HSiEt3, BF3.OEt2
R
+
O
H
Jørgensen etal4a
OH
O
H
O
Pd catalyst
B(OH)2
OH
R
AgBF4
+
O
Shi etal11
OH
O
R
(B) This work: Synthesis of bridged acetals with heterocycle skeleton
O
R
OH
1. chiral
sec amine
O
CHO
+
R
O
O
N
R1
OH
N
R1
2. TFA, CH2Cl2
Dioxiindoles have earlier been employed as bidentate reagents in asymmetric oragnocatalysis by
Melchiorre and co-workers for different conjugate addition reactions.16 We envisaged that if o-
hydroxy cinnamaldehydes are employed as a reaction partner, then the insitu formed hemi acetal
from first Michael reaction could be converted to bridged acetal motif with acid. We thus became
interested in developing a simple method for the asymmetric synthesis of bridged acetals having
spirooxindole moiety.
We initiated our exploration by performing a reaction between ortho-hydroxy-cinnamaldehyde
(1a) and N-benzyl dioxindole (2a) with proline in toluene (Table 1). However, no product
formation was detected (entry 1). Interestingly, stirring with diphenyl prolinol in combination with
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benzoic acid for 8 hours resulted in the formation of a hemicaetal which was converted to the
desired acetal 3a by further reaction with trifluoroacetic acid. Interestingly, only a single
diatereomer was detected by 1H NMR and the enantiomeric excess was 60%. Encouraged by this
result, different secondary amine catalysts were screened. Gratifyingly, the enantisoelectivity got
increased to 93% ee with Jørgesen-Hayshi catalyst III.17 Then catalysts IV and V having OTES
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and OTBS groups respectively were employed in the reaction (entries 2-4). Interestingly, though
catalyst IV could not enhance the enantioselectivity, higher enantiomeric excess (96% ee) was
achieved with catalyst V. Then we turned our attention on solvent optimization. Halogenated
solvent such as dichloromethane was not good for this reaction as poor conversion was seen.
Gratifiyngly, slight enhancement in enantioselectivity was observed in α,α,α-trifluorotoluene and
finally the best solvent emerged as acetonitrile in which 98% ee was achieved. Other acid additives
were also screened but benzoic acid was found to be the best (see supporting information for
details).
Table 1. Catalyst Screening and Optimization of Reaction Condition
O
1. catalyst (10 mol%)
PhCO2H (10 mol%)
solvent, rt, 8 h
OH
O
CHO
+
O
O
N
OH
N
2. TFA, CH2Cl2
12 h
Bn
Bn
1a
2a
3a
Ph
Ph
CO2H
N
N
OH
H
H
I
II
Ph
Ph
Ph
Ph
OTBS
Ph
OTMS
Ph
N
N
N
OTES
H
H
H
III
IV
V
entrya catalyst
solvent
yieldb
d.rc
eed
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1
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I
II
III
IV
V
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
CH2Cl2
PhCF3
0
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
-
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98
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V
V
V
CH3CN
a
All reactions were carried out with 0.12 mmol of 1a with 0.1 mmol of 2a in 0.5 ml solvent at
b
c
1
room temperature. Isolated yield after silica gel column chromatography. Determined by H
NMR. d Determined by HPLC using stationary phase chiral column.
The scope of the reaction was then investigated by testing a variety of o-hydroxyaromatic α,β-
unsaturated aldehydes 1 in this method and the results are shown in Table 2. To our delight, high
enantioselectivities were obtained in all of the cases and excellent diastereoselectivities were
maintained. At first, different 4-substituted α,β-unsaturated aldehydes 1b-1e were screened and
the corrseponding products were obtained in acceptable yields and with good stereoselectivities
(entries 2-5). The electronic effects of the substituents did not influence much on the outcome of
the reaction. Then 3-chloro and 5-methoxy substituted enals 1f and 1g were employed in the
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reaction and high enantioselectivities were achieved for the corresponding products (entries 6-7).
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In particular, 99% ee was observed for product 3f having 3-chloro substitution. Our methodology
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Table 2. Scope of o-Hydroxyaromatic-α,β-unsaturated aldehydes
O
V
1. catalyst (10 mol%)
R
OH
PhCO2H (10 mol%)
acetonirile, rt, time
3
6
O
2
CHO
+
4
R
5
O
O
N
2. TFA, CH2Cl2
12 h
N
1 OH
Bn
Bn
1a-j
3a-j
2a
Entrya
R
H
Time (h) Product Yield (%)b drc eed
1
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3
4
5
6
7
8
9
8
3a
3b
3c
3d
3e
3f
79
64
51
66
57
61
62
34
23
32
47
>20:1 98
>20:1 97
>20:1 98
>20:1 97
>20:1 98
>20:1 99
>20:1 97
>20:1 94
>20:1 95
>20:1 96
>20:1 98
4-Me
4-OMe
4-Cl
10
12
12
8
4-Br
3-Cl
12
20
20
20
20
12
5-OMe
4,6-diCl
4,6-diBr
3g
3h
3i
10 4-Cl, 6-Br
11 4-NHBoc
3j
3k
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aAll reactions were carried out with 0.12 mmol of 1 with 0.1 mmol of 2a in 0.5 mL acetonitrile.
bIsolated yield after silica gel column chromatography. cDetermined by 1H NMR. dDetermined by
chiral HPLC using stationary phase chiral column.
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is also suitable for 4,6-disubstituted enals and high diastereo- and enantioselectivities were
observed albeit moderate yields were detected (entries 8-10). To our delight, substrate 1k having
4-NHBoc group could also be employed in our methodology delivering product 3k in excellent
98% ee (entry 11).
Next, the generatlity of the reaction was further extended by engaging a variety of dioxindoles
(Table 3). Initially, different N-substitutions were checked and gratifyingly here also excellent
results were achieved preserving high diastereomeric ratio. For example, 80% yield and 98% ee
obtained for product 3l having N-methyl substitution and 99% ee was observed for product 3m
having N-iBu substitution (entries 1-2). Dioxindole 2d having N-allyl group and 2e having N-
prenyl group also participated in the reaction delivering products 3n and 3o respectively in
excellent enantioselectivities (entries 3-4). Then dioxindole 2f having N-4-CF3benzyl group was
employed in the reaction and smooth conversion was observed for 3p with 98% ee (entry 5).
Moreover our methodolgy was also suitable for N-unsbstituted oxindole 2g delivering the product
3q in 99% ee (entry 6). Then the aromatic part of the oxindole motif was varied and here also the
results were unaffected. Initially, 5-halo substituted N-benzyl dioxindoles 2h-2j were prepared and
engaged in the reaction (entries 7-9). The desired products 3r-3t were isolated in acceptable yields
with excellent enantioselectivities. The reactions with dioxindolex 2k and 2l having 6-bromo and
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7-chloro substitutions respectively was also satisfactory (entries 10-11). Finally 4-bromo
substituted oxiindole 2m participated in the reaction but the acetal formation was slow and only
after heating at 40 oC, moderate yield was detected (entry 12). Nevertheless these products having
halo substitutions are important as they can be elaborated easily by cross-coupling reactions.
