Synthesis of novel octahydro-1,5-imino-3-benzazocin-4,7,10-trione derivatives having a methyl group at the C-2 position as ABC ring models of saframycins

Chemical and Pharmaceutical Bulletin

Volumn 45, Issue 7, 1997, Pages 1120-1129

  Saito, Naoki ^a   Tanitsu, Masa Aki ^a   Betsui, Tamaki ^a   Suzuki, Rieko ^a   Kubo, Akinori ^a  

^a MEIJI PHARMACEUTICAL UNIVERSITY   (Japan)

Author keywords

1.5 imino 3 benzazocine; Alkylation; Piperazine 2,5 dione; Preparation; Saframycin

Indexed keywords

1,4 DIACETYL 3 METHYLPIPERAZINE 2,5 DIONE; 3 (2,4,5 TRIMETHOXY 3 METHYLBENZYLIDENE) 1,6 DIMETHYLPIPERAZINE 2,5 DIONE; 4 (4 METHOXYBENZYL) 3 (2,4,5 TRIMETHOXY 3 METHYLBENZYLIDENE) 1 METHYLPIPERAZINE 2,5 DIONE; BENZALDEHYDE DERIVATIVE; METHYL IODIDE; SAFRAMYCIN; TETRAHYDROFURAN; UNCLASSIFIED DRUG;

ARTICLE; CYCLIZATION; DRUG SYNTHESIS; METHYLATION; MOLECULAR WEIGHT; POLYMERIZATION; PROTON NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY;

EID: 0030790478     PISSN: 00092363     EISSN: None     Source Type: Journal    
DOI: 10.1248/cpb.45.1120     Document Type: Article

References (26)

1. a) Kubo A., Saito N., Yamato H., Masubuchi K., Nakamura M., J. Org. Chem., 53, 4295-4310 (1988);
2. b) Saito N., Ohira Y., Wada N., Kubo A., Tetrahedron, 46, 7711-7728 (1990).
3. a) Fukuyama T., Sachleben R. A., J. Am. Chem. Soc., 104, 4957-4958 (1982);
4. b) Fukuyama T., Yang L., Ajeck K. L., Sachleben R. A., ibid., 112, 3712-3713 (1990).
5. Saito N., Harada S., Inouye I., Yamaguchi K., Kubo A., Tetrahedron, 30, 8231-8246 (1995).
6. a) Kubo A., Saito N., Yamato H., Yamauchi R., Hiruma K., Inoue S., Chem. Pharm. Bull., 36, 2607-2614 (1988);
7. b) Saito N., Ohira Y., Kubo A., ibid., 38, 821-823 (1990);
8. c) Saito N., Obara Y., Azumaya M., Kubo A., ibid., 40, 2620-2626 (1992);
9. d) Saito N., Obara Y., Aihara T., Harada S., Shida Y., Kubo A., Tetrahedron, 50, 3915-3928 (1994). For an alternative synthesis of the ABC ring of saframycin, see ref. 5.
10. a) Kurihara H., Mishima H., Heterocycles, 17, 191-199 (1982);
11. b) Idem. Tetrahedron Lett., 23, 3639-3640 (1982);
12. c) Kurihara H., Mishima H., Aral M., Heterocycles, 24, 1549-1555 (1986).
13. Saito N., Kubo A., Mikami Y., Yazawa K., Arai T., Abstracts of Papers, The AFMC International Medicinal Chemistry Symposium 95. Tokyo, September 1995, P1T044.
14. Reaction of 2 with sodium hydride (1.1 eq) and methyl iodide (1.1 eq) in THF is slow, but heating under reflux for 3 h gave 3 in 93.0% yield (see Experimental).
15. Methylation of 3 with sodium hydride (1 eq) and methyl iodide (3eq) in DMF under reflux for 3 h gave 5a and 6 in 39.9% and 2.9% yields, respectively (21.9% of 3 recovered). Methylation of 2 with sodium hydride (2.1 eq) and methyl iodide (10eq) in DMF under reflux for 14 h gave 3, 5a, and 6 in 24.1%, 35.3%, and 1.0% yields, respectively.
16. Kanmera T., Lee S., Aoyagi H., Izumiya N., Tetrahedron Lett., 1979, 4483-4486.
17. 4: 212.0797. Found: 212.0794.
18. Chai C. L. L., Hay D. B., King A. R., Aust. J. Chem., 49, 605-610 (1996).
19. 3), 3.98 (1H, d, J = 18.2 Hz, 6-H), 4.07 (1H, q, J = 7.3 Hz, 3-H), 4.77 (1H, d, J = 18.2 Hz, 6-H). Condensation of (+)-27 with 9 in the presence of potassium tert-butoxide (1 eq) in DMF gave 7a in only 4.6% yield along with the C-6 alkylated compound 28 (8.4%) and recovered 9 (26.9%). Clearly, unfavorable anion formation at the C-6 position of 27 had occurred. Treatment of (+)-27 and 9 with 2 eq of sodium tert-butoxide in DMF at 25°C for 24 h gave 7a (10.9%) as a racemic form (see Experimental). (Matrix Presented)
20. This compound was a 3:2 mixture of two rotational isomers.
21. a) Saito N., Yamauchi R., Nishioka H., Ida S., Kubo A., J. Org. Chem., 54, 5391-5395 (1989);
22. b) Saito N., Tashiro K., Maru Y., Yamaguchi K., Kubo A., J. Chem. Soc., Perkin Trans. 1, 1997, 53-69.
23. 1,2 = 3.5 Hz), which was isolated in minute quantity from a bright blue marine sponge. Reniera sp.; Frincke J. M., Faulkner D. J., J. Am. Chem. Soc., 104, 265-269 (1982). (Matrix Presented)
24. 3 (6%).
25. 1b)
26. An H-6 proton is orthogonal to the H-5 proton.