Synthesis of spiro[indolizidine-1,3′-oxindole] from L-glutamic acid

Article abstract of DOI:10.1016/j.tet.2020.131261

Spiro[indolizidine-1,3′-oxindole] compounds have been synthesized in enantiomerically pure form from L-glutamic acid. The key oxidative ring contraction of chiral indolo[2,3-a]quinolizidinone was achieved by treatment with N-bromosuccinimide in tetrahydrofuran/water in the presence of catalytic trifluoroacetic acid. The stereochemistry of the reaction was controlled by the dibenzylamino group which could be subsequently removed using Cope elimination.

Full text of DOI:10.1016/j.tet.2020.131261

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of spiro[indolizidine-1,30-oxindole] from
-glutamic acid
L
Punlop Kuntiyong*, Nantachai Inprung, Kunita Phakdeeyothin, Artid Buaphan,
Kittisak Thammapichai
Department of Chemistry, Faculty of Science, Silpakorn University, Sanamchandra Palace, Muang Nakhon Pathom, 73000, Thailand
a r t i c l e i n f o
a b s t r a c t
Spiro[indolizidine-1,30-oxindole] compounds have been synthesized in enantiomerically pure form from
Article history:
Received 9 March 2020
Received in revised form
30 April 2020
Accepted 5 May 2020
Available online xxx
L
-glutamic acid. The key oxidative ring contraction of chiral indolo[2,3-a]quinolizidinone was achieved by
treatment with N-bromosuccinimide in tetrahydrofuran/water in the presence of catalytic trifluoroacetic
acid. The stereochemistry of the reaction was controlled by the dibenzylamino group which could be
subsequently removed using Cope elimination.
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
Spiro[indolizidine-oxindole]
Enantiomerically pure
Synthesis
L-glutamic acid
Oxidative rearrangement
1. Introduction
approach. For examples Martin’s synthesis of rhynchophylline in
2006 and Sen’s synthesis of non-natural spiro-heterocyclic scaf-
Spirooxindole is an important class of natural alkaloids with a
diversity of structural variations and intriguing biological activities
[1]. Some of these alkaloids are found in native plants of Thailand
which have been used for medicinal purposes, such as rhyncho-
phylline (1) and mitraphylline (2) from Uncaria plants [2] and
Mitragyna speciosa ‘Kratom’ [3]. These alkaloids have been found to
be non-competitive NMDA antagonists and calcium channel
blockers affecting the cardiovascular and central nervous systems.
Spirooxindole-pyrrolidines have also been under investigation for
antiproliferation and cytotoxic activity, therefore they are potential
chemotherapeutic agents for cancers [4]. For example, spiro-
folds in 2015 [8,9]. However, in these reported works the
spiroindolizidine-oxindole systems were obtained in racemic form.
Alternative approaches were also reported such as Carreira’s con-
struction of spiropyrrolo-oxindole framework via MgI2-mediated
ring-expansion reaction of a spiro[cyclopropane-1,30-oxindole]
with an aldimine. The resolution of the racemic spiropyrrolo-
oxindole product was carried out for the completion of a total
synthesis of (ꢀ)-spirotryprostatin B [10]. Most recently in 2017,
Perez and Amat reported an enantioselective synthesis of spiro
[indolizidine-1,30-oxindoles] via a three step procedure consisting
of a stereoselective cyclocondensation reaction between (S)-tryp-
tryprostatin
B
(3) is
a
spiropyrrolo-oxindole with 2,5-
tophanol and a
rocyclization [11].
We have previously reported a synthesis of benzoquinolizidine,
and benzoindolizidine systems from -glutamic acid and L-aspartic
d-oxoester, bromination and stereoselective spi-
diketopiperazine moiety found in Aspergillus fumigatus fungus. It
exhibits cytotoxicity via antimitotic property [5]. Other non-natural
spiroindolizidine-oxindoles have also been reported to have inter-
esting biological activities (Fig. 1) [6].
