A Concise Route to 19-Nor-10-azasteroids, a New Class of Steroid 5α-Reductase Inhibitors. 3.1 Synthesis of (+)-19-Nor-10-azatestosterone and (+)-17β-(Acetyloxy)-(5β)-10-azaestr-1-en-3-one

Journal of Organic Chemistry

Volumn 63, Issue 12, 1998, Pages 4111-4115

  Guarna, Antonio ^a   Occhiato, Ernesto G ^a   Machetti, Fabrizio ^a   Scarpi, Dina ^a  

^a UNIVERSITY OF FLORENCE   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

17BETA (ACETYLOXY) (5BETA) 10 AZAESTR 1 EN 3 ONE; 19 NOR 10 AZATESTOSTERONE; AZASTEROID; STEROID 5ALPHA REDUCTASE INHIBITOR; TESTOSTERONE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL ANALYSIS; CHEMICAL REACTION; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; STEROIDOGENESIS;

EID: 0032511116     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo971917s     Document Type: Article

References (41)

1. (a) Guarna, A.; Belle, C.; Machetti, F.; Occhiato, E. G.; Payne, H. P.; Cassiani, C.; Comerci, A.; Danza, G.; De Bellis, A.; Dini, S.; Marrucci, A.; Serio, M. J. Med. Chem. 1997, 40, 1112-1129.
2. (b) Guarna, A.; Occhiato, E. G.; Machetti, F.; Marrucci, A.; Danza, G.; Serio, M.; Paoli, P. J. Med. Chem. 1997, 40, 3466-3477.
3. (a) Russell, D. W.; Wilson, J. D. Annu. Rev. Biochem. 1994, 63, 25-61.
4. (b) Wilson, J. D.; Griffin, J. E.; Russell, D. W. Endocrine Rev. 1993, 14, 577-593.
5. (a) Geller, J. J. Am. Geriatr. Soc. 1991, 39, 1208-1266.
6. (b) Kenny, B.; Ballard, S.; Blagg, J.; Fox, D. J. Med. Chem. 1997, 40, 1293-1314 and references therein.
7. Dallob, A. L.; Sadick, N. S.; Unger, W.; Lipert, S.; Geissler, L. A.; Gregoire, S. L.; Nguyen, H. H.; Moore, E. C.; Tanaka, W. K. J. Clin. Endocrinol. Metab. 1994, 79, 703-706.
8. Smith, L. S.; Tegler, J. J. Annu. Rep. Med. Chem. 1989, 24, 177-186.
9. Gadwood, R. C.; Fiedler, V. C. Annu. Rep. Med. Chem. 1989, 24, 187-196.
10. Brooks, J. R. Clin. Endocrinol. Metabol. 1986, 15, 391-405.
11. (a) Holt, D. A.; Levy, M. A.; Metcalf, B. W. Inhibition of Steroid 5α-Reductase. In Advances in Medicinal Chemistry, Maryanoff, B. E., Maryanoff, C. A., Eds.; JAI Press Inc: Greenwich, CT, 1993; Vol. 2, PP 1-29.
12. (b) Abell, A. D.; Henderson, B. R. Curr. Med. Chem. 1995, 2, 583-597.
13. (c) Li, X.; Chen, C.; Singh, S.; Labrie, F. Steroids 1995, 60, 430-441.
14. (d) Frye, S. V. Curr. Pharm. Des. 1996, 2, 59-84.
15. (a) Geller, J. J. Clin. Endocrinol. Metab. 1990, 71, 1552-1555.
16. (b) Stoner E. J. Steroid Biochem. Mol. Biol. 1990, 37, 375-378.
17. (a) Brandi, A.; Cordero, F. M.; De Sarlo; F.; Goti, A.; Guarna, A. Synlett 1993, 1-8.
18. (b) Occhiato, E. G.; Guarna, A.; Brandi, A.; Goti, A.; De Sarlo, F. J. Org. Chem. 1992, 57, 4206-4211.
19. (c) Belle, C.; Cardelli, A.; Guarna; A. Tetrahedron Lett. 1991, 32, 6395-6398.
20. (a) Pilli, R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem. 1995, 60, 717-722.
21. (b) Pilli, R. A.; Dias, L. C.; Maldaner, A. O. Tetrahedron Lett. 1993, 34, 2729-2732.
22. (c) Pilli, R. A.; Dias, L. C. Synth. Commun. 1991 21 2213-2229
23. Biggs, C. B.; Pyke, T. R.; Wovcha, M. G. (Upjohn Co.) U.S. Pat. 4 062 729, 1977; Chem. Abstr. 1978, 88, 188129t.
24. Biggs, C. B.; Pyke, T. R.; Wovcha, M. G. (Upjohn Co.) U.S. Pat. 4 062 729, 1977; Chem. Abstr. 1978, 88, 188129t.
25. Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807-7808.
26. The conjugation between the N atom and the 3-oxo group through a double bond in the A ring is an essential feature for the biological activity of 19-nor-10-azasteroids (ref 1a).
27. Apart from the synthesis reported by us in ref 1a, only one synthesis of 11 has been reported so far: Bertin, D.; Perronet, J. Bull. Soc. Chem. Fr. 1969, 117-122.
28. Miller, R. A.; Humphrey, G. R.; Thompson, A. S. Tetrahedron Lett. 1995, 36, 7949-7952 and references therein.
29. Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48, 2424-2426.
30. Fischer, M. J.; Overman, L. E. J. Org. Chem. 1990, 55, 1447-1459.
31. The crude reaction mixture contained a certain amount of unidentified decomposition products. Repeated purifications by chromatography were necessary to obtain pure 8.
32. It is known that, in cyclic systems, the protons adjacent to the nitrogen atom and on the same side of the N lone pair undergo a strong deshielding effect, whereas the protons on the opposite side are strongly shielded: (a) Crabb, T. A.; Newton, R. F.; Jackson, D. Chem. Rev. 1971, 71, 109-126. (b) Wilson S. R.; Sawicki, R. A. J. Org. Chem. 1979, 44, 330-336. (c) King, F. D. J. Chem. Soc., Perkin Trans, 1 1986, 447-453. (d) Sonnet, P. E.; Netzel, D. A.; Mendoza, R. J. Heterocycl. Chem. 1979, 16, 1041-1047. (e) Bohlmann, F.; Shumann, D. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol. IX, Chapter 5.
33. It is known that, in cyclic systems, the protons adjacent to the nitrogen atom and on the same side of the N lone pair undergo a strong deshielding effect, whereas the protons on the opposite side are strongly shielded: (a) Crabb, T. A.; Newton, R. F.; Jackson, D. Chem. Rev. 1971, 71, 109-126. (b) Wilson S. R.; Sawicki, R. A. J. Org. Chem. 1979, 44, 330-336. (c) King, F. D. J. Chem. Soc., Perkin Trans, 1 1986, 447-453. (d) Sonnet, P. E.; Netzel, D. A.; Mendoza, R. J. Heterocycl. Chem. 1979, 16, 1041-1047. (e) Bohlmann, F.; Shumann, D. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol. IX, Chapter 5.
34. It is known that, in cyclic systems, the protons adjacent to the nitrogen atom and on the same side of the N lone pair undergo a strong deshielding effect, whereas the protons on the opposite side are strongly shielded: (a) Crabb, T. A.; Newton, R. F.; Jackson, D. Chem. Rev. 1971, 71, 109-126. (b) Wilson S. R.; Sawicki, R. A. J. Org. Chem. 1979, 44, 330-336. (c) King, F. D. J. Chem. Soc., Perkin Trans, 1 1986, 447-453. (d) Sonnet, P. E.; Netzel, D. A.; Mendoza, R. J. Heterocycl. Chem. 1979, 16, 1041-1047. (e) Bohlmann, F.; Shumann, D. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol. IX, Chapter 5.
35. It is known that, in cyclic systems, the protons adjacent to the nitrogen atom and on the same side of the N lone pair undergo a strong deshielding effect, whereas the protons on the opposite side are strongly shielded: (a) Crabb, T. A.; Newton, R. F.; Jackson, D. Chem. Rev. 1971, 71, 109-126. (b) Wilson S. R.; Sawicki, R. A. J. Org. Chem. 1979, 44, 330-336. (c) King, F. D. J. Chem. Soc., Perkin Trans, 1 1986, 447-453. (d) Sonnet, P. E.; Netzel, D. A.; Mendoza, R. J. Heterocycl. Chem. 1979, 16, 1041-1047. (e) Bohlmann, F.; Shumann, D. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol. IX, Chapter 5.
36. It is known that, in cyclic systems, the protons adjacent to the nitrogen atom and on the same side of the N lone pair undergo a strong deshielding effect, whereas the protons on the opposite side are strongly shielded: (a) Crabb, T. A.; Newton, R. F.; Jackson, D. Chem. Rev. 1971, 71, 109-126. (b) Wilson S. R.; Sawicki, R. A. J. Org. Chem. 1979, 44, 330-336. (c) King, F. D. J. Chem. Soc., Perkin Trans, 1 1986, 447-453. (d) Sonnet, P. E.; Netzel, D. A.; Mendoza, R. J. Heterocycl. Chem. 1979, 16, 1041-1047. (e) Bohlmann, F.; Shumann, D. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol. IX, Chapter 5.
37. The multiplet at 3.73 ppm for 3-H is consistent with its axial β orientation.
38. (a) Waldmann, H. Synthesis 1994, 535-551 and references therein.
39. (b) Waldmann, H.; Braun, M. J. Org. Chem. 1992, 57, 4444-4451.
40. Leonard, N. J.; Hay, A. S.; Fulmer, R. W.; Gash, V. W. J. Am. Chem. Soc. 1955, 77, 439-444.
41. Wille, H. J.; Pandit, U. K.; Huisman, H. O. Tetrahedron Lett. 1970, 4429-4432.