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Table 3. Scope of dioxindoles
O
V
1. catalyst (10 mol%)
OH
4
7
PhCO2H (10 mol%)
acetonirile, rt, time
O
CHO
5
6
R2
O
R2
+
O
N
R1
OH
2. TFA, CH2Cl2
12 h
N
R1
3k-v
1a
2b-m
Entrya
R1
Me
R2 Time (h) ProductYield(%)b drc
eed
1
2
H
H
H
H
10
12
8
3l
3m
3n
3o
3p
3q
3r
3s
80
71
68
65
51
64
59
46
37
49
>20:1 98
>20:1 99
>20:1 98
>20:1 99
>20:1 98
>20:1 99
>20:1 97
>20:1 99
>20:1 93
>20:1 98
iBu
3
allyl
prenyl
4
20
9
5
4-CF3Bn H
6
H
H
20
20
20
20
12
7
Bn
Bn
Bn
Bn
5-F
8
5-Cl
5-Br
6-Br
9
3t
10
3u
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Bn
Bn
7-Cl
4-Br
20
10
3v
55
22
>20:1 93
>20:1 85
3w
7
8
9
aAll reactions were carried out with 0.12 mmol of 1 with 0.1 mmol of 2a in 0.5 mL acetonitrile.
bIsolated yield after silica gel column chromatography. cDetermined by 1H NMR. dDetermined by
chiral HPLC using stationary phase chiral column.
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The synthetic utility of our method was demonstrated by performing Suzuki coupling reactions on
3e and 3t (Scheme 2). Thus, when phenyl boronic acid was treated with 3e and 3t in the presence
of palladium acetate and tricyclohexyl phosphine under basic conditions, the corresponding
products 4 and 5 were formed in moderate yields. Delightfully, the enantiopurity was preserved
for both products.
Scheme 2. Synthetic Transformations of 3e and 3s.
PhB(OH)2 (1.5 eq.)
O
O
Pd(OAc)2 (5 mol%)
PCy3 (6 mol%)
Br
O
Ph
O
O
O
Na2CO3 (2 eq.)
DMF, rt
N
N
Bn
Bn
4
, >20:1 dr, 97% ee
3e
, >20:1 dr, 98% ee
43%
PhB(OH)2 (1.5 eq.)
Pd(OAc)2 (5 mol%)
PCy3 (6 mol%)
O
O
O
O
Br
Ph
O
N
O
N
Na2CO3 (2 eq.)
DMF, rt
Bn
Bn
5
, >20:1 dr, 93% ee
3t
49%
, >20:1 dr, 93% ee
The absolute structure of product 3s was solved by X-ray crystallography18 and was found to be
(2R,3’S,5S). The configuration of other products are expected to be same by analogy.
Based on the configuration, a plausible mechanism has been shown in Scheme 3. It is believed that
catalyst V reacts with 1a in the presence of benzoic acid to provide aminal A19 whose presence
was detected by NMR by stoichiometric mixing of V and 1a. Interestingly intermediate A is
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nucleophilic in nature and it must be in equilibrium with iminium ion B which is electrophilic and
thus the active intermediate for our reaction. Since the Si face of the chiral iminium ion is blocked
by bulky OTBS group, the conjugate addition of dioxindole 2a takes place from the Re face to
generate intermediate 6 after hydrolysis. A Newman projection C was also drawn to understand
the diastereoselectivity of the reaction. The enamine group and the CONAr group orients in anti-
fashion possibly due to steric interaction. Intermediate 6 then undergoes acetalization reaction
diastereoselectively in the presence of TFA to deliver product 3a (Scheme 3).
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Scheme 3. The Proposed Mechanism
CHO
N
N
H
O
N
OH
OH
PhCO2
1a
A
B
..
N
OH
HO
C
O
Michael addition
N
H
Ar
2a
N
Bn
O
Bn
Ar = 2-OHC6H4
O
O
(R)
HO
OHC
R
OH
O
OH
(S)
HO
(S)
(S)
(S)
TFA
(S)
(S)
O
O
O
N
acetalization
N
N
Bn
Bn
Bn
6
3a
In summary, this paper reports the first catalytic asymmetric synthesis of bridged O,O-acetal with
spirooxindole skeleton. The methodology involves amine catalyzed conjugated addition followed
by diastereoselective acetalization with TFA. The desired spirooxindole products were obtained
in good to high yields with high diastereo- and enantioselectivities in operationally simple reaction
conditions. Also few products have been further functionalized via Suzuki coupling reaction.
Given the high pharmaceutical significance of spirooxindoles and bridged acetals our products
might be bioactive and such studies are currently in progress.
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Experimental Section
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General Information:
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Chemicals and solvents were purchased from commercial suppliers and used as received. 1H NMR
spectra were recorded on 400 MHz, 500 MHz and 600 MHz spectrometer. 13C NMR spectra were
recorded on 100 MHz , 126 MHz and 150 MHz. Chemical shifts were reported in parts per million
(ppm), and the residual solvent peak was used as an internal reference: proton (chloroform δ
7.260), carbon (chloroform δ 77.23). Multiplicity was indicated as follows: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), brs (broad singlet). Coupling constants
were reported in Hertz (Hz). Using +ESI-TOF mode HRMS spectra were recorded. Enantiomeric
ratios were determined by HPLC analysis performed on Chiral Columns using a Daicel Chiralpak
IA Column. For visualizing the products UV light and I2 were used. Melting points were measured
using BüCHI melting point B-540 apparatus. All melting points were measured in open glass
capillary and values are uncorrected. DCM was distilled over CaH2 under argon and stored over
4A° molecular sieves. Silica gel (60-120 mesh size) was used for the column chromatography.
Reactions were monitored by TLC on silica gel 60 F254 (0.25 mm).
General procedure for the synthesis of ortho-hydroxy-cinnamaldehydes:
Ortho-hydroxy-cinnamaldehydes were prepared according to reported procedure.20
In an oven dried round bottom flask, (triphenylphosphoranylidene) acetaldehyde (2 mmol, 1.0 eq.)
was added to the stirred solution of salicylaldehyde (2 mmol) in dry THF (2 mL) and the resulting
solution was heated at reflux overnight. Completion of reaction was checked by TLC (6–12 h).
After the completion of reaction, solvent was evaporated and reaction mixture was purified by
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flash column chromatography on silica gel eluting with hexane/ethyl acetate to afford desired
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products 1b-j.
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((E)-3-(2-hydroxy-5-methylphenyl)acrylaldehyde) (1b)
The title compound was prepared as a dark yellow solid in 51% yield (165.4 mg) according to the
general procedure, as described above. 1H NMR (400 MHz, MeOD) δ 9.59 (d, J = 8.0 Hz, 1H),
7.88 (d, J = 15.9 Hz, 1H), 7.35 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.85 (dd, J = 16.0, 8.0 Hz, 1H),
6.78 (d, J = 8.3 Hz, 1H), 2.26 (s, 3H).
((E)-3-(2-hydroxy-5-methoxyphenyl)acrylaldehyde) (1c)
The title compound was prepared as a dark yellow solid in 52% yield (185.3 mg) according to the
general procedure, as described above. 1H NMR (400 MHz, MeOD) δ 9.62 (d, J = 7.9 Hz, 1H),
7.92 (d, J = 16.0 Hz, 1H), 7.10 (d, J = 3.0 Hz, 1H), 6.87 (ddd, J = 13.9, 13.2, 7.1 Hz, 3H), 3.78 (s,
3H).
((E)-3-(5-chloro-2-hydroxyphenyl)acrylaldehyde) (1d)
The title compound was prepared as a yellow solid in 48% yield (175.3 mg) according to the
general procedure, as described above. 1H NMR (400 MHz, MeOD) δ 9.61 (d, J = 7.8 Hz, 1H),
7.82 (d, J = 16.0 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 6.92 – 6.80 (m, 2H).
