An efficient route to β-D-isoxazolidinyl nucleosides via diastereoselective Michael addition of hydroxylamine to unsaturated esters

Article abstract of DOI:10.1021/jo9710588

Enantioselective syntheses of β-D-isoxazolidinyl pyrimidine and purine nucleosides are described. Michael addition of N-methylhydroxylamine to α,β-unsaturated esters were investigated. Both E- and Z-esters 10E and 10Z produced the same intermediates which were cyclized to isoxazolidin-5-ones 8 with high diastereoselectivity. The major isoxazolidin-5-one 8a was reduced and acetylated to acetate 11 for the preparation of nucleosides. The coupling reaction of acetate 11 with silylated thymine, uracil, and N⁴- benzoylcytosine using TMSOTf as a Lewis acid yielded the corresponding nucleoside derivatives. The related purine analogue was produced by the BF₃·Et₂O-catalyzed condensation of acetate 11 with silylated 6- chloropurine. The predominant formation of the cis isomers for both pyrimidine and purine analogues was unexpected and the reaction mechanism was investigated. The nucleoside intermediates were converted to the corresponding 1,2-diols, which were latter oxidized and reduced to the desired monoalcohol products such as 14, 16, 19, and 24.

Full text of DOI:10.1021/jo9710588

7430
J . Org. Chem. 1997, 62, 7430-7434
An Efficien t Rou te to â-D-Isoxa zolid in yl Nu cleosid es via
Dia ster eoselective Mich a el Ad d ition of Hyd r oxyla m in e to
Un sa tu r a ted Ester s
Yuejun Xiang, Hung-J ang Gi, Deqiang Niu, Raymond F. Schinazi,† and Kang Zhao*
29 Washington Place, New York University, Department of Chemistry, New York, New York 10003
Received J une 11, 1997X
Enantioselective syntheses of â-D-isoxazolidinyl pyrimidine and purine nucleosides are described.
Michael addition of N-methylhydroxylamine to R,â-unsaturated esters was investigated. Both E-
and Z-esters 10E and 10Z produced the same intermediates which were cyclized to isoxazolidin-
5-ones 8 with high diastereoselectivity. The major isoxazolidin-5-one 8a was reduced and acetylated
to acetate 11 for the preparation of nucleosides. The coupling reaction of acetate 11 with silylated
thymine, uracil, and N4-benzoylcytosine using TMSOTf as a Lewis acid yielded the corresponding
nucleoside derivatives. The related purine analogue was produced by the BF3‚Et2O-catalyzed
condensation of acetate 11 with silylated 6-chloropurine. The predominant formation of the cis
isomers for both pyrimidine and purine analogues was unexpected and the reaction mechanism
was investigated. The nucleoside intermediates were converted to the corresponding 1,2-diols, which
were latter oxidized and reduced to the desired monoalcohol products such as 14, 16, 19, and 24.
In tr od u ction
Synthesis of nucleosides as antiviral and anticancer
agents has attracted great attention in the past decade.1
2′,3′-Dideoxynucleosides are an important class of anti-
HIV reverse transcriptase inhibitors. Many of the FDA-
approved anti-AIDS drugs such as AZT, ddC, ddI, d4T,
and 3TC belong to this class.2 Their cytotoxicities and
drug resistances have been the obstacles in the treatment
of AIDS patients, suggesting the need for further re-
search in this field.3 A general strategy is the develop-
ment of new classes of modified nucleoside analogues4
that feature novel analogues of ribose as the possible
bases for potent antiviral agents with cross resistances
and low cytotoxicities.5
F igu r e 1.
ring.6,7 3TC, which contains an oxathiolanyl ring, has
shown excellent antiviral (HIV and HBV) activities and
no significant drug resistance after 1 year of clinical trials
when used in combination with AZT.6 Interestingly,
many other diheteroatom ring analogues such as diox-
olanyl and oxathiolanyl nucleosides are being used as
antiviral agents while additional ones are undergoing
preclinical and clinical trials.7 The general methods for
the synthesis of these substances have involved the
insertion of oxygen or sulfur in 1,3-relationship as in five-
membered ring 1 (Figure 1). The preparation of the
corresponding 1,3-oxazolidine systems (1, X ) NR) has,
however, been difficult because of the unstable properties
of aminal moieties.8
In this context, exciting biological results have been
achieved from a new generation of nucleoside analogues
in which a second heteroatom is inserted in the furanosyl
† Georgia Research Center for AIDS and HIV Infections, Veterans
Affairs Medical Center, Decatur, GA 30033.
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) For selected reviews, see: (a) Nair, V.; J ahnke, T. S. Antimicrob.
Agents Chemother. 1995, 39, 1017. (b) Wilson, L. J .; Hager, M. W.;
El-Kattan, Y. A.; Liotta, D. C. Synthesis 1995, 1465. (c) De Clercq, E.
AIDS Res. Human Retroviruses, 1992, 8, 119. (d) Huryn, D. M.; Okabe,
M. Chem. Rev. 1992, 92, 1745.
(2) (a) De Clercq, E. J . Med. Chem. 1995, 38, 2491. (b) Dudley, M.