L
acids, respectively [12]. The synthesis was based on diaster-
Synthesis of spiro[indolizidine-1,30-oxindole] can be achieved
biosynthetically by oxidative rearrangement of indolo[2,3-a]qui-
nolizidine. Several syntheses of spiroindolizidine-oxindole have
been reported both as racemic and enantioselective routes [7].
Some of the reported syntheses are based on the biomimetic
eoselective cyclization of chiral N-acyliminium ion and was applied
for synthesis of natural a-glucosidase inhibitors schulzeines B and C
as well as analogs of cytotoxic crispine A and a spiro-tetracyclic core
of Erythrina alkaloids [13,14].
2. Results and discussion
* Corresponding author.
E-mail address: kuntiyong_p@su.ac.th (P. Kuntiyong).
In our previous study, chiral N-indolylethylglutarimide 5 was
https://doi.org/10.1016/j.tet.2020.131261
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Kuntiyong et al., Synthesis of spiro[indolizidine-1,30-oxindole] from L-glutamic acid, Tetrahedron, https://doi.org/
10.1016/j.tet.2020.131261

2
P. Kuntiyong et al. / Tetrahedron xxx (xxxx) xxx
Scheme 2. Oxidative rearrangement of tetracyclic indoloquinolizidine 6.
to be removed at later stage of the synthesis. This requires multi-
step manipulations such as oxidation/decarboxylation or deoxy-
genation [15].
We first investigated oxidative rearrangement of diastereomeric
tetracyclic indoloquinolizidinones 6 and 7. Previously reported
spirocyclic formations via this method starting from indoloqui-
noizidinone with substituents on the lactam ring gave products
with low diastereoselectivity [9]. Treatment of 6 with N-bromo-
succinimide in aqueous THF in the presence of catalytic amount of
trifluoroacetic acid gave a mixture of spiro[indolizidine-1,30-oxin-
dole] 9 and brominated spirooxindole 10 (Scheme 2). The mixture
was not separable by chromatography and the existence of the
brominated product was determined by high resolution mass
spectrometry. The HRMS analysis found the exact mass of 452.2324
[MþH]þ and 532.1412 [MþH]þ for compounds 9 and 10, respec-
tively. The mixture was reacted with m-CPBA to give the corre-
sponding unsaturated lactams. Unfortunately, the products were
also inseparable. However, the different patterns of the aromatic
protons of the Cope elimination products of 9 and 10 became
clearly visible.
Next, we investigated the oxidative ring contraction of indolo-
quinolizidinone 7 using the same condition. Gratifyingly, the
product spiroindolizidine-oxindole 11 was obtained as a single
diastereomer. The relative configurations of the spiro[indolizidine-
1,30-oxindole] products were determined by NOESY experiments.
Interestingly, no brominated product was observed. Cope elimi-
nation of the dibenzylamino group upon treatment with m-CPBA in
chloroform was accomplished in 15 min giving the corresponding
enamide 12a. Prolonged reaction time resulted in epimerization of
the spiroindolizidine-oxindole core to give inseparable mixture of
diastereomeric spiroindolizidine-oxindole 12a and 12b (ca. 1:1
mixture after 48 h) (Scheme 3). Epimerization of spirooxindole has
been reported to occur via retro-Mannich/Mannich process in
acidic conditions [16].
Fig. 1. Spirooxindole alkaloids.
obtained from tryptamine and 1-benzyl N,N-dibenzyl glutamate via
amide formation and subsequent cyclization. In this work, an
improved route was established where glutarimide 5 was formed
directly from condensation of tryptamine and dimethyl N,N-
dibenzylglutamate (4), prepared in two steps from L-glutamic acid,
in the presence of LDA with THF as the solvent. Subsequent steps
proceeded according to our reported route in which the gluta-
rimide 5 was selectively reduced at the less hindered carbonyl. N-
acyliminium ion cyclization occurred upon treatment of the
hydroxylactam with TMSOTf to give two diastereomeric indolo-
quinolizidines 6 and 7 which were separable by column chroma-
tography (dr ¼ 1:2.3). The two diastereomers were converted to a
pair of enantiomers via Cope elimination of the dibenzylamino
group following the protection of the indole nitrogen as a Boc
carbamate (Scheme 1)[12].
