Homochiral α-D- and β-D-isoxazolidinylthymidines via 1,3-dipolar cycloaddition

Article abstract of DOI:10.1021/jo990576a

The introduction of chiral auxiliaries at the C- or N-atom in starting nitrones has been investigated as a stereoselective synthetic route to heterocyclic nucleoside analogues. The carbohydrate auxiliary at nitrogen atom gave the best results, thus allowi

Full text of DOI:10.1021/jo990576a

VOLUME 64, NUMBER 26
DECEMBER 24, 1999
© Copyright 1999 by the American Chemical Society
Articles
Hom och ir a l r-D- a n d â-D-Isoxa zolid in ylth ym id in es via 1,3-Dip ola r
Cycloa d d ition †
Ugo Chiacchio,*,‡ Antonino Corsaro,‡ Giuseppe Gumina,‡ Antonio Rescifina,‡
Daniela Iannazzo,§ Anna Piperno,§ Giovanni Romeo,§ and Roberto Romeo§
Dipartimento di Scienze Chimiche, Viale A. Doria 6, Universita` di Catania, Italy, and
Dipartimento Farmaco-Chimico, Viale SS. Annunziata, Universita` di Messina, Italy
Received March 31, 1999
The introduction of chiral auxiliaries at the C- or N-atom in starting nitrones has been investigated
as a stereoselective synthetic route to heterocyclic nucleoside analogues. The carbohydrate auxiliary
at nitrogen atom gave the best results, thus allowing an easy and enantioselective synthesis of
isoxazolidinyl thymine 26.
In tr od u ction
HBV) activities with no significant drug resistance after
1 year of clinical trials when used in combination with
AZT5 (Figure 1).
The synthesis of modified nucleosides has recently
received considerable attention in the search for com-
pounds with antiviral and anticancer activity.1 In this
context, exciting biological results have been obtained
from a new generation of nucleoside analogues where the
ribose moiety has been replaced by alternative hetero-
cyclic rings.2 In particular, the insertion of a second
heteroatom in the furanosyl ring has led to the prepara-
tion of dioxolane-T (1) and 3TC (2), which contain a
dioxolane or oxathiolane ring, respectively.3,4 These
compounds have shown excellent antiviral (HIV and
Nucleosides 3 and 4, containing an isoxazoline or
isoxazolidine moiety, are of current interest as potential
antiviral agents.3d,6 As a consequence, following the first
report on the synthesis of compound 4,7 a series of
synthetic efforts have been devoted toward the prepara-
tion of suitable isoxazolidinyl nucleosides.8,9
(3) (a) Kim, H. O.; Schinazi, R. F.; Shanmuganathan, K.; J eong, L.
S.; Beach, J . W.; Nampally, S.; Channon, B. L.; Chu, C. K. J . Med.
Chem. 1993, 36, 519. (b) Weaver, R.; Gilbert, I. H. Tetrahedron 1997,
53, 5537. (c) Talekar, R. R.; Wightman, R. H. Tetrahedron 1997, 53,
3831. (d) Gi, H. J .; Xiang, Y.; Schinazi, R. F.; Zhao, K. J . Org. Chem.
1997, 62, 88.
(4) J eong, L. S.; Schinazi, R. F.; Beach, J . W.; Kim, H. O.; Nampally,
S.; Shanmuganathan, K.; Alves, A. J .; McMillan, A.; Chu, C. K.; Matis,
R. J . Med. Chem. 1993, 36, 181.
(5) Kuritzkes, D. In HIV Clinical Management; Medscape Inc.: 1999;
Vol. 13.
(6) Tronchet, J . M. J .; Iznaden, M.; Barbalat-Rey, F.; Komaromi, I.;
Dolatshahi, N.; Bernardinelli, G. Nucleosides Nucleotides 1995, 14,
1737.
† Electronic Conference on Heterocyclic Chemistry; Rzepa, H. S.,
Kappe, C. O., Eds.; 29 J une-24 J uly, 1998.
‡ Universita` di Catania.
§ Universita` di Messina.
(1) (a) Pe´rigaud, C.; Gosselin, G.; Imbach, J . L. Nucleosides Nucle-
otides 1992, 11, 903. (b) Thomas, H. Drugs Today 1992, 28, 311.
Bonnet, P. A.; Robins, R. K. J . Med. Chem. 1995, 36, 635. (c) Mani, S.;
Ratain, M. J . Curr. Opin. Oncol. 1995, 8, 525. (d) Unger, C. J . Cancer.
Res. Clin. Oncol. 1996, 122, 189. (e) Nair, V.; J ahnke, T. S. Antimicrob.
Agents Chemother. 1995, 39, 1017.
(2) (a) Huang, B.; Chen, B.; Hui, Y. Synthesis 1993, 769. (b) De
Clercq, E. J . Med. Chem. 1995, 38, 2491. (c) Schinazi, R. F.; Mead, J .
R.; Feorino, P. M. AIDS RES. Hum. Retroviruses 1992, 8, 963.
(7) Tronchet, J . M. J .; Iznaden, M.; Barlat-Rey, F.; Dhimane, H.;
Ricca, A.; Balzarini, J .; De Clercq, E. Eur. J . Med. Chem. 1992, 27,
555.
10.1021/jo990576a CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/02/1999

9322 J . Org. Chem., Vol. 64, No. 26, 1999
Chiacchio et al.
cis stereoisomer; unfortunately, all the attempts to obtain
pure compounds 8a and 8b failed.
The obtained results indicate that the reaction pro-
ceeds with a good control of cis/ trans diastereoselectivity
and a satisfactory level of asymmetric induction (5:1).
Nitrone 7 exists as a mixture of E and Z isomers, with
the more reactive E isomer predominating (4:1).13 Both
cycloadducts 8a and 8b arise from reaction of E nitrone
through an exo TS; the major stereoisomer was tenta-
tively assigned the stereochemistry indicated in 8a
(3S,5S), according to PM3 calculations, which show that
the E-exo transition state (addition of vinyl acetate to si
face of nitrone) leading to this compound is about 1.1 kcal/
mol more stable than E-exo transition state (re attack)
leading to its stereoisomer 8b (Figure 2).
We have, then, exploited an alternative route directed
to the synthesis of homochiral N,O-nucleosides, based on
the introduction of a stereocenter in R to the nitrone
functionality (Scheme 2).
F igu r e 1.
Nitrone 12 has been prepared starting from (-)-methyl
lactate 10, which has been silylated with tert-butyldi-
phenylsilyl chloride, reduced with DIBALH to the cor-
responding aldehyde 11, and finally converted into the
expected nitrone by reaction with methyl hydroxylamine
hydrochloride. Nitrone 12, in a Z configuration as con-
firmed by NOE experiments, has been reacted with vinyl
acetate to give two epimeric isoxazolidines 13 and 14 (1:1
ratio), in good overall yield (88%).14
We have previously reported the synthesis of nucleo-
sides 4,10 which bear pyrimidine bases, in a racemic form;
the synthetic scheme involves the 1,3-dipolar cycloaddi-
tion11 of C-substituted carbonylnitrones 5 to vinyl acetate,
followed by nucleosidation of the resulting 5-acetyloxy-
isoxazolidine derivatives with persylilated nucleobases.