N. J . Infect. Disease 1995, 171 (suppl 2), S99. (c) J ohnston, M. I.; Hoth,
D. F. Science 1993, 260, 1286.
(3) (a) De Clercq, E. Biochem. Pharm. 1994, 47, 155. (b) Richman,
D. D. AIDS Patient Care 1994, 8, 317. (c) J ohnson, V. A. J . Infect.
Disease 1995, 171 (suppl 2), S140. (d) Sommadossi, J .-P. J . Infect.
Disease 1995, 171(suppl 2), S88. (e) Chen, C.-H.; Cheng, Y.-C. J . Biol.
Chem, 1989, 264, 11934. (f) Schinazi, R. F.; LLoyd, R. M.; Ramanathan,
C. S.; Taylor, E. W. Antimicrob. Agents Chemother. 1994, 38, 268.
(4) Another popular therapy is to use two drugs concurrently,
including the combination of one dideoxynucleoside with another
dideoxynucleoside or a nonnucleoside HIV inhibitor. (a) De Clercq, E.
Ann. N.Y. Acad. Sci. 1994, 438. (b) Vela´zquez, S.; Alvarez, R.; San-
Fe´lix, A.; J imeno, M. L.; De Clercq, E.; Balzarini, J .; Camarasa, M. J .
J . Med. Chem. 1995, 38, 1641.
(5) For recent examples, see: (a) J eong, L. S.; Marquez, V. E.
Tetrahedron Lett. 1996, 37, 2353. (b) El-Subbagh, H. I.; Racha, S.;
Abushanab, E.; Panzica, R. P. J . Org. Chem. 1996, 61, 890. (c)
Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata,
S.; Sasaki, T.; Matsuda, A. J . Org. Chem. 1996, 61, 822. (d) Konkel,
M. J .; Vince, R. Tetrahedron 1996, 52, 799. (e) Wnuk, S. F.; Robins,
M. J . J . Am. Chem. Soc. 1996, 118, 2519. (f) Shaw-Ponter, S.; Mills,
G.; Robertson, M.; Bostwick, R. D.; Hardy, G. W.; Young, R. J .
Tetrahedron Lett. 1996, 37, 1867. (g) Lin, T.-S.; Luo, M.-L.; Liu, M.-C.
Tetrahedron. 1995, 51, 1055.
Isoxazolidine 2 illustrates a structure that allows the
stable placement of nitrogen into the furanosyl ring of
(6) For selected examples, see: (a) J eong, L. S.; Schinazi, R, F.;
Beach, J . W.; Kim, H. O.; Nampalli, S.; Shanmuganathan, K.; Alves,
A. J .; McMillan, A.; Chu, C. K.; Mathis, R. J . Med. Chem. 1993, 36,
181. (b) van Leeuwen, R.; Katlama, C.; Kitchen, V.; Boucher, C. A. B.;
Tubiana, R.; McBride, M.; Ingrand, D.; Weber, J .; Hill, A.; McDade,
H.; Danner, S. A. J . Infect. Dis. 1995, 171, 1166. (c) J in, H.; Siddiqui,
A.; Evans, C. A.; Tse, H. L. A.; Mansour, T. S. J . Org. Chem. 1995, 60,
2621.
(7) For selected recent examples, see: (a) Mansour, T. S.; J in, H.;
Wang, W.; Hooker, E. U.; Ashman, C.; Cammack, N.; Salomon, H.;
Belmonta, A. R.; Wainberg, M. A. J . Med. Chem. 1995, 1, 1. (b) Liang,
C.; Lee, D. W.; Newton, M. G.; Chu, C. K. J . Org. Chem. 1995, 60,
1546. (c) Branalt, J .; Kvarnstrom, I.; Classon, B.; Samuelsson, B. J .
Org. Chem. 1996, 61, 3611, and references therein.
(8) Graciet, J . C.; Faury, P.; Camplo, M.; Charvet, A. S.; Mourier,
N.; Trabaud, C.; Niddam, V.; Simon, V.; Kraus, J . L. Nucleosides
Nucleotides 1995, 14, 1379.
S0022-3263(97)01058-X CCC: $14.00 © 1997 American Chemical Society

An Efficient Route to â-D-Isoxazolidinyl Nucleosides
J . Org. Chem., Vol. 62, No. 21, 1997 7431
Sch em e 1
nucleoside analogues (Figure 1). The successful intro-
duction of isoxazolidinyl structures into nucleoside chem-
istry was achieved by Tronchet and his associates who,
in 1992, reported the first synthesis of compounds 2 (R
) Me, Ph; B ) thymine).9 Although these compounds do
not show anti-HIV activity, their novel structures hold
potential for the development of active compounds.10
Isoxazolines 3 and isoxazolidines 4-5,11 which are
substituted with a nucleoside base and a hydroxymethyl
group in a 1,3-relative position, can be suitable models
for the study of their antiviral properties. The key
structural elements of 3-5 are the hydroxymethyl group,
the nucleoside base, and the isoxazole core. First,
incorporation of the hydroxymethyl group potentially
allows enzymatic phosphorylation to triphosphate inter-
mediates which function as RT inhibitors or DNA chain
terminators. Second, the nucleoside base should be
conveniently coupled to the N-O-containing ring via a
glycosidic bond. Third, the connection of oxygen and
nitrogen might provide fair structural stability as a result
of the reduced basicity caused by the mutual inductive
effect of the two heteroatoms.
