First example of direct RuO4- catalyzed oxidation of isoxazolidines to 3-isoxazolidones

Article abstract of DOI:10.1021/jo070211n

(Chemical Equation Presented) RuO₂/NaIO₄ oxidation of 3-unsubstituted isoxazolidines, under ethyl acetate/water biphasic conditions, affords 3-isoxazolidones in good yields. The methodology can be used on both racemic and optically a

Full text of DOI:10.1021/jo070211n

First Example of Direct RuO4-Catalyzed
Oxidation of Isoxazolidines to 3-Isoxazolidones
Anna Piperno,*,† Ugo Chiacchio,‡ Daniela Iannazzo,†
Salvatore V. Giofre`,† Giovanni Romeo,† and
Roberto Romeo†
Dipartimento Farmaco-Chimico, UniVersita` di Messina, Via SS.
Annunziata, Messina 98168, Italy, and Dipartimento di Scienze
Chimiche, UniVersita` di Catania, Viale Andrea Doria 6,
Catania 95125, Italy
apiperno@pharma.unime.it
ReceiVed February 1, 2007
FIGURE 1. Some of the most important 3-isoxazolidinones.
neurotransmitter 4-aminobutyric acid 11 (GABA). Extensive
pharmacological investigations performed on DHM have shown
the existence of a powerful agonist activity at the postsynaptic
GABA receptor complex.6a,b
In the literature, only two synthetic approaches toward the
3-isoxazolidinone system have been reported. The first approach
is based on the cyclization of suitably functionalized hydroxamic
acids, which may be prepared in most cases by reaction of a
suitable acid derivative with a substituted hydroxylamine, with
yields lower than 50%.7 This procedure is severely limited by
the availability of the hydroxamic acid precursor and the low
yields of the cyclization process.
The second reaction pathway involves a 1,3-dipolar cycload-
dition of bromonitrile oxide with allylic alcohol, with subsequent
transformation of the cycloadducts to produce the target
compounds. The major drawback of this method is linked to
the synthesis of optically pure isoxazolidones. The use of a chiral
alkene, such as S-(+)-2,2-dimethyl-4-vinyl-1,3-dioxolane, re-
quires rather laborious manipulations to transform the obtained
cycloadducts 12 into the key intermediates 13 (Scheme 1).
Furthermore, the relative distribution of these intermediates is
strictly dependent upon the stereoselectivity induced from the
chiral alkene.8
The enzymatic resolution of the racemic intermediate 13 by
Lipase PS, after conversion into suitable esters, has been also
utilized to obtain optically pure (R)-(-)-3 and (S)-(+)-3.
However, this methodology can be applied only to ∆2-
isoxazoline or isoxazolin-3-one derivatives carrying a primary
alcoholic group, and the enantioselectivity of enzymatic resolu-
tion is strictly dependent upon both the size of the acyl moiety
and the shape of the group carrying the alcoholic part of the
ester.9
RuO2/NaIO4 oxidation of 3-unsubstituted isoxazolidines,
under ethyl acetate/water biphasic conditions, affords 3-isox-
azolidones in good yields. The methodology can be used on
both racemic and optically active isoxazolidines.
The 3-isoxazolidone nucleus constitutes the basic skeleton
of natural compounds such as the antibiotic D-cycloserine 1,1
the L-canavanine catabolite 2,2 and a series of compounds that
have been designed in medicinal chemistry as ligands for
different receptors of the central nervous system (Figure 1).3
Azamuscarone 3,4 structurally related to the natural muscarine
4, is a highly effective agonist of the muscarinic receptor, having
a potency comparable to that of compound 4. The muscarinic
receptor population represents a class of cholinergic receptors
abundant in the parasympathetic and in the central nervous
system, where they mediate both excitatory and inhibitory
effects. In this context, compounds 5-7, which incorporate the
isoxazolidin-3-one moiety, have been designed as analogues of
the potent yet nonselective muscarinic agonists oxotremorine 8
and oxotremorine-M 9. Compounds 5-7 displayed different
binding affinities at brain and heart muscarinic subtype
receptors.5a,b
The N-unsubstituted 3-isoxazolidinone system in the enolic
form, such as dihydromuscimol (DHM) 10, can be regarded as
a conformationally restricted analogue of the physiological
† Universita` di Messina.
‡ Universita` di Catania.
(1) Peisach, D.; Chipman, D. M.; Van Ophem, P.W.; Manning, J. M.;
Ringe, D. J. Am. Chem. Soc. 1998, 120, 2268.
