Oxidative Conversion of Isoxazolidines to Isoxazolines

Full text of DOI:10.1021/jo971021n

366
J . Org. Chem. 1998, 63, 366-369
Notes
a diastereomeric mixture of cycloadducts.5 To circumvent
Oxid a tive Con ver sion of Isoxa zolid in es to
this problem we have developed a method for the conver-
sion of isoxazolidines such as 4-6 to the corresponding
isoxazolines 3, as these will retain the optical integrity
of 4-6 gained in the synthesis.
Isoxa zolin es
Pan Li, Hung-J ang Gi, Lihong Sun, and Kang Zhao*
If the desired target 3 is to be formed from compounds
4-6, then a method for the selective cleavage of the N-R′
bond is necessary. In the pursuit of such a cleavage, we
have investigated alkylative, reductive, and oxidative
pathways. Initially, we encountered difficulties in re-
moving the methyl group of 4 by using the chloroformate
procedure which was reported to dealkylate tertiary
amines to secondary amine hydrochlorides in high yield.6
Next, the hydrogenolysis of 5 was tested for the selective
removal of the benzyl group, but the N-O bond was
preferentially cleaved to furnish the corresponding amine.7
Oxidative cleavage of the N-protected p-methoxybenzyl
group (pMB) in isoxazolidines 6 was able to affect
conversion to the desired isoxazolines 3.
Although oxidative removal of the pMB group from
nitrogen atoms is uncommon,8i it is well documented that
the pMB group can be used as a protecting group for
alcohols and removed by oxidative cleavage with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).8 Several
solvent systems, including aqueous acetonitrile, benzene,
tetrahydrofuran, dichloroethane, and dichloromethane,
were investigated for the DDQ conversion of 6 to 3. The
combination of aqueous dichloromethane and DDQ gives
good results (Table 1). This condition is sufficiently mild
that various functional groups such as nitriles, esters,
and benzyl moieties are unaffected (entries 1-10). On
the basis of decreased yields of acetal compounds (entries
11, 13, and 15), we speculated that the acetal moieties
of starting materials or products may be hydrolyzed
under these aqueous conditions and that the yield of the
reaction may be improved by decreasing the acidity of
the reaction mixture.9 The use of base in the DDQ
oxidation appeared to be questionable because it has been
reported that “addition of triethylamine or sodium bi-
Department of Chemistry, 29 Washington Place,
New York University, New York, New York 10003
Received J une 6, 1997
Isoxazolines, are versatile synthetic intermediates in
the preparation of a variety of compounds with 1,3-
difunctional groups and are readily constructed via the
1,3-dipolar cycloaddition of nitrile oxides 1 to olefins 2.1
Although these cycloadditions display high regioselec-
tivity,2 it remains challenging to form optically pure
isoxazolines via asymmetric cycloadditions.3 For ex-
ample, the isoxazoline nucleoside 3 (R ) CH2OH, Y )
6-chloropurine), which exhibits moderate anti-HIV-1
activity,4 has been prepared only in racemic form via [2
+ 3]-dipolar cycloaddition of nitrile oxide 1 (R )
CH2OTHP) with vinyl nucleoside bases 2 (Y ) 6-chloro-
purine). An attempt to use optically active materials 1
(R ) CH2OR*) for asymmetric induction in 3 furnished
(1) For selected reviews of 1,3-dipolar cycloaddition, see: (a) J ager,
V.; Grund, H.; Bub, V.; Scwab, W.; Muller, I.; Schohe, R.; Franz, R.;
Ehrler, R. Bull. Soc. Chim. Belg. 1983, 92, 1039. (b) Padwa, A. 1,3-
Dipolar Cycloaddition Chemistry; J ohn Wiley & Sons: New York, 1984;
Vols. 1 and 2. (c) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410. (d)
Paquette, L. A. Asymmetric Cycloaddition Reactions. Asymmetric
Synthesis; Morrison, J . D., Ed.; Academic Press: New York, 1984; Vol.
3, Chapter 7. (e) J ager, V.; Muller, I.; Schohe, R.; Frey, M.; Ehrler, R.;
Hafele, B.; Schroter, D. Lect. Heterocycl. Chem. 1985, 8, 79. (f) Curran,
D. P. Adv. Cycloadd., 1988, 1, 129. (g) Torssell, K. B. G. Nitrile Oxides,
Nitrones and Nitronates in Organic Synthesis; VCH Publishers:
Weinheim, 1988.