Sch em e 2
We have successfully prepared nucleosides 3-4 which
bear pyrimidine and purine bases.12 Compound 3, which
exhibits moderate anti-HIV-1 activity, was prepared in
a racemic form via a 1,3-dipolar cycloaddtion.12b,d The
racemic analogues 4 were prepared via a noncycloaddi-
tion method12a and the related L-isomer was constructed
by using an optically active lactone as the starting
material.12c In this paper, we report the diastereoselective
Michael addition of hydroxylamine derivatives to R,â-
unsaturated ester for the synthesis of the D-isomers of
4. The chemistry has been designed so that both D- and
L-isomers 4 can be efficiently prepared from readily
available starting materials. More interestingly, the
availability of 4 and related derivatives provide a great
possibility for future construction of the optically active
compounds 3.13
via the synthesis of 9, which would require the dia-
stereoselective Michael addition of N-methylhydroxy-
lamine to the required unsaturated esters.14,15
With this goal in mind, we investigated the preparation
of isoxazolidin-5-one 8 from ester 10 via the Michael
addition of hydroxylamine derivatives and the subse-
quent cyclization reactions (Scheme 2). The trans ester
10E was first treated with N-methylhydroxylamine in
THF for 12 h and the resultant solution was then allowed
to react with zinc chloride, producing two products 8a
and 8b with a ration of 20:1 in favor of the syn adduct
8a . The high diastereoselectivity in the Michael addition
of N-methylhydroxylamine to this acyclic conjugated
system was of considerable interest. The Z olefinic ester
10Z was then used to react with N-methylhydroxylamine,
and the syn adduct 8a was produced as the major product
(8a :8b/18:1). Since both olefins 10E and 10Z gave
similar results, it can be concluded that the stereochem-
istry of the unsaturated esters has very little influence
on the Michael addition diastereoselectivity. Although
the stereoselectivity can be assumed to result from the
intramolecular hydrogen bond between the hydroxyl
group and a ring oxygen or alternatively in terms of steric
hindrance,15,16 the mechanism remains to be proved. It
appears that the dimethyldioxolane derivatives play an
important role since these moieties have been frequently
used for chiral induction in the processes of nucleophilic
additions or dihydroxylation with complete syn or anti
selectivity.16
Resu lts a n d Discu ssion
Dia ster eoselective Mich a el Ad d ition of Hyd r oxyl-
a m in e to Un sa tu r a ted Ester s. We envisioned that the
D-isomer 6 could be obtained from 7 which, in turn, could
be prepared from compound 8 (Scheme 1). We further
imagined that a route to the desired target 8 would be
(9) Tronchet. J . M. J .; Iznaden, M.; Barbalat-Rey, F.; Dhimane, H.;
Ricca, A.; Balzarini, J .; De Clercq, E. Eur. J . Med. Chem. 1992, 27,
555.
(10) (a) Tronchet. J . M. J .; Iznaden, M.; Barbalat-Rey, F.; Komaromi,
I.; Dolatshahi, N.; Bernardinelli, G. Nucleosides Nucleotides 1995, 14,
1737. (b) Leggio, A.; Liguori, A.; Procopio, A.; Siciliano, C.; Giovann,
C. S. Tetrahedron Lett. 1996, 37, 1277.
(11) The synthesis of 5, which is anticipated to be more difficult than
that of 3-4, has not been studied.
(12) (a) Xiang, Y.; Chen, J .; Schinazi, R. F.; Zhao, K. Tetrahedron
Lett. 1995, 36, 7193. (b) Xiang, Y.; Chen, J .; Schinazi, R. F.; Zhao, K.
Bioorg. Med. Chem. Lett. 1996, 6, 1051. (c) Xiang, Y.; Gong, Y.; Zhao,
K. Tetrahedron Lett. 1996, 37, 4877. (d) Gi, H.; Xiang, Y.; Schinazi,
R.; Zhao, K. J . Org. Chem. 1997, 62, 88.
(13) Compound 3 was produced in low ee by using the dipolar
cycloaddition of various chiral synthons to vinylthymine. A method
for the oxidative conversion of the optically active isoxazolidines to
isoxazoline derivatives such as 3 has, however, been developed: Pan,
L.; Gi, H.; Zhao, K. J . Org. Chem. Submitted for publication.
(14) (a) Socha, D.; J urczak, M.; Chmielewski, M. Tetrahedron Lett.
1995, 36, 135. (b) J urczak, M.; Socha, D.; Chmielewski, M. Tetrahedron
1996, 52, 1411.
(15) (a) Baldwin, S. W.; Aube´, J . Tetrahedron Lett. 1987, 28, 179.
(b) Baldwin, J . E.; Harwood, L. M.; Lombard, M. J . Tetrahedron 1984,
40, 4363. (c) Fountain, K. R.; Erwin, R.; Early, T.; Kerl, H. Tetrahedron
Lett. 1975, 3027.
