Diastereoselective and enantioselective synthesis of 4'-aza analogues of 2',3'-dideoxynucleosides

Article abstract of DOI:10.1016/S0957-4166(00)00160-9

A diastereo- and enantioselective synthesis of 4'-aza analogues of 2',3'-dideoxynucleosides has been designed by the strategy of the 1,3-dipolar cycloaddition reaction of a Vasella-type nitrone. The reaction leads to (1'R)- and (1'S)-4'-aza analogues of 2',3'-dideoxythimidine and fluorouridine, in enantiomerically pure forms. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00160-9

Tetrahedron: Asymmetry 11 (2000) 2045±2048
Diastereoselective and enantioselective synthesis of 40-aza
analogues of 20,30-dideoxynucleosides
Ugo Chiacchio,a,* Antonio Resci®na,a Antonio Corsaro,a Venerando Pistara,a
Giovanni Romeob and Roberto Romeob
a
Á
Dipartimento di Scienze Chimiche, Universita di Catania, Viale A. Doria 6, Catania 95125, Italy
Dipartimento Farmaco Chimico, Universita di Messina, Viale Annunziata, Messina 98100, Italy
b
Á
Received 23 March 2000; accepted 28 April 2000
Abstract
A diastereo- and enantioselective synthesis of 40-aza analogues of 20,30-dideoxynucleosides has been
designed by the strategy of the 1,3-dipolar cycloaddition reaction of a Vasella-type nitrone. The reaction
leads to (10R)- and (10S)-40-aza analogues of 20,30-dideoxythimidine and ¯uorouridine, in enantiomerically
pure forms. # 2000 Elsevier Science Ltd. All rights reserved.
Modi®cation of naturally occurring nucleosides has led to the discovery of important HIV
agents as AZT, D4T and 3TC.1 In this context nucleosides 1 and 2 containing an isoxazoline or
isoxazolidine moiety are of current interest as potential antiviral agents.2,3
The synthesis of isoxazolidinyl nucleoside 3, unsubstituted at the nitrogen atom and in racemic
form, has been recently reported.4 In particular, ADT 3 shows important antiviral and anti AIDS
activity. Moreover, ADT inhibits HIV replication in C 8166, with an activity inversely related to
the multiplicity of infection used;4b however, it is well known that both enantiomeric purity and
absolute con®guration are key factors in determining the physiological activity of drugs.5
Herein, we report the ®rst example of an enantioselective and diastereoselective synthesis of
(10R)- and (10S)-40-aza analogues of 20,30-dideoxythimidine and ¯uorouridine 3 and 4. The key
step of our approach consists in the 1,3-dipolar cycloaddition of a chiral nitrone, containing a
* Corresponding author. Fax: +39 095 580138; e-mail: uchiacchio@dipchi.unict.it
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00160-9

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U. Chiacchio et al. / Tetrahedron: Asymmetry 11 (2000) 2045±2048
stereogenic centre at the nitrogen atom,6 to vinyl acetate in order to construct the isoxazolidine
ring. Thus, the Vasella-type nitrone 5, prepared according to the previously reported methodology,7
has been reacted with vinyl acetate in the absence of solvent, using a 1:10 relative ratio of dipole/
dipolarophile, for 36 h to give a mixture of two homochiral isoxazolidines 6 and 7 (90% global
yield), epimeric at C5 of the isoxazolidine ring,6,7 in a ratio 1.4:1 (Scheme 1).
Scheme 1. (a) Vinyl acetate, 70ꢀC; (b) silylated base, TMSOTf or SnCl4; (c) 1.5% HCl in EtOH
The epimeric isoxazolidines 6 and 7 were then coupled with silylated thymine in acetonitrile in
the presence of TMSOTf or with 5-¯uorouracil, in CH2Cl2 at 0ꢀC, in the presence of one
equivalent of SnCl4, to a€ord, with a moderate stereoselectivity and in good yields, the expected
isoxazolidinyl nucleosides 8a,b and 9a,b, respectively (8a/8b ratio 1.4:1, 9a/9b ratio 1.8:1), which
have been separated by HPLC chromatography.8 The assigned stereochemistry of the obtained
adducts is supported by NMR analyses. In fact, NOE measurements, performed on 8a,b and 9a,b
show a positive NOE e€ect for protons 400 when irradiating 100 thus indicating a cis relationship
between these protons.
