One-Pot Sequential [3 + 3] Dipolar Cycloaddition of Aldehyde or Ketone and Hydroxylamine with Spirocyclopropyl Oxindole

Article abstract of DOI:10.1021/acs.joc.8b02208

A Sc(OTf)₃-catalyzed highly diastereoselective one-pot sequential [3 + 3] dipolar cycloaddition reaction of aldehyde or ketone, N-alkyl hydroxylamine, and spirocyclopropyl oxindole is developed, allowing facile construction of spirocyclic oxind

Full text of DOI:10.1021/acs.joc.8b02208

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Article
One-pot Sequential [3+3] Dipolar Cycloaddition of Aldehyde
or Ketone, Hydroxylamine with Spirocyclopropyl Oxindole
Peng-Wei Xu, Chen Chen, Jia-Kuan Liu, Yu-Ting Song, Feng Zhou, Jun Yan, and Jian Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02208 • Publication Date (Web): 21 Sep 2018
Downloaded from http://pubs.acs.org on September 21, 2018
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Page 1 of 32
The Journal of Organic Chemistry
Oneꢀpot Sequential [3+3] Dipolar Cycloaddition of Aldehyde or Ketone,
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Hydroxylamine with Spirocyclopropyl Oxindole
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PengꢀWei Xu,
§
Chen Chen,
§
JiaꢀKuan Liu,‡ YuꢀTing Song,‡ Feng Zhou,*,
Jian Zhou*,†,§,¶
§ Jun Yan*,‡,║ and
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† Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development and § Shanghai Key
Laboratory of Green Chemistry and Chemical Process, East China Normal University, Shanghai 200062, P. R.
China.
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‡ MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University;
║ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, P. R. China
¶ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P.
R. China.
fzhou@chem.ecnu.edu.cn; yanjun@nju.edu.cn; jzhou@chem.ecnu.edu.cn
Abstract: A Sc(OTf)3 catalyzed highly diastereoselective oneꢀpot sequential [3+3] dipolar cycloaddition
reaction of aldehyde or ketone, Nꢀalkyl hydroxylamine and spirocyclopropyl oxindole is developed,
allowing facile construction of spirocyclic oxindoleꢀtetrahydroꢀ1,2ꢀoxazines in sufficient structural
diversity. The corresponding catalytic enantioselective oneꢀpot protocol of aldehydes is also reported,
affording the desired adducts in up to 97% ee. The biological evaluation of selected oxindoleꢀbased
spirocyclic tetrahydroꢀ1,2ꢀoxazines revealed that they exerted cytotoxic effects on human prostate
cancer cells with the capacity to inhibit NFκB signaling in prostate cancer cells.
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Introduction
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Spiro skeletons are widely distributed in bioactive natural products and pharmaceutically active
compounds.1 Notably, spirocyclic compounds play an active role in modern drug discovery &
development, because the incorporation of spiroꢀring fusion can reduce the conformational entropy
penalty upon binding with a protein target.2 As a result, much attention has been paid to the efficient
construction of densely functionalized spirocyclic compounds with structural diversity.3 This is further
fueled by the demand of probeꢀ and drugꢀdiscovery programmes for synthetic libraries that replicate the
structural features of natural products, to enhance the returns of highꢀthroughput screenings.4 In
particular, spirocyclic compounds derived from privileged scaffolds are highly desirable.
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Tetrahydroꢀ1,2ꢀoxazine moiety present in bioactive natural products such as nakadomarin A, (+)ꢀ
phyllantidine, FR900482 and FR 66979, as well as in synthetic bioactive compounds FK317 and
FK973.5 The merger of this heterocycle into spirocycles is interesting to develop novel molecules for
medicinal studies. Recently, inspired by the pioneering work of Young and Kerr in [3+3] cycloaddition
of nitrones and donorꢀacceptor (D–A) cyclopropanes for the flexible construction of tetrahydroꢀ1,2ꢀ
oxazines,6 as well as the efforts of Sibi and Tang groups in developing catalytic asymmetric versions,7
we developed a highly diastereoꢀ and enantioselective [3+3] cycloaddition of spirocyclopropyl
oxindoles8 with both aldonitrones and ketonitrones (Scheme 1A).9 This enables the facile synthesis of
oxindole based spirocyclic tetrahydroꢀ1,2ꢀoxazines. It is worth mentioning that spirocyclic oxindoles are
prominent structural motifs in drugs and bioactive compounds as well, the diverse construction of this
framework is of current interest.10 Because some nitrones are not easy to prepare or unstable due to
oligomerization under acidic conditions, along with their highly hydroscopic nature, the development of
more convenient and efficient protocols using nitrones formed in situ, without the isolation and handling
of the nitrones, is very helpful to build up libraries of oxindole based spirocyclic 1,2ꢀoxazines for
medicinal studies.
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Scheme 1. One-pot [3+3] Cycloaddition of Aldehyde or Ketone, Hydroxylamine with D-A
Cyclopropane.
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In 2004, Kerr et al. developed an elegant three component protocol using aldehydes, hydroxylamines
and D–A cyclopropanes (Scheme 1B).11 This strategy was further successfully applied to the total
synthesis of nakadomarin A12a and (+)ꢀphyllantidine12b as well as the construction of other privileged
scaffolds.12cꢀe Their meaningful results encouraged us to develop a oneꢀpot method for the facile
construction of a library of spirocylic oxindoleꢀ1,2ꢀoxazines for biological evaluation, although ketones
have not been incorporated to such oneꢀpot protocol and the corresponding catalytic enantioselective
oneꢀpot version remains undeveloped. As part of our research program for the efficient construction of
spirocyclic oxindoles for biological evaluation,9,13 we attempt to develop a highly diastereoselective
oneꢀpot [3+3] cycloaddition of aldehydes or ketones, hydroxylamines with spirocyclopropyl oxindoles,
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along with a catalytic enantioselective version (Scheme 1C). Here, we wish to report our research work
and the initial results of biological evaluation.
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Results and discussion
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We began our research by using the [3+3] cycloaddition of 4ꢀchlorobenzaldehyde 1a, Nꢀ
methylhydroxylamine hydrochloride 2a and Nꢀdiethoxyphosphoryl spirocyclopropyl oxindole 3a as
model reaction, with K2CO3 as base to neutralize the reaction. Typically, 1a and 2a were combined
initially in the presence of 4 Å molecular sieves (MS), 10 mol% Lewis acid catalyst and 0.75 equiv
K2CO3 at 50 oC for 1 h. After the complete formation of nitrone, 3a was added and the resulting reaction
mixture was stirred until 3a was fully consumed.
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Table 1. Conditions Optimization
Temp.
(oC)
50
Time
(h)
72
6
Yield
(%)
42
Entry
Cat.
Solvent
Dra
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2
Ni(OTf)2
Ni(OTf)2
Mg(OTf)2
Mg(OTf)2
Bi(OTf)3
Er(OTf)3
Y(OTf)3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
>20:1
3.7:1
9.6:1
4.0:1
>20:1
4.6:1
4.7:1
4.7:1
5.5:1
8.3:1
7.6:1
10.3:1
80
70
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50
72
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80
69
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24
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24
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70
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5
66
8
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
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5
73
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5
72
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24
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Sc(OTf)3 Toluene
Sc(OTf)3 EtOAc
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a Determined by 1H NMR analysis. Note: 3a was not fully consumed in
entry 1.
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Initially, the performance of different metal triflates was investigated using dichloroethane (DCE) as
solvent. When the reaction of 1a, 2a and 3a were conducted in the absence of Lewis acid catalyst, the
nitrone could be formed smoothly, but no further cycloaddition reaction could be detected. Ni(OTf)2, the
best catalyst we identified in previous work9, catalyzed the reaction to give the desired product 4a in >
20:1 dr, but resulted in incompletion of the [3+3] cycloaddition, and 4a was obtained in only 42% yield
even after 72 h (entry 1, Table 1). The relative configuration of 4a was determined by NMR analysis
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o
o
combined with the reference of previous work9. Raising reaction temperature from 50 C to 80 C
allowed the reaction to finish within 6 h, but afforded 4a in a much lower 3.7 1 dr (entry 2). Similar
:
results were observed when using Mg(OTf)2 as catalyst (entries 3ꢀ4). Bi(OTf)3 was a less active catalyst
for this reaction, giving 4a in only 24% yield (entry 5). Rare earth metal triflates such as Er(OTf)3,
Y(OTf)3, Yb(OTf)3, and Sc(OTf)3 could allow the reaction to finish in 5 h (entries 6ꢀ9), but Sc(OTf)3
gave the best result in term of reaction yield and dr value (entry 9). Subsequently, the solvent effects of
the reaction catalyzed by Sc(OTf)3 were investigated to improve the diastereoselectivity. THF as the
solvent resulted in higher dr but slower reaction rate (entry 11); however, the reaction in toluene could
finish in 6 h, affording 4a in 80% yield with 7.6:1 dr (entry 12). Gratifyingly, ethyl acetate (EtOAc)
turned out to be the best solvent of choice, and the reaction went for a completion within 6 h to give 4a
o
in 85% yield and 10.3:1 dr (entry 13). Finally, we determined to run the reaction at 50 C in EtOAc,
using 10 mol% Sc(OTf)3 as the catalyst.
The substrate scope of this oneꢀpot sequential protocol with respect to differently substituted
aldehydes 1, Nꢀalkyl hydroxylamines 2 and oxindoles 3 was then studied (Scheme 2). In general, phenyl
aldehydes with either electronꢀdeficient or electronꢀrich substituents were all viable substrates, giving
the desired products 4aꢀg in 77ꢀ83% yield and 6.5:1ꢀ10.0:1 dr. 2ꢀNaphthaldehyde, 2ꢀfuranaldehyde and
2ꢀthenaldehyde gave the corresponding products 4hꢀj in high yield and dr values. Aliphatic aldehydes
with an isopropyl or a cyclohexyl group also worked well, giving the corresponding products 4k and 4l
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in high yield and diastereroselectivity. α,βꢀUnsaturated aldehydes were compatible substrates as well, as
shown by the conversion of cinnamaldehyde to 4m in 90% yield and 14.0:1 dr. Furthermore, differently
substituted hydroxyamines and spirocyclopropyl oxindoles were examined. BnNHOH gave the desired
product 4n in 87% yield with 18.1:1 dr. On the other hand, the oxindoles 3 bearing a fluorine atom on
C5 position of oxindole ring or a 2ꢀnaphthyl group on the cyclopropane ring all readily furnished the
corresponding products 4oꢀp in good yield and diastereoselectivity.