In this paper, we have turned our attention to the
asymmetric version of this route, by the use of chiral
dipoles,12 and we report herein the successful implemen-
tation of this strategy directed toward the stereoselective
synthesis of isoxazolidinyl nucleosides 4.
The mixture of compounds 13 and 14 has been coupled
with silylated thymine to give, after deprotection with
TBAF, the enantiomerically pure R- and â-nucleosides
15 and 16 in a 3:2 ratio, respectively (57% and 38% yield;
[R]2D5 ) -24.7 for R-isomer and [R]2D5 ) +90.1 for â-iso-
mer).
Resu lts a n d Discu ssion
In the first approach, we exploited the introduction of
a chiral auxiliary, as (-)-menthol, in the starting nitrone.
Thus, nitrone 7 (prepared from 6) through a transesteri-
fication reaction with (-)-menthol (1:1.5 ratio) in the
presence of TiCl4 as catalyst and molecular sieves reacted
with vinyl acetate to give three stereoisomeric compounds
(80% global yield), two of them (8a and 8b) with a C3-
C5 trans configuration (relative ratio 5:1) and one (9) with
a C3-C5 cis configuration (cis/ trans ratio 1:8). Structures
of the obtained compounds have been assigned on the
basis of NMR data and by NOE measurements (Scheme
1).
Nucleosides 15 and 16 have been separated by flash
chromatography, and their structures have been mainly
established by 1H NOEDS. While, in compound 16,
diagnostic contacts were observed between H3′′ and H6
and between H3′ and H5′, no such effects were detectable
in the R anomeric counterpart. In addition, an NOE
between H3′ and H6, in compound 15, clearly indicated a
syn relationship for these protons.
The results thus obtained can be rationalized as
follows: the formation, in the coupling reaction, of enan-
tiomerically pure R- and â-nucleosides 15 and 16 indi-
cates that isoxazolidines 13 and 14 are epimeric only at
C5. Thus, the presence of the chiral center located in po-
sition R with respect to the nitrone functionality induces
a some degree of asymmetric induction: with respect to
the above-reported cycloaddition process, the cycloaddi-
tion reaction shows a nearly complete diastereofacial
selectivity. In fact, conformations A and B are the major
conformations available to the Z-nitrone for asymmetric
induction:15 PM3 calculations confirm that A is more
stable than B by about 3.0 kcal/mol (Figure 3).
Flash chromatography of the crude reaction mixture
allowed the separation of two trans derivatives from the
(8) (a) Adams, D. R.; Boyd, A. S. F.; Ferguson, R.; Grierson, D. S.;
Monneret, C. Nucleosides Nucleotides 1998, 17, 1053. (b) Merino, P.;
Franco, S.; Garces, N.; Merchan, F. L.; Tejero, T. J . Chem. Soc., Chem.
Commun. 1998, 493. (c) Leggio, A.; Liguori, A.; Procopio, A.; Siciliano,
C.; Sindona, G. Tetrahedron Lett. 1996, 37, 1277.
(9) (a) Xiang, Y.; Gi, H. J .; Niu, D.; Schinazi, R. F.; Zhao, K. J . Org.
Chem. 1997, 62, 7430. (b) Xiang, Y.; Gong, Y.; Zhao, K. Tetrahedron
Lett. 1996, 37, 4877. (c) Pan, S.; Amankulor, N. M.; Zhao, K.
Tetrahedron 1998, 54, 6587.
(10) Chiacchio, U.; Gumina, G.; Rescifina, A.; Romeo, R.; Uccella,
N.; Casuscelli, F.; Piperno, A.; Romeo, G. Tetrahedron 1996, 52, 8889.
(11) (a) Chiacchio, U.; Corsaro, A.; Pistara`, V.; Rescifina, A.; Romeo,
G.; Romeo, R. Tetrahedron 1996, 52, 7875. (b) Chiacchio, U.; Corsaro,
A.; Gumina, G.; Pistara`, V.; Rescifina, A.; Alessi, M.; Piperno, A.;
Romeo, G.; Romeo, R. Tetrahedron 1997, 53, 13855. (c) Chiacchio, U.;
Rescifina, A.; Romeo, G. In Targets in Heterocyclic Systems. Chemistry
and Properties; Attanasi, O. A., Spinelli, D., Eds.; Italian Society of
Chemistry: 1997; Vol. 1, p225. (d) Chiacchio, U.; Piperno, A.; Rescifina,
A.; Romeo, G.; Uccella, N. Tetrahedron 1998, 54, 5695. (e) Chiacchio,
U.; Iannazzo, D.; Rescifina, A.; Romeo, G. J . Org. Chem. 1999, 64, 28.
(12) (a) Frederickson, M. Tetrahedron 1997, 53, 403. (b) Gothelf, K.
V.; J ørgensen, K. A. Chem. Rev. 1998, 98, 863.
(13) (a) DeShong, P.; Dicken, C. M.; Staib, R. R.; Freyer, A. J .;
Weinreb, S. M. J . Org. Chem. 1982, 47, 4397. (b) Kametani, T.; Chu,
S.-D.; Honda, T. J . Chem. Soc., Perkin Trans. 1 1998, 1593.
(14) Compounds 13 and 14 have been separated by HPLC, and their
configuration have been assigned by NOEDS experiments.
(15) (a) Merchan, F. L.; Merino, P.; Tejero, T. In The Molecular
Modelling Electronic Conference (TMMeC-1); Ventura, O. N., XCachau,
R. E., Eds.; Montevideo Theoretical Chemistry Labratory: Universidad
de la Republica Montevideo (Uruguay), 1997; Internet: http://uqbar.n-
cifcrf.gov/agora/. (b) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero,
T. J . Org. Chem. 1996, 61, 9028.

Homochiral R-D- and â-D-Isoxazolidinylthymidines
J . Org. Chem., Vol. 64, No. 26, 1999 9323
Sch em e 1a
a
Reaction conditions: (a) TiCl4; (b) vinyl acetate, 70 °C, 48 h.
sides: the chiral auxiliary can be easily introduced before
the cycloaddition process and removed subsequently to
give an N,O-nucleoside unsubstituted at the nitrogen
atom.
Thus, 5-O-tert-butyldiphenylsilyl-2,3-O-isopropylidene-
D-ribofuranose (17) was reacted with hydroxylamine
hydrochloride to give, in a nearly quantitative yield, a
Z/ E mixture of the corresponding oxime 18 in equilib-
rium with the corresponding D-ribosyl hydroxylamine 19
(relative ratio 18/19 50:1). Subsequent treatment of 19
with ethyl glyoxylate and vinyl acetate at 60 °C for 14 h
gave, through the intermediate nitrone 20, a mixture of
two homochiral isoxazolidines 21 and 22, epimeric at C5,
F igu r e 2.
1
Sch em e 2a
in a relative ratio of trans/cis 1:1. Moreover, the H NMR
analysis of the crude reaction mixture shows the presence
of another unidentified diastereoisomer (minor) (Scheme
3).
