Asymmetric synthesis of dideazafolate antitumor agents via amidomethylation of nonracemic oxazolidinone imidates, synthesis of LY309887, a cytotoxic dideazafolate analog related to lometrexol

Tetrahedron Letters

Volumn 38, Issue 5, 1997, Pages 735-738

  Barnett, Charles J ^a   Wilson, Thomas M ^a   Evans, David A ^b   Somers, Todd C ^b  

^a ELI LILLY AND COMPANY   (United States)

^b HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CYTOTOXIC AGENT; FOLIC ACID DERIVATIVE; N [5 [2 (2 AMINO 1,4,5,6,7,8 HEXAHYDRO 4 OXOPYRIDO[2,3 D]PYRIMIDIN 6 YL)ETHYL] 2 THENOYL]GLUTAMIC ACID; UNCLASSIFIED DRUG;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; REACTION ANALYSIS; STEREOCHEMISTRY; TECHNIQUE;

EID: 0031015545     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(96)02418-5     Document Type: Article

References (20)

1. Palmer, D.C.; Skoticki, J.S.; Taylor, B.C. in Progress in Medicinal Chemistry; Ellis, G.P., West, G.B., Eds.; Elsevier: Amsterdam, vol 25, 1988; p 85-231.
2. Taylor, E. C. J. Heterocycl. Chem. 1990, 27, 1-12, and references cited therein.
3. Habeck, L.L.; Leitner, T.A.; Shackelford, K.A.; Gossett, L.S.; Schultz, R.M.; Andis, S.L.; Shih, C.; Grindey, G.B.; Mendelsohn, L.G. Cancer Res. 1994, 54, 1021-1026.
4. Worzalla, J.F.; Rutherford, P.G.; Self, T.D.; Seymour, P.D.; Theobald, K.S.; Mendelsohn, L.G.; Gossett, L.S.; Shih, C.; Schultz, R.M.; Grindey, G.B. Proc. Am. Assn. Cancer Res. 1995, abstr no. 2253.
5. Shih, C; Taylor, B.C. US Patent 4 882 334 (1989). For a description of the application of this approach to synthesis of (6RS)-lometrexol (1a) see: Taylor, E.C.; Wong, G.S.K. J. Org. Chem. 1989, 54, 3618-3624.
6. Shih, C; Taylor, B.C. US Patent 4 882 334 (1989). For a description of the application of this approach to synthesis of (6RS)-lometrexol (1a) see: Taylor, E.C.; Wong, G.S.K. J. Org. Chem. 1989, 54, 3618-3624.
7. Barnett, C.J.; Wilson, T.M.; Wendel, S.R.; Winningham, M.J.; Deeter J.B. J. Org. Chem.. 1994, 59, 7038-7045.
8. Evans, D.A.; Urpi, F.; Somers, T.C.; Clark, J.S.; Bilodeau, M.T. J. Am. Chem. Soc. 1990, 112, 8215-8216.
9. Gould, N.P.; Lee, T. J. Org. Chem. 1980, 45, 4528-4530.
10. All new compounds have been characterized spectroscopically and by either elemental analysis or high resolution mass spectroscopy.
11. Gage, J.R.; Evans, D.A. Organic Syntheses 68, 77 (1989). Available from Aldrich Chemical Company.
12. For a detailed procedure for the mixed pivaloyl anhydride acylation procedure see Evans, D.A.; Ellman, J.A. J. Am. Chem. Soc. 1989, 111, 1063-1072.
13. 2at -65 °ACC then warming to 0 °C according to the published procedure (ref 7).
14. 3) 5 7.36 (m, 5H), 5.53 (b, 1H), 5.14 (s, 2H), 4.63 (d J = 7.1 Hz, 2H), 3.34 (s, 3H).
15. 3) 5 7.36 (m, 5H), 5.53 (b, 1H), 5.14 (s, 2H), 4.63 (d J = 7.1 Hz, 2H), 3.34 (s, 3H).
16. HPLC of the crude product indicated that the reaction had proceeded with 96.4% d.e. Additional enhancement was obtained during Chromatographic purification. Starting 5 representing a recovery of 21% was also obtained from the column.
17. The moderate yield of 13 appeared to be due in part to difficulties in eluting the material completely from the silica gel column.
18. Procedures for the sulfurization and guanidine cyclization reactions were essentially as described previously. See reference 6.
19. Kaminski, Z. J. Tetrahedron Lett. 1985, 26, 2901.
20. The preparative HPLC separation of the C-6 diastereomers of LY309887 was developed by Dr. C. Shih and coworkers, Lilly Research Labs.