(2) Rosenthal, G. A. Plant Physiol. 1990, 94, 1.
(3) Grunwald, C.; Rundfeldt, C.; Lankau, H. J.; Arnold, T; Ho¨fgen, N.;
Dost, R.; Egerland, U.; Hofmann, H. J.; Unverferth, K. J. Med. Chem. 2006,
49, 1855.
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Santagostino-Barbone, M. G. Eur. J. Med. Chem. 1989, 24, 171.
(5) (a) Conti, P.; Dallanoce, C.; De Amici, M.; De Micheli, C.; Ebert,
B. Bioorg. Med. Chem. Lett. 1997, 7, 1033. (b) Dallanoce, C.; Conti, P.;
De Amici, M.; De Micheli, Barocelli, E.; Chiavarini, M.; Ballabeni, V.;
Bertoni, S.; Impicciatore, M. Bioorg. Med. Chem. 1999, 7, 1539.
(6) (a) Krogsgaard-Larsen, P.; Nielsen, L.; Falch, E.; Curtis, D. R.; Lodge,
D.; Johnston, G. A. J. Neurochem. 1979, 32, 1717. (b) Krogsgaard-Larsen,
P.; Nielsen, L.; Falch, E.; Curtis, D. R. J. Med. Chem. 1985, 28, 1612.
(7) Caldirola, P.; De Amici, M.; De Micheli, C. Tetrahedron Lett. 1986,
27, 4651.
(8) De Amici, M.; Magri, P.; De Micheli, C.; Cateni, F.; Bovara, R.;
Carrea, G.; Riva, S.; Casalone, G. J. Org. Chem. 1992, 57, 2825.
(9) Carrea, G.; De Amici, M.; De Micheli, C.; Liverani, P.; Carnielli,
M.; Riva, S. Tetrahedron: Asymmetry 1993, 4, 1063.
10.1021/jo070211n CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/10/2007
3958
J. Org. Chem. 2007, 72, 3958-3960

SCHEME 1. Synthetic Procedure toward Compounds 3 by
1,3-Dipolar Cycloaddition of a Chiral Alkene and
Bromonitrile Oxide
protected isoxazolidine 18, which was purified by flash chro-
matography. The oxidation of 18 was carried out in aqueous
ethyl acetate by using RuO4 (generated in situ from catalytic
RuO2.nH2O and NaIO4 in excess), leading to compound 19 with
a yield of 60%.
The oxidation process was also performed directly on 16,
after protection of the hydroxyl group with acetic anhydride,
but in this case, the yield decreased and the 1H spectrum of the
crude reaction mixture showed the presence of a complex
mixture of oxidized compounds. In this case, the ethereal
methylene group of the pyranosyl moiety is probably a
competitive site for the oxidation processes.
We have, then, exploited our methodology for the synthesis
of enantiomerically pure 3-isoxazolidones, starting from the
chiral isoxazolidines 17a and 17b prepared from the Vasella-
like nitrone 15.14 Thus, nitrone 15 was reacted with allylic
alcohol in toluene for 12 h to give a mixture of the two chiral
isoxazolidines 17a and 17b (50% and 40% yield, respectively),
epimeric at C-5, which were separated by MPLC chromatog-
raphy. The first eluted compound, 17a, was hydrolyzed by
treatment with 37% aqueous HCl in ethanol at reflux and
acetylated to give (+)-ent-18 [R] ) +31, whereas the reaction
on the second eluted compound 17b afforded the enantiomer
(-)-ent-18 [R] ) -31. These data confirm that 17a and 17b
are epimers at C5 of the isoxazolidine ring. Two purified
enantiomers 18 were independently oxidized, under the same
conditions used for racemic 18, to afford the dextrorotatory
isoxazolidinone 19, [R] ) +13, from (+)-ent- 18 and the
levorotatory isoxazolidinone 19, [R] ) -13 from (-)-ent-18.
However, the RuO4-mediated oxidation can be directly carried
out on acetylated 17a and 17b without preventive removal of
the sugar moiety at the nitrogen atom. Thus, from 17a and 17b
we obtained the corresponding 3-isoxazolidinone 20a, [R] )
-33.74, and 20b, [R] ) -29.03, with a yield of 65% for both
the substrates.
As reported in the literature,14 the oxidation process can be
explained according to two separate steps. The activation of
the R-CH bond, in a concerted five-membered transition state,
leads to an alcohol product, coordinated to the Ru(VI), which
undergoes a second hydrogen transfer giving the corresponding
oxygenated compound and Ru(IV) (Scheme 3).
