Novel isoxazolinyl spiropyrrolidinediones: 1,3-dipolar cycloaddition of 1-benzyl-3,3-dimethyl-5-methylenepyrrolidin-2,4-dione

Article abstract of DOI:10.1055/s-0030-1259926

A simple and highly efficient methodology for the first synthesis of isoxazolinyl spiropyrrolidinedione starting from keto ester, is presented. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259926

1154
LETTER
Novel Isoxazolinyl Spiropyrrolidinediones: 1,3-Dipolar Cycloaddition of
1-Benzyl-3,3-dimethyl-5-methylenepyrrolidin-2,4-dione
N
ovel Isoxazoliny
a
l
Spiropyrro
s
lidinedio
enes r Bathich, Sharifah Edayu binti Syed Monudeen Khan, Ahmad Sazali Hamzah*
Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi Mara, 40450 Shah Alam, Selangor, Malaysia
Fax +60(3)55443870; E-mail: bathich@gmail.com; E-mail: asazali@salam.uitm.edu.my
Received 9 February 2011
the best of our knowledge, none of these investigations
have been reported previously.
Abstract: A simple and highly efficient methodology for the first
synthesis of isoxazolinyl spiropyrrolidinedione starting from keto
ester, is presented.
Some of the isoxazolinyl spiropyrrolidinediones, (i.e., 11
and 12) were tested and demonstrated a unique selective
toxicity against the human lymphoma U937 cell line. In
contrast no similar effects were observed against neuro-
blastoma (SH-SY5Y), lung cancer (A549), leukaemia
(HL-60), neuron phenotypic cells (differentiated SH-
SY5Y), and normal lung (Hs888Lu) cell lines when ex-
posed to concentrations of synthetic spiroisoxazoline up
to 400 mM for 24 hours. The results showed that 11 and 12
were not toxic to the neuron cells, and 12 was able to pro-
tect against cell loss induced by H2O2. Thus this com-
pound may have a significant role towards the prevention
of neurodegenerative disease.8
Key words: spiroisoxazoline, 1,3-dipolar cycloaddition, spiropyr-
rolidine-2,4-dione, isoxazolinyl spiropyrrolidinedione, bioactivity
A series of spiroisoxazoline natural products, such as
aerothionin, homoaerothionin1, caissarine B (Figure 1),2
fistularin,3 calafianin,3 and their congeners have been iso-
lated from marine sponges,5 and were reported to show
significant bioactivity, mainly antimicrobial and cyto-
toxic activities. In addition, antihistamine activity of
archerine4 and K, Na-ATPase inhibitory activity of
ianthesin C were also reported.5
Protected pyrrolidine-2,4-dione 6 was obtained in three
steps using 3 as the starting material. Dimethylation of 3
was carried out using MeI and KeCO3 in the presence of
ionic liquid (bmimBF4) as the catalyst giving product 4 in
high yield.9 Initial dialkylation reaction using NaOMe and
MeI in methanol gave a very low yield of product 4.10
Halogenation of the methyl ketone 4 using CuBr211 gave
compound 5 which was immediately treated (without pu-
rification) with benzyl amine to give 6 via intercyclization
reaction (Scheme 1).12
O
O
(R)n
N
H
N
N
H
N
O
O
OH
Br
HO
Br
Br
Br
OMe
OMe
Figure
1
Structures of aerothionin (n = 4), homoaerothionin
(n = 5), caissarin B, fisturalin, calafianin3b
K2CO3, MeI
CuBr2
These spiroisoxazolines display a wide range of biologi-
cal activities, such as microbial, cytotoxic, and inflamma-
tory activities. Accordingly, many research groups have
recognized spiroisoxazoline natural products as attractive
synthetic targets.6
OMe
OMe
EtOAc
97% (crude)
(bmim)BF4
81%
O
O
O
O
4
3
O
These recent observations and the strong herbicidal activ-
ity of spirocyclic lactams, coupled with the absence of
toxicity to microorganisms,7 have stimulated our interest
in the synthesis of other spirocyclic derivatives.
Ph
N
PhCH2NH2
THF, 47%
OMe
Br
O
O
O
5
6
In the course of our research on a new route for the asym-
