In Situ Complexation Directs the Stereochemistry of N-Glycosylation in the Synthesis of Oxathiolanyl and Dioxolanyl Nucleoside Analogues

Journal of the American Chemical Society

Volumn 113, Issue 24, 1991, Pages 9377-9379

  Choi, Woo Baeg ^a   Wilson, Lawrence J ^a   Yeola, Suresh ^a   Liotta, Dennis C ^a   Schinazi, Raymond F ^b  

^a EMORY UNIVERSITY   (United States)

^b EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 12044254762     PISSN: 00027863     EISSN: 15205126     Source Type: Journal    
DOI: 10.1021/ja00024a058     Document Type: Article

References (19)

1. Richman, D. D.; et al. N. Engl. J. Med. 1987, 317, 192.
2. Broder, S.; Mitsuya, H.; Yarochoan, R. Science 1990, 249, 1533.
3. Mitsuya, H.; Matsukura, M.; Broder, S. In AIDS: Modern Concepts and Therapeutic Challenges; Broder, S., Ed.; Marcel Dekker: New York, 1987; p 303.
4. Belleau, B.; et al. Abstracts of Papers, Fifth International Conference on AIDS, Montreal; Abstract No. T.C.O.I, Ottawa, Ontario, 1989.
5. Belleau, B.; Belleau, P.; Nguyen-Ba, N. European Patent Office 90301335.7, 1990.
6. Liotta, D. C.; Choi, W. B. Patent Cooperation Treaty WO 91/11186, 1991.
7. Norbeck, D.; Sparton, S.; Broder, S.; Mitsuya, H. Tetrahedron Lett, 1989, 6263.
8. See refs 4 and 5. In ref 5, the authors report EC50 for Dioxolane-T to be 20 µM in ATH8 cells. However, our assay in human peripheral blood mononuclear cells infected with HIV-1 (LAV) indicates that Dioxolane-T has an EC5o of 0.09 µM and a therapeutic index greater than 1000. For comparison purposes, BCH-189 has an EC50 of 0.01 µM and a therapeutic index greater than 1000 in our assay.
9. Satsumabayashi, S.; et al. Bull. Chem. Soc. Jpn. 1972, 45, 913.
10. For example: (i) with TMSOTf, β:α = 1:1.
11. with HgCl2, Et2AlCI, and TiCl2(0-i-Pr)2, no coupling occurs.
12. Two equivalents of stannic chloride was needed to effect the reaction due to the basicity of the 4-amino substituent on the cytosine ring. This procedure avoids using the N-acetyl protected base. We have presented previous evidence in this regard involving 2-arylsulfenyl/SnCl4 controlled N-glycosylations with silylated thymine. See: Wilson, L. J.; Liotta, D. Tetrahedron Lett. 1990, 1815.
13. The X-ray crystal structure of 5 has been determined by Dr. Patrick Van Roey of the Medical Foundation of Buffalo. Details of this study will be published separately. In addition to the X-ray structure: (i) the material was identical to an authentic sample provided by Dr. Raymond Schinazi, Emory University; (ii) an NOE experiment on compound 11 showed a 4–7% enhancement at H4′ when H1′ was irradiated.
14. Unlike stannic chloride, titanium Lewis acids have not found general use in glycosylations. We found that stannic chloride gave a β:α ratio of 1:1 with acetate 13.
15. This glycosylation seemed to show a titanium Lewis acid dependent selectivity in both the β:α ratios and the yields (with TiCl4,β:α = 7:1 and 44% yield; with TiCl3(O-i-Pr), β:α = 10:1 and 74% yield). For comparison, reaction of acetate 13 with TMSOTf and silylated thymine (14) resulted in a β:α ratio of 1:1 in 73% yield.
16. This material gave satisfactory analytical and spectral data. An NOE experiment on compound 15 showed a 4% enhancement at H1′ upon irradiation of H4′. The same experiment performed on the α-isomer of 15 showed a 9% enhancement of H6 on the thymidine ring.
17. For N3: β:α =1:1. Chu, C. K.; Beach, J. W.; Ullas, G. V.; Kosugi, Y. Tetrahedron Lett. 1988, 5349.
18. For CN: β:α = 4:5. Okabe, M.; Sun, R.; Tam, S. T.; Todaro, L. J.; Coffen, D. L. J. Org. Chem. 1988, 53, 4780.
19. For SPh: β:α = 1:2. Chu, C. K.; Raghavachari, R.; Beach, J. W.; Kosugi, Y.; Ullas, G. V. Nucleosides Nucleotides 1989, 8, 903.