(2) For regioselective nitrile oxide cycloadditions, see recent ex-
amples: (a) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; J ager,
V.; Schohe, R.; Fronczek, F. R. J . Am. Chem. Soc. 1984, 106, 3880. (b)
Houk, K. N.; Duh, H.-Y.; Wu, Y.-D.; Moses, S. R. J . Am. Chem. Soc.
1986, 108, 2754. (c) Broggini, G.; Molteni, G.; Zecchi, G. J . Chem. Res.,
Synop. 1993, 203. (d) Easton, C. J .; Hughes, C. M.; Tiekink, E. R. T.;
Lubin, C. E.; Savage, G. P.; Simpson, G. W. Tetrahedron Lett. 1994,
35, 3589. (e) Weidner-Wells, M. A.; Fraga, S. A.; Demers, J . P.
Tetrahedron Lett. 1994, 35, 6473. (f) Kamimura, A.; Hori, K. Tetrahe-
dron 1994, 50, 7969. (g) Bulman, P., Philip, C.; Purdie, M.; Lathbury,
D. Tetrahedron 1997, 53, 1061. (h) Rai, K. M. L.; Hassner, A. Synth.
Commun. 1997, 27, 467.
(3) For selected diastereo- and enantioselective syntheses of isoxa-
zolidines or isoxazolines via dipolar cycloaddition reactions, see: (a)
Kozikowski, A. P.; Ghosh, A. K. J . Am. Chem. Soc. 1982, 104, 5788.
(b) Deshong, P.; Leginus, J . M.; J . Am. Chem. Soc. 1983, 105, 1686.
(c) Yuan, C.; Li, C. Tetrahedron Lett. 1993, 34, 5959. (d) Bravo, P.;
Bruche, L.; Diliddo, D.; Resnati, G. J . Chem. Res., Synop. 1993, 346.
(e) Blake, A. J .; Gould, R. O.; Paton, R. M.; Yong, A. A. J . Chem. Res.,
Synop. 1993, 482. (f) Ukaji, Y.; Sada, K.; Inomata, K. Chem. Lett. 1993,
1847. (g) Kanemasa, S.; Nishiuchi, M.; Kamimura, A.; Hori, K. J . Am.
Chem. Soc. 1994, 116, 2324 (h) Fisera, L.; Sauter, F.; Froehlich, J .;
Feng, Y.; Ertl, P.; Mereiter, K. Monatsh. Chem. 1994, 125, 553. (i)
Blake, A. J .; Kirkpatrick, G.; McGhie, K. E.; Paton, R. M.; Penman, K.
J . J . Carbohydr. Chem. 1994, 13, 409. (j) Boa, A. N.; Dawkins, D. A.;
Hergueta, A. R.; J enkins, P. R. J . Chem. Soc., Perkin Trans. 1 1994,
953. (k) de Blas, J .; Carretero, J . C.; Dominguez, E. Tetrahedron:
Asymmetry 1995, 6, 1035. (l) Schreiner, E. P.; Gstach, H. Synlett 1996,
1131. (m) Curran, D. P.; Yoon, M.-H. Tetrahedron 1997, 53, 1971.
(4) (a) Xiang, Y.; Chen, J .; Schinazi, R. F.; Zhao, K. Bioorg. Med.
Chem. Lett. 1996, 6, 1051. (b) Gi, H.-J .; Xiang, Y.; Schinazi, R. F.; Zhao,
K. J . Org. Chem. 1997, 62, 88.
(5) The nitrile oxide, which was generated from 1-(2-nitroethyl)-
2,3,4,6-pentaacetyl glucopyranoside by using phenyl isocyanate, gave
a mixture of two isomers in a ratio of about 1:1 and other related chiral
nitrile oxide produced the similar results.
(6) Olofson, R. A.; Martz, J . T.; Senet, J .-P.; Piteau, M.; Malfroot,
T. J . Org. Chem. 1984, 49, 2081.
(7) The N-O bond survives under several reduction conditions, but
it generally breaks by catalytic hydrogenation. (a) Curran, D. P. J .
Am. Chem. Soc. 1983, 105, 5826. (b) Sun, L.; Li, P.; Landry, D. W.;
Zhao, K. Tetrahedron Lett. 1996, 37, 1547.