Independent hydrolysis of isoxazolidines 21 and 22,
followed by oxidation with potassium permanganate, led
to 23. This result confirms that the isoxazolidines at hand
are epimeric at C5.17
Contrary to the poor cis/trans diastereoselectivity, the
diastereofacial selectivity of the cycloaddition process is
high. The results obtained in this cycloaddition may be
interpreted in terms of the “O-endo” transition-state
model18 as shown in C, by involving, according to MNDO-
MM+ calculations,19 which take in account the anomeric
effect,20 the E isomer as the more reactive form of
nonisolated nitrone 20: thus, two isomers 21 and 22 arise
from the exo and endo attack on the re face of 20,
respectively (Figure 4).
Subsequent coupling of 21 or 22 with silylated thymine
afforded the N,O-nucleosides 24 (â) and 25 (R) (1:2.5
relative ratio) in enantiomerically pure form (Scheme 3).
Configurational assignments have been performed on
the basis of NOE experiments. Irradiation of the H5′
signal in 24 induces a positive NOE effect on the
downfield resonance of methylene protons at C4′; in turn,
irradiation of this proton gives rise to enhancement of
the H3′ resonance, so indicating that these protons are
in a topological cis arrangement. Analogously, R-nucleo-
side 25 shows a NOE correlation between H5′ and the
downfield resonance at C4′, but only a negligible NOE
effect between this last resonance and H3′.
a
Reaction conditions: (a) TBDPSCl, imidazole, CH2Cl2, 0 °C,
3 h; (b) DIBALH, diethyl ether, -78 °C, 6 h; (c) N-methylhydrox-
ylamine hydrochloride, AcONa, EtOH, rt, 3 h; (d) vinyl acetate,
70 °C, 48 h; (e) O,O′-bis(trimethylsilyl)thymine, SnCl4, CH2Cl2,
overnight; (f) TBAF, THF, 3 h.
According to this rationale, the dipolarophile ap-
proaches the si face of nitrone and the cycloaddition
proceeds with no preference for an endo or exo TS, in
accord with the results reported with similar nitrones.13,15
On this basis, the configurational assignment to 15 and
16 has been performed by assuming that C3 has a S
configuration controlled by the chiral center present in
the starting nitrone, derived from the initial (-)-lactate.
The 1,3-dipolar cycloaddition methodology for the
enantioselective synthesis of N,O-nucleosides was ex-
tended to the examination of a nitrone containing the
chiral center at the nitrogen atom.16
(17) See below:
(18) Kasahara, K.; Iida, H.; Kibasyashi, C. J . Org. Chem. 1989, 54,
2225.
(19) Besler, B. H.; Merz, K. M.; Kollman, P. A. J . Comput. Chem.
1990, 11, 431.
N-Glycosylnitrones can serve as versatile building
blocks in the preparation of the target modified nucleo-
(16) (a) Vasella, A. Helv. Chim. Acta 1977, 60, 426. (b) Mzengeza,
S.; Whitney, R. A. J . Org. Chem. 1988, 53, 4074.
(20) Dewar, M. J . S.; Thiel, W. J . Am. Chem. Soc. 1977, 99, 4899;
1977, 99, 4907.

9324 J . Org. Chem., Vol. 64, No. 26, 1999
Chiacchio et al.
Sch em e 3a
a
Reaction conditions: (a) hydroxylamine hydrochloride, pyridine, rt, 1 h; (b) vinyl acetate, ethyl glyoxalate, 60 °C, 14 h; (c) BSA,
thymine, Me3SiOTf, MeCN, reflux, 1 h; (d) reaction of 25 with 3.7% HCl in EtOH, rt, 3 h.
and 22 can be directly converted into nucleosides 24, and
25 without any tedious HPLC purification, because they
are epimeric at C5. The synthetic pattern here described
shows its versatility in the potential construction of other
nucleosides with different purine and pyrimidine bases.
Furthermore, the process allows an easy entry to enan-
tiomerically pure N-unsubstituted compounds that have
already shown interesting biological activity in vitro.21
F igu r e 3.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected.
NMR spectra were recorded at 200 and 500 MHz (1H) and at
50 and 125 MHz (13C) and are reported in ppm downfield from
TMS. Thin-layer chromatography was done on plates coated
with Merck 60 F254 silica gel. Silica gel chromatography was
done with Macherey-Nagel 60 M (0.040-0.063 mm). Prepara-
tive radial chromatography was done on glass rotors coated
with Merck 60 PF254 silica gel (1-4 mm layer). All reactions
involving air-sensitive agents were conducted under a nitrogen
atmosphere. All reagents were purchased from Aldrich or
Acros Chimica and were used without further purification.
Solvents for chromatography were distilled at atmospheric
pressure prior to use and dried using standard procedures.
HPLC purifications were made with a semipreparative column
(Partisil-10 Magnum 9, 9.4 × 250 mm). The purity of all
homochiral compounds has been tested with a Nucleosil
Chiral-2, 4 × 250 mm column with mixtures of n-hexane-2-
propanol as eluent.
F igu r e 4.
(3S,5S)-, (3R,5R)-, a n d (3S,5R)-5-Acetyloxy-3-[(1′R,2′S,-
5′R)-m en th oxycar bon yl]-2-m eth ylisoxazolidin e (8a,b an d
9). TiCl4 (0.1 M solution in 1,2-dichloroethane, 10 mL, 1 mmol)
and (-)-menthol (2.81 g, 18 mmol) were added successively to
a stirred suspension of molecular sieves 4A (20 g) and nitrone
6 (1.57 g, 12 mmol) in dry 1,2-dichloroethane (300 mL) at room
temperature under a nitrogen atmosphere. After the mixture
was stirred for 24 h, a small amount of water and Celite were
added to the mixture, and the mixture was filtered through a
pad of Celite. The filtrate was diluted with water, extracted
Finally, the synthetic scheme devoted toward the
synthesis of homochiral N,O-nucleosides has been com-
pleted by the selective cleavage of the sugar moiety,
performed by treatment with 3.7% aqueous HCl. Thus,
25, as the selected model, furnishes the N-unsubstituted
nucleoside 26 in 60% yield (Scheme 3).
In conclusion, the 1,3-dipolar cycloaddition methodol-
ogy, using nitrones carrying the carbohydrate-derived
chiral auxiliaries developed by Vasella,16 provides the
basis for an enantioselective synthesis of modified N,O-
nucleosides. Moreover, the mixture of isoxazolidines 21
(21) Leggio, A.; Liguori, A.; Maiuolo, L.; Napoli, A.; Procopio, A.;
Siciliano, C.; Sindona, G. J . Chem. Soc., Perkin Trans. 1 1997, 3097.