metric synthesis of dysidamide C, which exhibits neuro- Scheme 1 Preparation of dimethylpyrrolidin-2,4-dione 6
toxic effects towards both mesencephalic and cortical
murine neurons at 0.8 mg/mL,1d,e we investigated the 1,3-
With compound 6 in our hands, our synthetic approaches
for the synthesis of dysidamide C require an insertion of a
dipolar cycloaddition of the pyrrolidin-2,4-dione 7 to a
variety of alkyl and arylnitrile oxides, to form isoxazo-
methylene group at C-5. We first employed Eschen-
lines spiro-fused through C-5 to pyrrolidin-2,4-dione. To
moser’s protocol but this failed to give the required prod-
uct 7.13 Fortunately, this transformation was successfully
achieved by employing diisopropylamine and formalde-
hyde giving product 7 in high yield (Scheme 2).
SYNLETT 2011, No. 8, pp 1154–1156
Advanced online publication: 29.03.2011
DOI: 10.1055/s-0030-1259926; Art ID: B03811ST
x
x.
x
x.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Isoxazolinyl Spiropyrrolidinediones
1155
O
O
Ph
Ph
N
N
(i-Pr)2NH
HCOH
THF, 78%
O
O
6
7
Scheme 2 Preparation of 5-methylenepyrrolidin-2,4-dione 7 by in-
sertion of a methylene group at C-5
Since 2-isoxazolines (4,5-dihydroisoxazoles) are present
in many natural products,14 we have a renewed interest in
synthesizing them via the 1,3-dipolar cycloaddition of ni-
trile oxides to alkenes. Cycloaddition of variety of achiral/
chiral nitrile oxides with the 5-methylene-5,5-dimeth-
ylpyrolidine-2,4-dione 7 proceeds under the formation of
a novel spiroisoxazolines 11–17 (Table 1). The exact con-
figuration of the spiroisoxazolines 12, 13a was confirmed
by means of X-ray crystal structure determination15
(Figure 2).
Figure 2 X-ray crystal structure of compound 12
Table 1 Yields and Melting Point Values of Spiroisoxazolines 11–
17 Prepared
In summary, we have developed a mild and operationally
simple procedure for the synthesis of novel spiroisoxazo-
lines of a range of chiral and achiral hydroximoyl chlo-
rides. In particular, it was shown that spiroisoxazolines
are highly useful precursors for targets containing tertiary
and quartenary amine-bearing stereocentres; this should
be beneficial in the future for synthesis of interesting
branched b-amino acid compounds.
Cl
R
N
, Et3N
O
HO
O
N
R
N
Et2O
O
N
O
O
7
11–17
Compound
R
Yield (%) Mp (°C)
Typical Procedure for the 1,3-Dipolar Cycloaddition Key Step
To 7 (1.0 g, 4.36 mmol) of 7 in Et2O (100 mL) ethyl chlorooxim-
idoacetate (800 mg, 5.28 mmoL, 1.2 equiv) was added with stirring
at 0 °C. To this reaction mixture Et3N solution (0.5 M, 10.56 mL,
5.28 mmol, 1.2 equiv) in Et2O was added dropwise with a rate of 8–
10 drops per min, and then kept stirring overnight.
11
76
61
92–93
O
12
13
99–100
The mixture was quenched with HCl (50 mL, 1.0 M), partitioned
against Et2O (3 × 50 mL), and the combined organic phases were
washed with sat. NaHCO3 (50 mL), H2O (2 × 50 mL), and then
dried (MgSO4), filtered, and concentrated to give 1.60 g of crude
yellowish oil. The oil was purified using column chromatography
(SiO2, 2 cm × 15 cm column, PE–EtOAc = 9:1 gradient to 7:3) and
gave 910 mg (61%) of compound 12 after crystallization from Et2O
as colourless crystals (mp 99–100 °C). The structure of 12 was con-
firmed by X-ray crystallography.
O
75
130–131
O
O
14
15
75
84
123–124
135–136
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
OMe
Acknowledgment
We are grateful to the Ministry of Higher Education (MOHE) and
Universiti Teknologi MARA for financial support.
16
17
65
81
96–97
111–112
Synlett 2011, No. 8, 1154–1156 © Thieme Stuttgart · New York

1156
Y. Bathich et al.
LETTER
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