(8) (a) Becker, H.-D. In Chemistry of the Quinoid Compounds; Patai,
S., Ed.; Wiley Press: New York, 1974; p 335. (b) Turner, A. B. In
Synthetic Reagents; Pizey, J . S., Ed.; Wiley Press: New York, 1977; p
193. (c) Oikawa, Y.; Yoshioka, T.; Mohri, K.; Yonemitsu, O. Heterocycles
1979, 12, 1457. (d) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahe-
dron Lett. 1982, 23, 885. (e) Oikawa, Y.; Tanaka, T.; Horita, K.;
Yonemitsu, O. Tetrahedron Lett. 1984, 25, 5393. (f) Horita, K.;
Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986,
42, 3021. (g) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991. (h) Chandrasekhar, S.;
Sumithra, G.; Yadav, J . S. Tetrahedron Lett. 1996, 37, 1645. (i)
Grunder-Klotz, E.; Ehrhardt, J . D. Tetrahedron Lett. 1991, 32, 751.
(9) 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone is reduced to the cor-
responding 1,4-diphenol derivative which may result in acidic condi-
tions.
S0022-3263(97)01021-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/23/1998

Notes
J . Org. Chem., Vol. 63, No. 2, 1998 367
both racemic11a and optically active D-11b or L-forms.11c
Two substrates were used to evaluate the DDQ oxidation
of the enantiomerically pure isoxazolidines. The purine
compound 7a (B ) 6-chloropurine) reacted with DDQ/
CH2Cl2/H2O in the presence of a catalytic amount of
triethylamine to afford the desired product 8a (72% yield)
which was transformed to the desired adenine analogue
9a , using the reported procedure.11b This method is also
suitable for the corresponding pyrimidine analogues since
the problematic cytosine derivative 8b (B ) N4-BOC-
cytosine) is obtained in 68% yield, and compound 8b was
similarly converted to isoxazoline analogue 9b in 34%
overall yield. Thus, we have demonstrated a unique case
for the selective cleavage of the N-R (R ) p-methoxy-
benzyl) bond via DDQ oxidation. As an extension, we
have found that catalytic amounts of Et3N not only
improve the yield of the aformentioned coversion but also
significantly increase yields in the cleavage of the widely
used p-methoxybenzyl ether protecting group. This
method may be efficaciously exploited to allow access to
optically active isoxazolines which are otherwise difficult
to obtain.
Ta ble 1. DDQ Oxid a tion of Isoxa zolid in es to
Isoxa zolin es
sub-
entry strate
yield
product conda (%)b
Y
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
6a
6a
6b
6b
6c
6c
6d
6d
6e
6e
6f
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
p-MeC6H4 Ph
p-MeC6H4 Ph
CN
CN
CN
CN
OAc
OAc
OAc
OAc
n-Pr
n-Pr
i-Pr
i-Pr
Ph
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
80
90
79
92
83
94
81
91
75
81
68
75
60
82
72
87
Ph
n-Pr
n-Pr
THPO(CH2)3
THPO(CH2)3
n-Pr
n-Pr
i-Pr
i-Pr
6f
3f
6g
6g
6h
6h
3g
3g
3h
3h
a
A: DDQ (2.5 equiv), CH2Cl2/H2O (10:1), rt, 3 h. B: DDQ (2.5
b
equiv), Et3N (0.1 equiv) CH2Cl2/H2O (10:1), rt, 1-2 h. Isolated
Exp er im en ta l Section
yield.
Gen er a l. 1H and 13C NMR spectra were recorded on 200 and
50 MHz, respectively. Unless specified, reagents and solvents
were purchased from Aldrich and Acros and were used without
further purification.
Sch em e 1
Syn th esis of Isoxa zolid in es (6a -h ).1 To a stirred solution
of N-(p-methoxybenzyl)hydroxylamine hrdrochloride12 (10 mmol)
in ethanol (50 mL) was added NaOMe (9 mmol) at rt. After
stirring at 10 °C for 10 min, the corresponding aldehyde RCHO
(10 mmol) was added. The reaction mixture was stirred at rt
for 5 h. Ethyl acetate (20 mL) was added to precipitate the
sodium chloride. After removal of the precipate by gravity
filtration, the solvents were evaporated under reduced pressure
to provide the intermediate nitrone, which was further purified
by flush chromotography on silica gel eluting with 5-10%
MeOH/EtOAc. To a solution of this nitrone (5 mmol) in dry
benzene (10 mL) was added the corresponding olefin 2 (CH2d
CHY, 15 mmol), and the reaction mixture was refluxed for 6 h
after which the solvent was removed under reduced pressure.
The residue was purified by column chromotography on silica
gel (20-30% EtOAc/petroleum ether) to give 6 as a mixture of
two diastereoisomers. Since both isomers gave the same isoxa-
zoline product, the mixture was used as the starting material
for the subsequent oxidation reaction without further separation.