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Scheme 2. Substrate Scope with Aldehyde
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R4
R1CHO
R4
1
2
3
4
5
6
R3
Sc(OTf)3 (10 mol%)
O
R2
N
1
(1.7 equivs)
R3
O
R1
O
K2CO3 (0.75 equiv)
4Å MS, EtOAc, 50 oC
+
N
R2NHOH—HCl
Pg
N
4
Pg
2
3
(1.5 equivs)
(0.2 mmol)
Pg = PO(OEt)2
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pꢀTol
pꢀTol
pꢀTol
pꢀTol
O
N
O
O
O
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N
N
N
Cl
Cl
Cl
Cl
pꢀClC6H4
O
Ph
O
pꢀFC6H4
O
pꢀBrC6H4
O
N
N
N
N
Pg
Pg
Pg
Pg
4a: 5 h, 83%, 10.0:1 dr
4b: 6 h, 83%, 9.2:1 dr
4c: 6 h, 79%, 8.1:1 dr
4d: 4 h, 77%, 9.3:1 dr
pꢀTol
pꢀTol
pꢀTol
pꢀTol
O
O
O
O
N
N
N
N
Cl
Cl
Cl
Cl
pꢀTol
O
PMP
O
3ꢀMeOC6H4
2ꢀNp
O
O
N
N
N
N
Pg
Pg
Pg
Pg
4e:
4f:
4g:
4h:
6 h, 81%, 8.0:1 dr
5 h, 78%, 6.5:1 dr
6 h, 83%, 8.4:1 dr
4 h, 69%, 8.0:1 dr
pꢀTol
pꢀTol
pꢀTol
pꢀTol
O
O
O
O
N
N
N
N
2ꢀfuryl
O
2ꢀthienyl
iPr
O
Cy
O
Cl
Cl
Cl
Cl
O
N
N
N
N
Pg
Pg
Pg
Pg
b
4i:
4j:
4k:
4l:
4 h, 81%, 10.0:1 dr
4 h, 81%, 11.3:1 dr
6 h, 86%, 8.6:1 dr
6 h, 86%, 10.9:1 dr
pꢀTol
pꢀTol
pꢀTol
2ꢀNp
O
O
O
O
Bn
N
N
O
N
N
Cl
Cl
F
Cl
Ph
O
Ph
O
Ph
O
Ph
N
N
N
N
Pg
Pg
Pg
4 h, 83%, 11.6:1 dr
Pg
c
4m:
4n:
4o:
4p:
4 h, 90%, 14.0:1 dr
4 h, 87%, 18.1:1 dr
4 h, 85%, 8.1:1 dr
a Dr value was determined by 1H NMR. b 2.0 mmol isobutyraldehyde was used. c Reaction run without K2CO3.
In the following, we investigated the feasibility of merging ketones into the oneꢀpot procedure to
construct spirocyclic tetrahydroꢀ1,2ꢀoxazines with adjacent quaternary and tetrasubstituted carbons.
Since ketonitrones formation was more difficult, the corresponding procedure of the oneꢀpot
manipulation was modified slightly in that EtOH was used as solvent for ketonitrone formation.14 While
the [3+3] cycloaddition of the thus obtained ketonitrone and spirocyclopropyl oxindoles could not take
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place in EtOH, we then tried to remove EtOH after the formation of ketonitrone and use other solvents
for the [3+3] cycloaddition reaction. All of the solvents screened could give the product 6a successfully,
albeit with different reaction outcome (Table 2). When DCE or THF was used, product 6a could be
obtained in 40% and 43% yield with 4.6:1 and 4.2:1 dr respectively (entry 1ꢀ2, Table 2). A higher yield
could be obtained using toluene and EtOAc as solvent, but the diastereoselectivity decreased slightly
(entries 3ꢀ4). Finally, when using iPrOAc as solvent, the reaction could finish in 24 h giving product 6a
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i
o
in 57% yield with 4.0:1 dr (entry 5, Table 2). We also tried to run the reaction in PrOAc at 80 C to
improve the efficiency of nitrone formation and the [3+3] cycloaddition of ketonitrone and
spirocyclopropyl oxindoles, but 6a was only obtained in 33% yield. (entry 6, Table 2). Finally, we
determined to run the reaction of ketones at 50 oC in EtOAc.
Table 2. Screening of Solvents for One-pot Sequential [3+3] Cycloaddition Using Ketone
Entry Solvent Temp. (oC)
Time (h)
36
Dra
Yield (%)b
1
2
3
4
5
6
DCE
THF
50
50
50
50
50
80
4.6:1
4.2:1
3.5:1
3.7:1
4.0:1
mess
40
43
49
54
57
33
36
Toluene
EtOAc
iPrOAc
iPrOAc
36
36
24
24
a Determined by 1H NMR analysis of crude mixture.
Under this condition, acetophenones with different phenyl substituents, along with methyl transꢀ
styrylketone were readily coordinated to the oneꢀpot synthesis to afford the desired spirocyclic
tetrahydroꢀ1,2ꢀoxazines 6aꢀe in 42ꢀ51% yields and moderate dr values (Scheme 3). Spirocyclopropyl
oxindoles with different substituents at the oxindole framework or at the cyclopropane moiety all
worked well to give the corresponding adducts 6fꢀ6h in reasonable yield and moderate dr value. The
o
reaction of cyclopentone was conducted at 80 C, furnishing the product 6i in excellent 20:1 dr, albeit
with moderate yield. The low yield may cause by the low conversion of nitrone formation step and the
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instability of the nitrone. We have also tried to isolate the ketonitrone derivated from cyclopentone but
failed. Despite the room for further improvement in terms of diasteresoselectivity, our results clearly
suggested the potential of in situ formation of unactivated ketonitrones for divertedꢀoriented synthesis.
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Scheme 3. Substrate Scope with Ketone
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We also tried the catalytic asymmetric version of the oneꢀpot sequential [3+3] cycloaddition
reaction. Chiral bisoxazoline 7/Ni(OTf)2, the previously established catalyst,9 was found to mediate the
oneꢀpot transformation well, affording the chiral spirocyclic products 4aꢀb, 4e and 4m in considerable
yield and excellent ee value, albeit with diminished dr value as compared with the corresponding
enantioselective cycloaddition of preꢀprepared aldonitrones9 (Scheme 4).
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Scheme 4. Asymmetric One-pot Sequential [3+3] Dipolar Cycloaddition Reaction
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Biological Studies
Next, we investigated the biological activities of the thus obtained spirocylic oxindoleꢀ1,2ꢀoxazines
in a NFκB signaling inhibitory assay. As a transcription factor, nuclear factor κB (NFκB) plays key roles
in regulation of cell proliferation, survival and immune responses.15 Constitutive activation of NFκB
signaling pathway is often detected in hormone refractory prostate cancer, which is the resistance stage
to androgen deprivation therapy. Moreover, the inhibition of NFκB activation has proved to be a
promising approach for prostate cancer treatment.16 Therefore, small molecule inhibitors that inhibit
NFκB transcriptional activity would be potential candidate to treat hormone refractory prostate cancer.
Several potent NFκB signaling inhibitors, such as JSHꢀ23, have been recently reported.17
We tested whether the thus obtained spirocylic oxindoleꢀ1,2ꢀoxazines can suppress NFκB activity in
a hormone refractory prostate cancer DU145 cell line. As a wellꢀknown inducer of NFκB activity, TNFα
treatment successfully increased the NFκB transcriptional activity (Figure 1). Notably, all of the four
selected compounds (4b, 4f, 6a and 6c) significantly inhibited the transcriptional activity of NFκB in
DU145 cells in a doseꢀdependent manner.
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Figure 1. Compounds 4b, 4f, 6a and 6c inhibited NFκB signaling pathway. DU145 cells were
transfected with 6xNFκBꢀluciferase reporter plasmid. After 24 h, the cells were preꢀtreated with 4b, 4f,
6a and 6c for 4 h, followed by 10 ng/mL TNFα treatment. The luciferase activities were calculated as a
rate of firefly luciferase activity/total protein. The relative luciferase activity of vehicle control was set
as 100%. N = 3. The data were repeated in three biological independent replicates and presented as
mean ± SD. *, p < 0.05; **, p < 0.01; ***, p < 0.001.
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Since constitutive activation of NFκB signaling is positively associated with prostate cancer cell
proliferation and survival, we next examine whether these four compounds (4b, 4f, 6a and 6c) can
induce cytotoxicity on hormone refractory prostate cancer cells. Two human hormone refractory prostate
cancer cell lines (DU145 and PC3) and one nonꢀmalignant prostate epithelial cell line (BPH1) with four
compounds for 48 h and then measured the cell viability using the MTT assay. The halfꢀmaximal
inhibitory concentration (IC50) values were measured in DU145, PC3 and BPH1 cells. All the
compounds given in Table 3 showed cytotoxic effects to prostate cancer cells. Interestingly, DU145 and
PC3 cells showed more sensitivity to these four compounds than BPH1 cells. Next, we compared these
four compounds with a wellꢀknown NFκB inhibitor (JSHꢀ23) on cytotoxic effects. The IC50 of JSHꢀ23
is higher than 4b, 4f, 6a and 6c in DU145 and PC3 cells (Table 3). Overall, these four new compounds
can be taken as potent inhibitors of NFκB signaling pathway and have higher cytotoxic effects than JSHꢀ
23 in DU145 and PC3 cells.
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Table 3. IC50 Values of Four Compounds in a Non-malignant Prostate Epithelial BPH1 Cells and
two Hormone Refractory Prostate Cancer DU145 and PC3 Cells
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9
IC50 (ꢁM, mean ± SD)
Compound
DU145 cell line
19.09±2.19
16.50±3.13
15.45±0.95
14.57±1.90
110.47
PC3 cell line
22.87±5.21
20.00±3.52
22.03±5.92
18.92±2.71
70.64
BPH1 cell line
4b
4f
>30
>30
>30
>30
ꢀ
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6a
6c
JSH-23
Conclusion
In summary, we have developed a oneꢀpot sequential [3+3] dipolar cycloaddition reaction of
aldehyde/ketone, Nꢀalkyl hydroxylamines and spirocyclopropyl oxindoles for the facile synthesis of
oxindoleꢀbased spirocyclic tetrahydroꢀ1,2ꢀoxazines. The biological studies indicate that the thus
obtained spirocyclic oxindoleꢀ1,2ꢀoxazines possess cytotoxic effect on hormone refractory prostate
cancer cells with the capacity to inhibit NFκB transcriptional activity. Further structural modification
and bioactivity studies of the thus obtained spirocyclic tetrahydroꢀ1,2ꢀoxazines are on going in our lab.
Experimental Section
General Information. Reactions were monitored by thin layer chromatography using UV light to
visualize the course of reaction. Purification of reaction products was carried out by flash
chromatography on silica gel. Chemical yields referred to pure isolated substances. Infrared (IR) spectra
1
were obtained using a Bruker tensor 27 infrared spectrometer. H NMR, 13C{1H}NMR, 31P NMR and
19F NMR spectra were obtained using Bruker DPXꢀ400 or DPXꢀ300 MHz spectrometer. Chemical shifts
were reported in ppm from tetramethylsilane with the solvent resonance. The following abbreviations
were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, h =
heptet, m = multiplet, br = broad.