Mixtures of diastereomeric invertomers could be observed for compounds 8 and 9; however,
the NMR data show, at room temperature, only one set of resonances thus suggesting the exist-
ence of only one isomer or a nitrogen inversion suciently fast to impart time-averaged prop-
erties to the observed compounds. Variable temperature NMR measurements were conducted:
only one invertomer could be observed. In fact, when lowering the temperature to ^80ꢀC, it was
impossible to reveal the presence of two invertomers.
PM39 and AM110 quantomechanical calculations allow for a clear rationalization of the obtained
0
results. Structural analyses regarding the stabilities of the isomers formed indicate that the N4 ±C1
0
trans isomers are more stable than the cis. An energy di€erence of 4.3 kcal/mol for compound 8a
was calculated in favour of the trans isomer: this barrier suciently explains the fact that
experimentally only one invertomer was formed. The calculated energy barrier for the nitrogen

U. Chiacchio et al. / Tetrahedron: Asymmetry 11 (2000) 2045±2048
2047
inversion is 13.91 kcal/mol: a value of 16.2 is reported for similar systems.11 The marked preference
for the trans form makes these compounds analogues of a-nucleosides. Thus, for obtained a and
0
b anomers, the di€erence of con®guration of their C1 atoms is compensated by the nitrogen
0
inversion and both anomers possess the same trans disposition of their N4 and C1 substituents.
0
On this basis and according with the quantomechanical calculations, the relative con®guration
0
0
at N4 and C1 for nucleosides 8 and 9 has been assigned as reported in Scheme 1. The major
stereoisomers 8a and 9a can be assigned the con®guration (10R) which is more stable than the
con®guration (10S) of about 0.8 kcal: this value is in agreement with the observed a/b ratio.
Finally, the synthetic scheme devoted towards the synthesis of homochiral 40-aza-20,30-dideoxy-
nucleosides has been completed by the selective cleavage of the sugar moiety, performed by
treatment with 1.5% aqueous HCl: in this way two separate enantiomers 3a,b and 4a,b have been
obtained.12
In conclusion, both anomers of 40-aza-20,30-dideoxynucleosides have been synthesized in an
enantiomerically pure form.13 According to the reported biological activity,4b shown in vitro by
this class of compounds, the designed methodology appears versatile and potentially extendable
to the synthesis of other aza-nucleosides containing di€erent purine and pyrimidine bases.
Acknowledgements
We thank the M.U.R.S.T. for its partial ®nancial support, Maria Grazia Saita and Maria
Siciliano for their technical assistance.
References
1. (a) Perigaud, C.; Gosselin, G.; Imbach, J. L. Nucleosides Nucleotides 1992, 11, 903. (b) Thomas, H. Drugs of Today
1992, 28, 311. Bonnet, P. A.; Robins, R. K. J. Med. Chem. 1995, 36, 635. (c) Mani, S.; Ratain, M. J. Curr. Opin.
Oncology 1995, 8, 525. (d) Unger, C. J. Cancer. Res. Clin. Oncol. 1996, 122, 189. (e) Nair, V.; Jahnke, T. S.
Antimicrob. Agents Chemother. 1995, 39, 1017. (f) Chiacchio, U.; Iannazzo, D.; Resci®na, A.; Romeo, G. J. Org.
Chem. 1999, 64, 28.
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. (d) Pan, S.; Amankulor, N. M.;
Zhao, K. Tetrahedron 1998, 54, 6587.
3. (a) Kim, H. O.; Schinazi, R. F.; Shanmuganathan, K.; Jeong, 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. (d) Adams, D. R.; Boyd, A. S. F.; Ferguson, R.; Grierson, D. S.; Monneret, C. Nucleosides
Nucleotides 1998, 17, 1053. (e) Merino, P.; Franco, S.; Garces, N.; Merchan, F. L.; Tejero, T. J. Chem. Soc., Chem.
Commun. 1998, 493.