Syn th esis of Isoxa zolid in e Nu cleosid es. The con-
version of 8 to D-nucleoside 14 has been accomplished
as in the reported procedure for the corresponding
L-compounds.12c Compound 8a was reduced by DIBAL
to give the corresponding lactols, which were acetylated
(16) For selected examples, see: (a) Fronza, G.; Fuganti, C.; Gras-
selli, P. Tetrahedron Lett. 1980, 2999. (b) Katsuki, T.; Lee, A. W. M.;
Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Tuddenham,
D.; Walker, F. J . J . Org. Chem. 1982, 47, 1373. (c) Robina, I.; Gearing,
R. P.; Buchanan, J . G.; Wightman, R. H. J . Chem. Soc., Perkin Trans
1 1990, 2622. (d) Patrocinio, V. L, Costa, P. R. R.; Correia, C. R. D.
Synthesis 1994, 474. (e) Nagumo, S.; Umezawa, I.; Akiyama, J .; Akita,
H. Chem. Pharm. Bull. 1995, 43, 171.

7432 J . Org. Chem., Vol. 62, No. 21, 1997
Xiang et al.
Sch em e 3
Sch em e 4
by a mixture of acetyl chloride (1.1 equiv), pyridine (1.0
equiv), and methylene chloride at 0 °C to afford the cyclic
compounds 11 as the major products in 66% yield
(Scheme 2). Condensation of acetate 11 with silylated
thymine in acetonitrile using TMSOTf as a Lewis acid
afforded the cis compound 12a (79%) and the correspond-
ing trans isomer 12b in 4.6% yield. Compound 12a was
deprotected by 60% aqueous acetic acid at 72 °C to give
diol nucleoside 13 (69%), which was oxidized by sodium
periodate and then reduced by sodium borohydride to the
desired compound 14 (75% overall yield). The configu-
ration of 14 followed from its identical 1H NMR spec-
troscopy with its racemic cis isomer.17
It was remarkable that the coupling reaction of acetate
11 with thymine formed the cis isomer as the major
compound. The silylated uracil was then used to further
investigate this coupling by varying reaction catalyst and
temperature (Scheme 3). The TMSOTf-promoted con-
densation at room temperature gave uracil derivatives
15a ,b (cis:trans) with a stereoselectivity of 47:1. The use
of Et2O‚BF3, however, allowed the isolation of the same
products in a ratio of 4:1 (43% total yield) by intercepting
the reaction after 2 h at room temperature. Alterna-
tively, heating at 80 °C for an additional 3 h increased
the ratio (81:1) and yield (58%). It appears that the cis
isomer 15a was predominately formed under both kinetic
and thermodynamic conditions. We have also observed
that the trans isomer 15b is not very stable under acid
conditions. In fact, compound 15b decomposed to uracil
in 60% acetic acid at 72 °C in 30 min. Under the same
condition, however, compound 15a afforded a diol (76%
yield) which was converted to the desired compound 16
in 92% yield.17
potential production of diastereoisomers (R or â) and
regioisomers (N-3, N-7, and N-9) (20, Scheme 4).18,19 The
coupling of isoxazolidine acetate 11 and silylated 6-chlo-
ropurine 20 was studied since this nucleoside base
requires no other protection and can be easily converted
to its amino derivative. Moreover, the undesired regio-
isomers may be isomerizable to the desired N-9 isomers
upon treatment with a Lewis acid at high temperature.19
The initial use of TMSOTf and acetonitrile gave the
desired compound 21 in very low yield at either room
temperature or 80 °C. The condensation of acetate 11
with base 20, promoted by Et2O‚BF3 at room tempera-
ture, gave one of the undesired regioisomers. Fortu-
nately, this isomer could be directly converted to com-
pound 21 (46% yield) at 80 °C by Et2O‚BF3.
The hydrolysis of acetonide 21 presented us with a
challenge. Several deprotection conditions such as cata-
lytic Dowex 50 (H+) in water, p-toluenesulfonic acid, and
PPTs in methanol cleaved the glycosidic bond of 21,
resulting in the release of 6-chloropurine. The use of 40%
aqueous acetic acid at room temperature overnight,
however, afforded the desired compound 22 in 37% yield
together with recovered starting material 21 (33% yield),
which could be recycled. Although the yield of 22 could
not be improved by varying the reaction time, acetic acid
concentration, and reaction temperature, it was very
gratifying to be able to achieve the removal of the
isopropylidene group in the presence of the purine
glycosidic bond. The subsequent steps of oxidation and
reduction converted diol 22 to alcohol 23 (83% yield),
which was then converted to the final product 24 in 72%
yield.17
The cytosine analogue 19 was also synthesized by a
similar method (Scheme 3). Condensation of silylated
N4-benzoylcytosine with acetate 11 using TMSOTf as a
Lewis acid gave the desired trans isomer 17 as a single
product (74% yield). The final compound 19 was obtained
by acetic acid hydrolysis, oxidative cleavage, subsequent
reduction, and debenzoylation with 47% overall yield.17
Syn th esis of P u r in e Nu cleosid es. The preparation
of purine analogues is generally difficult due to the
Con clu sion
High stereoselectivity was observed in the Michael
addition of hydroxylamine derivatives with chiral acyclic
R,â-unsaturated esters. The Michael adducts were sub-
sequently cyclized under mild conditions to afford, as a
single isomer, isoxazolidin-5-ones, which were easily
converted to acetate-protected isoxazolidin-5-ols. The
coupling of these intermediates and nucleoside bases
gave â-D-isoxazolidinyl nucleosides with high cis selectiv-
ity.