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All reactions were run in an atmosphere of N2 except noted. Anhydrous CH2ClCH2Cl (DCE) and
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2
3
CH3CN were prepared by first distillation over P2O5 and then from CaH2. Toluene and THF were
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5
i
prepared by distillation over sodiumꢀbenzophenone ketyl prior to use. Anhydrous EtOAc and PrOAc
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8
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were prepared by distillation over activated calcium sulfate and 5Å MS prior use. Activated molecular
sieves powder 4Å (MS 4 Å) was dried at 150 °C in vacuum before use. Metal triflates were purchased
from Strem Chemicals and used as it received. Nꢀdiethoxyphosphoryl spirocyclopropyl oxindoles were
synthesized according to the literature procedures.9 (4a-l, 4o-p, 6a-b, 6d, 6f-h are reported compound, 9
4m-n, 6c, 6e, 6i are new coupound)
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General procedure for one-pot sequential [3+3] dipolar cycloaddition with aldehyde.
To a Schlenk tube were sequentially added aldehydes 1 (0.34 mmol), hydroxyamines 2 (0.30 mmol),
4Å MS (100 mg), Sc(OTf)3 (9.8 mg, 0.02 mmol, 10 mol %) and K2CO3 (0.15 mmol, 20.7 mg), followed
o
by the addition of anhydrous EtOAc (2.0 mL). After the resulting solution was stirred at 50 C for 1 h,
spirocyclopropyl oxindoles 3 (0.20 mmol) was added. The reaction was kept stirring at 50 oC till the full
consumption of 3 by TLC analysis. Then EtOAc was removed under reduced pressure. The residue was
dissolved in CH2Cl2, rapidly passed through a glass funnel with a thin layer (2 cm) of silica gel, washed
with 10 mL CH2Cl2/EtOAc (5/1, v/v), and concentrated under reduced pressure. To determine the dr
value of the products, the residue was first dissolved in CDCl3, and took a little portion to determine
1
diastereoselectivity by H NMR analysis. Then the sample for analysis and rest crude product were
recombined for column chromatography purification to afford product 4, using CH2Cl2/EtOAc (40/1,
v/v) as the eluent.
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4a: White solid; 97.7 mg, yield 83%; H NMR
1
analysis revealed that the dr is 10.0:1. H NMR (400 MHz, CDCl3): 8.32 (s, 1H), 7.58 (d, J = 8.4 Hz,
1H), 7.34 (d, J = 8.0 Hz, 2H), 7.29 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.23ꢀ7.07 (m, 4H), 6.94 (d, J = 8.8
Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.50 (dd, J1 = 12.4 Hz, J2 = 2.4 Hz, 1H), 4.16 (s, 1H), 4.13ꢀ4.07 (m,
1H), 3.97ꢀ3.90 (m, 1H), 3.84ꢀ3.78 (m, 1H), 3.59ꢀ3.52 (m, 1H), 2.57ꢀ2.50 (m, 1H), 2.49 (s, 3H), 2.35 (s,
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3H), 1.89 (dd, J1 = 13.2 Hz, J2 = 2.4 Hz, 1H), 1.25 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H), 1.18 (td, J1 = 7.2
Hz, J2 = 0.8 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.0, 139.1 (d, J = 6.9 Hz), 138.3, 136.4,
134.1, 134.0, 132.2 (d, J = 9.3 Hz), 131.9, 129.3, 129.1, 129.0, 128.8, 128.1, 126.9, 126.6, 115.3, 75.6,
74.9, 64.7 (d, J = 5.7 Hz), 64.2 (d, J = 5.8 Hz), 54.4 (d, J = 5.8 Hz), 44.7, 41.1, 21.2, 15.9 (d, J = 6.9
Hz), 15.8 (d, J = 7.4 Hz); 31P NMR (162 MHz, CDCl3): ꢀ7.32;
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4b: White solid; 92.0 mg, 83% yield; H NMR
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analysis showed the dr value is 9.2:1. H NMR (400 MHz, CDCl3): 8.36 (s, 1H), 7.58 (d, J = 8.8 Hz,
1H), 7.35 (d, J = 8.0 Hz, 2H), 7.28 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.22ꢀ7.08 (m, 5H), 7.00ꢀ6.90 (m,
1H), 6.72ꢀ6.61 (m, 1H), 5.52 (dd, J1 = 12.0 Hz, J2 = 2.4 Hz, 1H), 4.18 (s, 1H), 4.14ꢀ4.08 (m, 1H), 3.96ꢀ
3.92 (m, 1H), 3.76ꢀ3.70 (m, 1H), 3.51ꢀ3.45 (m, 1H), 2.60ꢀ2.51 (m, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 1.89
(dd, J1 = 13.2 Hz, J2 = 2.4 Hz, 1H), 1.24 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H), 1.15 (td, J1 = 7.2 Hz, J2 = 0.8
Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.3, 139.2 (d, J = 7.1 Hz), 138.2, 136.6, 135.6, 132.6 (d,
J = 9.4 Hz), 130.6, 129.3, 128.9, 128.6, 128.1, 127.9, 127.7, 127.0, 126.6, 115.2, 75.6, 64.6 (d, J = 5.7
Hz), 64.0 (d, J = 5.5 Hz), 54.4 (d, J = 5.7 Hz), 44.7, 41.3, 21.2, 16.0 (d, J = 7.0 Hz) , 15.9 (d, J = 7.8
Hz); 31P NMR (162 MHz, CDCl3): ꢀ7.28;
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4c: White solid; 90.1 mg, 79% yield; H NMR
1
analysis revealed that the dr is 8.1:1. H NMR (400 MHz, CDCl3): 8.33 (s, 1H), 7.59 (d, J = 8.4 Hz,
1H), 7.34 (d, J = 8.4 Hz, 2H), 7.29 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.25ꢀ7.14 (m, 3H), 6.90ꢀ6.80 (m,
1H), 6.74ꢀ6.59 (m, 2H), 5.50 (dd, J1 = 12.0 Hz, J2 = 2.4 Hz, 1H), 4.17 (s, 1H), 4.16ꢀ4.08 (m, 1H), 3.98ꢀ
3.92 (m, 1H), 3.86ꢀ3.80 (m, 1H), 3.60ꢀ3.54 (m, 1H), 2.55ꢀ2.49 (m, 1H), 2.49 (s, 3H), 2.35 (s, 3H), 1.89
(dd, J1 = 13.2 Hz, J2 = 2.4 Hz, 1H), 1.25 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H), 1.18 (td, J1 = 7.2 Hz, J2 = 0.8
Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.2, 162.6 (d, J = 246.5 Hz), 139.1 (d, J = 7.0 Hz), 138.3,
136.4, 132.4 (d, J = 9.5 Hz), 132.2 (d, J = 7.9 Hz), 131.4 (d, J = 3.3 Hz), 129.4, 129.3, 129.1, 128.8,
126.9, 126.6, 115.3, 115.0, 114.8, 114. 6, 75.6, 74.7, 64.7 (d, J = 5.6 Hz), 64.2 (d, J = 5.6 Hz), 54.4 (d, J
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= 5.6 Hz), 44.6, 41.1, 21.2, 16.0 (d, J = 6.8 Hz), 15.9 (d, J = 7.6 Hz); P NMR (162 MHz, CDCl3): ꢀ
.7.27; 19F NMR (282 MHz, CDCl3): ꢀ113.24;
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1
Spirocyclic oxindole-tetrahydro-1,2-oxazines 4d: White solid; 97.5 mg, 77% yield; H NMR
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analysis revealed that the dr is 9.3:1. H NMR (400 MHz, CDCl3): 8.32 (s, 1H), 7.58 (d, J = 8.8 Hz,
1H), 7.36ꢀ7.27 (m, 4H), 7.19 (d, J = 8.0 Hz, 2H), 7.15ꢀ7.01 (m, 2H), 6.55 (d, J = 7.6 Hz, 1H), 5.50 (dd,
J1 = 12.4 Hz, J2 = 2.4 Hz, 1H), 4.15 (s, 1H), 4.14ꢀ4.07 (m, 1H), 3.98ꢀ3.88 (m, 1H), 3.84ꢀ3.76 (m, 1H),
3.59ꢀ3.49 (m, 1H), 2.54ꢀ2.49 (m, 1H), 2.48 (s, 3H), 2.35 (s, 3H), 1.89 (dd, J1 = 12.8 Hz, J2 = 2.4 Hz,
1H), 1.26 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H), 1.19 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H); 13C{1H}NMR (100
MHz, CDCl3): 178.0, 139.1 (d, J = 7.0 Hz), 138.3, 136.3, 134.5, 132.2, 132.1, 131.1 (d, J = 5.3 Hz),
129.3, 129.1, 128.8, 126. 9, 126.6, 122.3, 115.3, 75.6, 74.9, 64.7 (d, J = 5.5 Hz), 64.2 (d, J = 5.5 Hz),
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54.3 (d, J = 5.7 Hz), 44.7, 41.0, 21.2, 16.0 (d, J = 7.2 Hz), 15.9 (d, J = 7.8 Hz); P NMR (162 MHz,
CDCl3): ꢀ7.32;
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4e: White solid; 92.3 mg, 81% yield; H NMR
1
analysis revealed that the dr is 8.0:1. H NMR (400 MHz, CDCl3): 8.35 (s, 1H), 7.59 (d, J = 8.4 Hz,
1H), 7.34 (d, J = 8.0 Hz, 2H), 7.30ꢀ7.26 (m, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.8 Hz, 1H), 6.95
(d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 5.51 (dd, J1 = 12.0 Hz, J2 = 2.4
Hz, 1H), 4.14 (s, 1H), 4.12ꢀ4.06 (m, 1H), 3.96ꢀ3.90 (m, 1H), 3.73ꢀ3.67 (m, 1H), 3.46ꢀ3.40 (m, 1H),
2.54ꢀ2.51 (m, 1H), 2.48 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H), 1.87 (dd, J1 = 13.2 Hz, J2 = 2.4 Hz, 1H), 1.23
13
(td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H), 1.13 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H); C{1H}NMR (100 MHz,
CDCl3): 178.3, 139.1 (d, J = 6.9 Hz), 138.1, 137.7, 136.5, 132.7 (d, J = 9.5 Hz), 132.4, 130.6, 129.2,
128.9, 128.7, 128.5, 128.5, 127.4, 127.0, 126.6, 115.1, 75.6, 75.3, 64.6 (d, J = 5.6 Hz), 63.9 (d, J = 5.5
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Hz), 54.4 (d, J = 5.7 Hz), 44.6, 41.2, 21.2, 21.0, 16.0 (d, J = 7.0 Hz) , 15.9 (d, J = 7.9 Hz); P NMR
(162 MHz, CDCl3): ꢀ7.27;
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4f: White solid; 91.1 mg, 78% yield; H NMR
1
analysis revealed that the dr is 6.5:1. H NMR (400 MHz, CDCl3): 8.35 (s, 1H), 7.60 (d, J = 8.8 Hz,
1H), 7.35 (d, J = 8.0 Hz, 2H), 7.29 (dd, J1 = 8.8, J2 = 2.0, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.4
Hz, 1H), 6.67 (d, J = 9.2 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 5.51 (dd, J1 = 12.0