The dibenzylamino group was used for stereocontrol and was
subsequently removed in a single step via Cope elimination to give
enamide functionality that is suitable for further steps in the syn-
thesis such as installation of substituents on the piperidine ring via
Michael addition and a-alkylation. Several syntheses of Corynanthe
and related spirocyclic alkaloids used tryptophan as the chiral
starting material and the carboxyl or hydroxymethylene group has
We rationalize the stereochemical outcomes of the reactions by
Scheme 1. Synthesis of indoloquinolizidines (þ)- and (¡)-8.
Scheme 3. Oxidative rearrangement of tetracyclic indoloquinolizidine 7.
Please cite this article as: P. Kuntiyong et al., Synthesis of spiro[indolizidine-1,30-oxindole] from L-glutamic acid, Tetrahedron, https://doi.org/
10.1016/j.tet.2020.131261

P. Kuntiyong et al. / Tetrahedron xxx (xxxx) xxx
3
Scheme 6. Oxidative rearrangement of indoloquinolizidine 14.
mixture made it a less attractive starting material. Next, we
endeavored in oxidative rearrangement of unsubstituted indolo-
quinolizidinone 8. Treatment of this compound with NBS in
aqueous THF and catalytic TFA did not yield any desired product.
Removal of the Boc protecting group was required and gave the
unsaturated indoloquinolizidinone 14. To our pleasant surprise,
oxidative rearrangement of this compound gave brominated
spiroindolizidine-oxindole 15 as a single product and single dia-
stereomer (Scheme 6).
Conformation analysis of tetracyclic enamide 14 reveals that the
molecule is also flat like indoloquinolizidine 6. However additional
steric bias arises from the C1 allylic b-proton of the unsaturated
lactam. Bromination of the indole ring occurred from the bottom
and subsequent addition of water and rearrangement gave
spiroindolizidine-oxindole as a single diastereomer. Electrophilic
aromatic bromination then occurred at the accessible C5 to give the
brominated product 15 (Scheme 7). The unsaturated lactam func-
Scheme 4. Stereochemistry of oxidative rearrangement of 6.
considering the conformation of the starting materials. The syn-
diastereomer 6 has a molecular structure that is rather flat and
there is little steric bias between the two diastereotopic faces of the
molecule. The initial bromination of the indole ring from either face
of the molecule leads to different diastereomers. Furthermore, C5 of
the resulting oxindole 13 is more accessible for electrophilic aro-
matic bromination and gave the brominated product 10 while C5 of
spirooxindole 9 is hindered in the concave face of the indolizidine
moiety (Scheme 4).
On the other hand, the oxidative ring contraction of diaste-
reomer 7 gave a single product as a single diastereomer. This is
explicable by the molecular shape of the molecule which appears to
be arched as shown in Scheme 5. The initial bromination step
occurred only on the convex side of the molecule leading to a single
diastereomer of spirooxindole 11. Electrophilic aromatic bromina-
tion was not observed due to the steric hindrance of the indolizi-
dine moiety (Scheme 5). This result is very satisfactory considering
that it has been reported that oxidative rearrangement of indolo-
quinolizidine with substituents on the quiolizidine moiety gave
spiroindolizidine-oxindole product with low diastereoselectivities
[9]. In addition we envision that conversion of dibenzylamino-
lactam to unsaturated lactam would be more synthetically useful
for introduction of other substituents in the form of nucleophiles
for Michael and hetero-Michael reactions.
tionality is suitable for installation of substituents at the
via nucleophilic conjugate addition and potentially at the
b
a
-carbon
-carbon
via either tandem a-alkylation of the resulting enolate or subse-
quent C-alkylation of the lactam. To demonstrate this strategy,
unsaturated spirolactam 15 was treated with sodium methoxide in
methanol to install methyl ether substituent on C2. Gratifyingly, the
product 16 was obtained as a single diastereomer. The new ster-
eogenic center has the R-configuration due to methoxide attack
The low diastereoselectivity of oxidative rearrangement of
indoloquinolizidine 6 and the inseparable nature of the product
Scheme 7. Stereochemistry of oxidative rearrangement of 14 and subsequent conju-
Scheme 5. Stereochemistry of oxidative rearrangement of 7.
gate addition.
