Solid-phase synthesis of novel isoxazolocyclobutanones and isoxazolinocyclobutenones

Article abstract of DOI:10.1021/ol017194n

(equation presented) The preparation of novel isoxazolocyclobutanone and isoxazolinocyclobutenone derivatives via a traceless solid-phase sulfone linker strategy is described. Key steps in the solid-phase protocol reported here include (i) sulfinate → sul

Full text of DOI:10.1021/ol017194n

ORGANIC
LETTERS
2002
Vol. 4, No. 5
741-744
Solid-Phase Synthesis of Novel
Isoxazolocyclobutanones and
Isoxazolinocyclobutenones
Wei-Chieh Cheng, Melissa Wong, Marilyn M. Olmstead, and Mark J. Kurth*
Department of Chemistry, UniVersity of California, One Shields AVenue,
DaVis, California 95616-5295
mjkurth@ucdaVis.edu
Received December 8, 2001
ABSTRACT
The preparation of novel isoxazolocyclobutanone and isoxazolinocyclobutenone derivatives via a traceless solid-phase sulfone linker strategy
is described. Key steps in the solid-phase protocol reported here include (i) sulfinate f sulfone alkylation, (ii) four-member ring formation by
sulfone dianion alkylation, (iii) heterocycle formation by nitrile oxide 1,3-dipolar cycloaddition, and (iv) traceless product release by cyclobutanol
f cyclobutanone oxidation with concomitant linker cleavage by sulfinate elimination.
An important objective in solid-phase organic synthesis
(SPOS)1 is the development of chemistries applicable to
combinatorial techniques not limited by the tether and where
target molecules can be efficiently cleaved from the resin
by a specialized reagent or transformation.2 In this regard,
one of our goals has been to develop sulfone linkers for
SPOS and to explore sulfone-based chemical transformations
and cleavage strategies.3-5 Previous reports from our
laboratories3a,4,5 as well as others6 have detailed the use of a
sulfinate-functionalized resin (styrene/divinyl benzene co-
polymer beads ) b) as the starting point for these strategies.
The sulfone linkers derived from this sulfinate resin provide
tethers robust to various chemical transformations and
“traceless” when cleaved under appropriate conditions
(Figure 1).4,5 Herein, we report extension of this sulfone-
based chemistry to the synthesis of isoxazolocyclobutanones
and isoxazolinocyclobutenones.
(1) (a) Ellman, J. A. Acc. Chem. Res. 1996, 29, 132. (b) Lorsbach, B.
A.; Kurth, M. J. Chem. ReV. 1999, 99, 1549. (c) Sammelson, R. E.; Kurth,
M. J. Chem. ReV. 2001, 101, 137. (d) Hall, D. G.; Manku, S.; Wang, F. J.
Comb. Chem. 2001, 3, 125. (e) Dolle, R. E.; Nelson, K. H. J. Comb. Chem.
1999, 1, 235. (f) Wang, J.; Ramnarayan, K. J. Comb. Chem. 1999, 1, 524.
(2) (a) Franzen, R. G. J. Comb. Chem. 2000, 2, 195. (b) Booth, S.;
Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1998,
54, 15385. (c) Brown, R. C. D. J. Chem. Soc., Perkin Trans. 1 1998, 3293.
(d) Yan, B. Acc. Chem. Res. 1998, 31, 621. (e) Kantorowski, E. J.; Kurth,
M. J. Mol. DiVersity 1997, 2, 207.
(3) (a) Halm, C.; Evarts, J. B.; Kurth, M. J. Tetrahedron Lett. 1997, 38,
7709. (b) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996,
29, 144. (c) Terrett N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.;
Steele, J. Tetrahedron, 1995, 51, 8135.
(4) Cheng, W.-C.; Halm, C.; Evarts, J. B.; Olmstead, M. M.; Kurth, M.
J. J. Org. Chem. 1999, 64, 8557.
Key steps in the protocol reported here include (i) sulfinate
(1)4,7 f sulfone alkylation, (ii) four-member ring formation
by sulfone dianion alkylation of epichlorohydrin,8 (iii)
heterocycle formation by nitrile oxide 1,3-dipolar cycload-
(6) (a) Farrall, M. J.; Frechet, J. M. J. Org. Chem. 1976, 41, 3877. (b)
Fyles, T. M.; Leznoff, C. C. Can J. Chem. 1976, 54, 935. (c) Fyles, T. M.;
Leznoff, C. C. Can J. Chem. 1978, 56, 1031.
(7) The preparation of PS/DVB sulfinate (1) was similar to that in ref 4
except the reaction was quenched by HCl (6 N) and the polymer was treated
with K2CO3(aq) in DMF after the polymer was washed with THF, MeOH,
THF/H2O (80:20), THF, and ether.
(8) (a) Na´jera, C.; Sansano, J. M. Tetrahedron Lett. 1992, 33, 6543. (b)
Pascali, V.; Umani-Ronchi, A. J. Chem. Soc., Chem. Commun. 1973,
351.
(5) Cheng, W.-C.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 2001,
66, 5528.
10.1021/ol017194n CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/12/2002

