Solid-phase synthesis of isoxazole-based amino acids: A new scaffold for molecular diversity

Full text of DOI:10.1021/jo015758v

J . Org. Chem. 2001, 66, 6823-6825
6823
Solid -P h a se Syn th esis of Isoxa zole-Ba sed
Am in o Acid s: A New Sca ffold for Molecu la r
Diver sity
Lidia De Luca, Giampaolo Giacomelli,* and
Antonella Riu
F igu r e 1.
Dipartimento di Chimica, Universita` degli Studi di Sassari,
via Vienna 2, I-07100 Sassari, Italy
by recovering the alkyne after cleavage of a small portion
of the resin. The loading was complete after 48 h at room
temperature. After being washed, the resin 2 was treated
with 8 equiv of the aldoxime 3 and of N-chlorosuccinimide
(NCS) in methylene chloride in a one-pot three-compo-
nent reaction.
Successively, triethylamine was added slowly and
dropwise over a period of 2 h to generate the nitrile oxide.
The resulting mixture was shaken at room temperature
and monitored by infrared spectroscopy for the disap-
pearance of the alkyne stretch (ca. 24 h). The resin was
then filtered, washed, and dried. The isoxazole 5 was
cleaved off the resin 4 under standard conditions (5%
TFA in CH2Cl2).
ggp@ssmain.uniss.it
Received May 15, 2001
The rational design of therapeutic agents that over-
come the pharmacological limitations of peptides is one
of the major goals of medicinal chemistry. For this reason,
peptidomimetics have become very important for organic
and medicinal chemistry. Potentially useful peptidomi-
metics should resist in vivo hydrolysis and present some
conformational bias.1 With this goal in mind, several
building blocks able to stabilize some parts of the peptide
chain have been developed.2
A library of isoxazoles (Figure 2) was thus generated
by trapping in situ the anchored alkyne with the nitrile
oxide generated by the appropriate aldehyde, in a prac-
tical one-pot operation. The yields were satisfactory
(60%-90%), and the purity of recovered compounds after
cleavage were greater than 95%. In every case, only one
isomer was recovered.
The potential of the procedure was emphasized by the
synthesis of compounds 5i-k , derived from amino alde-
hydes obtained from the corresponding amino acids. In
particular, compounds 5j and 5k are very versatile
intermediates and can potentially be used for developing
an isoxazole-based library of new amino acids.
In recent years, we have reported the preparation of
heterocycle-containing optically active amino acids as
chiral building blocks for the design of peptidomimetics.3
Searching for new molecules that might be assembled
with themselves and/or other substrates using combina-
torial techniques, we propose here a new scaffold con-
taining an isoxazole moiety (Figure 1), following the
strategy of creating a rigid core molecule carrying dif-
ferent functional groups that could be subsequently
functionalized with different building blocks to generate
a library of molecular diversomers.
For the preparation of this compound, we envisioned
that the use of solid-phase 1,3-dipolar cycloaddition would
be a good alternative to the classical synthesis. The
synthesis of isoxazoles on trityl chloride resins has been
described earlier using polymer-supported nitrile oxide
precursors.4 However, we have decided to test the pos-
sibility of preparing isoxazoles and in particular com-
pounds such as A by anchoring the acetylenic com-
pounds5 on the resin and generating the nitrile oxide in
situ from suitable carbonyl compounds. Our efforts at
obtaining a representative library of isoxazoles are
presented below.
This has been demonstrated by carrying out several
transformations of the compound 5j, generating a series
of diversomers (Scheme 2).
Thus, polymer-supported isoxazole derivative 4j was
successfully converted to other functionalized derivatives;
cleavage of the oxazoline ring by p-toluenesulfonic acid
(PTSA)3d in dry methanol, followed by oxidation using
J ones’ conditions,6 afforded resin-bound amino acid 6,7
which gave amino acid derivative 10 in a 56% yield upon
treatment with TFA 5%. In addition, compound 5j was
oxidized to the carbaldehyde 8 and to the carboxylic acid
9, respectively, under Swern (90%)8 and J ones’ (95%)
conditions. The oxidative process carried out on com-
pound 7 furnished the bicarboxyl amino acid 11 (41%).