Please cite this article as: P. Kuntiyong et al., Synthesis of spiro[indolizidine-1,30-oxindole] from L-glutamic acid, Tetrahedron, https://doi.org/
10.1016/j.tet.2020.131261

4
P. Kuntiyong et al. / Tetrahedron xxx (xxxx) xxx
from the re face of the enamide while the si face was blocked by the
oxindole ring.
3H), 4.13e4.01 (m, 1H), 4.08 (d, J ¼ 13.9 Hz, 2H), 3.91e3.78 (m, 2H),
3.68 (d, J ¼ 14.0 Hz, 2H), 3.37 (t, J ¼ 6.8 Hz, 1H), 2.48 (dd, J ¼ 12.6,
10.3 Hz, 1H), 2.06 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H), 1.88e1.74 (m, 2H),
1.55 (dd, J ¼ 13.6, 5.8 Hz, 1H), 1.19 (dd, J ¼ 13.6, 8.1 Hz, 1H); dC
(75 MHz, CDCl3) 177.9, 171.0140.4, 140.2 (2C), 129.8, 128.7, 128.6
(4C), 128.2 (4C), 126.8 (2C), 124.0, 122.9, 110.4, 63.3, 57.5, 56.0, 55.3,
3. Conclusion
In conclusion we have synthesized spiroindolizidine-oxindoles
11 and 15 diastereoselectively in enantiomerically pure form. The
spiroindolizidine-oxindole 11 has the amino substituent that can be
converted to other amine base functionality and potentially can be
utilized for synthesis of N-substituted analog of spiroindolizidine-
oxindole. Elimination of this group by Cope elimination led to un-
saturated spirolactam 12a. Oxidative ring contraction of tetracyclic
enamide 14 gave a single diastereomer of brominated spiroox-
indole 15 which has opposite absolute configurations to spiroox-
indole 12b. The enantiomer (ꢀ)-8 would give ent-15 making this
44.0, 33.3, 29.6, 25.1, 22.2; ½a 2D5
ꢃ
þ45.5 (c 1.1, CHCl3);
nmax (film)
3202, 2946, 2890, 1723, 1618, 1471, 1333, 1315, 818 cmꢀ1; ESI-HRMS
calculated for C29H30N3O2 [MþH]þ 452.2332, found 452.2324.
4.1.2. Spiro[indolizidine-1,30-oxindole] 12a
To a solution of benzoindolizidine 11 (301 mg, 0.66 mmol) in
CH2Cl2 (10 mL) at 0 ꢁC was added m-CPBA (70%w/w, 197 mg,
0.80 mmol) and the mixture was stirred for 15 min. To this mixture
was added sat. aq. Na2CO3 (10 mL) and the mixture was stirred for
15 min. The phases were separated and the organic layer was dried
(anhyd Na2SO4), filtered and concentrated under reduced pressure.