((E)-3-(5-bromo-2-hydroxyphenyl)acrylaldehyde) (1e)
The title compound was prepared as a yellow solid in 77% yield (349.6 mg) according to the
general procedure, as described above. 1H NMR (400 MHz, MeOD) δ 9.60 (d, J = 7.9 Hz, 1H),
7.80 (d, J = 16.0 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 6.90 – 6.79 (m, 2H).
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((E)-3-(2-chloro-6-hydroxyphenyl)acrylaldehyde) (1f)
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The title compound was prepared as a pale yellow solid in 79% yield (288.5 mg) according to the
general procedure, as described above. 1H NMR (400 MHz, MeOD) δ 9.63 (d, J = 8.0 Hz, 1H),
7.96 (d, J = 16.0 Hz, 1H), 7.30 – 7.17 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H).
((E)-3-(2-hydroxy-4-methoxyphenyl)acrylaldehyde) (1g)
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The title compound was prepared as a yellow solid in 54% yield (192.4 mg) according to the
general procedure, as described above. 1H NMR (600 MHz, MeOD) δ 9.51 (d, J = 8.0 Hz, 1H),
7.84 (d, J = 15.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 6.76 (dd, J = 15.8, 8.1 Hz, 1H), 6.50 (d, J = 8.7
Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 3.80 (s, 3H).
((E)-3-(3,5-dichloro-2-hydroxyphenyl)acrylaldehyde) (1h)
The title compound was prepared as a pale yellow solid in 80% yield (347.2 mg) according to the
general procedure, as described above. 1H NMR (400 MHz, MeOD) δ 9.66 (d, J = 7.7 Hz, 1H),
7.86 (d, J = 16.1 Hz, 1H), 7.58 (d, J = 2.5 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 16.1, 7.7
Hz, 1H).
((E)-3-(3,5-dibromo-2-hydroxyphenyl)acrylaldehyde) (1i)
The title compound was prepared as a yellow solid in 78% yield (477.2 mg) according to the
general procedure, as described above. 1H NMR (400 MHz, MeOD) δ 9.56 (d, J = 7.7 Hz, 1H),
7.76 (d, J = 16.0 Hz, 1H), 7.65 (dd, J = 5.8, 2.3 Hz, 2H), 6.76 (dd, J = 16.0, 7.7 Hz, 1H).
((E)-3-(3-bromo-5-chloro-2-hydroxyphenyl)acrylaldehyde) (1j)
The title compound was prepared as a pale yellow solid in 45% yield (235.3 mg) according to the
general procedure, as described above. 1H NMR (400 MHz, MeOD) δ 9.69 (d, J = 7.7 Hz, 1H),
7.89 (d, J = 16.1 Hz, 1H), 7.60 (s, 1H), 7.49 (s, 1H), 6.90 (dd, J = 16.1, 7.7 Hz, 1H).
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(tert-butyl (E)-(4-hydroxy-3-(3-oxoprop-1-en-1-yl)phenyl)carbamate) (1k)
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The title compound was prepared as a pale yellow solid in 40% yield (210.6 mg) according to the
general procedure, as described above. 1H NMR (400 MHz, MeOD) δ 9.61 (s, 1H), 7.91 (d, J =
16.0 Hz, 2H), 6.83 (dd, J = 8.4, 3.2 Hz, 3H), 1.53 (s, 9H).
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General procedure for the synthesis of dioxindoles:
Dioxindoles were prepared according to reported procedures.21
In an oven dried round bottom flask, a solution of isatin (10 mmol) was slowly added to K2CO3
(25 mmol, 2.5 eq.) under argon atmosphere at 0 ºC. The reaction mixture was allowed to stir at 0
ºC for 10 minutes. Then, alkyl halide or benzyl halide (20 mmol, 2.0 eq.) was added to reaction
mixture and allowed to stir at RT for 12 hours. Reaction mixture was filtered through Celite with
about 50 mL DCM, dried over Na2SO4 and concentrated under reduced pressure. Water was added
until precipitation of the N-protected isatin. Crystallization from hexane/ethyl acetate afforded the
pure product.
N-protected isatins (10 mmol) were added in small portions to a stirred suspension of sodium
borohydride (15 mmol, 1.5 eq.) in 60 mL of a 1:1 dichloromethane/ethanol mixture at 0 ºC. The
mixture was vigorously stirred at this temperature until the suspension became colorless (about 5
min). Then water (1.0 mL) was added and the reaction mixture was stirred until bubbling stop.
The mixture was extracted with dichloromethane (3 50 mL). The combined organic extracts were
dried (Na2SO4) and the solvent evaporated under reduced pressure. The residue was used without
further purification.
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Characterisation of dioxindoles:
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(3-hydroxy-1-methylindolin-2-one) (2b)
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The title compound was prepared as a green solid in 68% yield (1.1 g) according to the general
procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz, 1H), 7.33 (t, J
= 7.6 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 7.7 Hz, 1H), 5.10 (s, 1H), 3.18 (s, 3H).
(3-hydroxy-1-isobutylindolin-2-one) (2c)
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The title compound was prepared as a dark yellow solid in 75% yield (1.5 g) according to the
general procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.3 Hz, 1H),
7.31 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 5.11 (s, 1H), 3.54 (dd,
J = 13.9, 7.6 Hz, 1H), 3.42 (dd, J = 13.9, 7.4 Hz, 1H), 2.13 (dt, J = 13.8, 7.0 Hz, 1H), 0.96 (d, J =
6.7 Hz, 6H).
(1-allyl-3-hydroxyindolin-2-one) (2d)
The title compound was prepared as an off-white solid in 79% yield (1.5 g) according to the general
procedure, as described above. 1H NMR (600 MHz, CDCl3) δ 7.47 (d, J = 7.3 Hz, 1H), 7.30 (t, J
= 7.7 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 5.83 (ddd, J = 22.5, 10.5, 5.4 Hz,
1H), 5.25 (t, J = 12.7 Hz, 2H), 5.13 (s, 1H), 4.38 (d, J = 16.3 Hz, 1H), 4.27 (d, J = 16.3 Hz, 1H).
(3-hydroxy-1-(3-methylbut-2-en-1-yl) indolin-2-one) (2e)
The title compound was prepared as an orange solid in 85% yield (1.8 g) according to the general
procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.3 Hz, 1H), 7.25 (dd,
J = 12.7, 4.9 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 5.13 (t, J = 6.7 Hz, 1H),
5.08 (s, 1H), 4.30 (dd, J = 15.5, 6.6 Hz, 1H), 4.20 (dd, J = 15.5, 6.7 Hz, 1H), 1.78 (s, 3H), 1.68 (s,
3H).
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(3-hydroxy-1-(4-(trifluoromethyl) benzyl) indolin-2-one) (2f)
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The title compound was prepared as a green solid in 80% yield (2.5 g) according to the general
procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.1 Hz, 2H), 7.49 (d, J
= 7.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.26 – 7.21 (m, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.67 (d, J =
7.8 Hz, 1H), 5.20 (s, 1H), 4.93 (q, J = 16.0 Hz, 2H).
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(3-hydroxyindolin-2-one) (2g)
The title compound was prepared as a white solid in 78% yield (1.2 g) according to the general
procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.5 Hz, 1H), 7.29 (d, J
= 7.7 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 5.08 (s, 1H).