been used extensively to modulate various biologically active
motifs.12 As reported here, we have also demonstrated reagent
versatility in steps (i) and (iii) suggesting this protocol is
suitable for library generation.
Solution-Phase Isoxazolocyclobutanone Synthesis. In a
preliminary solution-phase study (Scheme 1), treatment of
Scheme 1. Solution-Phase Studies
Figure 1. Traceless sulfone linker strategies.
dition,9 and (iv) traceless product release by cyclobutanol
f cyclobutanone oxidation with concomitant linker cleavage
by sulfinate elimination (Figure 2). The resulting products
Figure 2. Sulfinate SPOS route to cyclobutanones and cyclobuten-
ones.
allyl phenyl sulfone with o-methoxybenzaldehyde oxime and
NaOCl (the Huisgen method13 for in situ nitrile oxide
generation) gave isoxazolinosulfone 2 in good yield (80%).
Attempts to R-alkylate this isoxazolinosulfone (LDA or
nBuLi in THF) resulted only in decomposition. Likewise,
treating allyl phenyl sulfone with LDA followed by addition
of propylene oxide resulted in vinyl sulfone 4 as the sole
product instead of the anticipated allyl sulfone 3. These
observations led us to investigate first effecting sulfone R,R-
dialkylation (i.e., cyclobutyl formation) and then proceeding
with the 1,3-dipolar cycloaddition. Thus, 3-benzensulfonyl-
3-vinylcyclobutanol (5)4 was reacted with p-methoxyben-
zaldehyde oxime and NaOCl to give 1,3-dipolar cycloadduct
6 in 81% yield. On the basis of our experience14 and others,15
we were not surprised to find that 1,3-dipolar cycloaddition
(12/15/18) may provide useful molecular scaffolds for library
production10 as four-member ring-containing compounds are
both prevalent in nature and useful as building blocks for
further transformations.11 Moreover, these SPOS products
contain isoxazoline or isoxazole heterocycles, which have
(9) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984; Vols. 1 and 2.
(10) (a) Fauchere, J. L.;, Henlin, J. M.; Boutin, J. A. Analysis 1997, 25,
97. (b) Neustadt, B. R.; Smith, E. M.; Nechuta, T.; Zhang, Y. Tetrahedron
Lett. 1998, 39, 5317. (c) Pryor, K. E.; Shipps, W., Jr.; Skyler, D. A.; Rebek,
J., Jr. Tetrahedron 1998, 54, 4107. (d) del Fresno, M.; Alsina, J.; Royo,
M.; Barany, G.; Albericio, F. Tetrahedron Lett. 1998, 39, 2639.
(11) (a) Nemoto, H.; Fukumoto, K. Synlett 1997, 863. (b) Okuma, K.;
Tsubakihara, K.; Tanaka, Y.; Koda, G. Tetrahedron Lett. 1995, 36, 5591.
(c) Frimer, A.; Weiss, J.; Gottlieb, H.; Wolk, J. J. Org. Chem. 1994, 59,
780. (d) Dzhemilev, U. M.; Khusnutdinov, R. I.; Tolstikov, G. A. J.
Organomet. Chem. 1991, 409, 15. (e) Lee-Ruff, E. AdV. Strain Org. Chem.
1991, 1, 167. (d) Oppolzer, W. Acc. Chem. Res. 1982, 15, 135. (e) Moore,
H. W.; Yerxa, B. R. AdV. Strain Org. Chem. 1995, 4, 81. (f) Bellus, D.;
Ernst, B. Angew. Chem., Int. Ed. Engl. 1988, 27, 797. (g) Danheiser, R. L.;
Gee, S. K.; Perez, J. J. J. Am. Chem. Soc. 1986, 108, 806. (h) Kowalski, C.
J.; Lal, G. S. J. Am. Chem. Soc., 1988, 110, 3693. (I) Allan, R. D.; Hanrahan,
J. R.; Hambley, T. W.; Johnston, G. A.; Mewett, K. N.; Mitrovic, A. D. J.
Med. Chem. 1990, 33, 2905.
(12) (a) Khalil, M. A.; Maponya, M. F.; Ko, D.-H.; You, Z.; Oriaku, E.
T.; Lee, H. J. Med. Chem. Res. 1996, 6, 52. (b) Groutas, W. C.;
Vnkataraman, R.; Chong, L. S.; Yooder, J. E.; Epp, J. B.; Stanga, M. A.;
Kim, E.-H. Bioorg. Med. Chem. 1995, 3, 125. (c) Levin, J. I.; Chan, P. S.;
Coupet, J.; Bailey, T. K.; Vice, G.; Thibault, L.; Lai, F.; Venkatesan, A.
M.; Cobuzzi, A. Bioorg. Med. Chem. Lett. 1994, 4, 1703. (d) Simoni, D.;
Manfredini, S.; Tabrizi, M. A.; Bazzanini, R.; Guarneri, M.; Ferroni, R.;
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1991, 8, 119.
(13) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
742
Org. Lett., Vol. 4, No. 5, 2002