Similar reactions might be obviously carried out on
compound 4k . It is noteworthy that compounds 7, 9, and
10 represent valuable examples of a rigid core molecule
for generating molecular diversomers.
Alkynyl alcohol 1 was anchored on trityl chloride resin
(Scheme 1). The loading was controlled by monitoring via
infrared spectroscopy for the appearance of the alkyne
stretch at 3300 cm-1 and determined (∼45% after 12 h)
(1) See, for example: Gante, I. Angew. Chem., Int. Ed. Engl. 1994,
33, 1699. Liskamp, R. M. J . Recl. Trav. Chim. Pays-Bas 1994, 113, 1.
(2) Apella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.;
Huang, X.; Barchi, J . J .; Gellman, S. H. Nature 1997, 387, 381 and
references therein.
(3) (a) De Luca, L.; Giacomelli, G.; Porcheddu, A.; Spanedda, A. M.;
Falorni, M. Synthesis 2000, 1295. (b) Falorni, M.; Giacomelli, G.;
Porcheddu, A.; Dettori, G. Eur. J . Org. Chem. 2000, 3217. (c) De Luca,
L.; Falorni, M.; Giacomelli, G.; Porcheddu, A. Tetrahedron Lett. 1999,
40, 8701. (d) Falorni, M.; Giacomelli, G.; Spanu, E. Tetrahedron Lett.
1998, 39, 9241. (e) Falorni, M.; Giacomelli, G.; Spanedda, A. M.
Tetrahedron: Asymmetry 1998, 9, 3039.
In summary, 1,3-dipolar cycloaddition methodology for
the preparation of structurally different isoxazoles and
(6) Reginato, G.; Mordini, A.; Caracciolo, M. J . Org. Chem. 1997,
62, 6187.
(7) Although the trityl chloride resin was known to be acid-labile,
under the experimental conditions adopted, no detectable cleavage of
the resin was detected. Moreover, as reported in the literature, the
BOC group was also retained.3c,d,5
(4) (a) Shankar, B. B.; Yang, D. Y.; Girton, S.; Ganguly, A. K.
Tetrahedron Lett. 1998, 39, 2447. (b) Batra, S.; Rastogi, S. K.; Kundu,
B.; Patra, A.; Bhaduri, A. P. Tetrahedron Lett. 2000, 41, 5971.
(5) Kantorowski, E. J .; Kurth, M. J . J . Org. Chem. 1997, 62, 6797.
(8) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. Marx, M.;
Tidwell, T. T. J . Org. Chem. 1984, 49, 788.
10.1021/jo015758v CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/31/2001

6824 J . Org. Chem., Vol. 66, No. 20, 2001
Notes
F igu r e 2.
Sch em e 1
Sch em e 2
a series of isoxazole-based amino acids was developed
under solid-phase conditions. It is worth pointing out that
compounds 8 and 9 are excellent substrates, which can
be further diversified to obtain an array of isoxazole-
based novel compounds. Moreover, successive transfor-
mation on 9, 10, and respective homologues (n > 1)
should lead to the formation of amino acids similar to
11, which can be regarded as glutamic acid homologues.
Exp er im en ta l Section
All of the solvents and the reagents were used in the
commercially available grade of purity. The N-protected amino
acids were prepared according standard methods, and their
purity was established before utilization by melting point and
optical rotation. The aldehydes were commercial products or
were prepared from amino acids through known procedures.9
Oximes were prepared by reaction of the aldehydes with

Notes
J . Org. Chem., Vol. 66, No. 20, 2001 6825
hydroxylamine in the presence of pyridine in MeOH at room
temperature. The 1H NMR and 13C NMR were obtained at 300
and 75.4 MHz from CDCl3 solutions.