(1-benzyl-5-fluoro-3-hydroxyindolin-2-one) (2h)
The title compound was prepared as a green sticky solid in 70% yield (1.8 g) according to the
general procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.23 (m, 5H), 7.19
(d, J = 7.6 Hz, 1H), 6.88 (t, J = 8.9 Hz, 1H), 6.60 (dd, J = 8.6, 4.0 Hz, 1H), 5.16 (s, 1H), 4.90 (d,
J = 15.7 Hz, 1H), 4.79 (d, J = 15.7 Hz, 1H).
(1-benzyl-5-chloro-3-hydroxyindolin-2-one) (2i)
The title compound was prepared as a brown sticky solid in 84% yield (2.3 g) according to the
general procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.35 – 7.26
(m, 5H), 7.18 (dd, J = 8.4, 2.1 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 5.17 (s, 1H), 4.91 (d, J = 15.5
Hz, 1H), 4.81 (d, J = 15.7 Hz, 1H).
(1-benzyl-5-bromo-3-hydroxyindolin-2-one) (2j)
The title compound was prepared as a green sticky solid in 76% yield (2.4 g) according to the
general procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.33 – 7.23
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(m, 6H), 6.56 (d, J = 8.3 Hz, 1H), 5.19 (s, 1H), 4.89 (d, J = 15.5 Hz, 1H), 4.79 (d, J = 15.7 Hz,
1H).
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The title compound was prepared as a green solid in 74% yield (2.3 g) according to the general
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procedure, as described above. H NMR (400 MHz, CDCl3) δ 7.28 (dt, J = 15.0, 6.4 Hz, 6H),
7.18 (d, J = 7.9 Hz, 1H), 6.84 (s, 1H), 5.11 (s, 1H), 4.87 (d, J = 15.7 Hz, 1H), 4.74 (d, J = 15.7 Hz,
1H).
(1-benzyl-7-chloro-3-hydroxyindolin-2-one) (2l)
The title compound was prepared as a yellowish green solid in 75% yield (2.0 g) according to the
general procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.3 Hz, 1H),
7.34 – 7.29 (m, 2H), 7.23 (dd, J = 14.3, 7.8 Hz, 4H), 7.06 – 7.01 (m, 1H), 5.33 (d, J = 5.0 Hz, 2H),
5.18 (s, 1H).
(1-benzyl-4-bromo-3-hydroxyindolin-2-one) (2m)
The title compound was prepared as a dark yellow solid in 76% yield (2.4 g) according to the
general procedure, as described above. 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 13.3, 6.7 Hz,
5H), 7.17 (d, J = 8.2 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 5.17 (s, 1H), 4.87
(d, J = 3.1 Hz, 2H).
General procedure for the synthesis of catalyst:
The catalyst (III, IV and V) was prepared according to reported procedures.22, 23
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General procedure for the synthesis of compound 3:
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In an oven dried round bottom flask, 1 (17.7 mg, 0.12 mmol), 2 (23.9 mg, 0.1 mmol), 10 mol% of
catalyst (V) and 10 mol% of PhCO2H were taken. 0.5 mL of toluene was added to the reaction
mixture and stirred at rt for 8-20 hours. Completion of reaction was checked by TLC. After the
completion of reaction, solvent was concentrated and the reaction mixture was directly subjected
to TFA.
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Second step:
To the vacuum dried reaction mixture, DCM was added to the reaction mixture of first step and
allowed to stir at rt. 1.5 eq of TFA was added; the reaction mixture was allowed to stir overnight.
Progress of the reaction was monitored by TLC. After the completion of reaction, solvent was
concentrated and reaction mixture was directly purified by column chromatography on silica gel
eluting with hexane/ethyl acetate (10 %) to afford desired product 3a-v.
Characterisation of the products:
((2'R,3S,5'S)-1-benzyl-5'H-spiro[indoline-3,4'[2,5]methanobenzo[d][1,3]dioxepin]-2-one)
(3a) was obtained as a light yellow solid in 79% yield (29.2 mg) after column chromatography.
M.P. = 128-130 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.32 – 7.18 (m, 6H), 7.06 (t, J = 7.8
Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.61 (t, J = 7.3 Hz, 2H), 6.55 (d, J =
7.4 Hz, 1H), 6.04 (d, J = 3.5 Hz, 1H), 5.84 (d, J = 8.0 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 4.75 (d,
J = 15.6 Hz, 1H), 3.62 (dt, J = 11.6, 3.9 Hz, 1H), 3.25 (d, J = 3.9 Hz, 1H), 2.42 (d, J = 11.6 Hz,
1H). 13C {1H} NMR (151 MHz, Chloroform-d) δ 175.5 , 151.8 , 143.0 , 135.6 , 130.1 , 129.7 ,
129.0 , 128.9 , 127.9 , 127.4 , 125.9 , 125.7 , 125.5 , 122.6 , 120.8 , 116.5 , 109.1 , 101.3 , 90.8 ,
45.1 , 43.9 , 31.4. HPLC Analysis: ee = 98%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10,
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flow rate 1.0 mL/min, λ = 254 nm (tmajor = 11.0 min, tminor = 21.3 min). HRMS (+ESI-TOF): calcd.
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((2'R,3S,5'S)-1-benzyl-7'-methyl-5'H-spiro[indoline-3,4'[2,5]methanobenzo[d][1,3]
dioxepin]-2-one) (3b) was obtained as light yellow semi solid in 64% (24.5 mg) yield after column
chromatography. 1H NMR (400 MHz, Chloroform-d) δ 7.30 – 7.20 (m, 5H), 7.06 (t, J = 7.8 Hz,
1H), 6.99 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.62 (t, J = 6.6 Hz, 2H), 6.36 (s, 1H), 6.02
(d, J = 3.5 Hz, 1H), 5.86 (d, J = 7.6 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 4.73 (d, J = 15.6 Hz, 1H),
3.60 (dt, J = 11.6, 3.9 Hz, 1H), 3.19 (d, J = 3.9 Hz, 1H), 2.39 (d, J = 11.6 Hz, 1H), 2.11 (s, 3H).
13C {1H} NMR (101 MHz, Chloroform-d) δ 175.6 , 149.6 , 143.1 , 135.7 , 130.1 , 130.1 , 130.1
, 129.4 , 129.0 , 127.9 , 127.5 , 126.1 , 125.8 , 125.2 , 122.6 , 116.2 , 109.0 , 101.3 , 90.7 , 45.1 ,
43.9 , 31.6 , 20.5. HPLC Analysis: ee = 97%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10,
flow rate 1.0 mL/min, λ = 254 nm (tmajor = 9.9 min, tminor = 15.8 min). HRMS (+ESI-TOF): calcd.
For C25H22NO3 [M+H]+ 384.1594, found 384.1603.
((2'R,3S,5'S)-1-benzyl-7'-methoxy-5'H-spiro[indoline-3,4'[2,5]methanobenzo[d][1,3]
dioxepin]-2-one) (3c) was obtained as a yellow sticky solid in 51% (20.4 mg) yield after column
chromatography. 1H NMR (400 MHz, Chloroform-d) δ 7.31 – 7.20 (m, 5H), 7.06 (t, J = 7.8 Hz,
1H), 6.82 (d, J = 8.8 Hz, 1H), 6.75 (dd, J = 8.8, 2.9 Hz, 1H), 6.68 – 6.59 (m, 2H), 6.12 (d, J = 2.9
Hz, 1H), 6.01 (d, J = 3.5 Hz, 1H), 5.91 (d, J = 7.2 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 4.75 (d, J =
15.6 Hz, 1H), 3.65 – 3.55 (m, 4H), 3.18 (d, J = 3.9 Hz, 1H), 2.38 (d, J = 11.6 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 175.5 , 153.7 , 145.7 , 143.0 , 135.7 , 130.1 , 129.0 , 127.9 , 127.5 ,
126.0 , 125.7 , 122.8 , 117.0 , 114.9 , 114.6 , 109.1 , 101.2 , 90.6 , 76.9 , 56.1 , 45.3 , 43.9 , 31.60.