(17) The structure of the racemic cis isomer was assigned by the
analysis of its 2D NOE spectrum.12c It should be noted that the
chemical shift of the methylenye protons in the isoxazolidine ring can
also be used to determine the cis or trans structure. The chemical shifts
of the gem-hydrogens are broadly separated (2.98 and 2.29 ppm) in
cis compound 14, while the gem-hydrogens in the corresponding trans
compound have the same chemical shifts (2.39 ppm).12a Broadly
separated chemical shifts were also observed in the methylene groups
of the cis isoxazolidines such as 16, 19, and 24.
(18) (a) Hildebrand, C.; Wright, G. E. J . Org. Chem. 1992, 57, 1808.
(b) Chapeau, M.-C.; Marnett, L. J . J . Org. Chem. 1993, 58, 7258. (c)
Sugimura, H.; Osumi, K.; Kodaka, Y.; Sujino, K. J . Org. Chem. 1994,
59, 7653.
Exp er im en ta l Section
(19) (a) Vorbru¨ggen, H.; Ho¨fle, G. Chem. Ber. 1981, 114, 1256, and
references therein. (b) Dudycz, L. W.; Wright, G. E. Nucleosides
Nucleotides 1984, 3, 33. (c) Garner, P. Ramakanth, S. J . Org. Chem.
1988, 53, 1294.
General details are as previously described.12d
(3R,4′S)-2-N-Meth yl-3-(2,2-d im eth yl-1,3-d ioxola n -4-yl)-
1,2-isoxa zolid in -5-on e (8a ) a n d Its (3S,4′S)-Isom er (8b).

An Efficient Route to â-D-Isoxazolidinyl Nucleosides
J . Org. Chem., Vol. 62, No. 21, 1997 7433
A mixture of 10E (4.0 g, 20 mmol), HONHMe‚HCl (1.67 g, 20
mmol), Et3N (2.80 mL, 20 mmol), and THF (100 mL) was
stirred at rt overnight. Zinc chloride (2.68 g, 20 mmol) was
then added and the reaction mixture was stirred for 12 h. After
workup (H2O, 50 mL; EtOAc, 3 × 100 mL) and purification
(SiO2, 50% EtOAc/petroleum ether), compounds 8a (3.0 g, 75%)
and 8b (0.15 g, 3.8%) were isolated as clear oils. 8a : 1H NMR
(CDCl3) δ 4.15 (dt, J ) 6.4 Hz, J ) 6.4 Hz, 1H), 4.01 (dd, J )
6.4 Hz, J ) 8.4 Hz, 1H), 3.67 (dd, J ) 6.4 Hz, J ) 8.4 Hz, 1H),
3.23 (dt, J ) 7.3 Hz, J ) 10.2 Hz, 1H), 2.95 (s, 3H), 2.65 (m,
2H), 1.37 (s, 3H), 1.30 (s, 3H); 13C NMR (CDCl3) δ 173.3, 110.8,
12a : a white foam; 1H NMR (CDCl3) δ 9.65 (s, 1H), 7.63 (d, J
) 1.0 Hz, 1H), 6.04 (dd, J ) 3.7 Hz, J ) 7.4 Hz, 1H), 4.04 (m,
2H), 3.62 (m, 1H), 2.91 (m, 5H), 1.92 (m, 4H), 1.40 (s, 3H),
1.33 (s, 3H); 13C δ 164.7, 151.1, 136.1, 110.8, 83.4, 77.4, 70.8,
67.5, 45.8, 42.3, 27.2, 26.1, 13.3. 12b: a white foam; 1H NMR
(CDCl3) δ 8.81 (br s, 1H), 7.34 (s, 1H), 6.07 (dd, J ) 4.0 Hz, J
) 7.5 Hz, 1H), 4.20 (dd, J ) 6.9 Hz, J ) 13.2 Hz, 1H), 4.07
(dd, J ) 6.3 Hz, J ) 8.2 Hz, 1H), 3.66 (dd, J ) 6.5 Hz, J ) 8.2
Hz, 1H), 3.11 (m, 1H), 2.96 (s, 3H), 2.47 (m, 2H), 1.95 (s, 3H),
1.43 (s, 3H), 1.36 (s, 3H). Anal. Calcd for C14H21N3O5: C, 54.01
H, 6.80; N, 13.50. Found: C, 54.17; H, 6.85; N, 13.45.