3-n -P r op yl-5-(m et h oxyca r b on yl)-2-N-(p -m et h oxyb en z-
yl)isoxa zolid in e (6a ): oil. 1H NMR of the mixture (CDCl3) δ
7.31 (d, 2H, J ) 8.7 Hz), 6.85 (d, 2H, J ) 8.6 Hz), 4.59 (dd, 0.5H,
J ) 5.7, 9.4 Hz), 4.54 (dd, 0.5H, J ) 6.1, 8.9 Hz), 3.83-4.09 (m,
2H), (3.80, 3.79) (s, 3H), (3.76, 3.75) (s, 3H), (3.06, 2.89) (m, 1H),
2.70 (m, 1H), 2.28 (m, 1H), 1.45 (m, 4H), 0.87 (t, 3H, J ) 6.8
Hz); 13C NMR of the mixture (CDCl3) δ 173.4, 159.3, (130.8,
130.4), (130.2, 129.6), (114.2, 114.1), (76.2, 74.9), (65.0, 64.9),
(61.8, 60.1), 55.8, 52.8, (39.2, 39.1), 35.8, 20.5, 14.6. Anal. Calcd
for C16H23NO4: C, 65.49; H, 7.92, N, 4.78. Found: C, 65.62; H,
7.91; N, 4.76.
Sch em e 2
carbonate inhibits the DDQ oxidation”.8f We found that
this was the case if a stoichiometric amount of base is
used, but inclusion of a catalytic amount of triethylamine
in the reaction mixture actually accelerated the DDQ
oxidation of 6 with improved yield (entries 12, 14, and
16). We found a general trend of increased yields for all
substrates when catalytic Et3N was used. Although the
role of triethylamine in the DDQ oxidation remains
unclear, reaction condition B (0.1 equiv of Et3N) is
superior to condition A (without Et3N) for the oxidation
of isoxazolidine substrates (Table 1). As a corollary to
these findings, we discovered that the conversion of
p-methoxybenzyl ethers to the corresponding alcohols
could also be improved by adding catalytic amounts of
Et3N.10
3-I s o p r o p y l-5-(m e t h o x y c a r b o n y l)-2-N -(p -m e t h o x y -
ben zyl)isoxa zolid in e (6b): oil. 1H NMR of the mixture
(CDCl3) δ 7.30 (d, 2H, J ) 8.6 Hz), 6.83 (d, 2H, J ) 8.6 Hz), 4.61
(dd, 0.5H, J ) 5.9, 9.0 Hz), 4.48 (dd, 0.5H, J ) 7.0, 8.1 Hz), 4.07
(d, 1H, J ) 12.4 Hz), 3.85 (d, 1H, J ) 9.4 Hz), 3.76 (s, 3H), (3.74,
3.73) (s, 3H), 2.87 (q, 0.5H, J ) 6.6 Hz), 2.74 (q, 0.5H, J ) 7.2
Hz), 2.46 (m, 2H), 1.68 (m, 1H), 0.87 (m, 6H); 13C NMR of the
We have successfully extended this method to the
conversion of isoxazolidine nucleoside analogues such as
7 to the corresponding isoxazolines 8 (Scheme 2). The
requisite isoxazolidine nucleosides 7 were readily pre-
pared via a hydroxylamine-Michael-addition route in
(11) (a) Xiang, Y.; Chen, J .; Schinazi, R. F.; Zhao, K. Tetrahedron
Lett. 1995, 36, 7193. (b) Xiang, Y.; Gi, H.; Niu, D.; Schinazi, R. F.;
Zhao, K. J . Org. Chem. 1997, 62, 7430. (c) Xiang, Y.; Gong, Y.; Zhao,
K. Tetrahedron Lett. 1996, 37, 4877.
(12) Baldwin, J . E.; Cha, J . K.; Kruse, L. I. Tetrahedron 1985, 41,
5241.
(10) Unpublished results.

368 J . Org. Chem., Vol. 63, No. 2, 1998
Notes
mixture (CDCl3) δ (173.5, 172.6), 159.2, (130.7, 130.4), 129.9,
114.1, (76.7, 75.4), 70.8, (62.3, 60.7), 55.7, 52.7, (35.4, 35.1), (30.8,
30.7), (21.0, 20.9), (18.8, 18.4). Anal. Calcd for C16H23NO4: C,
65.49; H, 7.92, N, 4.78. Found: C, 65.39; H, 7.87; N, 4.73.
