Synthesis and conformational analysis of the multidrug resistance-reversing agent hapalosin and its non-N-methyl analog

Journal of Organic Chemistry

Volumn 61, Issue 19, 1996, Pages 6606-6616

  Dinh, Tam Q ^a   Du, Xiaohui ^a   Armstrong, Robert W ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; HAPALOSIN; UNCLASSIFIED DRUG;

ARTICLE; COMPUTER SIMULATION; DRUG SYNTHESIS; MASS SPECTROMETRY; MULTIDRUG RESISTANCE; NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY;

EID: 0029795238     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo9608329     Document Type: Article

References (45)

1. ) For reviews on multidrug resistance, including the involvement of P-glycoprotein, see: (a) Simon, S. M.; Schindler, M. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3497.
2. (b) Gottesman, M. M.; Pastan, I. Annu. Rev. Biochem. 1993, 62, 385.
3. (c) Ford, J. M.; Hait, W. N. Pharmacol. Rev. 1990, 42, 155.
4. (d) Endicott, J. A.; Ling, V. Annu. Rev. Biochem. 1989, 58, 137.
5. Stratmann, K.; Burgoyne, D. L.; Moore, R. E.; Patterson, G. M. L. J. Org. Chem. 1994, 59, 7219.
6. ) Ozols, R. F.; Cunnion, R. E.; Klecker, R. W.; Hamilton, T. C.; Ostchega, Y.; Parrillo, J. E.; Young, R. C. J. Clin. Oncol. 1987, 5, 641.
7. Dinh, T. Q.; Armstrong, R. W. J. Org. Chem. 1995, 60, 8118.
8. Ghosh, A. K.; Liu, W.: Xu, Y.; Chen, Z. Angew. Chem., Int. Ed. Engl. 1996, 35, 74.
9. ) Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977, 55, 906.
10. To minimize racemization of aldehyde 8, solvents were removed from 8 at ≤30 °C and flash chromatography with silica gel was done in <30 min.
11. Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432.
12. (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
13. (b) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110, 1535.
14. Subsequent formation of a single diastereomer of ester acid 5 proved that the ee of alcohol 10 was >95%.
15. Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett. 1988, 29, 4139.
16. Hillis, L. R.; Ronald, R. C. J. Org. Chem. 1985, 50, 470.
17. Several attempts to macrolactonize the diolacid corresponding to 3 were unsuccessful.
18. The original Mukaiyama conditions are in: Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49. The modification of Mukaiyama conditions is based on Evans' modification of Keck conditions for macrolactonization with DCC: Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001.
19. The original Mukaiyama conditions are in: Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49. The modification of Mukaiyama conditions is based on Evans' modification of Keck conditions for macrolactonization with DCC: Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001.
20. The low yield for the three steps was due to macrolactonization. The TBS ether of hapalosin could not be isolated in sufficient purity for the yield of the macrolactonization step to be accurately known.
21. The Evans paper in ref 14.
22. Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614.
23. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
24. Roush, W. R.; Blizzard, T. A. J. Org. Chem. 1984, 49, 1772.
25. Corey, E. J.; Hua, D. H.; Pan, B.-C.; Seitz, S. P. J. Am. Chem. Soc. 1982, 104, 6818.
26. 13C NMR spectra are in the supporting information.
27. Evans; D. A.; Miller, S. J.; Ennis, M. D. J. Org. Chem. 1993, 58, 471.
28. In a work published after this paper was submitted, cycloamidation of the amino acid with a free β-hydroxyl group using diphenyl phosphorazidate and DIPEA in DMF generated hapalosin in 44% yield: Ohmori, K.; Okuno, T.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1996, 37, 3467.
29. Aristoff, P. A.; Johnson, P. D.; Harrison, A. W. J. Am. Chem. Soc. 1985, 107, 7967.
30. Carlsen; P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936.
31. Bailey, P. S. Ind. Eng. Chem. 1958, 50, 993.
32. (a) Li, W.-R.; Ewing, W. R.; Harris, B. D.; Joullie, M. M. J. Am. Chem. Soc. 1990, 112, 7659.
33. (b) Harris, B. D.; Joullie, M. M. Tetrahedron 1988, 44, 3489.
34. 2 at 0-25 °C.
35. 4 reduction of the N-Me variant of 23 for the synthesis of hapalosin would probably demonstrate insignificant stereoselectivity since this was so when MOM-protected trans-4-hydroxy-L-proline was used in lieu of the L-phenylalanine moiety in 23.
36. Hydroxybenzyl ester 28 was made in 87% yield by reaction of (S)-α-hydroxyisovaleric acid, BnBr, and DBU in MeCN at 25 °C. The protocol was culled from: Rao, C. G. Org. Prep. Proc. Int. 1980, 12, 225.
37. Since it was best not to purify the zwitterionic amino acid resulting from bis-deprotection of 22, the yield of this step is not specifically known but is probably good.
38. Baker, R.; Castro, J. L. J. Chem. Soc. Perkin Trans. 1 1990, 47.
39. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.
40. Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J. Am. Chem. Soc. 1990, 112, 6127.
41. Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989, 111, 4379.
42. The number of conformations contained in clusters 1-12 of hapalosin is six, four, five, two, two, one, one, five, two, two, one, and one, respectively.
43. The number of conformations contained in clusters 1-3 of the non-N-Me analog is three, seven, and two, respectively.
44. The number of conformations belonging to ring shapes 1, 2, 4, and 7 for the major conformer of hapalosin is four, two, one, and two, respectively.
45. The number of conformations belonging to ring shapes 1 and 2 for the non-N-Me analog is three and one, respectively.