76.9, 70.4, 66.7, 47.6, 33.5, 27.0, 25.7. Anal. Calcd for C9H15
-
Hyd r olysis-Oxid a tion -Red u ction Sequ en ce for Con -
ver t in g Dioxola n es t o H yd r oxym et h yl Der iva t ives:
(3′R,5′S)-1-[2-N-Met h yl-3-(h yd r oxym et h yl)-1,2-isoxa zo-
lid in yl]th ym in e (14). A solution of 12a (200 mg, 0.64 mmol)
in 60% AcOH (50 mL) was heated at 72 °C for 30 min and
then concentrated. The residue was coevaporated with toluene
(2 × 10 mL) and then purified by column chromatography
(SiO2, 10% MeOH/CHCl3) to give diol 13 (120 mg, 0.44 mmol),
which was then mixed with MeOH (20 mL), water (5 mL), and
NaIO4 (0.17 g, 0.80 mmol) at 0 °C. The mixture was stirred
at 0 °C for 1 h and NaBH4 (78 mg, 2 mmol) was then added.
The reaction mixture was kept at 0 °C for 5 min and then
neutralized with AcOH. The mixture was filtered and con-
centrated. The residue was purified by column chromatogra-
phy (SiO2, 15% MeOH/CHCl3), affording compound 14 (80 mg,
75%), which was crystallized from MeOH-Et2O-petroleum
NO4: C, 53.72; H, 7.51; N, 6.96. Found: C, 53.46; H, 7.54; N,
6.80. 8b: 1H NMR (CDCl3) δ 4.15 (m, 2H), 3.76 (m, 1H), 3.26
(m, 1H), 2.90 (m, 5H), 1.41 (s, 3H), 1.33 (s, 3H); 13C NMR
(CDCl3) δ 175.1, 110.5, 75.3, 68.7, 67.4, 47.3, 31.2, 26.9, 25.4.
Anal. Calcd for C9H15NO4: C, 53.72; H, 7.51; N, 6.96. Found:
C, 53.70; H, 7.56; N, 6.90.
(3R,4′S)-5-Acet oxy-2-N-m et h yl-3-(2,2-d im et h yl-1,3-d i-
oxola n -4-yl)-1,2-isoxa zolid in e (11). To a solution of 8a (6.6
g, 32.5 mmol) in dry CH2Cl2 (100 mL) at -78 °C was added
DIBAL (23 mL, 1.5 M in toluene). The reaction mixture was
stirred at -78 °C for 1 h, quenched with MeOH (2 mL), and
warmed to rt. After workup (saturated NaHCO3, 100 mL;
CHCl3, 5 × 100 mL) and purification (SiO2, EtOAc), a lactol
(5.80 g) was isolated in 87% yield.
A mixture of pyridine (2.4 mL, 39 mmol), AcCl (2.21 mL,
31 mmol), and CH2Cl2 (100 mL) was stirred at 0 °C for 15 min
and a solution of the above-prepared lactol (4.96 g, 24 mmol)
in CH2Cl2 (10 mL) was then added over 30 min. After it was
warmed to rt and stirred for 2 h, the reaction mixture was
washed with 1% HCl (50 mL), saturated NaHCO3 (100 mL),
and water (100 mL). After purification (SiO2, 60% EtOAc/
petroleum ether), an oil 11 (3.90 g, 66%) was isolated as a
mixture of R and â isomers. 1H NMR (CDCl3) δ 6.25 (m, 1H),
4.12 (m, 2H), 3.63 (m, 1H), 3.10 (m, 1H), 2.91 (m, 3H), 2.24
(m, 2H), 2.04 (m, 3H), 1.39 (s, 3H), 1.31 (s, 3H); 13C (CDCl3) δ
170.3, 110.3, 97.2, 77.7, 68.4, 67.1, 49.3, 39.3, 27.2, 25.8, 21.9.
Anal. Calcd for C11H17NO5: C, 53.87; H, 7.81; N, 5.71.
Found: C, 53.77; H, 7.75; N, 5.66.
Con d en sa tion Meth od for th e Cou p lin g of 11 a n d
Nu cleosid e Ba ses: (3′R,4′′S,5′S)-1-[2-N-Met h yl-3-(2,2-d i-
m eth yl-1,3-d ioxola n -4-yl)-1,2-isoxa zolid in yl]u r a cil (15a )
a n d Its (3′R,4′′S,5′R)-Isom er (15b). Meth od A. To a solu-
tion of silylated uracil, which was prepared by refluxing the
solution of uracil (0.56 g, 5 mmol), hexamethyldisilazane (20
mL), and ammonium sulfate (cat.) for 2 h, in dry CH3CN (20
mL), was added a solution of 11 (0.37 g, 1.5 mmol), dry CH3-
CN (5 mL), and TMSOTf (0.96 mL, 5 mmol). The reaction
mixture was stirred at rt overnight. After workup (cooled
saturated NaHCO3, 50 mL; EtOAc, 3 × 50 mL) and purifica-
tion (SiO2, EtOAc), compounds 15a (210 mg, 47%) and 15b (5
mg, 1%) were isolated as white foams.