Hz, J2 = 2.0 Hz, 1H), 4.13 (s, 1H), 4.12ꢀ4.08 (m, 1H), 3.97ꢀ3.90 (m, 1H), 3.77ꢀ3.71 (m, 1H), 3.67 (s,
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3H), 3.52ꢀ3.46 (m, 1H), 2.54ꢀ2.51 (m, 1H), 2.48 (s, 3H), 2.35 (s, 3H), 1.88 (dd, J1 = 13.2 Hz, J2 = 2.4
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Hz, 1H), 1.24 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H), 1.15 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H); C{1H}NMR
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(100 MHz, CDCl3): 178.4, 159.2, 139.2 (d, J = 7.0 Hz), 138.2, 136.6, 132.8 (d, J = 9.4 Hz), 131.9,
129.3, 128.9, 128.6, 128.6, 127.5, 126.9, 126.6, 115.2, 113.5, 113.0, 75.6, 75.0, 64.6 (d, J = 5.7 Hz),
64.0 (d, J = 5.5 Hz), 55.0, 54.5 (d, J = 5.7 Hz), 44.6, 41.3, 21.2, 16.0 (d, J = 6.9 Hz), 15.9 (d, J = 7.7
Hz); 31P NMR (162 MHz, CDCl3): ꢀ7.26;
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4g: White solid; 97.0 mg, 83% yield; H NMR
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analysis revealed that the dr is 8.4:1. H NMR (400 MHz, CDCl3): 8.38ꢀ8.32 (m, 1H), 7.64ꢀ7.58 (m,
1H), 7.34 (d, J = 7.6 Hz, 2H), 7.29ꢀ7.26 (m, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.05ꢀ6.62 (m, 3H), 6.25ꢀ6.20
(m, 1H), 5.51 (dd, J1 = 12.0 Hz, J2 = 2.4 Hz, 1H), 4.16ꢀ4.09 (m, 2H), 4.00ꢀ3.94 (m, 1H), 3.78ꢀ3.72 (m,
2H), 3.57ꢀ3.41 (m, 3H), 2.58ꢀ2.45 (m, 1H), 2.52 (s, 3H), 2.35 (s, 3H), 1.95ꢀ1.82 (m, 1H), 1.25 (td, J1 =
13
7.2 Hz, J2 = 0.8 Hz, 3H), 1.17 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H); C{1H}NMR (100 MHz, CDCl3):
178.2, 159.0, 139.5, 139.4, 139.2, 138.2, 136.9, 136.6, 133.0, 133.0, 129.2, 128.9, 128.7, 128.5, 126.9,
126.6, 122.7, 120.1, 116.4, 116.2, 115.4, 115.2, 112.8, 111.2, 75.7, 75.6, 75.2, 64.7, 64.7, 64.1, 64.1,
54.9, 54.3, 54.3, 44.6, 41.3, 41.2, 21.2, 16.0, 15.9, 15.8; 31P NMR (162 MHz, CDCl3): ꢀ7.29;
1
Spirocyclic oxindole-tetrahydro-1,2-oxazines 4h: White solid; 83.4 mg, 69% yield; H NMR
1
analysis revealed that the dr is 8.0:1. H NMR (400 MHz, CDCl3): 8.44ꢀ8.43 (m, 1H), 7.77ꢀ7.37 (m,
9H), 7.29ꢀ7.26 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.09ꢀ6.78 (m, 1H), 5.59ꢀ5.56 (m, 1H), 4.36ꢀ4.35 (m,
1H), 4.06ꢀ3.89 (m, 1H), 3.84ꢀ3.67 (m, 1H), 3.48ꢀ3.00 (m, 2H), 2.62ꢀ2.56 (m, 1H), 2.53 (s, 3H), 2.36 (s,
3H), 1.99ꢀ1.91 (m, 1H), 1.13ꢀ1.07 (m, 3H), 0.96ꢀ0.67 (m, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.2,
139.1, 139.0, 138.3, 136.6, 133.2, 132.8, 132.7, 129.6, 129.3, 129.0, 128.7, 128.2, 127.8, 127.5, 127.4,
127.1, 126.6, 126.4, 126.3, 124.8, 115.1, 75.8, 75.7, 75.6, 64.6, 64.5, 63.8, 63.8, 54.7, 54.6, 44.9, 44.7,
41.2, 21.2, 15.8, 15.8, 15.4, 15.4; 31P NMR (162 MHz, CDCl3): ꢀ7.47;
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4i: White solid; 88.0 mg, 81% yield; H NMR
1
analysis revealed that the dr is 10.0:1. H NMR (400 MHz, CDCl3): 8.29 (s, 1H), 7.80 (d, J = 8.8 Hz,
1H), 7.37ꢀ7.30 (m, 3H), 7.22ꢀ7.14 (m, 3H), 6.08 (dd, J1 = 3.2 Hz, J2 = 1.6 Hz, 1H), 5.47 (d, J = 3.6 Hz,
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1H), 5.43 (dd, J1 = 12.0 Hz, J2 = 2.4 Hz, 1H), 4.31 (s, 1H), 4.24ꢀ4.10 (m, 2H), 3.88ꢀ3.81 (m, 1H), 3.62ꢀ
3.56 (m, 1H), 2.53ꢀ2.39 (m, 1H), 2.45 (s, 3H), 2.34 (s, 3H), 1.88 (dd, J1 = 13.2 Hz, J2 = 2.4 Hz, 1H),
1.29 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H), 1.15 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 3H); 13C{1H}NMR (100 MHz,
CDCl3): 178.1, 149.0, 142.3, 139.4 (d, J = 7.0 Hz), 138.2, 136.4, 133.2 (d, J = 9.4 Hz), 129.3, 129.1,
128.8, 126.9, 126.6, 115.3, 110.4, 109.5, 75.8, 68.6, 64.9 (d, J = 5.8 Hz), 64.2 (d, J = 5.6 Hz), 52.6 (d, J
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= 5.8 Hz), 44.2, 41.2, 21.2, 16.0 (d, J = 6.7 Hz), 15.8 (d, J = 7.5 Hz); P NMR (162 MHz, CDCl3): ꢀ
7.30;
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4j: White solid; 90.8 mg, 81% yield; H NMR
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analysis revealed that the dr is 11.3:1. H NMR (400 MHz, CDCl3): 8.34 (s, 1H), 7.74 (d, J = 8.8 Hz,
1H), 7.36 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.33 (d, J = 8.0 Hz , 2H), 7.18 (d, J = 7.6 Hz , 2H), 7.07 (d,
J = 5.2 Hz, 1H), 6.83 (s, br, 1H), 6.77ꢀ6.76 (m, 1H), 5.49 (dd, J1 = 12.0 Hz, J2 = 2.4 Hz, 1H), 4.48 (s,
1H), 4.20ꢀ4.12 (m, 1H), 4.08ꢀ3.98 (m, 1H), 3.73ꢀ3.63 (m, 1H), 3.39ꢀ3.29 (m, 1H), 2.53ꢀ2.46 (m, 1H),
2.44 (s, 3H), 2.34 (s, 3H), 1.93 (dd, J1 = 13.2 Hz, J2 = 2.4 Hz, 1H), 1.26 (td, J1 = 7.2 Hz, J2 = 0.8 Hz,
3H), 1.09 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.0, 139.9 (d, J = 7.0
Hz), 138.3, 136.4, 136.3, 132.6 (d, J = 9.4 Hz), 129.3, 129.2, 129.1, 128.7, 127.3, 127.2, 126.6, 125.5,
115.3, 75.6, 71.4, 64.8 (d, J = 5.8 Hz), 64.8 (d, J = 5.5 Hz), 53.9 (d, J = 5.8 Hz), 44.4, 41.0, 21.2, 16.0
(d, J = 6.9 Hz), 15.8 (d, J = 7.8 Hz); 31P NMR (162 MHz, CDCl3): ꢀ7.31;
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4k: Colorless oil; 89.5 mg, 86% yield; H NMR
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analysis revealed that the dr is 8.6:1. H NMR (400 MHz, CDCl3): 8.14 (s, 1H), 7.87 (d, J = 8.4 Hz,
1H), 7.31 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.24 (dd,
J1 = 12.0 Hz, J2 = 2.4 Hz, 1H), 4.37ꢀ4.08 (m, 4H), 3.16 (d, J = 3.2 Hz, 1H), 2.76 (s, 3H), 2.32ꢀ2.31 (m,
4H), 1.84ꢀ1.74 (m, 1H), 1.60 (dd, J1 = 13.2 Hz, J2 = 2.4 Hz, 1H), 1.36 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H),
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1.31 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H), 0.69 (dd, J1 = 13.2 Hz, J2 = 6.8 Hz, 6H); C{1H}NMR (100
MHz, CDCl3): 179.8, 138.7 (d, J = 7.2 Hz), 138.0, 136.6, 134.0 (d, J = 9.6 Hz), 129.2, 129.0, 128.3,
127.5, 126.5, 115.5, 75.1, 73.2, 65.1 (d, J = 6.1 Hz), 64.7 (d, J = 5.9 Hz), 52.3 (d, J = 5.5 Hz), 45.1,
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44.2, 29.9, 21.3, 21.1, 19.3, 16.1 (d, J = 5.4 Hz), 16.0 (d, J = 5.1 Hz); P NMR (162 MHz, CDCl3): ꢀ
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4l: White solid; 96.5 mg, 86% yield; H NMR
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analysis revealed that the dr is 10.9:1. H NMR (400 MHz, CDCl3): 8.13 (s, 1H), 7.89 (d, J = 8.4 Hz,
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1H), 7.32 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.23 (dd,
J1 = 12.0 Hz, J2 = 2.0 Hz, 1H), 4.37ꢀ4.10 (m, 4H), 3.16 (d, J = 3.2 Hz, 1H), 2.77 (s, 3H), 2.37ꢀ2.25 (m,
1H), 2.32 (s, 3H), 1.58ꢀ1.47 (m, 7H), 1.38 (td, J1 = 6.8 Hz, J2 = 0.8 Hz, 3H), 1.32 (td, J1 = 7.2 Hz, J2 =
0.8 Hz, 3H), 0.98ꢀ0.79 (m, 4H), 0.50ꢀ0.44(m, 1H); 13C{1H}NMR (100 MHz, CDCl3): 179.7, 138.4 (d, J
= 7.2 Hz), 138.0, 136.6, 134.4 (d, J = 9.7 Hz), 129.2, 128.9, 128.3, 127.4, 126.5, 115.4, 75.1, 73.4, 65.0
(d, J = 6.0 Hz), 64.6 (d, J = 6.0 Hz), 51.9 (d, J = 5.6 Hz), 44.9, 44.6, 41.9, 31.0, 30.6, 27.4, 27.4, 26.4,
21.2, 16.1 (d, J = 7.1 Hz), 16.0 (d, J = 6.7 Hz); 31P NMR (162 MHz, CDCl3): ꢀ6.64;
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4m: White solid; 104.6 mg, 90% yield; m.p. 69ꢀ70
oC; 1H NMR analysis revealed that the dr is 14.0:1. 1H NMR (400 MHz, CDCl3): 8.20 (s, 1H), 7.36 (dd,
J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.31 (d, J = 8.0 Hz , 1H), 7.21ꢀ7.16 (m, 5H), 7.07ꢀ7.05 (m, 2H), 5.61 (d, J
= 12.0 Hz, 1H), 5.39 (dd, J1 = 12.0 Hz, J2 = 9.6 Hz, 1H), 5.35 (d, J = 9.6 Hz, 1H), 4.20ꢀ4.13 (m, 1H),
4.07ꢀ4.01 (m, 1H), 3.85ꢀ3.79 (m, 1H), 3.73 (d, J = 9.6 Hz, 1H), 3.67ꢀ3.61 (m, 1H), 2.65 (s, 3H), 2.42
(dd, J1 = 13.2 Hz, J2 = 12.0 Hz, 1H), 2.34 (s, 3H), 1.82 (dd, J1 = 13.2 Hz, J2 = 2.4 Hz, 1H), 1.22 (td, J1 =
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6.8 Hz, J2 = 1.2 Hz, 3H), 0.90 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H); C{1H}NMR (100 MHz, CDCl3):
178.6, 139.2 (d, J = 7.0 Hz), 138.2, 136.6, 135.6, 135.3, 132.8 (d, J = 9.5 Hz), 129.3, 129.2, 128.7,
128.6, 128.3, 126.5, 126.5, 126.4, 123.5, 115.3, 75.8, 73.5, 64.8 (d, J = 5.6 Hz), 64.3 (d, J = 5.5 Hz),
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53.8 (d, J = 5.6 Hz), 44.8, 40.6, 21.2, 16.0 (d, J = 6.8 Hz), 15.6 (d, J = 7.4 Hz); P NMR (162 MHz,
CDCl3): ꢀ7.00; IR (ATR): 2915, 1743, 1464, 1308, 1286, 1149, 1022 cmꢀ1; MS (EI): 580 (M+, 4), 419
(58), 162 (36), 144 (100), 115 (30), 91 (35), 77 (21), 43 (23); HRMS (EIꢀTOF): Exact mass calcd for
C31H34N2O5P35Cl [M]+: 580.1894, Found: 580.1891.
