Total chiral synthesis of azole antifungals via α-hydroxylation of ketones

Tetrahedron Letters

Volumn 37, Issue 45, 1996, Pages 8117-8120

  Gala, Dinesh ^a   DiBenedetto, Donald J ^a   Mergelsberg, Ingrid ^a   Kugelman, Max ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIFUNGAL AGENT; RAVUCONAZOLE; SCH 42427; UNCLASSIFIED DRUG;

ARTICLE; DRUG SYNTHESIS; ENANTIOMER; REACTION ANALYSIS;

EID: 0030569272     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(96)01887-4     Document Type: Article

References (21)

1. 1) (a) For ER-30346 see Toshihiko N.; Katsura, H.; Akihiko T. Drugs of the Future 1996, 21, 20;
2. (b) For Sch 42427/SM9164 see Drugs of the Future 1995, 20, 1300.
3. 2) (a) Miyauchi, H.; Kozuki, K.; Tanio, T.; Ohashi, N. Bioorg. & Med. Chem. Lett. 1995, 5, 1479;
4. (b) Miyauchi, H.; Tanio, T.; Ohashi, N. Bioorg. & Med. Chem. Lett 1995, 5, 933;
5. (c) Saji, I.; Tamoto, K.; Tanaka, Y.; Miyauchi, H.; Fujimoto, K.; Ohashi, N. Bull Chem. Soc. Jpn. 1994, 67, 1427.
6. 3) (a) Gala, D.; DiBenedetto, D. J.; Clark, J. E; Murphy, B. L.; Schumacher, D.; Steinman, M. Tetrahedron Lett. 1996, 37, 611;
7. (b) Gala, D.; DiBenedetto, D. J. Tetrahedron Lett. 1994, 33, 8299;
8. (c) Miyauchi, H.; Tanio, T.; Ohashi, N. Bioorg. & Med. Chem. Lett. 1995, 5, 933;
9. (d) Bennett, F.; Ganguly, A. K.; Girijavallabhan, V. M.; Pinto, P. A. Synlett 1995, 1110.
10. 4) (a) Davis; F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. G. J. Org. Chem. 1986, 51, 4083;
11. (b) Davis, F. A.; Weismiller, M. C. J. Org. Chem. 1990, 55, 3715.
12. 5) Of the bases evaluated (Na, K, or Li HMDS) Na ion led to the best outcome. NaHMDS was better than NaH, or NaOtBu. Among a variety of solvents evaluated (tBuOMc, Toluene, DME, Ether, THF, diglyme, mixtures there of, with or without trace of DMSO) THF followed by DME were found most suitable.
13. 3, 1. 4 eq. propionyl chloride, r.t. to 65°C; product extraction in tBuOMe followed by distillation of 4 at 50°C, 2mm).
14. 7) The ees reported in the literature were determined by NMR. The ees reported in this article were determined by chiral HPLC (Chiracel OB; 4-7% iPrOH/Hexane, 0.7 to 1.1 ml/min, UV 220nm).
15. 8) For instability of 2 and 5 see: Gala, D.; Puar, M. S.; Kugelman, M.; DiBenedetto, D. J. J. Pharm. Sci., 1992, 81, 1199. The higher yields were obtained by maintaining cooler (0-10°C0 temperature, inert atmosphere and neutral pH during the workup and storage of the products as indicated in ref. 3a, and 3b.
16. 9) All oxaziridines used for this research were prepared according to references 4a and 4b.
17. 10) Davis , F. A.; Shepard, A. C.; Chen, B.-C; Haque, M. S. J. Am Chem. Soc. 1990, 112, 6679.
18. 1H NMR between -40° to -90°C.
19. 12) In the reported work (ref. 4b), the trichloro byproducts were isolated. In our hand, only the tetrachloro impurity was formed.
20. 13) For a 3b synthesis free of 3d, see: Gala, D.; DiBenedetto, D. J.; Mergelsberg, I. Tetrahedron. Lett. 1992, 33, 161.
21. 14) A recovery of 3a was also demonstrated using this procedure.