1
ether: mp 129-130 °C; H NMR (CD3OD) δ 7.93 (d, J ) 1.2
Hz, 1H), 6.16 (dd, J ) 4.0 Hz, J ) 7.8 Hz, 1H), 3.75 (dd, J )
3.4 Hz, J ) 11.9 Hz, 1H), 3.63 (dd, J ) 3.4 Hz, J ) 11.9 Hz,
1H), 2.81 (m, 5H), 2.29 (m, 1H), 1.89 (s, 3H). Anal. Calcd for
C10H15N3O4: C, 49.79; H, 6.27; N, 17.42. Found: C, 49.78; H,
6.26; N, 17.34.
(3′R,5′S)-1-[2-N-Meth yl-3-(h yd r oxym eth yl)-1,2-isoxa zo-
lid in yl]u r a cil (16). The hydrolysis-oxidation-reduction
sequence was used for converting compound 15 to analogue
1
16 (70%): mp 148-150 °C; H NMR (CD3OD) δ 8.09 (d, J )
8.1 Hz, 1H), 6.12 (dd, J ) 3.7 Hz, J ) 7.8 Hz, 1H), 5.68 (d, J
) 8.1 Hz, 1H), 3.73 (dd, J ) 3.5 Hz, J ) 11.9 Hz, 1H), 3.61
(dd, J ) 3.5 Hz, J ) 11.9 Hz, 1H), 3.00 (dt, J ) 7.9 Hz, J )
13.3 Hz, 1H), 2.81 (m, 4H), 2.27 (m, 1H). Anal. Calcd for
C9H13N3O4: C, 47.57; H, 5.77; N, 18.49. Found: C, 47.65; H,
5.74; N, 18.59.
(3′R,4′′S,5′S)-N4-Ben zoyl-1-[2-N-m eth yl-3-(2,2-d im eth yl-
1,3-d ioxola n -4-yl)-1,2-isoxa zolid in yl]cytosin e (17). Con-
densation method A was used for converting 11 to analogue
1
17 (74%). 17: a white foam; H NMR (CDCl3) δ 8.21 (d, J )
7.5 Hz, 1H), 7.87 (d, J ) 8.4 Hz, 2H), 7.49 (m, 4H), 5.97 (dd,
J ) 2.9 Hz, J ) 7.3 Hz, 1H), 3.98 (m, 2H), 3.56 (m, 1H), 2.93
(m, 5H), 2.00 (m, 1H), 1.37 (s, 3H), 1.29 (s, 3H); 13C (CDCl3) δ
167.0, 162.8, 155.4, 145.1, 133.5, 129.4, 128.1, 110.7, 96.5, 85.5,
77.6, 70.7, 67.5, 45.8, 42.8, 27.2, 26.0. Anal. Calcd for
C20H24N4O5‚0‚60 H2O: C, 58.41; H, 6.18; N, 13.62. Found: C,
58.56; H, 6.12; N, 13.15.
Meth od B. A mixture of the silylated uracil (5 mmol), 14
(0.49 g, 2 mmol), BF3‚Et2O (0.48 mL, 4 mmol), and CH3CN
(20 mL) was stirred at rt for 2 h. Compounds 15a (210 mg,
35%) and 15b (50 mg, 8.4%) were similarly isolated.
Meth od C. A mixture of the silylated uracil (5 mmol), 11
(490 mg, 2 mmol), BF3‚Et2O (0.48 mL, 4 mmol), and CH3CN
(20 mL) was stirred at rt for 2 h and then refluxed for another
3 h. Compounds 15a (340 mg, 57%) and 15b (4 mg, 0.7%) were
similarly isolated.
(3′R,5′S)-1-[2-N-Meth yl-3-(h yd r oxym eth yl)-1,2-isoxa zo-
lid in yl]cytosin e (19). Product 18, which was obtained from
17 by using the hydrolysis-oxidation-reduction sequence, was
dissolved in 20 mL of saturated methanolic ammonia and
stirred at rt overnight. The solvent was evaporated and the
residue was purified by column chromatography (SiO2
, 35%
MeOH/CHCl3) to give 19 (65 mg, 87%) as a white solid which
was crystallized from MeOH-EtOAc-petroleum ether: mp
157-158 °C; 1H NMR (CD3OD) δ 8.03 (d, J ) 7.4 Hz, 1H),
6.07 (dd, J ) 3.8 Hz, J ) 7.5 Hz, 1H), 5.88 (d, J ) 7.4 Hz, 1H),
3.70 (dd, J ) 3.8 Hz, J ) 11.8 Hz, 1H), 3.56 (dd, J ) 3.8 Hz,
J ) 11.8 Hz, 1H), 3.03 (dt, J ) 7.6 Hz, J ) 13.5 Hz, 1H), 2.83
(m, 4H), 2.15 (m, 1H). Anal. Calcd for C9H14N4O4‚ 0.60H2O:
C, 45.60; H, 6.46; N, 23.64. Found: C, 45.31; H, 6.45; N, 23.29.