3-P h e n yl-5-(m e t h oxyca r b on yl)-2-N -(p -m e t h oxyb e n z-
yl)isoxa zolid in e (6c): oil. 1H NMR of the mixture (CDCl3) δ
37 (m, 7H), 6.84 (d, 2H, J ) 8.7 Hz), 4.70 (dd, 1H, J ) 5.2, 8.8
Hz), 3.85-4.20 (m, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 2.75 (m, 2H);
13C NMR of the mixture (CDCl3) δ 172.7, 159.3, (139.1, 133.9),
(130.7, 130.2), 129.2, (128.9, 128.7) 128.4, 128.1, (114.2, 114.0),
75.8, 69.4, 60.5, 55.8, 52.9, 43.4. Anal. Calcd for C19H21NO4:
C, 69.70; H, 6.48, N, 4.28. Found: C, 69.73; H, 6.50; N, 4.22.
3-P h en yl-5-(p -m et h ylp h en yl)-2-N-(p -m et h oxyb en zyl)-
isoxa zolid in e (6d ): oil. 1H NMR of the mixture (CDCl3) δ
7.11-7.50 (m, 11H), 6.84 (d, 2H, J ) 8.7 Hz), 5.22 (t, 1H, J )
7.7 Hz), 3.85-4.12 (m, 3H), (3.80, 3.79) (s, 3H), 3.10 (td, 0.7H, J
) 7.3, 12.3 Hz), 2.63 (m, 0.3H), 2.34 (m, 1H), (2.36, 2.34) (s, 3H);
13C NMR of the mixture (CDCl3) δ 159.2, 140.5, 140.1, 137.5,
137.3, (130.9, 130.7), (129.6, 129.5), 128.3, (128.1, 128.0), 127.0,
126.6, 114.0, (79.1, 78.9), (71.1, 70.5), 60.2, 55.8, (49.0, 48.7), 21.7;
HRMS calcd for C24H25NO2: 359.1885. Found: 359.1896.
3-n -P r op yl-5-cya n o-2-N -(p -m e t h oxyb e n zyl)isoxa zoli-
d in e (6e): oil. 1H NMR of the mixture (CDCl3) δ 7.30 (d, 2H,
J ) 8.8 Hz), 6.88 (d, 2H, J ) 8.7 Hz), 4.70 (m, 1H), 4.12 (d, 1H,
J ) 12.8 Hz), 4.00 (d, 1H, J ) 12.8 Hz), 3.80 (3H, s), 2.81 (m,
2H), 2.34 (m, 1H), 1.45 (m, 4H), 0.92 (m, 3H); 13C NMR of the
mixture (CDCl3) δ 159.4, (130.8, 130.2), (129.2, 129.1), 119.8,
(114.4, 114.3), (65.3, 65.0), (64.5, 64.0), (61.7, 59.7), 55.8, (41.1,
Oxid a tion of Isoxa zolid in es. Gen er a l Con d ition B. To
a mixture of N-pMB-isoxazolidine (0.7 mmol), methylene chloride
(7 mL), H2O (0.7 mL), and triethylamine (0.07 mmol) was added
DDQ (1.8 mmol) at rt. After stirring at this temperature for
about 2 h (monitored by TLC), 15 mL of aqueous NaHCO3
solution was added and extracted with CH2Cl2. The combined
CH2Cl2 layers were dried (MgSO4), and the solvents were
removed in vacuo to give a crude product. This material was
then chromotographed on silica gel eluting with 20-60% EtOAc/
petroleum ether to give the pure product.
3-n -P r op yl-5-(m eth oxyca r bon yl)-2-isoxa zolin e (3a ): oil.
1H NMR (CDCl3) δ 4.97 (t, 1H, J ) 9.0 Hz), 3.77 (s, 3H), 3.19 (d,
2H, J ) 9.0 Hz), 2.34 (t, 2H, J ) 7.7 Hz), 1.60 (m, 2H), 0.95 (t,
3H, J ) 7.3 Hz); 13C NMR (CDCl3) δ 171.4, 158.7, 77.3, 53.2,
41.5, 29.7, 20.3, 14.3; HRMS calcd for C8H13NO3: 171.0895.
Found: 171.0896.
3-Isop r op yl-5-(m eth oxyca r bon yl)-2-isoxa zolin e (3b): oil.