4. (a) Leggio, A.; Liguori, A.; Procopio, A.; Siciliano, C.; Sindona, G. Tetrahedron Lett. 1996, 37, 1277. (b) Leggio,
A.; Liguori, A.; Procopio, A.; Siciliano, C.; Sindona, G. Nucleosides Nucleotides 1997, 16, 1515.
5. Collins, A. N.; Sheldrake, G. N.; Crosby, J. Chirality in Industry; Wiley: Chichester, 1992.
6. (a) Vasella, A. Helv. Chim. Acta 1977, 60, 426 and 1273. (b) Mzengeza, S.; Whitney, R. A. J. Org. Chem. 1988, 53,
4074.
7. Chiacchio, U.; Corsaro, A.; Gumina, G.; Resci®na, A.; Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, R. J. Org.
Chem. 1999, 64, 9321.
8. HPLC separation for 8a and 8b: linear gradient of 2-propanol (6±10%, 0±15 min, ¯ow 3.5 mL/min) in hexane.
Compound 8a: tR 13.2 min; 42% yield; white solid; mp 61±63ꢀC; ‰ꢀŠD25=^34.1 (c=0.36; CHCl3); 1H NMR (CDCl3,
500 MHz): ꢁ 1.07 (s, 9H), 1.35 (s, 3H), 1.54 (s, 3H), 1.87 (d, 3H, J=1.1 Hz), 2.23 (ddt, 1H, J=3.1, 7.1 and 13.3 Hz,

2048
U. Chiacchio et al. / Tetrahedron: Asymmetry 11 (2000) 2045±2048
0
H2 a), 2.73 (dq, 1H, J=7.1 and 13.3 Hz, H2 b), 3.18 (t, 2H, J=7.1 Hz, H3 ), 3.72 (dd, 1H, J=6.3 and 10.7 Hz,
0
0
00
H5 a), 3.74 (dd, 1H, J=6.0 and 10.7 Hz, H5 b), 4.25 (ddd, 1H, J=2.9, 6.0 and 6.3 Hz, H4 ), 4.58 (dd, 1H, J=2.9
00
00
00
00
00
and 6.3 Hz, H3 ), 4.72 (dd, 1H, J=2.5 and 6.3 Hz, H2 ), 4.82 (d, 1H, J=2.5 Hz, H1 ), 5.99 (dd, 1H, J=3.1 and 7.1
0
Hz, H1 ), 7.40 (q, 1H, J=1.1 Hz, H6), 7.36±7.68 (m, 10H), 8.59 (bs, 1H, NH). 13C NMR (CDCl3, 125 MHz): ꢁ
12.64, 19.23, 25.40, 26.78, 27.18, 36.76, 48.26, 64.19, 81.19, 82.77, 84.16, 85.99, 90.04, 110.73, 113.31, 127.74,
129.80, 129.86, 133.18, 135.55, 150.00, 163.70. Anal. calcd for C32H41N3O7Si: C, 63.24; H, 6.80; N, 6.91%. Found:
C, 63.22; H, 6.81; N, 6.90%. Compound 8b: tR 14.7 min; 30% yield; white solid; mp 57±58ꢀC; ‰ꢀŠD25=+24.5
(c=0.29; CHCl3); 1H NMR (CDCl3, 500 MHz): ꢁ 1.06 (s, 9H), 1.35 (s, 3H), 1.53 (s, 3H), 1.83 (d, 3H, J=1.2 Hz),
0
2.18 (dddd, 1H, J=3.2, 6.5, 7.0 and 14.0 Hz, H2 a), 2.76 (dddd, 1H, J=7.0, 7.2, 8.0 and 14.0 Hz, H2 b), 3.12 (ddd,
0
0
0
1H, J=6.5, 8.0 and 10.5 Hz, H3 a), 3.17 (dt, 1H, J=7.0 and 10.5 Hz, H3 b), 3.72 (dd, 1H, J=5.6 and 10.7 Hz,
00 00 00
5 a), 3.75 (dd, 1H, J=6.1 and 10.7 Hz, H5 b), 4.29 (ddd, 1H, J=1.5, 5.6 and 6.1 Hz, H4 ), 4.63 (d, 1H, J=1.4
H
Hz, H1 ), 4.71 (dd, 1H, J=1.5 and 9.5 Hz, H3 ), 4.72 (dd, 1H, J=1.4 and 9.5 Hz, H2 ), 6.25 (dd, 1H, J=3.2 and
00
00
00
7.2 Hz, H1 ), 7.29 (q, 1H, J=1.2 Hz, H6), 7.36±7.67 (m, 10H), 8.51 (bs, 1H, NH). 13C NMR (CDCl3, 125 MHz): ꢁ