to olefin 5 proceeded to give isoxazolinocyclobutanol 6 with
complete regioselectivity.
CH2Cl2/THF (1:1) effected the 1,3-dipolar cycloaddition to
give isoxazolino resin 11. Since this transformation exhibited
no reliably diagnostic absorption peaks in the IR spectrum,
the oxidative release step was undertaken with some trepida-
tion. Fortunately, Swern oxidation of resin 11 successfully
delivered the isoxazolocyclobutanone 12a in 35% overall
yield from starting resin 1, an average yield of >75% for
each of the four solid-phase reactions.
We next employed the nitrile oxides generated in situ from
o- and p-methoxybenzaldehyde oximes in the 1,3-dipolar
cycloaddition reaction with resin 10 to deliver resin 11b and
11c, respectively (Figure 3). Oxidative elimination of resin-
The chemical shifts of the C4 and C5 isoxazolino protons
in 6 appeared at δ 3.4 and 4.6, respectively, and were
diagnostic in judging its conversion to the isoxazolo ring of
“sulfone released” product 12c. To effect this transformations
the equivalent of substrate release when performed on resins
the cyclobutanol moiety of 6 was oxidized (Swern)16 to the
corresponding cyclobutanone (7). We were not surprised to
find that, under the basic conditions of this reaction, oxidation
6 f 7 was accompanied by concomitant sulfinate elimina-
tion17 (7 f 8). Likewise, given the relative energetics of
placing the C,C-double bond in the cyclobutyl vs isoxazolo
rings, we fully expected isoxazolinocyclobutenone 8 to
isomerize into isoxazolocyclobutanone 12c. We were sur-
prised at the ease with which this isomerization occurred,
giving 12c (the C5 methine at δ 4.6 in 6 had disappeared
and the two proton signal at δ 3.4 now appeared as a one
proton singlet at δ 6.3) in a one-pot overall yield of 82%
from 6. The observed CdO stretch at 1799 cm-1 is fully
consistent with the unconjugated cyclobutanone of 12c; a
computer generated X-ray structure of 12c is depicted in
Scheme 1.
Solid-Phase Isoxazolocyclobutanone Synthesis. With a
successful solution-phase route to isoxazolocyclo-butanone
12c in hand, we turned to the development of a viable solid-
phase protocol and began with the preparation of polymer-
bound benzenesulfinate 1 following our published protocol4,5
(Scheme 2). This resin (0.8 mmol/g) was converted to 3-(PS/
Scheme 2. Solid-Phase Synthesis
Figure 3. Product diversity.
ous sulfinate from these intermediates delivered isoxazolo-
cyclobutanones 12b and 12c.
To further illustrate the versatility of this chemistry,
3-chloro-2-methylpropene and 4-vinylbenzyl (this alkylating
agent introduces a phenyl “spacer” between the isoxazolino
and cyclobutenone moieties) chloride were used to S-alkylate
polymeric sulfinate 1 giving polymer-bound sulfones, which
were then R,R-dialkylated with epichlorohydrin to give
polymers 13 and 16, respectively. Subsequent conversions
to isoxazolinocyclobutanols 14a-c and 17a-c were ac-
DVB-sulfonyl)-3-vinylcyclobutanol 10 via S-allylation with
allyl bromide (f 9) and R,R-dialkylation with epichlorohy-
drin4 (Scheme 2). Treatment of resin 10 with 2,6-dichlo-
robenzaldehyde oxime in the presence of NaOCl (aq) in
(15) (a) Martin, S. F.; Dupre, B. Tetrahedron Lett. 1983, 24, 1337. (b)
Manikandan, S.; Shanmugasundaram, M.; Raghunathan, R.; Malar, E. J.
P. Heterocycles 2000, 53, 579. (c) Kamimura, A.; Hori, K. Tetrahedron
1994, 50, 7969. (d) Kozikowski, A. P.; Adamczyk, M. J. Org. Chem. 1983,
48, 366.
(14) (a) Alonso, C.; Nantz, M.; Kurth, M. J. Tetrahedron Lett. 2000,
41, 5617. (b) Kantorowski, E. J.; Kurth, M. J. J. Org. Chem. 1997, 62,
6797. (c) Lorsbach, B. A.; Miller, R. B.; Kurth, M. J. J. Org. Chem. 1996,
61, 8716. (d) Park, K.-H.; Kurth, M. J. J. Org. Chem. 2000, 65, 3520. (e)
Sammelson, R. E.; Miller, R. B.; Kurth, M. J. J. Org. Chem. 2000, 65,
2225.
(16) (a) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41,
3329. (b) Mancuso, A.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(17) (a) Julia, M.; Badet, B. Bull. Soc. Chim. Fr. 1976, 525. (b) Kondo,
K.; Tunemoto, D. Tetrahedron Lett. 1975, 1007. (c) Uneyama, K.; Torii,
S. Tetrahedron Lett. 1976, 443.
Org. Lett., Vol. 4, No. 5, 2002
743