1H NMR (CDCl3) δ 4.96 (t, 1H, J ) 8.9 Hz), 3.77 (s, 3H), 3.21 (d,
2H, J ) 8.9 Hz), 2.73 (septet, 1H, J ) 6.8 Hz), 1.18 (d, 6H, J )
6.8 Hz); 13C NMR (CDCl3) δ 171.4, 163.3, 77.4, 53.2, 39.6, 28.2,
20.7, 20.6; HRMS calcd for C8H13NO3: 171.0895. Found:
171.0893. Anal. Calcd for C8H13NO3: C, 56.13; H, 7.65, N, 8.18.
Found: C, 56.22; H, 7.65; N, 8.14.
3-P h en yl-5-(m eth oxyca r bon yl)-2-isoxa zolin e (3c): white
1
solid. mp 72-73 °C; H NMR (CDCl3) δ 7.68 (m, 2H), 7.41 (m,
3H), 5.19 (dd, 1H, J ) 8.06, 10.18 Hz), 3.82 (s, 3H), 3.65 (dd,
2H, J ) 8.06, 10.18 Hz); 13C NMR (CDCl3) δ 171.1, 156.4, 130.9,
129.2, 127.4, 78.5, 53.3, 39.5; HRMS calcd for C11H11NO3:
205.0739. Found: 205.0745. Anal. Calcd for C11H11NO3: C,
64.38; H, 5.40, N, 6.83. Found: C, 64.39; H, 5.45; N, 6.81.
3-P h en yl-5-(4-m eth ylp h en yl)-2-isoxa zolin e (3d ): white
40.6), (36.1, 35.1), (20.4, 20.2), (14.7, 14.5). Anal. Calcd for C15
20N2O2: C, 69.19; H, 7.76, N, 10.76. Found: C, 69.02; H, 7.73;
N, 10.79.
-
H
1
solid. mp 94-95 °C; H NMR (CDCl3) δ 7.73 (m, 2H), 7.43 (m,
3-[3-[(Tetr a h yd r o-2H-p yr a n -2-yl)oxy]p r op yl]-5-cya n o-2-
N-(p-m eth oxyben zyl)isoxa zolid in e (6f): oil. 1H NMR of the
mixture (CDCl3) δ (7.28, 7.27) (d, 2H, J ) 8.6 Hz), 6.85 (d, 2H,
J ) 8.7 Hz), 4.71 (dd, 0.5 H, J ) 4.1, 9.2 Hz), 4.67 (dd, 0.5 H, J
) 5.3, 8.8 Hz), 4.52 (m, 1H), 3.65-4.15 (m, 4H), 3.77 (3H, s),
3.40 (m, 2H), 2.83 (m, 2H), 2.35 (m, 1H), 1.65 (m, 10H); 13C NMR
of the mixture (CDCl3) δ (159.6, 159.4), (131.3, 130.8, 130.2),
(129.3, 129.1, 129.0), (120.1, 119.7), (114.3, 114.2, 114.1), (99.5,
99.4), 67.6, (65.3, 65.2, 65.0), (64.5, 64.0), 63.0, (61.7, 69.7), 55.8,
(41.0, 40.5), 31.3, (31.0, 30.9, 29.8), (27.3, 27.1), 26.1, 20.3. Anal.
Calcd for C20H28N2O4: C, 66.63; H, 7.84, N, 7.77. Found: C,
66.62; H, 7.77; N, 7.87.
3-n -P r op yl-5-a cet oxy-2-N-(p -m et h oxyb en zyl)isoxa zoli-
d in e (6g): oil. 1H NMR of the mixture (CDCl3) δ (7.28, 7.27)
(d, 2H, J ) 8.7 Hz), (6.86, 6.85) (d, 2H, J ) 8.7 Hz), 6.29 (overlap,
1H), 3.75-4.15 (two overlap dd, 2H), 3.79 (3H, s), (3.19, 2.81)
(m, 1H), 2.69 (dd, 0.5H, J ) 8.4, 6.4 Hz), 2.50 (ddd, 0.5H, J )
1.1, 6.4, 13.2 Hz), 1.97-2.19 (m, 1H), (2.06, 2.05) (s, 3H), 1.42
(m, 4H), 0.90 (two overlap t, 3H); 13C NMR of the mixture
(CDCl3) δ (171.0, 170.4), (159.4, 159.3), 131.0, (129.7, 129.0),
(114.2, 114.1), (98.0, 96.0), (64.7, 63.8), (63.3, 60.7), 55.8, (42.9,
42.5), (36.5, 35.1), (22.1, 22.0), 20.6, (14.8, 14.6). Anal. Calcd
for C16H23NO4: C, 65.49; H, 7.92, N, 4.78. Found: C, 65.65; H,
7.95; N, 4.84.