Homochiral R-D- and â-D-Isoxazolidinylthymidines
J . Org. Chem., Vol. 64, No. 26, 1999 9325
with dichloromethane, dried over sodium sulfate, and concen-
trated in vacuo. The residue, purified by column flash chroma-
tography on silica gel (cyclohexane/ethyl acetate 1:4), gave an
E/Z mixture (4:1) of C-[(1R,2S,5R)-menthoxycarbonyl]-N-meth-
ylnitrone (7)22 (2.75 g, 95%) as a light yellow oil: [R]2D5 ) -63.9
(40 mL) was heated at 70 °C, in a sealed tube, for 24 h. The
reaction mixture was evaporated, and the residue was purified
by column chromatography (cyclohexane/ethyl acetate 3:1) and
then by HPLC with a linear gradient of 2-propanol (2-2.5%,
0-6 min, flow 3.5 mL/min) in n-hexane. The first eluted
product was (3S,5R)-5-acetyloxy-3-[(1S)-1-(tert-butyldiphenyl-
silyloxy)ethyl]-2-methylisoxazolidine 14 (tR 5.6 min, 0.5 g, 44%)
as a colorless oil: [R]2D5 ) +76.4 (c 0.14, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 1.05 (d, 3H, J ) 6.3 Hz), 1.07 (s, 9H),
2.01 (s, 3H), 2.45 (ddd, 1H, J ) 1.8, 5.9, 11.2 Hz, H4a), 2.61
(ddd, 1H, J ) 6.0, 8.8, 11.2 Hz, H4b), 2.62 (ddd, 1H, J ) 3.0,
5.9, 8.8 Hz, H3), 2.68 (s, 3H), 3.91 (dq, 1H, J ) 3.0, 6.3 Hz,
H3′), 6.23 (dd, 1H, J ) 1.8, 6.0 Hz, H5) 7.36-7.44 (m, 6H), 7.66-
7.74 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 20.3, 21.3, 26.9,
29.7, 38.5, 45.4, 68.0, 73.4, 95.3, 127.5, 127.6, 129.6, 129.7,
133.4, 134.4, 135.9, 136.1, 170.6. Anal. Calcd for C24H33NO4-
Si: C, 67.41; H, 7.78; N, 3.28. Found: C, 67.30; H, 7.79; N,
3.28. Further elution gave (3S,5S)-5-acetyloxy-3-[(1S)-1-(tert-
butyldiphenylsilyloxy)ethyl]-2-methylisoxazolidine 13 (tR 5.9
min, 0.5 g, 44%) as a colorless oil: 1H NMR (CDCl3, 500 MHz)
δ 1.08 (s, 9H), 1.09 (d, 3H, J ) 6.2 Hz), 2.06 (s, 3H), 2.45 (ddd,
1H, J ) 1.8, 5.5, 11.6 Hz, H4a), 2.65 (ddd, 1H, J ) 6.1, 9.2,
11.6 Hz, H4b), 2.97 (ddd, 1H, J ) 5.5, 5.8, 9.2 Hz, H3), 2.81 (s,
3H), 3.79 (dq, 1H, J ) 5.8, 6.2 Hz, H3′), 6.22 (dd, 1H, J ) 1.8,
6.1 Hz, H5) 7.36-7.44 (m, 6H), 7.66-7.72 (m, 4H); 13C NMR
(CDCl3, 125 MHz) δ 19.3, 20.3, 26.8, 29.7, 38.4, 45.2, 69.0, 75.6,
97.7, 127.4, 127.6, 129.6, 129.7, 133.3, 134.4, 135.8, 136.1,
170.6. Anal. Calcd for C24H33NO4Si: C, 67.41; H, 7.78; N, 3.28.
Found: C, 67.55; H, 7.76; N, 3.29.
The crude epimeric mixture of isoxazolidines 13 and 14 (950
mg, 2.22 mmol) and O,O′-bis(trimethylsilyl)thymine (0.82 g,
3.0 mmol) were dissolved in anhydrous CH2Cl2 (10 mL) under
a nitrogen atmosphere. This solution was cooled to 0 °C, and
SnCl4 (0.5 mmol) was added. The reaction mixture was then
warmed to room temperature, left to stir overnight, and finally,
poured slowly into a mixture of cold saturated aqueous
NaHCO3 (5 mL) and CHCl3 (10 mL). The resulting emulsion
was separated by filtration through Celite, the aqueous layer
was further extracted with ethyl acetate (3 × 10 mL), and
the combined organic layers were dried over Na2SO4 and
evaporated under reduced pressure. The residue, obtained as
a light yellow oil, was characterized as an anomeric mixture
(R:â 3:2) of (3′S,5′S)- and (3′S,5′R)-1-(5′-acetyloxy-3′-[(1S)-1-
(tert-butyldiphenylsilyloxy)ethyl]-2′-methyl-1′,2′-isoxazolidinyl)-
thymine (0.943 g, 86%): 1H NMR (CDCl3, 200 MHz) δ 1.04 (s,
9H), 1.05 (s, 9H), 1.81 (d, 3H, J ) 1.1 Hz), 1.92 (d, 3H, J ) 1.1
Hz), 2.02 (s, 3H), 2.05 (s, 3H), 2.45-3.02 (m, 6H), 2.62 (s, 6H),
3.90 (m, 2H), 6.08 (m, 2H, H5) 7.30-7.78 (m, 22H).
1
(c 1.08, CHCl3); H NMR (CDCl3, 200 MHz) E-isomer δ 0.85
(d, 3H, J ) 7.0 Hz), 0.88 (d, 3H, J ) 6.9 Hz), 0.91 (d, 3H, J )
6.9 Hz), 1.65 (m, 2H), 1.81-1.95 (m, 4H), 2.43 (m, 3H), 4.18
(s, 3H), 4.71 (ddd, 1H, J ) 4.5, 10.8, 10.8 Hz), 7.04 (s, 1H); 13
C
NMR (CDCl3, 50 MHz) δ 17.6, 19.5, 22.3, 23.2, 26.2, 31.7, 34.1,
40.9, 48.3, 50.5, 76.1, 128.6, 165.1. Anal. Calcd for C13H23NO3:
C, 64.70; H, 9.61; N, 5.80. Found: C, 64.57; H, 9.62; N, 5.80.
A solution of nitrone 7 (2.7 g, 11.2 mmol) in vinyl acetate
(40 mL) was heated at 70 °C, in a sealed tube, for 24 h. The
reaction mixture was evaporated and the residue subjected to
flash chromatography (cyclohexane/ethyl acetate 9:1). First
eluted fractions gave an inseparable mixture of 8a ,b (5:1) (2.11
g, 72%) as a colorless oil: 1H NMR (CDCl3, 200 MHz) δ 0.76
(d, 3H, J ) 7.0 Hz), 0.90 (d, 3H, J ) 6.9 Hz), 0.91 (d, 3H, J )