The crude product was purified by flash chromatography (silica gel,
1:2 hexane/EtOAc) to give enamide (þ)-12a (106 mg, 62%) as a
colorless oil; Rf (1:2 hexane/EtOAc) 0.20; dH (300 MHz, CDCl3) 8.06
(brs, 1H), 7.30 (td, J ¼ 7.7, 1.1 Hz, 1H), 7.14 (d, J ¼ 7.0 Hz, 1H), 7.10 (t,
J ¼ 7.7 Hz, 1H), 6.97 (d, J ¼ 7.7 Hz, 1H), 6.45 (ddd, J ¼ 9.8, 6.2, 2.0 Hz,
1H), 5.95 (dd, J ¼ 9.8, 2.9 Hz, 1H), 4.28 (dd, J ¼ 13.9, 5.7 Hz, 1H) 4.05
(dd, J ¼ 11.2, 10.5 Hz, 1H), 3.99 (ddd, J ¼ 10.7, 7.6, 7.6 Hz, 1H), 2.53
(dt, J ¼ 12.7, 10.5 Hz, 1H), 2.12 (ddd, J ¼ 12.5, 7.4, 1.3 Hz, 1H, 2.04 (dt,
J ¼ 17.5, 6.0 Hz, 1H), 1.84 (dddd, J ¼ 17.1, 14.2, 2.7, 2.7 Hz, 1H); dC
(75 MHz, CDCl3); 177.2, 163.9, 139.9, 138.3, 129.9, 128.8, 125.1, 124.6,
procedure enantiodivergent from the same starting material, L-
glutamic acid. The functionalities of spiroindolizidine-oxindole 15,
namely, aryl bromide, enamide and oxindole NH, provide points for
further functionalization and synthesis of analogs for biological
activity screening. The synthesis of the analogs and their biological
assay are ongoing in our laboratory and will be reported in due
course.
4. Experimental
4.1. General
Starting materials and reagents were obtained from commercial
sources and were used without further purification. Solvents were
dried by distillation from the appropriate drying reagents imme-
diately prior to use. Tetrahydrofuran and ether were distilled from
sodium and benzophenone under argon. Toluene, triethylamine,
and dichloromethane were distilled from calcium hydride under
argon. Moisture- and air-sensitive reactions were carried out under
an atmosphere of argon. Reaction flasks and glassware were oven-
dried at 105 ꢁC overnight. Unless otherwise stated, concentration
was performed under reduced pressure. Analytical thin-layer
chromatography (TLC) was conducted using Fluka precoated TLC
plates (0.2 mm layer thickness of silica gel 60 F-254). Compounds
were visualized by ultraviolet light and/or by heating the plate after
dipping in a 1% solution of vanillin in 0.1 M sulfuric acid in EtOH.
Flash chromatography was carried out using Scientific Absorbents
Inc. silica gel (40 mm particle size). Optical rotations were
measured with a PerkinElmer 243 polarimeter at ambient tem-
perature using a 0.9998 dm cell with 1 mL capacity. Infrared (IR)
spectra were recorded on a Nicolet 5DXB FT-IR spectrometer. Pro-
ton and carbon nuclear magnetic resonance (NMR) spectra were
obtained using a Bruker Avance-300 spectrometer. The ESI-HRMS
experiments were performed at the Chulabhorn Research Insti-
tute, Bangkok, Thailand, using Bruker Micro TOF mass
spectrometer.
123.2, 110.2, 62.4, 57.3, 43.6, 33.7, 25.3; ½a 2D5
þ20.5 (c 1.0, CHCl3);
ꢃ
n
max (film) 3204, 2926, 1720, 1655, 1471, 1336, 1228, 1155, 822,
795 cmꢀ1; ESI-HRMS calculated for C15H15N2O2 [MþH]þ 255.1134,
found 255.1126.
4.1.3. Indoloquinolizidine-enamide 14
To
a
solution of N-Boc-indoloquinolizidine-enamide (þ)-8
(260 mg, 0.77 mmol) in THF (10 mL) at 0 ꢁC was added TFA (0.12 mL,
1.54 mmol) and the mixture was stirred for 3 h. To this mixture was
added sat. aq. NaHCO3 (10 mL). The phases were separated and the
organic layer was dried (anhyd Na2SO4), filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (silica gel, 1:2 hexane/EtOAc) to give
indoloquinolizidine-enamide (þ)-14 (174 mg, 95%) as a colorless
oil; Rf (1:2 hexane/EtOAc) 0.50; dH (300 MHz, CDCl3); 7.91 (brs, 1H),
7.54 (d, J ¼ 7.5 Hz, 1H), 7.36 (d, J ¼ 7.5 Hz, 1H), 7.20 (t, J ¼ 7.5 Hz, 1H),
7.15 (t, J ¼ 7.5 Hz, 1H), 6.67 (ddd, J ¼ 9.8, 6.4, 2.4 Hz, 1H), 6.10 (dd,
J ¼ 9.8, 3.0 Hz, 1H), 5.03 (ddd, J ¼ 12.8, 4.6, 3.1 Hz, 1H), 4.89 (dd,
J ¼ 13.6, 4.7 Hz, 1H), 2.98e2.82 (m, 4H), 2.46 (dddd, J ¼ 16.6, 14.0,
2.6, 2.6 Hz, 1H); dC (75 MHz, CDCl3); 163.5, 136.7, 135.0, 130.9, 126.9,
125.6, 121.1, 118.1, 116.8, 109.8, 108.0, 50.0, 37.3, 29.7, 19.4;
½
a D25
ꢃ
þ50.0 (c 1.3, CHCl3);
nmax (film) 3261, 2847, 1656, 1599, 1325,
1303, 1138, 1056, 816 cmꢀ1; ESI-HRMS calculated for C15H14N2NaO
[MþNa]þ 261.0998, found 261.0996.