3-Isop r op yl-5-a cetoxy-2-N-(p-m eth oxyben zyl)isoxa zoli-
d in e (6h ): oil. 1H NMR of the mixture (CDCl3) δ 7.27 (d, 2H,
J ) 8.7 Hz), (6.84, 6.83) (d, 2H, J ) 8.7 Hz), 6.30 (overlap, 1H),
3.80-4.17 (two overlap dd, 2H), 3.78 (3H, s), 3.01 (td, 0.3H, J )
7.1, 8.1 Hz), 2.72 (td, 0.7H, J ) 6.5, 8.5 Hz), 2.45 (m, 1H), 2.17
(m, 1H), (2.08, 2.04) (s, 3H), 1.60-1.92 (m, 1H), 0.89 (overlap,
6H); 13C NMR of the mixture (CDCl3) δ (170.9, 170.3), 159.3,
(130.9, 130.8), (130.2, 129.3), (114.2, 114.1), (98.8, 96.4), (69.6,
69.3), (65.0, 61.4), 55.8, (39.6, 37.9), (32.1, 29.6), (22.1, 22.0),
(21.3, 20.8), (19.0, 17.8). Anal. Calcd for C16H23NO4: C, 65.49;
H, 7.92, N, 4.78. Found: C, 65.37; H, 7.89; N, 4.74.
Oxid a tion of Isoxa zolid in es. Gen er a l Con d ition A. To
a mixture of N-pMB-isoxazolidine 6 (0.7 mmol), methylene
chloride (7 mL), and H2O (0.7 mL) was added DDQ (1.8 mmol)
at rt. After stirring at this temperature for about 3 h (monitored
by TLC), 15 mL of aqueous NaHCO3 solution was added and
extracted with CH2Cl2. The combined CH2Cl2 layers were dried
(MgSO4), and the solvents removed in vacuo to give a crude
product. This material was then chromotographed on silica gel
eluting with 20-60% EtOAc/petroleum ether (5-10% MeOH/
EtOAc for 8a and 8b) to give the pure product.
3H), 7.31 (d, 2H, J ) 8.14 Hz), 7.20 (d, 2H, J ) 8.14 Hz), 5.72
(dd, 1H, J ) 10.95, 8.50 Hz), 3.76 (dd, 1H, J ) 10.95, 16.66 Hz),
3.34 (dd, 1H, J ) 8.50, 16.66 Hz), 2.37 (s, 3H); 13C NMR (CDCl3)
δ 156.6, 138.5, 138.4, 130.5, 129.8, 129.2, 127.2, 126.4, 83.1, 43.6,
21.8; HRMS calcd for C16H15NO: 237.1154. Found: 237.1149.
Anal. Calcd for C16H15NO: C, 80.98; H, 6.37, N, 5.90. Found:
C, 81.08; H, 6.45; N, 5.87.
3-n -P r opyl-5-cyan o-2-isoxazolin e (3e): oil. 1H NMR (CDCl3)
δ 5.17 (dd, 1H, J ) 10.3, 6.1 Hz), 3.30 (m, 2H), 2.40 (t, 2H, J )
7.7 Hz), 1.64 (m, 2H), 0.99 (t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3)
δ 159.0, 117.8, 66.1, 43.7, 29.5, 20.2, 14.3; HRMS calcd for
C7H10N2O: 138.0793. Found: 138.0801.
3-[3-[(Tetr a h yd r o-2H-p yr a n -2-yl)oxy]p r op yl]-5-cya n o-2-
isoxa zolin e (3f): oil. 1H NMR (CDCl3) δ 5.17 (dd, 1H, J )
10.52, 6.46 Hz), 4.56 (t, 1H, J ) 1.84 Hz), 3.82 (m, 2H), 3.40 (m,
4H), 2.55 (t, 2H, J ) 7.70 Hz), 1.91 (m, 2H), 1.60 (m, 6H); 13C
NMR (CDCl3) δ 159.0, 117.8, 99.6, 66.9, 66.1, 63.1, 43.9, 31.2,
26.9, 25.9, 25.0, 20.3; HRMS calcd for C12H18N2O3: 238.1317.
Found: 238.1299.
