Oxonium ion-mediated synthesis of 4-substituted spiro-isoxazolines

Article abstract of DOI:10.1016/j.tetlet.2008.11.053

The stereoselective synthesis of 4-bromo-spiro-isoxazolines was achieved in one step through the bromination of various isoxazoles that contain a pendant alcohol or carboxylic acid functional group. Isoxazole bromination leads to a bromonium ion intermedi

Full text of DOI:10.1016/j.tetlet.2008.11.053

Tetrahedron Letters 50 (2009) 533–535
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxonium ion-mediated synthesis of 4-substituted spiro-isoxazolines
Eric McClendon a, Ann O. Omollo a, Edward J. Valente b, Ashton T. Hamme II a,
*
a Department of Chemistry, College of Science, Engineering and Technology, Jackson State University, Jackson, MS 39217, USA
b Department of Chemistry and Biochemistry, Mississippi College, Clinton, MS 39058, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of 4-bromo-spiro-isoxazolines was achieved in one step through the bro-
mination of various isoxazoles that contain a pendant alcohol or carboxylic acid functional group. Isox-
azole bromination leads to a bromonium ion intermediate, which opens either by neighboring oxygen
lone pair electrons or by intramolecular nucleophilic attack. Single X-ray crystal data provide evidence
that the two contiguous stereocenters of the spiro-isoxazoline are formed by the anti intramolecular
attack of the nucleophile relative to bromine, since there is an anti stereochemical relationship between
the spirocyclic ring oxygen and the bromine atom.
Received 17 October 2008
Revised 12 November 2008
Accepted 17 November 2008
Available online 20 November 2008
Keywords:
Intramolecular cyclization
Cycloaddition
Published by Elsevier Ltd.
Stereoselectivity
Regioselectivity
Heterocycles
Spirocycles
Spiro-isoxazolines are found in a number of natural products,1
and due to their biological activity,1a,c–f,2 many compounds within
the psammaplysin and ceratinamide families have the potential to
serve as a structural template that could lead to synthetic analogues
that target a variety of diseases. The spiro-isoxazoline ring core is
the central structural feature within the aforementioned natural
products, and only a few publications address the synthesis of this
unique ring system.3,4 In the psammaplysin natural products, the
oxepine oxygen and the 4-hydroxy group on the isoxazoline are anti
to each other. A synthetic methodology that provides a stereoselec-
tive construction of spiro-isoxazolines that mimic the stereochem-
ical features of the psammaplysin natural product is warranted.
Herein, we report the application of an oxonium-mediated stereo-
selective intramolecular cyclization of a brominated isoxazole
intermediate by a pendant alkoxide or carboxylate ion (Fig. 1).
Since the spiro-isoxazoline of the psammaplysin family of nat-
ural products contains an isoxazoline ring that has a substituent
on the 4-position, the exploration of the possibility of reacting an
isoxazole possessing a pendant nucleophilic functional group with
an electrophile was performed in order to determine if an intramo-
lecular cyclization would take place.5 Our retrosynthetic rationale
is depicted in Scheme 1.
R1 = R2 = H Psammaplysin A
R
R
R
1 = OH, R2= H Psammaplysin B
Br
1 = OH, R2 = CH3 Psammaplysin C
1 = H, R2 = CO(CH2)11CH(CH3)2 Psammaplysin D
H3CO
Br
O
O
O
N
R1
H
N
R1 = H, R2
=
Psammaplysin E
Br
HO
R2
O
O
N
H
O
R
R
1 = H, R2 = CH3 Psammaplysin F
1 = H, R2 = CHO Ceratinamide A
R1 = H, R2 = CO(CH2)11CH(CH3)2 Ceratinamide B
Br
Figure 1. Psammaplysin and ceratinamide family of natural products.
* Corresponding author. Tel.: +1 601 979 3713; fax: +1 601 979 3674.
E-mail address: ashton.t.hamme@jsums.edu (A. T. Hamme II).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.11.053