0
12.66, 19.22, 25.15, 26.79, 36.01, 48.46, 64.24, 81.45, 83.01, 84.15, 86.35, 99.75, 113.28, 127.75, 127.77, 129.88,
133.07, 135.40, 135.46, 135.51, 150.01, 163.72. Anal. calcd for C32H41N3O7Si: C, 63.24; H, 6.80; N, 6.91%. Found:
C, 63.30; H, 6.79; N, 6.92%. HPLC separation for 9a and 9b: linear gradient of 2-propanol (5±7.5%, 0±13 min,
¯ow 3.5 mL/min) in hexane. Compound 9b: tR 15.2 min; 26% yield; white solid; mp 69±71ꢀC; ‰ꢀŠD25=^39.1
(c=0.32; CHCl3); 1H NMR (CDCl3, 500 MHz): ꢁ 1.07 (s, 9H), 1.30 (s, 3H), 1.54 (s, 3H), 2.23 (ddt, 1H, J=2.8, 7.5
0
and 13.5 Hz, H2 a), 2.76 (ddt, 1H, J=6.9, 7.5 and 13.5 Hz, H2 b), 3.16 (t, 2H, J=7.5 Hz, H3 ), 3.72 (dd, 1H, J=5.9
0
0
00
and 10.8 Hz, H5 a), 3.73 (dd, 1H, J=5.9 and 10.8 Hz, H5 b), 4.27 (dt, 1H, J=2.9 and 5.9 Hz, H4 ), 4.57 (dd, 1H,
00
00
00
00
00
J=2.8 and 6.2 Hz, H3 ), 4.71 (dd, 1H, J=2.5 and 6.2 Hz, H2 ), 4.84 (d, 1H, J=2.5 Hz, H1 ), 5.92 (dd, 1H, J=2.8
0
and 6.9 Hz, H1 ), 7.36±7.68 (m, 10H), 7.73 (d, 1H, J=6.0 Hz, H6), 9.49 (bs, 1H, NH). 13C NMR (CDCl3, 125
MHz): ꢁ 14.08, 19.24, 25.38, 26.79, 27.18, 36.98, 47.88, 64.15, 81.15, 82.77, 84.50, 86.05, 98.70, 113.42, 124.34 (d,
J=34.1 Hz), 127.70, 127.74, 129.81, 129.87, 133.16, 133.19, 135.55, 135.56, 148.67, 157.32. Anal. calcd for
C31H38FN3O7Si: C, 60.87; H, 6.26; N, 6.87%. Found: C, 60.89; H, 6.25; N, 6.87%. Compound 9a: tR 16.0 min;
25
46% yield; white solid; mp 52±54ꢀC; ‰ꢀŠD =+15.2 (c=0.49; CHCl3); H NMR (CDCl3, 500 MHz): ꢁ 1.07 (s, 9H),
1
0
1.35 (s, 3H), 1.52 (s, 3H), 2.19 (dddd, 1H, J=2.0, 3.0, 7.0 and 13.5 Hz, H2 a), 2.78 (dddd, 1H, J=2.0, 7.5, 8.0 and
0
0
13.5 Hz, H2 b), 3.05 (ddd, 1H, J=2.0, 8.0 and 10.5 Hz, H3 a), 3.16 (ddd, 1H, J=2.0, 7.0 and 10.5 Hz, H3 b), 3.70
0
00
(dd, 1H, J=6.0 and 11.0 Hz, H5 a), 3.74 (dd, 1H, J=6.0 and 11.0 Hz, H5 b), 4.30 (dt, 1H, J=1.5 and 6.0 Hz, H4 ),
00
00
00
00
00
4.62 (d, 1H, J=1.5 Hz, H1 ), 4.70 (dd, 1H, J=1.5 and 7.5 Hz, H3 ), 4.71 (dd, 1H, J=1.5 and 7.5 Hz, H2 ), 6.20
0
(dd, 1H, J=3.0 and 7.5 Hz, H1 ), 7.37±7.66 (m, 10H), 7.58 (d, 1H, J=6.0 Hz, H6), 9.19 (bs, 1H, NH). 13C NMR
(CDCl3, 125 MHz): ꢁ 14.10, 19.22, 25.10, 26.80, 26.84, 36.35, 48.56, 64.19, 81.41, 82.98, 84.60, 86.36, 99.98, 113.37,
124.10 (d, J=33.6 Hz), 127.76, 127.79, 129.91, 129.99, 132.95, 133.01, 135.44, 135.49, 148.58, 156.88. Anal. calcd
for C31H38FN3O7Si: C, 60.87; H, 6.26; N, 6.87%. Found: C, 60.88; H, 6.27; N, 6.86%.
9. Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209 and 221.
10. Dewar, J. M. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am. Chem. Soc. 1985, 107, 3902.
11. (a) 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. (b) Tronchet, J. M. J.; Iznaden, M.; Barbalat-Rey, F.; Komaromi, I.; Dolatshahi, N.;
Bernardinelli, G. Nucleosides Nucleotides 1995, 14, 1737.
12. Compound 3a: 97.5% yield; white solid; mp 202±204ꢀC; ‰ꢀŠD25=^93.7 (c=0.16; CH3OH); 1H NMR (DMSOd6, 500
0
MHz): ꢁ 1.75 (d, 3H, J=1.1 Hz), 2.55 (dddd, 1H, J=3.1, 8.0, 9.0 and 14.0 Hz, H2 a), 2.62 (dddd, 1H, J=6.0, 7.1,
0
0
0
9.0 and 14.0 Hz, H2 b), 3.67 (ddd, 1H, J=6.0, 8.0 and 10.5 Hz, H3 a), 3.97 (ddd, 1H, J=7.1, 9.0 and 10.5 Hz, H3 b),
0
6.21 (dd, 1H, J=3.1 and 7.9 Hz, H1 ), 7.37 (q, 1H, J=1.1 Hz, H6), 11.18 (bs, 1H, NH). 13C NMR (DMSOd6, 125
MHz): ꢁ 14.51, 30.96, 47.14, 85.52, 110.18, 136.87, 151.06, 164.22. Anal. calcd for C8H11N3O3: C, 48.73; H, 5.62; N,
21.31%. Found: C, 48.71; H, 5.61; N, 21.33%. Compound 3b: 98% yield; white solid; mp 202±204ꢀC; ‰ꢀŠD25=+87.5
(c=0.09; CH3OH). Anal. calcd for C8H11N3O3: C, 48.73; H, 5.62; N, 21.31%. Found: C, 48.72; H, 5.62; N,
25
21.32%. Compound 4a: 87% yield; white solid; mp 153±155ꢀC; ‰ꢀŠD =+78.6 (c=0.07; CH3OH); H NMR (D2O,
1
0
0
500 MHz): ꢁ 2.36 (ddt, 1H, J=3.0, 6.2 and 14.1 Hz, H2 a), 2.55 (ddt, 1H, J=6.2, 7.4 and 14.1 Hz, H2 b), 3.13 (t, 2H,
J=6.2 Hz, H3 ), 5.95 (dd, 1H, J=3.0 and 7.4 Hz, H1 ), 7.71 (d, 1H, J=7.3 Hz, H6). 13C NMR (D2O, 125 MHz): ꢁ
38.24, 49.34, 90.88, 129.00 (d, J=34.4 Hz), 140.91, 145.54, 151.92. Anal. calcd for C7H8FN3O3: C, 41.80; H, 4.01; N,
20.89%. Found: C, 41.79; H, 4.00; N, 20.90%. Compound 4b: 88% yield; white solid; mp 152±155ꢀC; ‰ꢀŠD25=^75.3
(c=0.05; CH3OH). Anal. calcd for C7H8FN3O3: C, 41.80; H, 4.01; N, 20.89%. Found: C, 41.77; H, 4.02; N, 20.91%.
13. The purity of all homochiral compounds has been tested with a 25 cm chiral Daicell OJ column with mixtures of
n-hexane/2-propanol as eluent.
0
0