The mixture was shaken at room temperature for 36 h untila
test for detection of OH group was positive.10 The resin was then
filtered and washed several times with THF and CH2Cl2 and
then rinsed with THF/acetone 1:1. The mixture was cooled at 0
°C and treated with 0.2 mL of J ones’ reagent and shaken at room
temperature. A few beads of the resin were tested for the
presence of free COOH groups;11 after 12h, the test being
positive, the resin 6 was filtered and washed with THF followed
by CH2Cl2. Then, the resin was cleaved as above; filtration gave
an organic phase, which was treated with Na2CO3 aqueous 10%
solution. The aqueous phase was collected, washed with di-
ethyl ether and with HCl 1 N, extracted with CH2Cl2, and dried
(Na2SO4). Removal of the solvent gave 0.066 g of N-tert-bu-
toxycarbonylamino-(5-methanolisoxazol-3-yl)acetic acid 10. 1H
NMR: δ 11.4 (s, 1H), 7.92 (s, 1H), 6.27 (s, 1H), 5.75 (s, 1H), 5.07
(bs, 1H), 4.71 (s, 2H), 1.44 (s, 9H). 13C NMR: δ 176.5, 162.8,
158.9, 150.0, 99.5, 71.2, 65.2, 62.7, 28.7. Anal. Calcd for
C11H16N2O6 (272.25): C, 48.53; H, 5.92; N, 10.29. Found: C,
48.71; H, 5.92; N, 10.22.
Gen er a l P r oced u r e for th e Solid -P h a se P r ep a r a tion of
Isoxa zoles. The syntheses were carried out in a manual 20 mL
reactor equipped with a sintered glass and using a nitrogen flow
for agitation and filtration. A solution of alkynyl alcohol 1 (7.4
mmol) in dry pyridine (3.0 mL) was added dropwise to trityl
chloride resin (0.35 g of a 1.24 mmol/g Novabiochem sample,
0.43 mmol, swollen in CH2Cl2) in 7.0 mL of pyridine. The mixture
was shaken at room temperature for 48 h, filtered, washed
several times with pyridine and dry diethyl ether, and dried to
afford the corresponding alkyne resin 2. FTIR (KBr): 3289 cm-1
.
The resin was then separated into portions for the construction
of the library.
To the resin (0.16 mmol), swollen with CH2Cl2, were added
CH2Cl2 (5.0 mL), oxime 3 (1.72 mmol), and N-chlorosuccinimide
(0.9 g, 6.9 mmol); after 2 h, Et3N (1 mL, 7.2 mmol) was added
dropwise, and the mixture was shaken at room temperature and
monitored for the disappearance of the alkyne stretch (24 h).
The resin was then filtered and washed several times with
CH2Cl2 affording polymeric isoxazoles 4a -k . Substrate cleav-
age was accomplished by treating 4 with a freshly prepared
TFA/CH2Cl2 (5:95) solution at room temperature (20 min).
Filtration and resin washing with CH2Cl2 gave an organic phase,
which was washed with Na2CO3 aqueous 10% solution and dried
(Na2SO4). Removal of the solvent gave the target isoxazoles
5a -k in 60%-90% yield.
Ack n ow led gm en t. The work was financially sup-
ported by the University of Sassari (Fondi 60%).
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
of compounds 5a -k and the preparation of compounds 7-9
and 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
P r ep a r a tion of th e P olym er ic Am in o Acid 6 a n d of
Com p ou n d 10. A sample of resin 4j prepared from trityl
chloride resin (0.35 g), propargyl alcohol (0.41 g, 7.4 mmol), and
the oxime of Garner’s aldehyde (0.42 g, 1.72 mmol) in THF (10
mL) was treated with p-toluenesulfonic acid (0.04 g, 0.2 mmol).
J O015758V
(10) Attardi, M. E.; Falchi, A.; Taddei, M. Tetrahedron Lett. 2000,
41, 7395. Attardi, M. E.; Taddei, M. Tetrahedron Lett. 2001, 42, 2927.
(11) Attardi, M. E.; Porcu, G.; Taddei, M. Tetrahedron Lett. 2000,
41, 7391.
(9) Garner, P.; Park, J . M. J . Org. Chem. 1991, 56, 18.