Spirocyclic oxindole-tetrahydro-1,2-oxazines 4n: White solid; 109.8 mg, 87% yield; m.p. 180ꢀ181
oC; 1H NMR analysis revealed that the dr is 18.1:1. 1H NMR (400 MHz, CDCl3): 8.38 (s, 1H), 7.59 (d, J
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= 8.8 Hz , 1H), 7.29ꢀ7.26 (m, 5H), 7.20ꢀ7.18 (m, 5H), 7.13ꢀ7.11 (m, 3H), 6.98ꢀ6.94 (m, 1H), 6.78 (d, J =
8.0 Hz , 1H), 5.47 (dd, J1 = 2.4 Hz, J2 = 2.4 Hz, 1H), 4.43 (s, 1H), 4.15ꢀ4.07 (m, 1H), 4.00ꢀ3.92 (m, 2H),
3.79ꢀ3.73 (m, 1H), 3.62 (d, J = 14.8 Hz , 1H), 3.54ꢀ3.48 (m, 1H), 2.51(t, J = 12.4 Hz, 1H), 2.32 (s, 3H),
1.96 (dd, J1 = 2.4 Hz, J2 = 2.4 Hz, 1H), 1.25 (td, J1 = 7.2 Hz, J2 = 6.8 Hz, 3H), 1.17 (td, J1 = 7.2 Hz, J2 =
6.4 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.3, 139.2 (d, J = 7.1 Hz), 137.8, 137.6, 136.6, 135.4,
132.7 (d, J = 9.5 Hz ) 130.7, 129.1, 128.9, 128.8, 128.6, 128.2, 128.0, 127.8, 127.0, 126.9, 126.2, 115.2,
77.4, 77.0, 76.7, 75.0, 73.3, 64.7 (d, J = 5.9 Hz), 64.1 (d, J = 5.5 Hz), 59.3, 54.7 (d, J = 5.7 Hz), 41.0,
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21.2, 16.0 (d, J = 6.5 Hz), 15.9 (d, J = 7.2 Hz); P NMR (162 MHz, CDCl3): ꢀ7.28; IR (ATR): 2995,
1737, 1602, 1465, 1298, 1127, 1026 cmꢀ1; MS (EI): 630 (M+, 2), 419 (35), 212 (20), 195 (12), 194 (12),
91 (100), 65 (13), 44 (14); HRMS (EIꢀTOF): Exact mass calcd for C35H36N2O5P35Cl [M]+: 630.2050,
Found: 630.2045.
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4o: White solid; 89.3 mg, 83% yield; H NMR
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analysis revealed that the dr is 11.6:1. H NMR (400 MHz, CDCl3): 8.13ꢀ8.10 (m, 1H), 7.60 (dd, J1 =
9.2 Hz, J2 = 4.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.21ꢀ7.07 (m, 5H), 6.99 (td, J1 = 9.2 Hz, J2 = 2.8 Hz,
2H), 6.93 (s, 1H), 6.70ꢀ6.68 (m, 1H), 5.52 (dd, J1 = 12.0 Hz, J2 = 2.4 Hz, 1H), 4.19 (s, 1H), 4.14ꢀ4.06
(m, 1H), 3.99ꢀ3.91 (m, 1H), 3.76ꢀ3.70 (m, 1H), 3.52ꢀ3.45 (m, 1H), 2.53 (t, J = 13.2 Hz ,1H), 2.50 (s,
3H), 2.34 (s, 3H), 1.88 (dd, J1 = 12.8 Hz, J2 = 2.0 Hz, 1H), 1.24 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 3H), 1.15
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(td, J1 = 6.8 Hz, J2 = 0.8 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): 178.6, 159.2 (d, J = 240.2 Hz),
138.2, 136.6, 136.5 (dd, J1 = 7.0 Hz, J2 = 2.3 Hz), 135.6, 132.5 (t, J = 8.9 Hz), 130.6, 129.3, 128.0,
127.9, 127.7, 126.6, 115.1 (d, J = 8.9 Hz), 114.9 (d, J = 6.1 Hz), 114.6 (d, J = 25.0 Hz), 75.6, 75.6, 64.6
(d, J = 5.7 Hz), 63.9 (d, J = 5.6 Hz), 54.5 (dd, J1 = 5.9 Hz, J2 = 1.8 Hz), 44.6, 41.4, 21.2, 16.0 (d, J = 7.0
Hz), 15.9 (d, J = 7.8 Hz); 31P NMR (162 MHz, CDCl3): ꢀ7.09; 19F NMR (282 MHz, CDCl3): ꢀ118.66.
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 4p: White solid; 100.2 mg, 85% yield; H NMR
(400 MHz, CDCl3): 8.42 (s, 1H), 7.91 (s, 1H), 7.88ꢀ7.82 (m, 3H), 7.61ꢀ7.57 (m, 2H), 7.50ꢀ7.47 (m, 2H),
7.29 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.26ꢀ7.09 (m, 3H), 6.97 (s, br, 1H), 6.70 (s, br, 1H), 5.73 (dd, J1
= 12.0 Hz, J2 = 2.4 Hz, 1H), 4.25 (s, 1H), 4.14ꢀ4.06 (m, 1H), 4.00ꢀ3.90 (m, 1H), 3.77ꢀ3.69 (m, 1H),
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3.54ꢀ3.44 (m, 1H), 2.62 (dd, J1 = 12.8 Hz, J2 = 12.0 Hz, 1H), 2.56 (s, 3H), 2.01 (dd, J1 = 13.2 Hz, J2 =
2.8 Hz, 1H), 1.24 (td, J1 = 6.8 Hz, J2 = 0.8 Hz, 3H), 1.16 (td, J1 = 6.8 Hz, J2 = 1.2 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3): 178.3, 139.2 (d, J = 7.0 Hz), 137.0, 135.5, 133.3, 133.3, 132.7 (d, J =
9.4 Hz), 130.6, 129.0, 128.7, 128.4, 128.2, 128.1, 128.0, 127. 8, 127.7, 127.0, 126.3, 126.2, 125.6,
124.4, 115.2, 75.8, 75.6, 64.7 (d, J = 5.7 Hz), 64.1 (d, J = 5.6 Hz), 54.5 (d, J = 5.8 Hz), 44.8, 41.4, 16.0
(d, J = 6.5 Hz), 15.9 (d, J = 7.3 Hz); 31P NMR (162 MHz, CDCl3): ꢀ7.28.
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General procedure for one-pot sequential [3+3] dipolar cycloaddition with ketone
To a Schlenk tube was sequentially added 5 (0.34 mmol), 2a (0.30 mmol, 25.2 mg), 4 Å MS (100
mg) and K2CO3 (0.15 mmol, 20.7 mg), followed by the addition of anhydrous EtOH (1.0 mL), and the
o
resulting solution was stirred at 50 C for 4 h. After the complete formation of nitrone, EtOH was
removed under reduced pressure. The residua was kept under vacuum for 1 h to remove EtOH
i
thoroughly. Then Sc(OTf)3 (9.8 mg, 0.02 mmol), spirocyclopropyl oxindole 3 (0.20 mmol) and PrOAc
o
i
were added. The reaction was kept stirring at 50 C for 24 h. Then PrOAc was removed under reduced
pressure. The following workꢀup procedure to obtain product 6 was the same as mentioned for product
4.