6.9 Hz), 1.02 (sept, 1H, J ) 6.9 Hz), 1.48 (m, 3H), 1.72 (m,
3H), 1.82 (m, 1H), 2.05 (m, 1H), 2.08 (s, 3H), 2.64 (m, 1H),
2.84 (m, 1H), 2.94 (s, 3H), 3.72 (dd, 1H, J ) 7.6, 7.8 Hz), 4.75
(ddd, 1H, J ) 4.4, 10.8, 10.8 Hz), 6.37 (d, 1H, J ) 4.8 Hz); 13
C
NMR (CDCl3, 50 MHz) δ 16.17, 16.22, 20.70, 20.73, 20.76,
21.26, 21.28, 21.90, 21.92, 23.33, 23.36, 26.24, 26.30, 31.4, 34.1,
39.9, 40.1, 40.4, 40.7, 46.9, 67.1, 67.3, 75.7, 75.8, 96.7, 169.0,
169.1, 169.8. Anal. Calcd for C17H29NO5: C, 62.36; H, 8.93; N,
4.28. Found: C, 62.28; H, 8.91; N, 4.29.
(3′S,5′S)- a n d (3′S,5′R)-1-(3′-[(1S)-1-(Hyd r oxyeth yl)]-2′-
m eth yl-1′,2′-isoxa zolid in yl)th ym in e (15 a n d 16). To a
stirred solution of 10 (2.08 g, 2.0 mmol) and imidazole (3.24
g, 4.8 mmol) in dry dichloromethane (60 mL) at 0 °C was
dropwise added a solution of tert-butyldiphenylsilyl chloride
(6.2 mL, 2.4 mmol) in dry dichloromethane (20 mL), and the
reaction mixture was stirred at room temperature until TLC
showed the disappearance of the starting material (3 h). The
solution was then evaporated, and the residue was purified
by flash chromatography (cyclohexane/ethyl acetate 95:5)
to afford methyl (2S)-2-tert-butyldiphenylsilyloxypropanoate
(5.75 g 84%) as a colorless oil: [R]2D5 ) -34.7 (c 1.18, CHCl3);
1H NMR (CDCl3, 200 MHz) δ 1.09 (s, 9H), 1.37 (d, 3H, J ) 6.7
Hz), 3.55 (s, 3H), 4.28 (q, 1H, J ) 6.7 Hz), 7.33-7.71 (m, 10H);
13C NMR (CDCl3, 50 MHz) δ 19.2, 21.2, 26.8, 51.5, 68.9, 127.5,
127.6, 129.7, 133.1, 133.5, 135.7, 135.8, 174.1. Anal. Calcd for
C
20H26O3Si: C, 70.14; H, 7.65. Found: C, 69.98; H, 7.66.
To a stirred solution of the above protected lactate (2.74 g,
8.0 mmol) in anhydrous diethyl ether (70 mL) at -78 °C, under
nitrogen, was slowly added via cannula DIBALH (15 mL, 1.0
M solution in toluene) with stirring. After 6 h, the reaction
was then quenched with ethyl acetate (2 mL). The mixture
was left to warm to room temperature, water (2 mL) was
added, and and the mixture was stirred for 3 h. The solvent
was removed under reduced pressure, and the residue was
purified by silica gel column chromatography (cyclohexane/
ethyl acetate 95:5) to afford (2S)-2-tert-butyldiphenylsilyloxy-
propanal (2.20 g, 88%) as a colorless oil: [R]2D5 ) - 15.0 (c
To a THF solution (20 mL) of the above protected nucleo-
sides (0.943 g, 1.91 mmol) was added a TBAF solution (2.13
mL, 2.1 mmol, 1 M solution in THF), and the mixture was
stirred at room temperature for 3 h. At that time, the solvent
was removed and the residue was subjected to silica gel column
chromatography (chloroform/methanol 95:5). The first eluted
product was the R-anomer 15 (0.277 g, 57%) as a sticky oil:
[R]2D5 ) -24.7 (c 1.70, CHCl3); H NMR (CDCl3, 200 MHz) δ
1
1
1.07, CHCl3); H NMR (CDCl3, 200 MHz) δ 1.11 (s, 9H), 1.22
1.19 (d, 3H, J ) 6.3 Hz), 1.91 (d, 3H, J ) 1.2 Hz), 2.48 (bs,
1H, OH), 2.56 (m, 1H), 2.69 (m, 1H), 2.81 (s, 3H), 2.88 (m,
1H), 3.96 (dq, 1H, J ) 6.3, 6.8 Hz), 6.15 (dd, 1H, J ) 4.0, 6.8
Hz), 7.60 (bs, 1H, NH), 7.68 (q, 1H, J ) 1.2 Hz); 13C NMR
(CDCl3, 50 MHz) δ 12.6, 19.6, 36.8, 43.6, 63.8, 73.1, 82.8, 110.2,
135.9, 150.7, 164.2. Anal. Calcd for C11H17N3O4: C, 51.76; H,
6.71; N, 16.46. Found: C, 51.88; H, 6.72; N, 16.45. Further
elution afforded â-anomer 16 (0.185 g, 38%) as a sticky oil:
(d, 3H, J ) 6.8 Hz), 4.09 (dq, 1H, J ) 1.0, 6.8), 7.32-7.70 (m,
10H), 9.64 (d, 1H, J ) 1.0 Hz); 13C NMR (CDCl3, 50 MHz) δ
18.4, 19.2, 26.8, 74.4, 127.7, 127.8, 129.9, 130.0, 133.2, 133.4,
135.7, 135.8, 203.7. Anal. Calcd for C19H24O2Si: C, 73.03; H,
7.74. Found: C, 72.83; H, 7.75.
Nitrone 12, prepared following the literature method,11 was
obtained exclusively as Z isomer in 81% yield as a white
solid: mp 131-133 °C; [R]2D5 ) +65.0 (c 2.18, CHCl3); 1H NMR
(CDCl3, 200 MHz) δ 1.08 (s, 9H), 1.35 (d, 3H, J ) 6.4 Hz),
3.40 (s, 3H), 5.03 (dq, 1H, J ) 5.7, 6.4 Hz), 6.57 (d, 1H, J )
5.7 Hz), 7.30-7.68 (m, 10H); 13C NMR (CDCl3, 50 MHz) δ 19.0,
19.6, 26.8, 52.0, 65.5, 127.6, 129.7, 133.3, 133.6, 133.7, 135.5,
143.8. Anal. Calcd for C20H27NO2Si: C, 70.34; H, 7.97; N, 4.10.
Found: C, 70.60; H, 7.99; N, 4.10.
[R]2D5 ) +90.1 (c 1.51, CHCl3); H NMR (CDCl3, 200 MHz) δ
1
1.22 (d, 3H, J ) 6.3 Hz), 1.94 (d, 3H, J ) 1.2 Hz), 2.09 (m,
1H), 2.43 (bs, 1H, OH), 2.78 (m, 1H), 2.92 (s, 3H), 3.02 (m,
1H), 3.78 (dq, 1H, J ) 6.3, 6.8 Hz), 6.14 (dd, 1H, J ) 4.2, 7.3
Hz), 7.64 (q, 1H, J ) 1.2 Hz), 9.00 (bs, 1H, NH); 13C NMR
(CDCl3, 50 MHz) δ 12.6, 21.0, 41.1, 46.6, 69.2, 73.0, 83.2, 110.6,
135.7, 150.6, 164.1. Anal. Calcd for C11H17N3O4: C, 51.76; H,
6.71; N, 16.46. Found: C, 51.68; H, 6.71; N, 16.47.
A solution of nitrone 12 (0.92 g, 2.7 mmol) in vinyl acetate
(3R,5R)- a n d (3R,5S)-5-Acet yloxy-2-(5′-O-ter t-b u t yl-
d ip h en ylsilyl-2′,3′-O-isop r op ylid en e-â-D-r ibofu r a n osyl)-
(22) Irma, P.; Czeslaw, B. Pol. J . Chem. 1981, 55, 977.

9326 J . Org. Chem., Vol. 64, No. 26, 1999
Chiacchio et al.