HPLC Analysis: ee = 98%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0
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mL/min, λ = 254 nm (tmajor = 13.1 min, tminor = 23.8 min). HRMS (+ESI-TOF): calcd. For
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((2'R,3S,5'S)-1-benzyl-7'-chloro-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]
dioxepin]-2-one) (3d) was obtained as a white semi solid in 66% (26.6 mg) yield after column
chromatography. 1H NMR (400 MHz, Chloroform-d) δ 7.28 (dt, J = 15.3, 7.1 Hz, 5H), 7.17 (dd,
J = 8.6, 2.5 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.69 (t, J = 7.6 Hz, 1H),
6.65 (d, J = 7.8 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 6.03 (d, J = 3.5 Hz, 1H), 5.94 (d, J = 7.0 Hz,
1H), 4.88 (d, J = 15.6 Hz, 1H), 4.75 (d, J = 15.6 Hz, 1H), 3.64 (dt, J = 11.8, 3.9 Hz, 1H), 3.22 (d,
J = 3.9 Hz, 1H), 2.37 (d, J = 11.7 Hz, 1H). 13C {1H} NMR (101 MHz, Chloroform-d) δ 175.2 ,
150.5 , 143.1 , 135.5 , 130.4 , 129.5 , 129.1 , 128.5 , 128.0 , 127.4 , 127.0 , 125.7 , 125.7 , 125.3 ,
122.9 , 117.8 , 109.3 , 101.3 , 90.7 , 44.9 , 44.0 , 31.2 . HPLC Analysis: ee = 97%, Chiralpak IA
Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 11.3 min, tminor
21.6 min). HRMS (+ESI-TOF): calcd. For C24H19ClNO3 [M+H]+ 404.1048, found 404.1055.
=
((2'R,3S,5'S)-1-benzyl-7'-bromo-5'H-spiro[indoline-3,4'[2,5]methanobenzo[d][1,3]
dioxepin]-2-one) (3e) was obtained as a light yellow sticky solid in 57% (25.5 mg) yield after
column chromatography. 1H NMR (400 MHz, Chloroform-d) δ 7.34 – 7.27 (m, 3H), 7.27 – 7.21
(m, 3H), 7.10 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.73 – 6.67 (m, 2H), 6.65 (d, J = 7.8
Hz, 1H), 6.03 (d, J = 3.5 Hz, 1H), 5.94 (d, J = 7.5 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 4.75 (d, J =
15.6 Hz, 1H), 3.64 (dt, J = 11.8, 3.9 Hz, 1H), 3.22 (d, J = 3.9 Hz, 1H), 2.37 (d, J = 11.7 Hz, 1H).
13C {1H} NMR (101 MHz, Chloroform-d) δ 175.2 , 151.0 , 143.1 , 135.5 , 132.5 , 131.4 , 130.5
, 129.1 , 128.0 , 127.4 , 125.8 , 125.3 , 122.9 , 118.3 , 112.9 , 109.3 , 101.3 , 90.7 , 44.9 , 44.0 ,
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31.2. HPLC Analysis: ee = 98%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0
mL/min, λ = 254 nm (tmajor = 11.9 min, tminor = 20.9 min). HRMS (+ESI-TOF): calcd. For
C24H19BrNO3 [M+H]+ 448.0543, found 448.0542.
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((2'R,3S,5'S)-1-benzyl-6'-chloro-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]
dioxepin]-2-one) (3f) was obtained as a light yellow semi solid in 61% (24.6 mg) yield after
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column chromatography. H NMR (400 MHz, CDCl3) δ 7.34 – 7.22 (m, 5H), 7.18 – 7.07 (m,
2H), 6.83 (dd, J = 10.5, 8.1 Hz, 2H), 6.66 (t, J = 7.6 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 6.06 (d, J
= 3.5 Hz, 1H), 5.94 (d, J = 7.0 Hz, 1H), 4.96 (d, J = 15.9 Hz, 1H), 4.78 (d, J = 15.9 Hz, 1H), 3.89
(d, J = 4.1 Hz, 1H), 3.62 (dt, J = 11.8, 3.9 Hz, 1H), 2.36 (d, J = 11.8 Hz, 1H). 13C {1H} NMR (101
MHz, CDCl3) δ 175.2 , 152.9 , 142.9 , 135.5 , 133.5 , 130.2 , 129.8 , 129.0 , 127.8 , 127.1 , 125.3
, 124.8 , 123.8 , 122.8 , 121.6 , 115.2 , 109.3 , 101.2 , 90.8 , 43.8 , 42.0 , 30.7. HPLC Analysis: ee
= 99%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor
= 11.8 min, tminor = 21.5 min). HRMS (+ESI-TOF): calcd. For C24H19ClNO3 [M+H]+ 404.1048,
found 404.1051.
((2'R,3S,5'S)-1-benzyl-8'-methoxy-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]
dioxepin]-2-one) (3g) was obtained as a light yellow sticky solid in 62% (24.7 mg) yield after
column chromatography. 1H NMR (400 MHz, Chloroform-d) δ 7.30 (ddd, J = 17.5, 12.7, 6.0 Hz,
6H), 7.11 (t, J = 7.8 Hz, 1H), 6.74 – 6.64 (m, 2H), 6.55 – 6.47 (m, 2H), 6.35 (dd, J = 8.3, 2.5 Hz,
1H), 6.07 (d, J = 3.5 Hz, 1H), 5.98 (d, J = 7.5 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.79 (d, J = 15.6
Hz, 1H), 3.81 (s, 3H), 3.65 (dt, J = 11.6, 3.9 Hz, 1H), 3.25 (d, J = 3.9 Hz, 1H), 2.42 (d, J = 11.5
Hz, 1H). 13C {1H} NMR (101 MHz, Chloroform-d) δ 175.7 , 161.0 , 152.8 , 143.2 , 135.8 , 130.2
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, 129.5 , 129.2 , 128.0 , 127.6 , 126.2 , 126.0 , 122.8 , 118.0 , 109.2 , 106.7 , 102.2 , 101.4 , 91.1 ,
55.7 , 44.7 , 44.0 , 32.0. HPLC Analysis: ee = 97%, Chiralpak IA Column, n-Hexane/i-PrOH =
90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 12.9 min, tminor = 20.1 min). HRMS (+ESI-
TOF): calcd. For C25H22NO4 [M+H]+ 400.1543, found 400.1548.