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 6a: White solid; 58.5 mg, 50% yield; H NMR
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analysis showed the dr value is 3.9:1. H NMR (400 MHz, CDCl3): 8.53 (s, 1H), 7.41 (d, J = 8.8 Hz,
1H), 7.36 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.12 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.09 (s,
br, 2H), 6.98 (s, 3H), 5.53 (dd, J1 = 12.4 Hz, J2 = 2.8 Hz, 1H), 4.10ꢀ3.98 (m, 2H), 3.96ꢀ3.94 (m, 2H),
2.66 (dd, J1 = 13.6 Hz, J2 = 12.4 Hz, 1H), 2.61 (s, 3H), 2.35 (s, 3H), 2.12 (s, 3H), 1.66 (dd, J1 = 13.2 Hz,
J2 = 2.8 Hz, 1H), 1.35 (td, J1 = 6.8 Hz, J2 = 0.8 Hz, 3H), 1.24 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3): 178.3, 140.7, 138.3 (d, J = 6.9 Hz), 138.2, 136.9, 133.9 (d, J = 9.6
Hz), 129.3, 128.6, 128.2, 128.0, 127.8, 126.9, 126.8, 126.6, 114.4, 74.8, 67.8, 64.5, 64.4, 56.7 (d, J = 5.5
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Hz), 38.7, 38.0, 21.2, 16.1 (d, J = 7.2 Hz), 15.9 (d, J = 6.8 Hz), 10.0; P NMR (162 MHz, CDCl3): ꢀ
6.85.
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 6b: White solid; 55.9 mg, 48% yield; H NMR
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analysis showed the dr value is 4.2:1. H NMR (400 MHz, CDCl3): 8.54 (s, 1H), 7.42 (d, J = 8.8 Hz,
1H), 7.36 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.14 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 6.97 (d, J
= 7.6 Hz, 2H), 6.78 (d, J = 7.6 Hz, 2H), 5.53 (dd, J1 = 12.4 Hz, J2 = 2.8 Hz, 1H), 4.15ꢀ4.03 (m, 2H),
3.99ꢀ3.92 (m, 2H), 2.66 (dd, J1 = 13.6 Hz, J2 = 12.4 Hz, 1H), 2.59 (s, 3H), 2.35 (s, 3H), 2.14 (s, 3H),
2.10 (s, 3H), 1.65 (dd, J1 = 13.6 Hz, J2 = 2.8 Hz, 1H), 1.34 (td, J1 = 6.8 Hz, J2 = 1.2 Hz, 3H), 1.24 (td, J1
= 7.2 Hz, J2 = 1.2 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.3, 138.3 (d, J = 6.7 Hz), 138.1,
137.7, 137.0, 136.3, 134.1 (d, J = 9.8 Hz), 129.3, 128.6, 128.2, 128.0, 127.7, 127.6, 126.6, 114.4, 74.8,
67.6, 64.5 (d, J = 4.0 Hz), 64.4 (d, J = 3.8 Hz), 56.8 (d, J = 5.6 Hz), 38.7, 38.1, 21.2, 21.2, 20.8, 16.0 (d,
J = 7.5 Hz), 16.0 (d, J = 6.8 Hz), 10.1; 31P NMR (162 MHz, CDCl3): ꢀ6.88.
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 6c: White solid; 59.5 mg, 51% yield; m.p. 78ꢀ79 oC;
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1H NMR analysis showed the dr value is 4.5:1. H NMR (400 MHz, CDCl3): 8.54 (s, 1H), 7.44 (d, J =
8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.15 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H),
7.00 (s, 2H), 6.50 (d, J = 8.4 Hz, 2H), 5.53 (dd, J1 = 12.4 Hz, J2 = 3.2 Hz, 1H), 4.11ꢀ4.05 (m, 2H), 3.99ꢀ
3.93 (m, 2H), 3.65 (s, 3H), 2.65 (dd, J1 = 13.6 Hz, J2 = 12.4 Hz, 1H), 2.57 (s, 3H), 2.35 (s, 3H), 2.09 (s,
3H), 1.65 (dd, J1 = 13.6 Hz, J2 = 3.2 Hz, 1H), 1.34 (td, J1 = 8.4 Hz, J2 = 1.2 Hz, 3H), 1.23 (td, J1 = 8.0
Hz, J2 = 1.2 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.3, 158.0, 138.4 (d, J = 6.7 Hz), 138.2,
136.9, 134.1 (d, J = 9.6 Hz), 132.6, 129.3, 129.0, 128.5, 128.2, 128.0, 126.6, 114.5, 112.2, 74.8, 67.3,
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64.5, 56.8 (d, J = 5.4 Hz), 55.0, 38.6, 38.0, 21.2, 16.2 (d, J = 7.3 Hz), 16.0 (d, J = 7.1 Hz), 10.2; P
NMR (162 MHz, CDCl3): ꢀ6.79; IR (ATR): 2914, 1736, 1511, 1465, 1314, 1182, 1023 cmꢀ1; MS (EI):
598 (M+, 1), 419 (12), 163 (26), 162 (21), 148 (100), 133 (22), 105 (11), 91 (11); [M+H]+; HRMS (EIꢀ
TOF): Exact mass calcd for C31H36N2O6P35Cl [M]+: 598.2000, Found: 598.2007.
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 6d: White solid; 59.5 mg, 46% yield; H NMR
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analysis showed the dr value is 2.3:1. H NMR (400 MHz, CDCl3): 8.50 (s, 1H), 7.40 (d, J = 8.8 Hz,
1H), 7.35 (d, J = 8.0 Hz, 2H), 7.20ꢀ7.16 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.98 (s, 2H), 5.52 (dd, J1 =
12.4 Hz, J2 = 2.8 Hz, 1H), 4.12ꢀ4.06 (m, 2H), 3.98ꢀ3.94 (m, 2H), 2.65 (dd, J1 = 13.6 Hz, J2 = 12.4 Hz,
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1H), 2.56 (s, 3H), 2.35 (s, 3H), 2.10 (s, 3H), 1.66 (dd, J1 = 13.6 Hz, J2 = 2.8 Hz, 1H), 1.33 (td, J1 = 7.2
Hz, J2 = 1.2 Hz, 3H), 1.26 (td, J1 = 7.2 Hz, J2 = 0.8 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 177.9,
139.8, 138.3, 138.2 (d, J = 6.9 Hz), 136.7, 133.5 (d, J = 9.5 Hz), 130.0, 129.6, 129.3, 128.5, 128.8,
128.3, 126.5, 121.0, 114.6, 74.8, 67.6, 64.6 (d, J = 5.5 Hz), 64.5 (d, J = 5.8 Hz), 56.5 (d, J = 5.7 Hz),
38.7 (d, J = 1.9 Hz), 37.7, 21.2 (d, J = 1.8 Hz), 16.1 (d, J = 7.1 Hz), 16.0 (d, J = 7.0 Hz), 9.9; 31P NMR
(162 MHz, CDCl3): ꢀ6.96.
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 6e: White solid; 49.9 mg, 42% yield; m.p. 63ꢀ64 oC;
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1H NMR analysis showed the dr value is 5.3:1. H NMR (400 MHz, CDCl3): 8.50 (s, 1H), 7.47 (d, J =
8.8 Hz, 1H), 7.36 (dd, J1 = 12.8 Hz, J2 = 2.4 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.21ꢀ7.16 (m, 5H), 6.91
(dd, J1 = 7.6 Hz, J2 = 3.0 Hz, 2H), 6.45 (d, J = 12.4 Hz, 1H), 5.59 (d, J = 12.4 Hz, 1H), 5.42 (dd, J1 =
12.4 Hz, J2 = 2.8 Hz, 1H), 4.01ꢀ3.82 (m, 4H), 2.60 (dd, J1 = 13.2 Hz, J2 = 12.4 Hz, 1H), 2.56 (s, 3H),
2.35 (s, 3H), 1.84 (s, 3H), 1.64 (dd, J1 = 13.6 Hz, J2 = 2.8 Hz, 1H), 1.20 (td, J1 = 7.2 Hz, J2 = 1.2 Hz,
3H), 1.00 (td, J1 = 6.8 Hz, J2 = 1.2 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.0, 138.9 (d, J = 6.9
Hz), 138.2, 136.9, 134.0 (d, J = 9.6 Hz), 131.1, 130.6, 129.3, 128.8, 128.6, 128.5, 128.0, 127.8, 126.5,
126.3, 114.9, 75.5, 65.8 64.7 (d, J = 5.8 Hz), 64.2 (d, J = 5.5 Hz), 56.2 (d, J = 5.5 Hz), 38.8, 37.7, 21.2,
31
15.9 (d, J = 7.0 Hz), 15.8 (d, J = 9.2 Hz), 8.1; P NMR (162 MHz, CDCl3): ꢀ6.72; IR (ATR): 2985,
1749, 1464, 1372, 1280, 1157, 1021 cmꢀ1; MS (EI): 594 (M+, 2), 419 (42), 316 (38), 159 (38), 158
(100), 144(65), 115 (33), 91 (36); [M]+; HRMS (EIꢀTOF): Exact mass calcd for C32H36N2O5P35Cl [M]+:
594.2055, Found: 594.2050.
1
Spirocyclic oxindole-tetrahydro-1,2-oxazines 6f: White solid; 61.3 mg, 50% yield; H NMR
analysis showed the dr value is 3.5:1. 1H NMR (400 MHz, CDCl3): 8.42 (d, J = 8.8 Hz, 1H), 7.70 (d, J =
2.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.29 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H),
7.08 (s, 2H), 6.99 (s, 3H), 5.53 (dd, J1 = 12.0 Hz, J2 = 2.8 Hz, 1H), 4.14ꢀ4.06 (m, 2H), 4.00ꢀ3.92 (m,
2H), 2.64 (dd, J1 = 14.0 Hz, J2 = 12.8 Hz, 1H), 2.59 (s, 3H), 2.35 (s, 3H), 2.13 (s, 3H), 1.63 (dd, J1 =
13
14.0 Hz, J2 = 2.8 Hz, 1H), 1.36 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 6.8 Hz, 3H); C{1H}NMR (100 MHz,
CDCl3): 178.4 140.9 (d, J = 6.4 Hz), 140.8, 138.2, 137.0, 131.2 (d, J = 9.5 Hz), 129.8, 129.3, 127.8,
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126.9, 126.5, 125.7, 122.0, 116.7, 74.9, 67.7, 64.5 (d, J = 3.4 Hz), 64.5 (d, J = 3.2 Hz), 56.4 (d, J = 5.4
Hz), 38.7 (d, J = 2.0 Hz), 38.2, 21.2 (d, J = 2.2 Hz), 16.0 (d, J = 7.4 Hz), 16.0 (d, J = 6.9 Hz), 10.1; 31P
NMR (162 MHz, CDCl3): ꢀ6.89.