Because of these considerations, we have devised a new
synthetic route for the 3-isoxazolidone system, which can be
successfully exploited for the preparation of enantiomerically
pure derivatives. In this paper we report the first example of a
direct oxidation of the isoxazolidine nucleus to the 3-isoxazoli-
done system by the use of RuO2/NaIO4, under ethyl acetate/
water biphasic conditions. This two-phase oxidation was
reported some years ago for the conversion of cyclic R-ami-
noacids into R-aminodicarboxylic acids,10a-c and more recently,
this procedure has been applied to the conversion of protected
proline derivatives into pyroglutamic acid derivatives.11a,b The
oxidation reaction of the isoxazolidine nucleus is uncommon
because of the sensitivity of the N-O bond toward the usual
oxidizing agents; only a few papers report the oxidative
treatmentofisoxazolidinestogivecorrespondingisoxazolines.12a,b,13
The starting 3-unsubstituted isoxazolidine 18 has been
prepared in racemic form by the 1,3-dipolar cycloaddition
reaction of the N-pyranosyl nitrone 14 with allylic alcohol
(Scheme 2). This cycloaddition produced the expected mixture
of inseparable diastereomers 16. Deprotection by treatment with
p-toluensulphonic acid and subsequent acetylation gave the
a
SCHEME 2. General Procedure for the Oxidation Reaction of 18 with RuO2/NaIO4
a Reaction conditions: (a) allyl alcohol, toluene, reflux, 12 h, yield 90%; (b) PTSA, MeOH, 2 h, reflux or 37% aqueous HCl in ethanol at reflux; (c)
Ac2O, ETA, DCM, 3 h, yield 99%; (d) RuO2, NaIO4, ethyl acetate, H2O, yield 60-65%.
J. Org. Chem, Vol. 72, No. 10, 2007 3959

SCHEME 3. Mechanism of the RuO4-Catalyzed Oxidation
of Activated CH2 Groups
(17b): yield 40%; oil, Rf (cyclohexane/ethyl acetate 5/5) ) 0.45;
[R]25D) +4.58 (c 0.48 , CHCl3).
General Procedure for the Hydrolysis of Cycloadducts and
Subsequent Acetylation. A solution of cycloadducts 16 (10 mmol)
and p-toluensulfonic acid (0.5 mmol) in MeOH (20 mL) or
isoxazolidines 17a,b and 37% HCl solution (w/w) in EtOH (20
mL) was heated at reflux for 12 h. The reaction mixture was
neutralized with potassium carbonate and evaporated. The residue
was purified by chromatography (chloroform/methanol 9:1) to
furnish the corresponding isoxazolidin-5-ylmethanol, with a yield
of 70%, identified by 1H NMR (CDCl3, 300 MHz): 2.05(m, 1H),
2.15(m, 1H), 2.68(sb, 2H), 3.08(t, 2H, J ) 5.3 Hz), 3.61(dd, 1H,
J ) 4.55, 9.8 Hz), 3.81(dd, 1H, J ) 3.6, 9.8 Hz), 4.20(m, 1H). To
a solution of isoxazolidin-5-ylmethanol (7 mmol) and N(Et)3 (14.5
mmol) in dry CH2Cl2 (20 mL) was added dropwise acetyl chloride
(14.5 mmol), and the reaction mixture was stirred at room
temperature for 4 h and then concentrated in vacuo. The residue
was treated with ethyl acetate and filtered; the solution was washed
with aqueous sodium bicarbonate, dried over sodium sulfate,
filtered, and evaporated to dryness to afford 18 in a quantitative
yield.
The regioselectivity of the oxidation, which occurs exclusively
at position 3 of the isoxazolidine ring, can be also rationalized,
in accord with literature data,14 by considering that the presence
of the activating nitrogen atom promotes the conversion rate.
In conclusion, we report the first example of a direct oxidation
of the isoxazolidine nucleus to 3-isoxazolidones by the use of
RuO2/NaIO4. The method can be used on both racemic and
optically active isoxazolidines. The methodology is general and,
as suggested by preliminary data, may be efficaciously exploited
for homochiral isoxazolidines, differently C-4 and/or C-5
substituted, to allow access to the corresponding optically active
3-isoxazolidones, which are otherwise difficult to prepare.