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((2'S,3S,5'S)-1-benzyl-7',9'-dichloro-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]
dioxepin]-2-one) (3h) was obtained as a yellow sticky solid in 34% (15.0 mg) yield after column
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chromatography. H NMR (400 MHz, Chloroform-d) δ 7.34 (d, J = 2.4 Hz, 2H), 7.33 (s, 1H),
7.29 (d, J = 7.0 Hz, 3H), 7.16 (t, J = 7.8 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H),
6.55 (d, J = 2.4 Hz, 1H), 6.20 (d, J = 3.4 Hz, 1H), 6.01 (d, J = 7.5 Hz, 1H), 4.93 (d, J = 15.6 Hz,
1H), 4.79 (d, J = 15.6 Hz, 1H), 3.73 (dt, J = 11.9, 3.8 Hz, 1H), 3.30 (d, J = 3.9 Hz, 1H), 2.42 (d, J
= 11.9 Hz, 1H). 13C {1H} NMR (101 MHz, Chloroform-d) δ 174.9 , 146.8 , 143.1 , 135.4 , 130.6
, 129.9 , 129.1 , 128.0 , 128.0 , 127.5 , 127.1 , 125.7 , 125.6 , 124.8 , 123.0 , 122.4 , 109.5 , 101.7
, 90.7 , 45.0 , 44.1 , 31.1 , 29.9. HPLC Analysis: ee = 94%, Chiralpak IA Column, n-Hexane/i-
PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 11.0 min, tminor = 19.5 min). HRMS
(+ESI-TOF): calcd. For C24H18Cl2NO3 [M+H]+ 438.0658, found 438.0655.
((2'S,3S,5'S)-1-benzyl-7',9'-dibromo-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]
dioxepin]-2-one) (3i) was obtained as a light yellow semi solid in 23% (12.1 mg) yield after
column chromatography. 1H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 2.2 Hz, 1H), 7.38 –
7.32 (m, 2H), 7.28 (d, J = 16.5 Hz, 4H), 7.16 (t, J = 7.8 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 6.74 –
6.67 (m, 2H), 6.20 (d, J = 3.3 Hz, 1H), 6.00 (d, J = 7.4 Hz, 1H), 4.93 (d, J = 15.6 Hz, 1H), 4.78 (d,
J = 15.6 Hz, 1H), 3.72 (dt, J = 11.9, 3.8 Hz, 1H), 3.28 (d, J = 3.9 Hz, 1H), 2.41 (d, J = 11.8 Hz,
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1H). 13C {1H} NMR (101 MHz, Chloroform-d) δ 174.9 , 148.4 , 143.1 , 135.4 , 130.7 , 130.6 ,
129.1 , 128.4 , 128.0 , 127.5 , 125.8 , 124.8 , 123.0 , 112.8 , 109.5 , 101.8 , 90.7 , 45.0 , 44.0 , 31.1
, 29.9. HPLC Analysis: ee = 95%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0
mL/min, λ = 254 nm (tmajor = 11.5 min, tminor = 19.6 min). HRMS (+ESI-TOF): calcd. For C24H18
Br2NO3 [M+H]+ 525.9648, found 525.9647.
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((2'S,3S,5'S)-1-benzyl-9'-bromo-7'-chloro-5'H-spiro[indoline-3,4'[2,5]methanobenzo[d][1,3]
dioxepin]-2-one) (3j) was obtained as a light yellow semi solid in 32% (15.5 mg) yield after
column chromatography. 1H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 2.4 Hz, 1H), 7.38 –
7.32 (m, 2H), 7.28 (d, J = 16.3 Hz, 4H), 7.16 (t, J = 7.8 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 6.70 (d,
J = 7.8 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.20 (d, J = 3.4 Hz, 1H), 6.00 (d, J = 7.0 Hz, 1H), 4.93
(d, J = 15.6 Hz, 1H), 4.78 (d, J = 15.6 Hz, 1H), 3.72 (dt, J = 11.9, 3.8 Hz, 1H), 3.28 (d, J = 3.8 Hz,
1H), 2.41 (d, J = 11.9 Hz, 1H). 13C {1H} NMR (151 MHz, Chloroform-d) δ 174.9 , 147.8 , 143.0
, 135.4 , 132.7 , 130.6 , 129.1 , 128.0 , 127.8 , 127.4 , 126.0 , 125.7 , 123.0 , 110.9 , 109.5 , 101.8
, 90.6 , 45.0 , 44.0 , 31.1. HPLC Analysis: ee = 96%, Chiralpak IA Column, n-Hexane/i-PrOH =
90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 10.8 min, tminor = 20.9 min). HRMS (+ESI-
TOF): calcd. For C24H18BrClNO3 [M+H]+ 482.0153, found 482.0157.
(tert-butyl((2'R,3S,5'S)-1-benzyl-2-oxo-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]
dioxepin]-7'-yl)carbamate) (3k) was obtained as a dark yellow semi solid in 47% (22.7 mg) yield
after column chromatography. 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.27 (m, 5H), 7.18 (d, J =
6.6 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.72 – 6.64 (m, 3H), 6.05 (d, J =
3.5 Hz, 1H), 6.00 (d, J = 6.9 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.78 (d, J = 15.6 Hz, 1H), 3.64
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(dt, J = 11.6, 3.9 Hz, 1H), 3.26 (d, J = 3.9 Hz, 1H), 2.42 (d, J = 11.5 Hz, 1H), 1.45 (s, 9H). 13C
{1H} NMR (101 MHz, CDCl3) δ 175.5, 147.7, 143.1, 135.6, 131.5, 130.2, 129.1, 127.9, 127.4,
125.9, 125.8, 125.7, 122.8, 116.7, 109.2, 101.3, 90.6, 45.1, 44.0, 31.6, 28.5. HPLC Analysis: ee
= 98%, Chiralpak LUX C1 Column, n-Hexane/i-PrOH = 70/30, flow rate 1.0 mL/min, λ = 254 nm
(tmajor = 22.4 min, tminor = 9.5 min). HRMS (+ESI-TOF): calcd. For C29H28N2NaO5 [M+Na]+
507.1890, found 507.1876.
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((2’R,3S,5’S)-1-methyl-5’H-spiro[indoline-3,4’-[2,5]methanobenzo[d][1,3]dioxepin]-2-one)
(3l) was obtained as a yellow sticky solid in 80% (23.5 mg) yield after column chromatography.
1H NMR (400 MHz, CDCl3) δ 7.38 – 7.32 (m, 2H), 7.23 (t, J = 7.7 Hz, 1H), 7.06 (t, J = 7.6 Hz,
1H), 6.91 (d, J = 8.0 Hz, 1H), 6.84 (dd, J = 13.3, 7.5 Hz, 2H), 6.78 (d, J = 7.4 Hz, 1H), 6.09 (d, J
= 3.4 Hz, 1H), 3.28 – 3.25 (m, 1H), 3.09 (s, 3H), 2.93 (dt, J = 11.8, 3.8 Hz, 1H), 2.50 (d, J = 11.9
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Hz, 1H). C {1H} NMR (101 MHz, CDCl3) δ 174.1, 151.7, 143.2, 130.3, 129.5, 129.4, 126.9,
125.2, 123.4, 122.7, 121.0, 115.9, 108.6, 100.7, 90.7, 46.9, 33.1, 26.7. HPLC Analysis: ee = 98%,
Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 9.2
min, tminor = 17.3 min). HRMS (+ESI-TOF): calcd. For C18H16NO3 [M+H]+ 294.1125, found
294.1131.