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Spirocyclic oxindole-tetrahydro-1,2-oxazines 6g: White solid; 55.7 mg, 49% yield; H NMR
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analysis showed the dr value is 3.0:1. H NMR (400 MHz, CDCl3): 8.53 (s, 1H), 7.47 (d, J = 7.2 Hz,
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2H), 7.43ꢀ7.37 (m, 3H), 7.34ꢀ7.31 (m, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.09 (s, br, 2H), 6.98 (s, 3H), 5.57
(dd, J1 = 12.4 Hz, J2 = 2.8 Hz, 1H), 4.14ꢀ4.07 (m, 2H), 3.99ꢀ3.95 (m, 2H), 2.69ꢀ2.66 (m, 1H), 2.63 (s,
3H), 2.13 (s, 3H), 1.69 (dd, J1 = 13.6 Hz, J2 = 3.2 Hz, 1H), 1.35 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz,
3H); 13C{1H}NMR (100 MHz, CDCl3): 178.2, 140.6, 139.9, 138.3 (d, J = 6.9 Hz), 133.9 (d, J = 9.6 Hz),
128.6, 128.5, 128.3, 128.2, 128.0, 127.8, 126.9, 126.8, 126.5, 114.5, 74.9, 67.8, 64.5 (d, J = 1.6 Hz),
64.5 (d, J = 1.6 Hz), 56.7 (d, J = 5.5 Hz), 38.8 (d, J = 1.8Hz), 38.1, 16.1 (d, J = 7.4 Hz), 16.0 (d, J = 6.8
Hz), 10.04; 31P NMR (162 MHz, CDCl3): ꢀ6.85.
1
Spirocyclic oxindole-tetrahydro-1,2-oxazines 6h: White solid; 66.5 mg, 55% yield; H NMR
1
analysis showed the dr value is 3.0:1. H NMR (400 MHz, CDCl3): 8.60 (s, 1H), 7.90 (d, J = 9.6 Hz,
1H), 7.87ꢀ7.84 (m, 3H), 7.61 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.50ꢀ7.48 (m, 2H), 7.44 (d, J = 8.4 Hz,
1H), 7.16ꢀ7.12 (m, 3H), 7.00 (s, 3H), 5.76 (dd, J1 = 12.4 Hz, J2 = 2.8 Hz, 1H), 4.14ꢀ4.06 (m, 2H), 4.02ꢀ
3.94 (m, 2H), 2.78 (d, J = 12.8 Hz, 1H), 2.68 (s, 3H), 2.19 (s, 3H), 1.78 (dd, J1 = 13.6 Hz, J2 = 2.8 Hz,
1H), 1.36 (t, J = 6.8 Hz, 3H), 1.24 (t, J = 3.2 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3): 178.2, 140.6,
138.3 (d, J = 6.9 Hz), 137.3, 133.9 (d, J = 9.6 Hz), 133.3, 133.3, 128.6, 128.4, 128.3, 128.1, 128.0,
127.7, 126.9, 126.8, 126.3, 126.2, 125.6, 124.3, 114.5, 75.0, 67.9, 64.5, 64.5, 56.7 (d, J = 5.6 Hz), 38.8
31
(d, J = 2.2 Hz), 38.1, 16.1 (d, J = 7.2 Hz), 16.0 (d, J = 6.8 Hz), 10.1; P NMR (162 MHz, CDCl3): ꢀ
6.85.
Spirocyclic oxindole-tetrahydro-1,2-oxazines 6i: Nitrone preparation and cycloaddition reaction
o
o
1
were conducted at 80 C. White solid; 23.5 mg, 22% yield; m.p. 59ꢀ60 C; H NMR analysis showed
the dr value is >20:1. 1H NMR (400 MHz, CDCl3): 8.38 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.31 (dd, J1 =
8.0 Hz, J2 = 2.8 Hz, 1H), 7.25 (d, J = 6.8 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 5.28 (dd, J1 = 12.0 Hz, J2 =
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2.8 Hz, 1H), 4.30ꢀ4.14 (m, 4H), 2.80 (dd, J1 = 14.8 Hz, J2 = 7.2 Hz, 1H), 2.55 (s, 3H), 2.49 (t, J = 12.8
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Hz, 1H), 2.32 (s, 3H), 2.16ꢀ2.12 (m, 1H), 1.84ꢀ1.82 (m, 1H), 1.69ꢀ1.64 (m, 1H), 1.50ꢀ1.48 (m, 3H),
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1.38ꢀ1.34 (m, 3H), 1.33ꢀ1.29 (m, 3H), 1.28ꢀ1.24 (m, 1H), 0.75ꢀ0.74 (m, 1H); C{1H}NMR (100 MHz,
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CDCl3): 178.8, 139.6 (d, J = 7.0 Hz), 138.0, 137.1, 134.7 (d, J = 9.9 Hz), 129.2, 128.9, 128.2, 127.5,
126.5, 114.8, 75.4, 73.6, 64.8 (d, J = 6.1 Hz), 64.7 (d, J = 5.8 Hz), 56.6 (d, J = 5.3 Hz), 39.9, 38.0, 35.6,
27.1, 26.0, 24.0, 21.2, 16.1 (d, J = 3.4 Hz), 16.0 (d, J = 3.2 Hz); 31P NMR (162 MHz, CDCl3): ꢀ6.50; IR
(ATR): 2955, 2918, 2872, 1738, 1463, 1313, 1277, 1020 cmꢀ1; MS (EI): 532 (M+, 3), 316 (100), 260
(66), 180 (43), 119 (48), 114 (34), 91 (55), 68 (41); HRMS (EIꢀTOF): Exact mass calcd for
C27H34N2O5P35Cl [H]+: 532.1894, Found: 532.1890.
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Catalytic asymmetric three-component [3+3] dipolar cycloaddition reaction
To a Schlenk tube was sequentially added Ni(OTf)2 (10.7 mg, 0.030 mmol, 20 mol %) and 7 (11.8
mg, 0.033 mmol, 11 mol %), followed by the addition of anhydrous THF (1.0 mL), then the resulting
solution was stirred at room temperature for 2 h.
To another Schlenk tube was sequentially added 1 (0.18 mmol), 2a (0.15 mmol, 12.6 mg), 4 Å MS
(80 mg) and K2CO3 (0.075 mmol, 10.3 mg), followed by the addition of anhydrous THF (1.0 mL). After
o
the resulting solution was stirred at 50 C for 1 h, the solvent of 7/ Ni(OTf)2 complex in 1.0 mL THF
o
and oxindole 3a (0.33 mmol, 138.3 mg) was added. The reaction was kept stirring at 50 C for 24 h.
Then THF was removed under reduced pressure. And the following workꢀup procedure to obtain
enantioenriched 4 was the same as mentioned for product 4.
Note: the chiral catalyst system is selected according to our previous report.9
1
Enantioenriched spirocyclic oxindole-tetrahydro-1,2-oxazines 4a: 65.3 mg, 74% yield; H NMR
i
analysis showed the dr value was 3.0:1. HPLC analysis (Chiralcel IC, PrOH/hexane = 10/90, 1.0
mL/min, 230 nm; tr (major) = 8.73 min, tr (minor) = 11.27 min) gave the isomeric composition of the
product: 97% ee.
Enantioenriched spirocyclic oxindole-tetrahydro-1,2-oxazines 4b: 49.9 mg, 60% yield; 1H NMR
i
analysis showed the dr value was 2.0:1. HPLC analysis (Chiralcel IC, PrOH/hexane = 10/90, 1.0
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mL/min, 230 nm; tr (major) = 9.21 min, tr (minor) = 10.75 min) gave the isomeric composition of the
product: 95% ee.
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Enantioenriched spirocyclic oxindole-tetrahydro-1,2-oxazines 4e: 57.1 mg, 67% yield; 1H NMR
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i
analysis showed the dr value was 2.2:1. HPLC analysis (Chiralcel IC, PrOH/hexane = 10/90, 1.0
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mL/min, 230 nm; tr (major) = 9.69 min, tr (minor) = 11.10 min) gave the isomeric composition of the
product: 96% ee.
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Enantioenriched spirocyclic oxindole-tetrahydro-1,2-oxazines 4m: 59.2 mg, 68% yield; 1H NMR
i
analysis showed the dr value was 6.2:1. HPLC analysis (Chiralcel IC, PrOH/hexane = 10/90, 1.0
mL/min, 230 nm; tr (major) = 8.41 min, tr (minor) = 10.47 min) gave the isomeric composition of the
product: 96% ee, [α]25D = ꢀ49.1 (c = 1.0, CHCl3).
General Procedure of the Biological Studies
Cell cultures: Human prostate cancer DU145 and PC3 cell lines were purchased from the Cell Bank
of Type Culture Collection of Chinese Academy of Sciences (Shanghai, China). Human nonꢀmalignant
prostate epithelial BPH1 cell line was kindly provided by Dr. Simon Hayward at the Vanderbilt
University Medical Center, Nashville, TN, USA.17 Cells were maintained in RPMI 1640 with 10% FBS
(Life Technologies, Carlsbad, CA) at 37 oC in a humidified air atmosphere containing 5% CO2.
MTT assay: Cells (3,000/well) were seeded into 96ꢀwell plates overnight, followed by the treatment
with compounds for 48 h. Afterwards, the cells were incubated with 5 mg/mL 3ꢀ(4,5ꢀdimethylthiazolꢀ2ꢀ
o
yl)ꢀ2,5ꢀdiphenyltetrazolium bromide (MTT, SigmaꢀAldrich, St. Louis, MO) for 2 h at 37 C. Formazan
was dissolved with DMSO and measured at 490 nm with a reference wavelength of 680 nm using a
spectrophotometer.
Luciferase assay: 6xNFκBꢀLuc reporter plasmid contains six NFκBꢀbinding sites, which could be
activated by TNFα. DU145 cells (2.5 x104/well) were seeded into 24ꢀwell plates. Afterwards, the cells
were transfected with 200 ng/well 6xNFκBꢀLuc plasmid by lipofectamine 3000 (Invitrogen). As for
TNFα treatment assay, twentyꢀfour hours after the transfection, the cells were pretreated with
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compounds of interest for 4 h, followed by TNFα (10 ng/mL, R&D Systems, Minneapolis, MN) addition
for 20 h and harvested. Luciferase activity was measured with the dual luciferase assay system (E1910,
Promega). Cells were lysed in Passive Lysis Buffer (E1941, Promega) and harvested by centrifugation at
12,000 rpm to remove the cell debris. The protein concentration was measured with the PierceTM BCA
protein assay kit (23225, Thermo Fisher). The luciferase activities were calculated as a rate of firefly
luciferase activity/total protein. The relative luciferase activity of vehicle control was set as 100%.
Statistical analysis: Each experiment was repeated three times. The mean values with standard
deviations (SD) from the triplicates were plotted. The significant difference between control and
experimental groups was analyzed using a Student tꢀtest (*, p < 0.05; **, p < 0.01; ***, p < 0.001).
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Supporting Information Available: Copies of H NMR, 19F NMR, 31P NMR, 13C{1H}NMR and
HPLC of all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgement. Financial supports from NSFC of China (21725203 and 81672873), the
Fundamental Research Funds for the Central Universities, the National Key Research and Development
Plan of China (2016YFC0902202) and the State Key Laboratory of Pharmaceutical Biotechnology of
Nanjing University (KFꢀGNꢀ201201) are highly appreciated.