3-eth oxyca r bon ylisoxa zolid in es (21 a n d 22). To a stirred
solution of ribofuranose 2,3-acetonide23 (3.44 g, 18.09 mmol)
and imidazole (2.71 g, 39.8 mmol) in dry dichloromethane (60
mL) at 0 °C was dropwise added a solution of tert-butyldi-
phenylsilyl chloride (5.47 g, 19.9 mmol) in dry dichloromethane
(20 mL), and the reaction mixture was stirred at room
temperature until TLC showed the disappearance of the
starting material (3 h). The solution was then evaporated, and
the residue purified by flash chromatography (cyclohexane/
ethyl acetate 9:1) gave an oil that was identified as an
anomeric mixture (R:â ) 1:5) of 5-O-tert-butyldiphenylsilyl-
2,3-O-isopropilidene-D-ribofuranose (17) (6.05 g, 78%) as a
colorless oil: [R]D25 ) -19.7 (c 25.95, CHCl3); 1H NMR (CDCl3,
500 MHz) δ R-anomer 1.07 (s, 9H), 1.39 (s, 3H), 1.55 (s, 3H),
3.63 (dd, 1H, J ) 2.5, 11.0 Hz, H5a), 3.80 (dd, 1H, J ) 3.0,
11.0 Hz, H5b), 3.98 (d, 1H, J ) 11.0 Hz, OH), 4.15 (dd, 1H, J
) 2.5, 3.0 Hz, H4), 4.66 (dd, 1H, J ) 4.0, 6.0 Hz, H2), 4.78 (d,
1H, J ) 6.0 Hz, H3), 5.62 (dd, 1H, J ) 4.0, 11.0 Hz, H1); 13C
NMR (CDCl3, 125 MHz) δ 18.9, 24.6, 26.4, 29.6, 65.9 67.9, 81.2,
81.8, 97.9, 112.9, 127.8, 127.9, 129.8, 129.9, 132.4, 132.6, 135.4,
135.6. 1H NMR (CDCl3, 500 MHz) δ â-anomer 1.09 (s, 9H),
1.31 (s, 3H), 1.46 (s, 3H), 3.66 (dd, 1H, J ) 3.0, 11.5 Hz, H5a),
3.81 (dd, 1H, J ) 3.5, 11.5 Hz, H5b), 4.28 (dd, 1H, J ) 3.0, 3.5
Hz, H4), 4.50 (d, 1H, J ) 10.0 Hz, OH), 4.60 (d, 1H, J ) 6.0
Hz, H2), 4.73 (d, 1H, J ) 5.5 Hz, H3), 5.35 (d, 1H, J ) 10.0 Hz,
H1); 13C NMR (CDCl3, 125 MHz) δ 19.0, 24.9, 26.5, 26.8, 65.5,
81.7, 87.0, 87.1, 103.2, 112.0, 127.9, 128.0, 130.0, 130.2, 131.7,
131.8, 135.5, 135.6. Anal. Calcd for C24H32O5Si: C, 67.26; H,
7.53. Found: C, 67.13; H, 7.54.
1H, J ) 7.1, 10.9 Hz), 3.77 (dd, 1H, J ) 9.7, 10.5 Hz, H5′b),
3.88 (dq, 1H, J ) 7.1, 10.9 Hz), 4.10 (dd, 1H, J ) 4.3, 8.3 Hz,
H3), 4.30 (dd, 1H, J ) 5.3, 9.7 Hz, H4′), 4.78 (d, 1H, J ) 6.2
Hz, H2′), 4.78 (s, 1H, H1′), 4.82 (d, 1H, J ) 6.2 Hz, H3′), 6.43
(dd, 1H, J ) 2.0, 6.2 Hz, H5), 7.36-7.66 (m, 10H); 13C NMR
(CDCl3, 125 MHz) δ 13.8, 19.2, 21.2, 25.0, 26.6, 26.8, 37.6, 61.4,
62.4, 63.8, 82.9, 83.7, 87.6, 98.1, 100.3, 112.3, 127.69, 127.73,
129.7, 133.4, 135.5, 169.8, 170.6. Anal. Calcd for C32H43NO9-
Si: C, 62.62; H, 7.06; N, 2.28. Found: C, 62.60; H, 7.06; N,
2.28. Further elution gave 22 (tR 8.0 min, 2.83 g, 48%): white
solid; mp 54-58 °C; [R]2D5 ) +59.5 (c 2.05, CHCl3); H NMR
1
(CDCl3, 500 MHz) δ 1.04 (s, 9H), 1.13 (t, 3H, J ) 7.1 Hz), 1.32
(s, 3H), 1.49 (s, 3H), 1.97 (s, 3H), 2.61 (ddd, 1H, J ) 5.0, 9.0,
13.5 Hz, H4a), 2.75 (dd, 1H, J ) 1.5, 13.5 Hz, H4b), 3.73 (dd,
1H, J ) 5.8, 10.7 Hz, H5′a), 3.85 (dd, 1H, J ) 7.0, 10.7 Hz,
H
5′b), 4.01 (dq, 1H, J ) 7.1, 10.9 Hz), 4.04 (dq, 1H, J ) 7.1,
10.9 Hz), 4.20 (ddd, 1H, J ) 1.7, 5.8, 7.0 Hz, H4′), 4.28 (dd,
1H, J ) 1.5, 9.0 Hz, H3), 4.52 (d, 1H, J ) 1.5 Hz, H1′), 4.73
(dd, 1H, J ) 1.7, 6.2 Hz, H3′), 4.86 (dd, 1H, J ) 1.5, 6.2 Hz,
H2′), 6.45 (d, 1H, J ) 5.0 Hz, H5), 7.36-7.66 (m, 10H); 13C NMR
(CDCl3, 125 MHz) δ 14.1, 19.2, 21.0, 25.0, 26.7, 26.8, 37.0, 59.4,
61.3, 64.1, 81.5, 83.5, 87.1, 95.8, 98.9, 112.7, 127.72, 127.73,
129.7, 133.23, 133.32, 135.50, 135.53, 169.6, 170.1. Anal. Calcd
for C32H43NO9Si: C, 62.62; H, 7.06; N, 2.28. Found: C, 62.51;
H, 7.04; N, 2.29.
(3R)-2-(5′-O-ter t-Bu t yld ip h en ylsilyl-2′,3′-O-isop r op yl-
id en e-â-D-r ibofu r a n osyl)-3-eth oxyca r bon ylisoxa zolid in -
5-on e (23). Isoxazolidine 21 or 22 (200 mg, 0.334 mmol) was
dissolved in aqueous methanol (10:1 MeOH/H2O; 4.4 mL)
containing potassium carbonate (25 mg, 0.18 mmol), and the
resulting solution was stirred at room temperature for 1 h.
The solution was brought to pH 6.0 with aqueous 10% HCl;
the solvent was removed under reduced pressure, and the
residue was dissolved in water (2 mL). The aqueous solution
was extracted with ether (3 × 3 mL), and the combined organic
layers were dried over sodium sulfate, filtered, and evaporated
to give the crude lactol that was further utilized without
purification.
To a vigorously stirred solution of the crude lactol (0.180 g,
0.323 mmol) in acetone (3 mL) was added KMnO4 (0.077 g,
0.485 mmol) in portions over a 1 h period. The temperature of
the mixture was maintained between 25 and 45 °C (water
bath). Stirring was continued at room temperature for 2 h.