(3′R,4′′S,5′S)-6-Ch lor o-9-[2-N-m et h yl-3-(2,2-d im et h yl-
1,3-d ioxola n -4-yl)-1,2-isoxa zolid in yl]p u r in e (21). Con-
densation method C (reaction conditions: rt, 30 min; reflux,
30 min) was used for converting 11 to analogue 21 (46%). 21:
15a : 1H NMR (CDCl3) δ 10.0 (br s, 1H), 7.81 (d, J ) 8.1
Hz, 1H), 6.00 (dd, J ) 3.3 Hz, J ) 7.3 Hz, 1H), 5.69 (d, J ) 8.1
Hz, 1H), 4.03 (m, 2H), 3.59 (m, 1H), 2.98 (m, 5H), 1.96 (m,
1H), 1.38 (s, 3H), 1.30 (s, 3H); 13C δ 164.2, 151.1, 140.6, 110.8,
102.3, 83.7, 77.3, 70.6, 67.5, 45.7, 42.5, 27.2, 26.0. 15b: 1H
NMR (CDCl3) δ 9.72 (br s, 1H), 7.57 (d, J ) 8.1 Hz, 1H), 6.03
(dd, J ) 3.4 Hz, J ) 6.9 Hz, 1H), 5.75 (d, J ) 8.1 Hz, 1H), 4.08
(m, 2H), 3.63 (t, J ) 7.3 Hz, 1H), 3.03 (m, 1H), 2.93 (s, 3H),
2.49 (m, 1H), 2.37 (m, 1H), 1.96 (m, 1H), 1.38 (s, 3H), 1.30 (s,
3H).
1
(3′R,4′′S,5′S)-1-[2-N-Meth yl-3-(2,2-dim eth yl-1,3-dioxolan -
4-yl)-1,2-isoxazolidin yl]th ym in e (12a) an d Its (3′R,4′′S,5′R)-
Isom er (12b). Condensation method A was used for convert-
ing 11 to thymidine analogues 12a (79%) and 12b (4.6%).
an oil; H NMR (CDCl3) δ 8.65 (s, 1H), 8.55 (s, 1H), 6.41 (dd,
J ) 6.3 Hz, J ) 7.6 Hz, 1H), 4.11 (m, 1H), 3.99 (t, J ) 6.3 Hz,
1H), 3.62 (dd, J ) 6.3 Hz, J ) 8.3 Hz, 1H), 3.09 (dt, J ) 7.9
Hz, J ) 13.3 Hz, 1H), 2.92 (m, 4H), 2.32 (m, 1H), 1.39 (s, 3H),

7434 J . Org. Chem., Vol. 62, No. 21, 1997
Xiang et al.
1.30 (s, 3H); 13C (CDCl3) δ 152.2, 151.2, 144.2, 132.1, 112.8,
110.9, 82.0, 77.1, 70.7, 67.4, 45.6, 41.7, 27.2, 26.0. Anal. Calcd
for C14H18N3O3‚ 0.75H2O: C, 47.60; H, 5.56; N, 19.82. Found:
C, 47.90; H, 5.50; N, 19.69.
(3′R,5′S)-6-Ch lor o-9-[2-N-m et h yl-3-(h yd r oxym et h yl)-
1,2-isoxa zolid in yl]p u r in e (23). Product 23 was similarly
prepared in 31% yield from 21 by using the hydrolysis-
oxidation-reduction sequence. 23: a white solid, mp 133-
134 °C; 1H NMR (CD3OD) δ 8.99 (s, 1H), 8.72 (s, 1H), 6.58
(dd, J ) 2.5 Hz, J ) 8.0 Hz, 1H), 3.84 (dd, J ) 2.9 Hz, J )
12.1 Hz, 1H), 3.73 (dd, J ) 2.9 Hz, J ) 12.1 Hz, 1H), 3.17 (dt,
J ) 8.1 Hz, J ) 12.3 Hz, 1H), 2.82 (m, 5H). Anal. Calcd for
C10H12ClN5O2: C, 44.50; H, 4.48; N, 25.97. Found: C, 44.50;
H, 4.54; N, 25.91.
column chromatography (SiO2, 30% MeOH/CHCl3) to give 24
(60 mg, 72%) as a white solid which was crystallized from
MeOH-CHCl3-petroleum ether: mp 220-222 °C; 1H NMR
(DMSO-d6) δ 8.44 (s, 1H), 8.17 (s, 1H), 7.30 (br s, 2H), 6.38
(dd, J ) 2.6 Hz, J ) 8.1 Hz, 1H), 5.08 (t, J ) 5.3 Hz, 1H), 3.69
(m, 2H), 3.07 (dt, J ) 8.4 Hz, J ) 12.5 Hz, 1H), 2.72 (m, 5H).
Anal. Calcd for C10H14ClN6O2: C, 47.99; H, 5.64; N, 33.58.
Found: C, 47.77; H, 5.61; N, 33.33.
Ack n ow led gm en t. We wish to thank Professors
Gilbert Stork and Dennis Liotta for valuable comments
and Mr. David Santosa for technical assistance. We
acknowledge the New York University Technology
Transfer Fund and the NSF Faculty Early Career
Development Program for their financial support.
(3′R,5′S)-9-[2-N-Meth yl-3-(h yd r oxym eth yl)-1,2-isoxa zo-
lid in yl]a d en in e (24). A mixture of 23 (90 mg, 0.33 mmol)
and saturated methanolic ammonia (20 mL) was heated at 100
°C in a steel bomb overnight. After it was cooled, the reaction
mixture was concentrated. The residue was purified by
J O9710588