References
(1) (a) Heathcock, C. L.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T. The Total Synthesis
of Natural Products (Ed. ApSimon, J.), John Wiley & Sons, New York, 1983, 5, 264–313. (b) Smith, L.
K.; Baxendale, I. R. Total Syntheses of Natural Products Containing Spirocarbocycles. Org. Biomol.
Chem. 2015, 13, 9907–9933. (c) Undheim, K. Preparation and Structure Classification of
Heteraspiro[m.n]alkanes. Synthesis 2014, 46, 1957–2006.
(2) Zheng, Y.; Tice, C. M.; Singh, S. B. The Use of Spirocyclic Scaffolds in Drug Discovery. Bioorg.
Med. Chem. Lett. 2014, 24, 3673–3682.
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(3) For reviews: (a) Rios, R. Enantioselective Methodologies for the Synthesis of Spiro Compounds.
1
2
Chem. Soc. Rev. 2012, 41, 1060–1074. (b) Franz, A. K.; Hanhan, N. V.; BallꢀJones, N. R. Asymmetric
Catalysis for the Synthesis of Spirocyclic Compounds. ACS Catal. 2013, 3, 540−553. (c) D’yakonov, V.
A.; Trapeznikova, O. A.; de Meijere, A.; Dzhemilev, U. M. Metal Complex Catalysis in the Synthesis of
Spirocarbocycles. Chem. Rev. 2014, 114, 5775−5814. (d) Smith, L. K.; Baxendale, I. R. Total Syntheses
of Natural Products Containing Spirocarbocycles. Org. Biomol. Chem. 2015, 13, 9907−9933. (e)
Carreira, E. M.; Fessard, T. C. FourꢀMembered RingꢀContaining Spirocycles: Synthetic Strategies and
Opportunities. Chem. Rev. 2014, 114, 8257−8322. (f) Ding, A.; Meazza, M.; Guo, H.; Yang, J. W.; Rios
R. New Development in the Enantioselective Synthesis of Spiro Compounds. Chem. Soc. Rev. 2018, 47,
5946ꢀ5996.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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23
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26
27
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42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) Sharma, I.; Tan, D. S. Drug Discovery: Diversifying Complexity. Nat. Chem. 2013, 5, 157–158.
(5) (a) Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. Nakadomarin A, a Novel Hexacyclic
ManzamineꢀRelated Alkaloid from Amphimedon Sponge. J. Org. Chem. 1997, 62, 9236–9239. (b)
Horii, Z.; Imanishi, T.; Yamauchi, M.; Hanaoka, M.; Parello, J.; Munavalli, S. Structure of Phyllantidine.
Tetrahedron Lett. Tetrahedron Lett. 1972, 13, 1877–1880. (c) Parello, J.; Munavalli, S. Phyllantine et
Phyllantidine Alcaloides du Phyllantus Discoides Muell Arg (Euphorbiacees). C. R. Hebd. Seances
Acad. Sci. 1965, 260, 337–340. (d) Lajis, N. H.; Guan, O. B.; Sargent, M. V.; Skelton, B. W.; White, A.
H. Viroallosecurinine and entꢀPhyllanthidine from the Leaves of BreyniaꢀCoronata (Euphorbiaceae).
Aust. J. Chem. 1992, 45, 1893–1897. (e) Uchida, I.; Takase, S.; Kayakiri, H.; Kiyoto, S.; Hashimoto,
M.; Tada, T.; Koda, S.; Morimoto, Y. Structure of FR 900482, a Novel Antitumor Antibiotic from a
Streptomyces. J. Am. Chem. Soc. 1987, 109, 4108–4109. (f) Terano, H.; Takase, S.; Hosoda, J.;
Kohsaka, M. A New Antitumor Antibiotic, FRꢀ66979. J. Antibiot. 1989, 42, 145–148. (g) Naoe, Y.;
Inami, M.; Kawamura, I.; Nishigaki, F.; Tsujimoto, S.; Matsumoto, S.; Manda, T.; Shimomura, K.
Cytotoxic Mechanisms of FK317, a New Class of Bioreductive Agent with Potent Antitumor Activity.
Jpn. J. Cancer Res. 1998, 89, 666–672. (h) Naoe, Y.; Inami, M.; Matsumoto, S.; Nishigaki, F.;
Tsujimoto, S.; Kawamura, I.; Miyayasu, K.; Manda, T.; Shimomura, K. FK317: A Novel Substituted
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Dihydrobenzoxazine with Potent Antitumor Activity Which Does Not Induce Vascular Leak Syndrome.
Cancer Chemother. Pharmacol. 1998, 42, 31–36. (i) Masuda, K.; Nakamura, T.; Mizota, T.; Mori, J.;
Shimomura, K. Antitumor Activity and Hematotoxicity of a New, Substituted Dihydrobenzoxazine,
FK973, in Mice. Cancer Res. 1988, 48, 5172–5177.
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2
3
4
5
6
7
8
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(6) Young, I. S.; Kerr, M. A. A Homo [3 + 2] Dipolar Cycloaddition: The Reaction of Nitrones with
Cyclopropanes. Angew. Chem., Int. Ed. 2003, 42, 3023–3026.
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58
59
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(7) (a) Sibi, M. P.; Ma, Z.; Jasperse, C. P. Enantioselective Addition of Nitrones to Activated
Cyclopropanes. J. Am. Chem. Soc. 2005, 127, 5764–5765. (b) Kang, Y.ꢀB.; Sun, X.ꢀL.; Tang, Y. Highly
Enantioselective and Diastereoselective Cycloaddition of Cyclopropanes with Nitrones and Its
Application in the Kinetic Resolution of 2ꢀSubstituted Cyclopropaneꢀ1,1ꢀdicarboxylates. Angew. Chem.,
Int. Ed. 2007, 46, 3918ꢀ3921.
(8) Spirocyclopropyl oxindoles could serve as monoactivated DꢀA cyclopropanes for reaction design.
This is pioneered by Carreira et al in 1999, who successfully developed Lewis acidꢀcatalyzed annulation
of spirocyclopropyl oxindoles with imines, and applied this methodology for the total synthesis of
natural products. See: (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M. Facile,
Novel Methodology for the Synthesis of Spiro[pyrrolidinꢀ3,3'ꢀoxindoles]: Catalyzed Ring Expansion
Reactions of Cyclopropanes by Aldimines. Angew. Chem., Int. Ed. 1999, 38, 3186−3189. (b) Lerchner,
A.; Carreira, E. M. First Total Synthesis of (±)ꢀStrychnofoline via a Highly Selective RingꢀExpansion
Reaction. J. Am. Chem. Soc. 2002, 124, 14826−14827. (c) Meyers, C.; Carreira, E. M. Total Synthesis
of (ꢀ)ꢀSpirotryprostatin B. Angew. Chem., Int. Ed. 2003, 42, 694−696. (d) Marti, C.; Carreira, E. M.
Total Synthesis of (ꢀ)ꢀSpirotryprostatin B: Synthesis and Related Studies. J. Am. Chem. Soc. 2005, 127,
11505−11515; For a review: (e) Marti, C.; Carreira, E. M. Construction of Spiro[pyrrolidineꢀ3,3′ꢀ
oxindoles]ꢀRecent Applications to the Synthesis of Oxindole Alkaloids. Eur. J. Org. Chem. 2003, 2209–
2219.
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(9) Xu, P.ꢀW.; Liu, J.ꢀK.; Shen, L.; Cao, Z.ꢀY.; Zhao, X.ꢀL.; Yan, J.; Zhou, J. Diastereoꢀ and
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3
4
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Enantioselective [3 + 3] Cycloaddition of Spirocyclopropyl Oxindoles Using both Aldonitrones and
Ketonitrones. Nat. Commun. 2017, 8, 1619.
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(10) (a) Hong, L.; Wang, R. Recent Advances in Asymmetric Organocatalytic Construction of 3,3′ꢀ
Spirocyclic Oxindoles. Adv. Synth. Catal. 2013, 355, 1023–1052. (b) Singh, G. S.; Desta, Z. Y. Isatins
as Privileged Molecules in Design and Synthesis of Spiro Fused Cyclic Frameworks. Chem. Rev. 2012,
112, 6104−6155. (c) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas III, C. F. Organocatalytic Asymmetric
Assembly Reactions: Synthesis of Spirooxindoles via Organocascade Strategies. ACS Catal. 2014, 4,
743−762. (d) Lin, L.; Feng, X. Recent Progress in Enantioselective Synthesis of C3ꢀFunctionalized
Oxindoles: Rare Earth Metals Take Action. Chem. Sci. 2012, 3, 327−334. (e) Zhou, F.; Liu, Y.ꢀL.;
Zhou, J. Catalytic Asymmetric Synthesis of Oxindoles Bearing a Tetrasubstituted Stereocenter at the Cꢀ
3 Position. Adv. Synth. Catal. 2010, 352, 1381–1407. (f) Cao, Z.ꢀY.; Zhou, J. Org. Chem. Front. 2015,
2, 849–858.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) Young, I. S.; Kerr, M. A. ThreeꢀComponent Homo 3 + 2 Dipolar Cycloaddition. A Diversityꢀ
Oriented Synthesis of Tetrahydroꢀ1,2ꢀoxazines and FR900482 Skeletal Congeners. Org. Lett. 2004, 6,
139–141.
(12) (a) Young, I. S.; Kerr, M. A. Total Synthesis of (+)ꢀNakadomarin A. J. Am. Chem. Soc. 2007,
129, 1465ꢀ1469. (b) Carson, C. A.; Kerr, M. A. Total Synthesis of (+)ꢀPhyllantidine. Angew. Chem., Int.
Ed. 2006, 45, 6560–6563. (c) Young, I. S.; Williams, J. L.; Kerr, M. A. Diastereoselective Synthesis of
Pyrrolidines Using a Nitrone/Cyclopropane Cycloaddition: Synthesis of the Tetracyclic Core of
Nakadomarin A. Org. Lett. 2005, 7, 953–955. (d) Dias, D. A.; Kerr, M. A. Domino Synthesis of Bridged
Bicyclic Tetrahydroꢀ1,2ꢀoxazines: Access to Stereodefined 4ꢀAminocyclohexanols. Org. Lett. 2009, 11,
3694–3697. (e) Ganton, M. D.; Kerr, M. A. Magnesium Iodide Promoted Reactions of Nitrones with
Cyclopropanes: A Synthesis of Tetrahydroꢀ1,2ꢀoxazines. J. Org. Chem. 2004, 69, 8554ꢀ8557.
(13) Review: (a) Cao, Z.ꢀY.; Zhou, F.; Zhou, J. Development of Synthetic Methodologies via Catalytic
Enantioseꢀlective Synthesis of 3,3ꢀDisubstituted Oxindoles. Acc. Chem. Res. 2018, 51, 1443–1454.
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