The mixture was filtered, and the solid was washed with fresh
acetone (2 × 5 mL). The combined filtrate was evaporated to
yield a residue that was dissolved in Et2O (10 mL) and washed
with water (3 × 2 mL). After the residue was dried over sodium
sulfate, the solvent was evaporated, and the residue was then
purified by radial chromatography (cyclohexane/ethyl acetate
85:15) to give 23 (100.8 mg, 53% overall yield) as a light yellow
oil: [R]2D5 ) +16.3 (c 2.30, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 1.06 (s, 9H), 1.13 (t, 3H, J ) 7.1 Hz), 1.33 (s, 3H), 1.51 (s,
3H), 2.91 (dd, 1H, J ) 7.0, 10.2 Hz, H4a), 2.92 (dd, 1H, J )
5.2, 10.2 Hz, H4b), 3.73 (dd, 1H, J ) 4.8, 10.7 Hz, H5′a), 3.82
(dd, 1H, J ) 6.6, 10.7 Hz, H5′b), 4.01 (dq, 1H, J ) 7.1, 10.9
Hz), 4.10 (dq, 1H, J ) 7.1, 10.9 Hz), 4.24 (ddd, 1H, J ) 1.6,
4.8, 6.6 Hz, H4′), 4.37 (dd, 1H, J ) 5.2, 7.0 Hz, H3), 4.69 (dd,
1H, J ) 2.4, 6.2 Hz, H2′), 4.75 (dd, 1H, J ) 1.6, 6.2 Hz, H3′),
4.84 (d, 1H, J ) 1.6 Hz, H1′), 7.39-7.66 (m, 10H); 13C NMR
(CDCl3, 125 MHz) δ 13.9, 19.1, 25.1, 26.8, 29.6, 30.5, 59.4, 62.1,
63.7, 80.8, 82.3, 86.1, 99.6, 113.5, 127.8, 127.9, 129.7, 132.8,
132.9, 135.4, 135.5, 169.1, 174.5. Anal. Calcd for C30H39NO8-
Si: C, 63.25; H, 6.90; N, 2.46. Found: C, 63.20; H, 6.91; N, 2.46.
To a solution of 17 (5.76 g, 13.44 mmol) in dry pyridine (100
mL) was added hydroxylamine hydrochloride (11.2 g, 161.28
mmol), and the reaction mixture was stirred for 1 h at room
temperature. At the end of this time, water (240 mL) was
added, and the mixture was extracted with dichloromethane
(4 × 150 mL); the combined organic layers were washed with
brine (200 mL), dried over sodium sulfate, and evaporated
under reduced pressure to afford a residue that was subjected
to flash chromatography (cyclohexane/ethyl acetate 3:1) to give
an E/Z mixture (2.9:1) of (4S,5R)-5-[(1R)-2-[[1-(tert-butyl)-1,1-
diphenylsilyl]oxy]-1-hydroxyethyl]-2,2-dimethyl-1,3-dioxolane-
4-carbaldehyde oxime (18) (5.84 g, 98%) as a light yellow oil:
[R]2D5 ) +8.5 (c 10.6, CHCl3); H NMR (CDCl3, 500 MHz) δ E
1
isomer 1.07 (s, 9H), 1.33 (s, 3H), 1.34 (s, 3H), 3.53 (bs, 1H,
OH), 3.76 (dd, 1H, J ) 2.9, 9.0 Hz, H5′), 3.80 (d, 1H, J ) 10.4
Hz, H5′′a), 3.88 (dd, 1H, J ) 2.9, 10.4 Hz, H5′′b), 4.25 (dd, 1H, J
) 6.3, 9.0 Hz, H5), 4.82 (dd, 1H, J ) 6.3, 7.5 Hz, H4), 7.52 (d,
1H, J ) 7.5 Hz, H4′), 7.35-7.72 (m, 10H), 9.88 (bs, 1H, N-OH);
13C NMR (CDCl3, 125 MHz) δ 19.2, 25.2, 26.85, 27.6, 65.24,
69.6, 75.23, 77.1, 109.7, 127.65, 127.7, 129.71, 129.75, 132.8,
132.9, 135.4, 135.5, 148.2; 1H NMR (CDCl3, 500 MHz) δ Z
isomer 1.08 (s, 9H), 1.34 (s, 3H), 1.35 (s, 3H), 3.18 (bs, 1H,
OH), 3.72 (dd, 1H, J ) 2.9, 8.2 Hz, H5′), 3.81 (d, 1H, J ) 10.6
Hz, H5′′b), 3.84 (dd, 1H, J ) 2.9, 10.6 Hz, H5′′b), 4.43 (dd, 1H, J
) 6.2, 8.2 Hz, H5), 5.41 (dd, 1H, J ) 6.2, 6.3 Hz, H4), 6.88 (d,
1H, J ) 6.3 Hz, H4′), 7.34-7.72 (m, 10H), 9.47 (bs, 1H, N-OH);
13C NMR (CDCl3, 125 MHz) δ 19.1, 25.1, 26.78, 27.4, 65.12,
70.7, 75.20, 77.5, 109.4, 127.5, 127.61, 129.61, 129.67, 135.55,
135.57, 150.2. Anal. Calcd for C24H33NO5Si: C, 64.98; H, 7.50;
N, 3.16. Found: C, 65.03; H, 7.49; N, 3.17.
A solution of the oxime 18 (4.23 g, 9.87 mmol), vinyl acetate
(18.2 mL, 197.44 mmol), and ethyl glyoxalate (2.54 mL, 12.8
mmol; 50% solution in toluene) was heated at 60 °C, in a sealed
tube, for 14 h. The reaction mixture was evaporated, and the
residue was purified by column chromatography (cyclohexane/
ethyl acetate 4:1) and then by HPLC (n-hexane/2-propanol
96.5:3.5). The first eluted product was 21 (tR 7.1 min, 2.78 g,
47%): white solid; mp 55-58 °C; [R]2D5 ) -56.5 (c 1.35,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 0.93 (t, 3H, J ) 7.1 Hz),
1.05 (s, 9H), 1.31 (s, 3H), 1.48 (s, 3H), 2.06 (s, 3H), 2.52 (ddd,
1H, J ) 2.0, 8.3, 13.9 Hz, H4a), 2.91 (ddd, 1H, J ) 4.3, 6.2,
13.9 Hz, H4b), 3.65 (dd, 1H, J ) 5.3, 10.5 Hz, H5′a), 3.76 (dq,
(3′R,5′S)- a n d (3′R,5′R)-1-[2′-(5′′-O-ter t-Bu tyld ip h en yl-
silyl-2′′,3′′-O-isop r op ylid en e-â-D-r ibofu r a n osyl)-3′-eth oxy-
ca r bon yl-1′,2′-isoxa zolid in yl]th ym in e (24 a n d 25). A sus-
pension of thymine (78 mg, 0.618 mmol) in dry acetonitrile (3
mL) was treated with bis(trimethylsilyl)acetamide (0.62 mL,
2.54 mmol) and refluxed for 15 min. To the clear solution
obtained was added a solution of isoxazolidine 21 or 22 (310
mg, 0.517 mmol) in dry acetonitrile (3 mL). Trimethylsilyltri-
flate (174 mg, 0.78 mmol) was added dropwise, and the
reaction mixture was refluxed for 1 h. After being cooled to 0
°C, the solution was neutralized by careful addition of aqueous
(23) Kaskar, B.; Heise, G. L.; Michalak, R. S.; Vishnuvajjala, B. R.