(2-Acetylisoxazolidin-5yl)methyl acetate (18): yield 70%; yel-
low oil, Rf (chloroform/methanol 98/2) ) 0.36; (+)-ent-18 [R]25
D
) +31 (c 0.44, CH2Cl2); (-)-ent-18 [R]25D ) -31 (c 0.44, CH2-
Cl2).
General Procedure for RuO2/NaIO4 Oxidation. To a solution
of NaIO4 (4.0 g, 18.71 mmol) in water (67 mL) was added RuO2‚
H2O (0.2 g 1.48 mmol) under nitrogen. The resulting green-yellow
solution was stirred for 30 min and was followed by addition of
protected isoxazolidine (7.49 mmol) in EtOAc (32 mL) in one
portion. The solution remained yellowish during the reaction; if its
color changed to black more NaIO4 was added (4.0 g, 18.71 mmol),
and after 6 h of stirring at room temperature the mixture was diluted
with EtOAc and filtered through a pad of Celite. The organic layer
was washed with saturated NaHSO3, which resulted in precipitation
of black Ru. The precipitate was filtered off through a pad of Celite.
The EtOAc layer was washed with brine and dried with anhydrous
Na2SO4; the solvent was removed by evaporation in a rotary
evaporator to obtain the crude product. All products were purified
by MPLC chromatography.
Experimental Section
General Procedure for 1,3-Dipolar Cycloaddition Reaction
of N-Pyranosyl (14) and N-(5-O-tert-Butyldiphenylsilyl-2,3-O-
isopropylidene-â-D-ribofuranosyl) nitrone (15). A mixture of
5-hydroxypentanal oxime15 (5.5 mmol) or E/Z (2.9/1) mixture of
(4S,5R)-5-[(1R)-2-[[1-(tert-butyl)-1,1-diphenylsilyl]oxy]-1-hydroxy-
ethyl]-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde oxime16 (5.5 mmol),
paraformaldehyde (11 mmol), and allylic alcohol (11 mmol) in
toluene (70 mL) was heated at reflux for 12 h. The reaction mixture
was filtered and then evaporated under reduced pressure to give
the cycloadducts, which were purified by MPLC chromatography
with cyclohexane/ethyl acetate (5:5) as eluent.
(2-Acetyl-3-oxoisoxazolidin-5-yl)methyl acetate (19): yield
60%; white oil, Rf (EtOAc/cyclohexane 4/6) ) 0.42; (+)-ent-19
[R]25D ) +13 (c 0.26, CH2Cl2); (-)-ent-19 [R]25D ) -13 (c 0.26,
CH2Cl2).
[2-(Tetrahydro-2H-pyran-2-yl)isoxazolidin-5-yl]methanol (16):
yield 87.5%; yellow oil.
(2-(6-((tert-Butyldiphenylsilyloxy)methyl)-2,2-dimethyltet-
rahydrofuro[3,4-d][1,3]dioxol-4-yl) isoxazolidin-5-yl)methanol
(17a): yield 50%; oil, Rf (cyclohexane/ethyl acetate 5/5) ) 0.55;
(2-(6-((tert-Butyldiphenylsilyloxy)methyl)-2,2-dimethyltet-
rahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-oxoisoxazolidin-5-yl)me-
thyl acetate (20a): yield 65%; white oil, Rf (EtOAc/cyclohexane
[R]25 ) +3.01 (c 0.32, CHCl3).
D
(2-(6-((tert-Butyldiphenylsilyloxy)methyl)-2,2-dimethyltet-
rahydrofuro[3,4-d][1,3]dioxol-4-yl)isoxazolidin-5-yl)methanol
3/7) ) 0.66; [R]25 ) -33.74 (c 0.31, CHCl3).
D
(2-(6-((tert-Butyldiphenylsilyloxy)methyl)-2,2-dimethyltet-
rahydrofuro[3,4-d] [1,3]dioxol-4-yl)-3-oxoisoxazolidin-5-yl)-
methyl acetate (20b): yield 65%; white oil, Rf (EtOAc/cyclohexane
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5/5) ) 0.54; [R]25 ) -29.03° (c 0.15, CHCl3).
D
Acknowledgment. This work was partially supported by
M.I.U.R. (Progetto P.R.I.N 2005).
Supporting Information Available: Experimental procedures
1
and complete characterization of all compounds; copies of the H
NMR spectra for compounds 17a, 17b, 19, 20a, 20b; and 13C NMR
spectra for compound 19. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO070211N
3960 J. Org. Chem., Vol. 72, No. 10, 2007