534
E. McClendon et al. / Tetrahedron Letters 50 (2009) 533–535
O
N
X
C
OH
N
E
O
E+
X
O
( )n
X
OH
( )n
( )n
N
n = 0,1
X = O, H2
O
n = 0,1
n = 0,1
H
X = O, H2
X = O, H2
Scheme 1. Retrosynthetic analysis of 4-bromo-substituted spiro-isoxazolines.
HO
N
OH
( )n
Cl
N
H
N
O
Br3
O
( )n
(C2H5)3N, CH2Cl2
OH
K2CO3, CH2Cl2
Br
N
( )n
H
O
5, n = 0, 71%
6, n = 1, 62%
Single Diastereomer
3, n = 1, 88%
4, n = 2, 56%
1, n = 1
2, n = 2
Scheme 2. Synthesis of furan and pyran-based spiro-isoxazolines.
HO
N
O
H
OH
( )n
Cl
N
H
N
Br3
O
O
O
(C2H5)3N, CH2Cl2
OH
K2CO3, CH2Cl2
Br
( )n
N
( )n
O
11, n = 0, 61%
12, n = 1, 67%
Single Diastereomer
O
9, n = 1, 72%
10 n = 2, 83%
7, n = 1
8, n = 2
Scheme 3. Synthesis of lactone containing spiro-isoxazolines.
In order to test our hypothesis, alkyne 1 was reacted with the
nitrile oxide that was generated in situ from the base-promoted
reaction of
a-chlorobenzaldoxime with triethyl amine to afford
isoxazole6 (3) regioselectively.7 Spiro-isoxazolines 5 and 6 were
effectively formed as single diastereomers upon the respective
treatment of 3 and 4 with pyridinium tribromide (Scheme 2).
Extension of this methodology to the synthesis of spiro-isoxaz-
olines with an inherent lactone ring system commenced from the
1,3-dipolar cycloaddition of 7 with the nitrile oxide from a-chloro-
benzaldoxime to afford 9.4,8 Pyridinium tribromide-promoted spi-
rolactonization of 9 stereoselectively afforded 11 as shown in
Scheme 3.9 Spiro-isoxazoline (12) was also obtained in an analo-
gous manner. Compound 12 was also assembled as a single isomer
based upon the NMR of the unpurified material. Fortunately, com-
pound 11 was a crystalline solid, and X-ray crystallographic analy-
sis of 11 showed that the bromine and the lactone oxygen are anti
to each other10 (Fig. 2). Based upon this stereochemical evidence, a
mechanism describing the formation of 11 is proposed in Scheme
4.
Figure 2. Thermal ellipsoid plot of the structure of 11.
In our proposed mechanism, bromination of carboxylate ion
(13) affords the bromonium ion intermediate (14). If intermediate
14 follows pathway A, oxonium ion intermediate (15) is formed.
Intramolecular cyclization of 15 by the carboxylate ion gives rise
to 11. Likewise, 14 can potentially follow route B where the bromo-
nium ion is directly attacked in an intramolecular fashion by the
carboxylate ion. In both pathways, the large bromine atom likely
controls the direction of nucleophilic attack to form the corre-
sponding spiro-isoxazoline, where the bromine and spirocyclic lac-
tone oxygen atom have an anti relationship.
In summary, this investigation shows the application of an oxo-
nium ion-mediated synthesis of 4-bromo-spiro-isoxazolines,
where two contiguous stereocenters are formed stereoselectively
through the bromination and intramolecular cyclization of isoxaz-
oles possessing a pendant alcohol or carboxylic acid. Future inves-
tigations involving the enantioselective synthesis of spiro-
isoxazolines with substituents other than bromine on the 4-posi-
tion, and a mechanistic theoretical study of the intramolecular
cyclization are currently underway.