3-n -P r op yl-5-a cetoxy-2-isoxa zolin e (3g): oil. 1H NMR
(CDCl3) δ 6.66 (dd, 1H, J ) 6.7, 1.4 Hz), 3.21 (dd, 1H, J ) 18.0,
6.7 Hz), 2.87 (dd, 1H, J ) 18.0, 1.4 Hz), 2.43 (t, 2H, J ) 7.6 Hz),
2.06 (s, 3H), 1.64 (m, 2H), 0.99 (t, 3H, J ) 7.4 Hz); 13C NMR
(CDCl3) δ 170.2, 159.7, 95.8, 43.9, 29.7, 21.7, 20.4, 14.2; HRMS
calcd for C8H13NO3: 171.0895. Found: 171.0894. Anal. Calcd
for C8H13NO3: C, 56.13; H, 7.65, N, 8.18. Found: C, 56.68; H,
7.50; N, 7.67.
3-Isop r op yl-5-a cetoxy-2-isoxa zolin e (3h ): oil. 1H NMR
(CDCl3) δ 6.65 (dd, 1H, J ) 6.7, 1.4 Hz), 3.21 (dd, 1H, J ) 18.5,
6.7 Hz), 2.89 (dd, 1H, J ) 18.5, 1.4 Hz), 2.81 (septet, 1H, J )
6.9 Hz), 1.22 (d, 6H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 170.2, 156.2,
95.9, 42.2, 28.3, 21.7, 20.8, 20.5; HRMS calcd for C8H13NO3:
171.0895. Found: 171.0886.
(5′S)-6-Ch lor o-9-[3-(2,2-d im et h yl-1,3-d ioxola n -4-yl)-4,5-
dih ydr o-1,2-isoxazol-5-yl]pu r in e (8a): oil.11c 1H NMR (CDCl3)
δ 8.71 (s, 1H), 8.18 (s, 1H), 6.77 (t, 1H, J ) 5.6 Hz), 5.11 (t, 1H,
J ) 6.1 Hz), 4.36 (dd, 2H, J ) 1.1, 6.0 Hz), 3.75 (d, 2H, J ) 5.9
Hz), 1.46 (s, 3H), 1.41 (s, 3H).
(5′S)-N4-(ter t-Bu t yloxyca r b on yl)-1-[3-(2,2-d im et h yl-1,3-
d ioxola n -4-yl)-4,5-d ih yd r o-1,2-isoxa zol-5-yl]cytosin e (8b):
oil.11c 1H NMR (CDCl3) 7.62 (d, 1H, J ) 7.5 Hz), 7.21 (d, 1H,
7.3 Hz), 6.53 (dd, 1H, J ) 2.5, 8.6 Hz), 4.96 (t, 1H, J ) 5.5 Hz),
3.94 (m, 1H), 3.72 (dd, 1H, 8.4, 19.0 Hz), 3.17 (dd, 1H, J ) 2.6,
19.1 Hz), 1.51 (s, 9H), 1.39 (s, 3H), 1.37 (s, 3H).

Notes
(5′S) 9-[3-{Hyd r oxym eth yl)-4,5-d ih yd r o-1,2-isoxa zol-5-
J . Org. Chem., Vol. 63, No. 2, 1998 369
financial support from the NSF Faculty Early Career
Development Program (CHE-9502068), New York Uni-
versity Technology Transfer Fund, and Pharmalytics.
yl]a d en in e (9a ): white crystal. mp 76-78 °C; 1H NMR
(CD3OD) δ 8.20 (s, 1H), 8.14 (s, 1H), 6.85 (dd, 1H, J ) 4.2, 8.1
Hz), 4.53 (s, 2H), 3.73 (dd, 1H, J ) 6.2, 8.0 Hz), 3.33 (dd, 1H, J
) 4.3, 8.0 Hz). Anal. Calcd for C9H10N6O2 2H2O: C, 39.94; H,
5.22, N, 31.08. Found: C, 40.40; H, 5.57; N, 29.61.
(5′S)-1-[3-(Hydr oxym eth yl)-4,5-dih ydr o-1,2-isoxazol-5-yl]-
cytosin e (9b): mp 168 °C dec; [R]25D ) +270.1 (c 0.11, MeOH).
1H NMR (CD3OD) δ 7.74 (d, 1H, J ) 7.8 Hz), 6.57 (dd, 1H, J )
2.6, 9.2 Hz), 6.11 (d, 1H, J ) 7.8 Hz), 4.40 (s, 2H), 3.71 (dd, 1H,
J ) 9.2, 17.8 Hz), 3.37 (dd, 1H, J ) 2.4, 17.0 Hz). Anal. Calcd
for C8H9N3O4‚0.5H2O: C, 43.64; H, 4.51, N, 19.08. Found: C,
43.45; H, 4.38; N, 18.64.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of the intermediates and final products (36
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Ack n ow led gm en t. We thank Lauren Goldenstein
for her technical assistance. We acknowledge the
J O971021N