((2’R,3S,5’S)-1-isobutyl-5’H-spiro[indoline-3,4’-[2,5] methanobenzo[d][1,3]dioxepin]-2-one)
(3m) was obtained as a white semi solid in 71% (23.8 mg) yield after column chromatography. 1H
NMR (400 MHz, CDCl3) δ 7.25 (dd, J = 10.6, 4.8 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.93 (d, J =
8.1 Hz, 1H), 6.81 – 6.74 (m, 2H), 6.67 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 7.4 Hz, 1H), 6.06 (d, J =
3.5 Hz, 1H), 5.88 (d, J = 7.5 Hz, 1H), 3.63 (dt, J = 11.6, 3.9 Hz, 1H), 3.54 (dd, J = 13.9, 7.8 Hz,
1H), 3.39 (dd, J = 13.9, 7.3 Hz, 1H), 3.22 (d, J = 4.0 Hz, 1H), 2.42 (d, J = 11.6 Hz, 1H), 2.19 –
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2.10 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H). 13C {1H} NMR (101 MHz, CDCl3) δ 175.6, 151.9, 143.7,
130.1, 129.6, 128.9, 125.9, 125.8, 125.6, 122.3, 120.8, 116.5, 108.6, 101.3, 90.7, 47.5, 45.2, 31.4,
27.1, 20.4. HPLC Analysis: ee = 99%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow
rate 1.0 mL/min, λ = 254 nm (tmajor = 5.8 min, tminor = 8.7 min). HRMS (+ESI-TOF): calcd. For
C21H22NO3 [M+H]+ 336.1594, found 336.1598.
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((2’R,3S,5’S)-1-allyl-5’H-spiro[indoline-3,4’-[2,5]methanobenzo[d][1,3]dioxepin]-2-one)
(3n) was obtained as a light yellow semi solid in 68% (21.7 mg) yield after column
chromatography. 1H NMR (400 MHz, CDCl3) δ 7.25 (dd, J = 9.9, 5.7 Hz, 1H), 7.19 (t, J = 7.8
Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.78 (dd, J = 13.5, 7.6 Hz, 2H), 6.69 (t, J = 7.6 Hz, 1H), 6.59
(d, J = 7.5 Hz, 1H), 6.06 (d, J = 3.5 Hz, 1H), 5.84 (ddd, J = 15.7, 12.0, 6.7 Hz, 2H), 5.30 – 5.22
(m, 2H), 4.35 (dd, J = 16.3, 5.3 Hz, 1H), 4.23 (dd, J = 16.3, 5.3 Hz, 1H), 3.62 (dt, J = 11.6, 3.9
Hz, 1H), 3.25 (d, J = 4.0 Hz, 3H), 2.43 (d, J = 11.6 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3)
δ 175.1, 151.8, 143.1, 131.3, 130.1, 129.7, 128.9, 125.9, 125.7, 125.5, 122.6, 120.8, 118.0, 116.5,
108.9, 101.3, 90.8, 45.1, 42.5, 31.4. HPLC Analysis: ee = 98%, Chiralpak IA Column, n-
Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 8.0 min, tminor = 11.3 min).
HRMS (+ESI-TOF): calcd. For C20H18NO3 [M+H] + 320.1281, found 320.1274.
(2'R,3S,5'S)-1-(3-methylbut-2-en-1-yl)-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]
dioxepin]-2-one (3o) was obtained as a light yellow semi solid in 65% (22.6 mg) yield after
column chromatography. 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.21 (m, 1H), 7.19 (t, J = 7.8 Hz,
1H), 6.93 (d, J = 8.1 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.67 (t, J = 7.6 Hz,
1H), 6.59 (d, J = 7.4 Hz, 1H), 6.05 (d, J = 3.5 Hz, 1H), 5.87 (d, J = 7.5 Hz, 1H), 5.18 (t, J = 6.1
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Hz, 1H), 4.31 (dd, J = 15.4, 6.4 Hz, 1H), 4.22 (dd, J = 15.5, 6.8 Hz, 1H), 3.62 (dt, J = 11.6, 3.9
Hz, 1H), 3.24 (d, J = 3.9 Hz, 1H), 2.42 (d, J = 11.6 Hz, 1H), 1.83 (s, 3H), 1.73 (s, 3H). 13C {1H}
NMR (101 MHz, CDCl3) δ 174.9, 151.9, 143.3, 137.1, 130.1, 129.6, 128.9, 125.9, 125.6, 122.4,
120.7, 118.1, 116.5, 108.8, 101.3, 90.9, 44.9, 38.3, 31.4, 25.8, 18.3. HPLC Analysis: ee = 99%,
Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 6.7
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min, tminor = 12.4 min). HRMS (+ESI-TOF): calcd. For C22H22NO3 [M+H] 348.1594, found
348.1596.
(2'R,3S,5'S)-1-(4-(trifluoromethyl)benzyl)-5'H-spiro[indoline-3,4'[2,5]methanobenzo
[d][1,3]dioxepin]-2-one (3p) was obtained as a green semi solid in 51% (22.3 mg) yield after
column chromatography. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.0
Hz, 2H), 7.28 – 7.24 (m, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.4
Hz, 1H), 6.69 (t, J = 7.3 Hz, 1H), 6.64 – 6.58 (m, 2H), 6.09 (d, J = 3.5 Hz, 1H), 5.90 (d, J = 7.0
Hz, 1H), 4.91 (q, J = 16.0 Hz, 2H), 3.64 (dt, J = 11.6, 3.9 Hz, 1H), 3.30 (d, J = 3.9 Hz, 1H), 2.48
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(d, J = 11.6 Hz, 1H). C {1H} NMR (101 MHz, CDCl3) δ 175.6, 151.9, 142.7, 139.7, 130.2,
130.2(q, JC-F = 32.33 Hz), 129.8, 128.9, 127.7, 126.2, 126.1(q, JC-F = 3.03 Hz), 125.8, 125.5, 125.3,
124.1(q, JC-F = 272.70 Hz) 123.0, 120.9 116.6, 108.8, 101.3, 90.8, 45.2, 43.5, 31.5. HPLC
Analysis: ee = 98%, Chiralpak IA Column Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0
mL/min, λ = 254 nm (tmajor = 11.1 min, tminor = 19.4 min). HRMS (+ESI-TOF): calcd. For
C25H19F3NO3 [M+H] + 438.1312, found 438.1312.
(2’R,3S,5’S)-5’H-spiro[indoline-3,4’-[2,5]methanobenzo[d][1,3]dioxepin]-2-one (3q) was
obtained as a light pink solid in 64% (17.9 mg) yield after column chromatography. M.P. = 115-
117 oC. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.25 (dd, J = 9.5, 6.0 Hz, 1H), 7.16 (t, J =
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7.7 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.80 (dd, J = 13.7, 7.4 Hz, 2H), 6.67 (t, J = 7.6 Hz, 1H),
6.58 (d, J = 7.4 Hz, 1H), 6.06 (d, J = 3.5 Hz, 1H), 5.87 (d, J = 7.6 Hz, 1H), 3.55 (dt, J = 11.6, 3.9
Hz, 1H), 3.31 (d, J = 3.9 Hz, 1H), 2.44 (d, J = 11.6 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3)
δ 177.8, 151.8, 140.9, 130.2, 129.7, 128.9, 126.2, 126.2, 125.4, 122.6, 120.8, 116.5, 110.1, 101.3,
91.2, 44.9, 31.2. HPLC Analysis: ee = 99%, Chiralpak IA Column n-Hexane/i-PrOH = 85/15,
flow rate 1.0 mL/min, λ = 254 nm (tmajor = 8.8 min, tminor = 16.3 min). HRMS (+ESI-TOF): calcd.
For C17H14NO3 [M+H]+ 280.0968, found 280.0970.