4.1.1. Spiro[6-dibenzylaminoindolizidine-1,30-oxindole] 11
To
a
solution of dibenzylamino-indoloquinolizidinone
7
4.1.4. Spiro[indolizidine-1,30-bromooxindole] 15
(452 mg, 1.04 mmol) in THF (10 mL) and H2O (10 mL) was added
NBS (407 mg, 2.20 mmol) in one portion. To this mixture was added
To a solution of indoloquinolizidinone 14 (160 mg, 0.67 mmol)
in THF (8 mL) and H2O (8 mL) was added NBS (263 mg, 1.48 mmol)
TFA (10
m
L) and the mixture was stirred for 16 h. Saturated aqueous
in one portion. To this mixture was added TFA (6 mL) and the
solution of NaHCO3 (10 mL) and EtOAc (10 mL) were added and the
phases were separated. The aqueous phase was extracted with
EtOAc (2 ꢂ 10 mL). The combined organic layers were dried (anh.
Na2SO4) and concentrated under reduced pressure. The crude
product was purified by flash chromatography (silica gel, 1:2 hex-
ane/EtOAc) to give the spiroindolizidine-oxindole 11 as colorless oil
(366 mg, 78%); Rf (1:2 hexane/EtOAc) 0.29; dH (300 MHz, CDCl3)
9.00 (s, 1H), 7.42 (d, J ¼ 7.2 Hz, 4H) 7.34e7.16 (m, 7H), 7.08e6.93 (m,
mixture was stirred for 16 h. Saturated aqueous solution of NaHCO3
(10 mL) and EtOAc (10 mL) were added and the phases were
separated. The aqueous phase was extracted with EtOAc
(2 ꢂ 10 mL). The combined organic layers were dried (anh. Na2SO4)
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (silica gel, 1:2 hexane/EtOAc) to
give the spiroindolizidine-bromooxindole 15 as a colorless oil
(163 mg, 73%); Rf (1:2 hexane/EtOAc) 0.20; dH (300 MHz, CDCl3)
Please cite this article as: P. Kuntiyong et al., Synthesis of spiro[indolizidine-1,30-oxindole] from L-glutamic acid, Tetrahedron, https://doi.org/
10.1016/j.tet.2020.131261

P. Kuntiyong et al. / Tetrahedron xxx (xxxx) xxx
5
8.81 (brs, 1H), 7.43 (dd, J ¼ 8.3, 1.9 Hz, 1H), 7.27 (d, J ¼ 1.9 Hz, 1H),
Acknowledgments
6.89 (d, J ¼ 8.3 Hz, 1H), 6.46 (ddd, J ¼ 9.8, 6.1, 2.0 Hz, 1H), 5.99 (dd,
J ¼ 9.8, 2.5 Hz, 1H), 4.26 (dd, J ¼ 14.0, 5.6 Hz, 1H), 4.07 (t, J ¼ 10.8 Hz,
1H), 3.92e3.80 (m, 1H), 2.53 (dt, J ¼ 12.7, 10.3 Hz, 1H), 2.13 (ddd,
J ¼ 12.9, 7.8, 1.6 Hz, 1H), 2.06 (dt, J ¼ 17.4, 5.7 Hz, 1H), 1.88 (dddd,
J ¼ 17.4, 14.2, 2.7, 2.7 Hz, 1H); dC (75 MHz, CDCl3) 174.8, 161.8, 137.0,
139.3, 136.1, 129.7, 129.6, 125.2, 122.9, 113.6, 109.6, 60.2, 55.4, 41.2,
The funding for this work is provided by the Thailand Research
Fund (TRF) grants RSA6180040, DBG6080007, The National
Research Council of Thailand (NRCT) grant 2562#11892 and the
Faculty of Science, Silpakorn University grant SRF-JRG-2561-05. The
Development and Promotion of Science and Technology Talents
(DPST) provides a scholarship for NI and the Science Achievement
Scholarship of Thailand (SAST) for KP. We would like to acknowl-
edge the Chulabhorn Research Institute for assistance with the ESI-
HRMS analyses.