complished as described for 10 f 11. Oxidation of these
cyclobutanols with concomitant cleavage of the sulfone linker
produced isoxazolinocyclobutenones 15a-c and 18a-c,
respectively. Obviously, olefin isomerization is unlikely in
these case, and as expected, the IR spectra of these products
displayed CdO absorptions between 1753 and 1769 cm-1
indicating that cyclobutenones and not cyclobutanones were
obtained.
Finally, it is noteworthy that the procedures developed for
10 f 12, 13 f 15 gave reduced overall yields of the
liberated isoxazoline products (18-23% range). This led us
to further scrutinize the solid-phase reaction conditions for
13 f 14. We discovered that performing the 1,3-dipolar
cycloaddition reactions twice (i.e., after first treatment with
3 equiv of oxime plus NaOCl for 12 h, the reaction was
filtered and then an additional 3 equiv of oxime plus NaOCl
were added a second time for an additional 12 h) significantly
improved the yields of 15a-c (34-38% range). Presumably,
the disubstituted olefin in 14 is less reactive in the solid-
phase 1,3-dipolar cycloaddition than the monosubstituted
olefin in 10.
ones with diversity in the aryl, isoxazolo/isoxazolino, cy-
clobutanone/cyclobutenone, and “spacer” moieties (see Fig-
ure 2). The solid-phase chemistry proceeds with formation
of three C,C-bondsstwo by sulfone R,R-dialkylation and one
by nitrile oxide 1,3-dipolar cycloadditionsas well as a novel
sulfinate oxidative elimination step. The solid-phase prepara-
tion of nine diverse isoxazolocyclobutanones and isoxazoli-
nocyclobutenones in 27-38% overall yield from polymer-
bound benzenesulfinate 1 demonstrates the versatility of this
chemistry.
Acknowledgment. We thank the National Science Foun-
dation and the Cystic Fibrosis Foundation for financial
support of this work. The 400 and 300 MHz NMR
spectrometers used in this study were funded in part by a
grant from the NSF (CHE-9808183).
Supporting Information Available: Experimental pro-
cedures, full characterization for compounds for 12a-c and
1
15a-c, and H and 13C NMR spectra for 18a-c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed a traceless solid-phase
route to isoxazolocyclobutanones and isoxazolinocyclobuten-
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Org. Lett., Vol. 4, No. 5, 2002