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(2'R,3S,5'S)-1-benzyl-5-fluoro-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]-
2-one (3r) was obtained as a light grey semi solid in 59% (22.9 mg) yield after column
chromatography. 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.29 (m, 2H), 7.25 (dd, J = 12.0, 4.1 Hz,
4H), 6.93 (d, J = 8.0 Hz, 1H), 6.82 – 6.74 (m, 2H), 6.59 (d, J = 7.5 Hz, 1H), 6.54 (dd, J = 8.6, 4.1
Hz, 1H), 6.06 (d, J = 3.5 Hz, 1H), 5.55 (dd, J = 8.5, 2.6 Hz, 1H), 4.87 (d, J = 15.7 Hz, 1H), 4.77
(d, J = 15.7 Hz, 1H), 3.63 (dt, J = 11.7, 3.9 Hz, 1H), 3.28 (d, J = 3.9 Hz, 1H), 2.45 (d, J = 11.6 Hz,
1H). 13C {1H} NMR (101 MHz, CDCl3) δ 175.3, 158.9 (d, JC-F = 241.39 Hz), 151.7, 138.9, 138.9,
135.3, 130.0, 129.1, 128.9, 128.1, 127.6 (d, JC-F = 8.08 Hz), 127.4, 127.4, 124.9, 121.0, 116.7,
116.4 (d, JC-F = 24.24 Hz), 114.1 (d, JC-F = 26.26 Hz), 109.6 (d, JC-F = 8.08 Hz), 101.4, 90.8, 90.7,
45.2, 44.1, 31.4. HPLC Analysis: ee = 97%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10,
flow rate 1.0 mL/min, λ = 254 nm (tmajor = 11.9 min, tminor = 23.6 min). HRMS (+ESI-TOF): calcd.
For C24H19FNO3 [M+H]+ 388.1343, found 388.1346.
(2'R,3S,5'S)-1-benzyl-5-chloro-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]-
2-one (3s) was obtained as a light brown solid in 46% (18.6 mg) yield after column
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chromatography. M.P. = 167-170 C. H NMR (600 MHz, CDCl3) δ 7.34 (t, J = 7.3 Hz, 2H),
7.31 – 7.25 (m, 4H), 7.07 (dd, J = 8.3, 2.1 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.84 (td, J = 7.5, 1.0
Hz, 1H), 6.60 (d, J = 7.5 Hz, 1H), 6.57 (d, J = 8.3 Hz, 1H), 6.09 (d, J = 3.5 Hz, 1H), 5.75 (d, J =
2.1 Hz, 1H), 4.88 (d, J = 15.7 Hz, 1H), 4.80 (d, J = 15.7 Hz, 1H), 3.62 (dt, J = 11.7, 3.9 Hz, 1H),
3.29 (d, J = 3.9 Hz, 1H), 2.50 (d, J = 11.6 Hz, 1H). 13C {1H} NMR (151 MHz, CDCl3) δ 175.0,
151.7, 141.4, 135.2, 130.0, 129.9, 129.1, 128.9, 128.1, 128.1, 127.5, 127.4, 126.5, 124.9, 121.0,
116.7, 110.0, 101.4, 90.7, 45.2, 44.0, 31.3. HPLC Analysis: ee = 99%, Chiralpak IA Column, n-
Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 12.6 min, tminor = 25.1 min).
HRMS (+ESI-TOF): calcd. For C24H19ClNO3 [M+H]+ 404.1048, found 404.1049.
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(2'R,3S,5'S)-1-benzyl-5-bromo-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]-
2-one (3t) was obtained as a light yellow sticky solid in 37% (16.6 mg) yield after column
chromatography. 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 14.8, 7.2 Hz, 3H), 7.21 (t, J = 5.0
Hz, 3H), 7.16 (dd, J = 8.3, 2.0 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.54 (d,
J = 7.5 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 6.03 (d, J = 3.5 Hz, 1H), 5.82 (d, J = 2.0 Hz, 1H), 4.82
(d, J = 15.7 Hz, 1H), 4.74 (d, J = 15.7 Hz, 1H), 3.56 (dt, J = 11.7, 3.9 Hz, 1H), 3.23 (d, J = 3.9 Hz,
1H), 2.44 (d, J = 11.7 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ 174.9, 151.7, 141.9, 135.1,
132.8, 130.0, 129.3, 129.1, 128.9, 128.1, 127.8, 127.4, 124.9, 121.0, 116.8, 115.5, 110.5, 101.4,
90.7, 45.3, 44.0, 31.3. HPLC Analysis: ee = 93%, Chiralpak IA Column, n-Hexane/i-PrOH =
90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 13.5 min, tminor = 26.0 min). HRMS (+ESI-
TOF): calcd. For C24H19BrNO3 [M+H]+ 448.0543, found 448.0544.
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(2'R,3S,5'S)-1-benzyl-6-bromo-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]-
2-one (3u) was obtained as a light brown semi solid in 49% (22.0 mg) yield after column
chromatography. 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.78 (m, 2H), 7.78 – 7.67 (m, 4H), 7.38
(d, J = 8.0 Hz, 1H), 7.29 – 7.21 (m, 3H), 7.05 (d, J = 7.5 Hz, 1H), 6.52 (d, J = 3.5 Hz, 1H), 6.16
(d, J = 8.6 Hz, 1H), 5.35 (d, J = 15.7 Hz, 1H), 5.20 (d, J = 15.7 Hz, 1H), 4.07 (dt, J = 11.7, 3.9 Hz,
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1H), 3.72 (d, J = 3.9 Hz, 1H), 2.91 (d, J = 11.7 Hz, 1H). C {1H} NMR (101 MHz, CDCl3) δ
175., 151.7, 144.3, 135.1, 129.9, 129.2, 128.9, 128.2, 127.4, 127.2, 125.6, 125.1, 124.7, 124.0,
121.0, 116.6, 112.5, 101.3, 90.4, 45.1, 44.0, 31.4. HPLC Analysis: ee = 98%, Chiralpak IA
Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 9.7 min, tminor
20.9 min). HRMS (+ESI-TOF): calcd. For C24H19BrNO3 [M+H]+ 448.0543, found 448.0546.
=
(2’R,3S,5’S)-1-benzyl-7-chloro-5’H-spiro[indoline-3,4’-[2,5]methanobenzo[d][1,3]
dioxepin]-2-one (3v) was obtained as a brown semi solid in 55% (22.2 mg) yield after column
chromatography. 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.2 Hz, 2H), 7.25 (dd, J = 14.3, 6.0
Hz, 5H), 7.09 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.64 – 6.56
(m, 2H), 6.08 (d, J = 3.5 Hz, 1H), 5.87 (d, J = 7.5 Hz, 1H), 5.32 (s, 2H), 3.64 (dt, J = 11.7, 3.9 Hz,
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1H), 3.28 (d, J = 3.9 Hz, 1H), 2.46 (d, J = 11.7 Hz, 1H). C {1H} NMR (101 MHz, CDCl3) δ
176.2, 151.8, 139.0, 137.2, 132.7, 129.9, 129.0, 128.8, 128.8, 127.5, 126.6, 125.1, 124.5, 123.5,
120.9, 116.5, 115.4, 101.4, 90.2, 45.6, 45.1, 31.4. HPLC Analysis: ee = 93%, Chiralpak IA
Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 8.8 min, tminor
15.9 min). HRMS (+ESI-TOF): calcd. For C24H19ClNO3 [M+H]+ 404.1048, found 404.1046.
=
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