Synthesis 1990, 1031.

Homochiral R-D- and â-D-Isoxazolidinylthymidines
J . Org. Chem., Vol. 64, No. 26, 1999 9327
5% sodium bicarbonate, and then it was concentrated in vacuo.
After addition of dichloromethane (8 mL), the organic phase
was separated, washed with water (2 × 10 mL), dried over
sodium sulfate, filtered, and evaporated to dryness. The
residue was purified by radial chromatography (cyclohexane/
ethyl acetate 3:2) and then by HPLC with a linear gradient of
2-propanol (6-10%, 0-10 min, flow 3.5 mL/min) in n-hexane.
The first eluted product was 24 (tR 11.4 min, 82.6 mg, 24%):
white solid; mp 52-56 °C; [R]2D5 ) +4.5 (c 1.32, CHCl3); 1H
NMR (CDCl3, 500 MHz) δ 1.06 (s, 9H), 1.13 (t, 3H, J ) 7.1
Hz), 1.34 (s, 3H), 1.52 (s, 3H), 1.89 (d, 3H, J ) 1.1 Hz), 2.56
(ddd, 1H, J ) 3.5, 4.5, 13.9 Hz, H4′a), 2.87 (ddd, 1H, J ) 7.8,
9.7, 13.9 Hz, H4′b), 3.73 (dd, 1H, J ) 4.1, 11.0 Hz, H5′′a), 3.82
(dd, 1H, J ) 6.3, 11.0 Hz, H5′′b), 3.98 (dq, 1H, J ) 7.1, 10.8
Hz), 4.07 (dq, 1H, J ) 7.1, 10.8 Hz), 4.12 (dd, 1H, J ) 3.5, 9.7
Hz, H3′), 4.22 (ddd, 1H, J ) 2.0, 4.1, 6.3 Hz, H4′′), 4.70 (dd, 1H,
J ) 2.9, 6.3 Hz, H2′′), 4.75 (dd, 1H, J ) 2.0, 6.3 Hz, H3′′), 4.77
(d, 1H, J ) 2.9 Hz, H1′′), 6.43 (dd, 1H, J ) 4.0, 7.8 Hz, H5′),
7.38-7.65 (m, 11H), 8.54 (bs, 1H, NH); 13C NMR (CDCl3, 125
MHz) δ 12.5, 13.9, 19.2, 25.2, 26.9, 27.0, 29.6, 37.7, 60.8, 61.9,
63.9, 81.0, 82.7, 84.7, 85.7, 100.3, 111.0, 113.5, 127.8, 129.9,
132.8, 133.0, 135.4, 135.5, 150.3, 163.4, 170.9. Anal. Calcd for
Hz, H3′′), 4.90 (d, 1H, J ) 2.5 Hz, H1′′), 6.23 (dd, 1H, J ) 6.8,
7.0 Hz, H5′), 7.36-7.46 (m, 6H), 7.47 (q, 1H, J ) 1.3 Hz, H6),
7.63-7.65 (m, 4H), 8.35 (bs, 1H, NH); 13C NMR (CDCl3, 125
MHz) δ 12.5, 13.9, 19.2, 25.2, 26.8, 27.0, 37.9, 61.8, 61.9, 63.6,
81.2, 83.1, 85.9, 99.1, 111.1, 113.5, 127.8, 129.9, 132.9, 133.1,
135.2, 135.5, 135.6, 150.0, 163.3, 169.6. Anal. Calcd for
C
35H45N3O9Si: C, 61.84; H, 6.67; N, 6.18. Found: C, 61.89; H,
6.68; N, 6.17.
(3′R,5′R)-1-(3′-Eth oxyca r bon yl-1′,2′-isoxa zolid in yl)th y-
m in e (26). Compound 25 (100 mg, 0.15 mmol) was dissolved
in a 3.7% HCl solution in EtOH (2.5 mL), and the reaction
mixture was stirred at room temperature for 3 h. The solution
was brought to pH 10 by adding aqueous 10% sodium carbon-
ate and extracted with dichloromethane (2 × 10 mL). The
organic phase, dried over sodium sulfate, was filtered and
evaporated to dryness. The residue was purified by radial
chromatography (chloroform/methanol 9:1) to furnish 26 (19.9
mg, 60%) as a sticky oil: [R]2D5 ) +75.0 (c 0.6, CHCl3); 1H
NMR (CDCl3, 500 MHz) 1.25 (t, 3H, J ) 7.1 Hz), 1.57 (bs, 1H,
NH), 1.52 (s, 3H), 1.88 (d, 3H, J ) 1.2 Hz), 2.71 (dd, 1H, J )
5.8, 7.8, 13.8 Hz, H4′a), 2.96 (ddd, 1H, J ) 7.6, 8.2, 13.8 Hz,
H
4′b), 4.18 (q, 2H, J ) 7.1 Hz), 4.21 (dd, 1H, J ) 5.8, 8.2 Hz,
C
35H45N3O9Si: C, 61.84; H, 6.67; N, 6.18. Found: C, 61.82; H,
H3′), 5.95 (dd, 1H, J ) 5.2, 7.6 Hz, H5′), 7.64 (q, 1H, J ) 1.2
Hz, H6), 8.55 (bs, 1H, NH); 13C NMR (CDCl3, 125 MHz) δ 12.7,
14.1, 37.5, 60.7, 62.1, 80.7, 112.5, 134.2, 150.1, 163.3, 171.1.
Anal. Calcd for C11H15N3O5: C, 49.07; H, 5.62; N, 15.61.
Found: C, 49.17; H, 5.64; N, 15.57.
6.67; N, 6.17. Further elution gave 25 (tR 13.2 min, 203.1 mg,
59%): white solid; mp 53-57 °C; [R]2D5 ) -36.3 (c 1.04,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 1.06 (s, 9H), 1.14 (t, 3H,
J ) 7.1 Hz), 1.35 (s, 3H), 1.52 (s, 3H), 1.87 (d, 3H, J ) 1.3
Hz), 2.41 (ddd, 1H, J ) 6.8, 7.8, 13.5 Hz, H4′a), 2.98 (ddd, 1H,
J ) 2.4, 7.0, 13.5 Hz, H4′b), 3.74 (dd, 1H, J ) 4.9, 11.0 Hz,
Ack n ow led gm en t . The autors are grateful to
MURST for its financial support and to Emma Vecchio
and Mariagrazia Saita for their technical assistance.
H
5′′a), 3.77 (dd, 1H, J ) 6.6, 11.0 Hz, H5′′b), 4.05 (dq, 1H, J )
7.1, 10.8 Hz), 4.09 (dq, 1H, J ) 7.1, 10.8 Hz), 4.17 (dd, 1H, J
) 2.4, 7.8 Hz, H3′), 4.24 (ddd, 1H, J ) 2.2, 4.9, 6.6 Hz, H4′′),
4.72 (dd, 1H, J ) 2.5, 6.4 Hz, H2′′), 4.75 (dd, 1H, J ) 2.2, 6.4
J O990576A