31.4, 23.1; ½a D25
ꢃ
þ35.1 (c 1.1, CHCl3);
nmax (film) 3195, 3018, 2920,
2891, 1725, 1656, 1596, 1473, 1336, 1205, 1165, 823, 800 cmꢀ1; ESI-
HRMS calculated for C15H13BrN2NaO2 [MþNa]þ 355.0058, found
355.0053.
4.2. Spiro[7-methoxyindolizidine-1,30-bromooxindole] 16
Supplementary Material
To a solution of NaOMe in MeOH (26 mg of Na, 1.14 mmol, in
5 mL of MeOH) was added a solution of benzoindolizidine 15
(127 mg, 0.38 mmol) in MeOH (3 mL) at 0 ꢁC and the mixture was
stirred for 3 h. To this mixture were added sat. 1 N HCl (8 mL) and
CH2Cl2 (12 mL). The phases were separated and the organic layer
was dried (anhyd Na2SO4), filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(silica gel, 1:2 hexane/EtOAc) to give spiro[7-methoxyindolizidine-
1,30-bromooxindole] 16 (90 mg, 65%) as a colorless oil; Rf (1:2
hexane/EtOAc) 0.38; dH (300 MHz, CDCl3); 8.32 (brs, 1H), 7.41 (dd,
J ¼ 8.3, 2.0 Hz, 1H), 7.05 (d, J ¼ 1.7 Hz, 1H), 6.86 (d, J ¼ 8.3 Hz, 1H),
4.21 (dd, J ¼ 11.5, 3.6 Hz, 1H), 4.06e3.78 (m, 2H), 3.76e3.68 (m, 1H),
3.29 (s, 3H), 2.75e2.20 (m, 3H), 2.09 (ddd, J ¼ 12.9, 8.7, 2.0 Hz, 1H),
1.89 (ddd, J ¼ 13.7, 6.1, 3.6 Hz, 1H), 1.00 (td, J ¼ 13.7, 2.0 Hz, 1H); dC
(75 MHz, CDCl3); 175.2, 166.1, 137.5, 130.5, 130.1, 125.2, 114.3, 110.2,
Supplementary material containing nuclear magnetic resonance
(NMR) spectra of new compounds synthesized in this study are
available for online publication. Supplementary data associated
with this article can be found, in the online version, at.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131261.
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58.5, 55.5, 54.6, 42.3, 34.6, 31.5, 28.1, 25.8; ½a 2D5
ꢃ
-45.5 (c 0.4, CHCl3);
max (film) 3455, 2970, 2920, 2850, 1737, 1725, 1615, 1365, 1228,
n
1217, 1205, 1262, 764, 749 cmꢀ1
; ESI-HRMS calculated for
C
16H18BrN2O3 [MþH]þ 365.0501, found 365.0495.
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Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
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Please cite this article as: P. Kuntiyong et al., Synthesis of spiro[indolizidine-1,30-oxindole] from L-glutamic acid, Tetrahedron, https://doi.org/
10.1016/j.tet.2020.131261