E. McClendon et al. / Tetrahedron Letters 50 (2009) 533–535
535
N
H
Br Br
Br3
Br
A
O
Br
A
O
O
N
K2CO3, CH2Cl2
O
N
B
N
O
O
14
O
O
15
13
(oxonium ion)
B
O
Br
O
N
O
11
O
Scheme 4. Proposed mechanism for the stereoselective formation of compound 11.
reaction mixture was stirred at rt until the disappearance of the starting
materials, as evidenced by TLC. After the reaction was complete,
Acknowledgments
a
minimum amount of silica gel was added, and the solvent was evaporated
under reduced pressure. The crude products were purified by flash column
chromatography over silica gel using 1:1 hexanes–ethyl acetate ratio as an
eluant system.
We thank the National Institutes of Health RCMI program
(G12RR13459 (NMR and Analytical CORE facilities)) and the Na-
tional Science Foundation NSF-RISE program (HRD-0734645).
E.J.V. gratefully acknowledges the support of the National Science
Foundation grant MRI 0618148 and the W. M. Keck Foundation
for crystallographic resources.
8. General procedure for 1,3-dipolar cycloaddition of the alkynoic acid: Deionized
water (3.5 mL) was added into
a round-bottomed flask containing the
hydroximoyl chloride (6.5 mmol) with stirring. The alkynoic acid
(3.25 mmol) was added into this mixture. Potassium carbonate (4.88 mmol)
was then added in small portions. The reaction mixture was stirred at rt until
the reaction was complete as evidenced by TLC/NMR analysis. The reaction
mixture was acidified with 4 N HCl and treated with diethyl ether and water
(1:1, 20 mL). Sodium hydroxide was added to this mixture until the mixture
was basic (litmus paper). The mixture was extracted with diethyl ether
(3 Â 10 mL), and 4 M HCl was then added to the aqueous layer until the
solution was acidic (litmus paper). Extraction of the acidified aqueous layer
with ethyl acetate (3 Â 15 mL), and the resulting organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure to provide the crude
product which was purified via column chromatography over silica gel using
1:1 hexanes–ethyl acetate ratio as an eluant system.
References and notes
1. (a) Rotem, M.; Carmely, S.; Kashman, Y.; Loya, Y. Tetrahedron 1983, 39, 667; (b)
Roll, D. M.; Chang, C. W. J.; Schueuer, R. J.; Gray, G. A.; Shoolery, J. N.;
Matsumoto, G. K.; VanDuyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1985, 107, 2916;
(c) Copp, B. R.; Ireland, C. M. J. Nat. Prod. 1992, 55, 822; (d) Ichiba, T.; Scheuer, P.
J. Org. Chem. 1993, 58, 4149; (e) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N.
Tetrahedron 1996, 52, 8181; (f) Liu, S.; Fu, X.; Schmitz, F. J.; Kelly-Borges, M. J.
Nat. Prod. 1997, 60, 614.
9. General procedure for bromination/intramolecular cyclization: A solution of the
isoxazole (2 mmol) and K2CO3 (4 mmol) in 5 mL of dry dichloromethane was
stirred in an ice-water bath. Pyridinium tribromide (4 mmol) was added slowly
to the cold mixture. The reaction mixture was stirred for 2 h at 0 °C, and was
allowed to slowly warm to rt overnight. The reaction mixture was stirred at rt
until the disappearance of the starting materials, as evidenced by TLC. The
reaction mixture was poured into a cold, saturated NH4Cl solution (5 mL),
extracted with ethyl acetate (3 Â 10 mL), and washed with saturated CuSO4
solution (3 Â 10 mL). The organic layer was dried with MgSO4, filtered, and
concentrated under reduced pressure. The crude products were purified by
flash column chromatography over silica gel using the appropriate hexanes–
ethyl acetate ratio as an eluant system.
2. (a) Nicholas, G. M.; Eckman, L. L.; Newton, G. L.; Fahey, R. C.; Ray, S.; Bewley, C.
A. Bioorg. Med. Chem. 2003, 11, 601; (b) Nicholas, G. M.; Eckman, L. L.; Ray, S.;
Hughes, R. O.; Pfefferkorn, J.; Barluenga, S.; Nicolaou, K. C.; Bewley, C. A. Bioorg.
Med. Chem. Lett. 2002, 12, 2487.
3. (a) Smietana, M.; Gouverneur, V.; Mioskowski, C. Tetrahedron Lett. 1999, 40,
1291; (b) Colinas, P. A.; Jager, V.; Lieberknecht, A.; Bravo, R. D. Tetrahedron Lett.
2003, 44, 1071; (c) Okamoto, K. T.; Clardy, J. Tetrahedron Lett. 1987, 28, 4969.
4. D’Alcontres, G. S.; Caristi, C.; Ferlazzo, A.; Gattuso, M. J. Chem. Soc., Perkin Trans.
1 1976, 1694.
5. Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2001, 40, 4709.
6. De, D.; Seth, M.; Bhaduri, A. P. Ind. J. Chem. Sec. B. Org. Chem. Including Med.
Chem. 1990, 29B, 231.
10. Structural information for 11 has been deposited with the CCDC as 695718,
available free of charge from www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033).
7. General procedure for 1,3-dipolar cycloaddition of the alkynol: A solution of the
alkynol (3 mmol) and the hydroximoyl chloride (3 mmol) in 10 mL of
dichloromethane was treated with triethylamine (0.46 mL, 3.3 mmol). The