Total synthesis of seco (+)- and ent-(-)-oxaduocarmycin SA: Construction of the (chloromethyl)indoline alkylating subunit by a novel intramolecular aryl radical cyclization onto a vinyl chloride

Journal of Organic Chemistry

Volumn 62, Issue 25, 1997, Pages 8868-8874

  Patel, Vinod F ^a   Andis, Sherri L ^a   Enkema, Julia K ^a   Johnson, David A ^a   Kennedy, Joseph H ^a   Mohamadi, Fariborz ^a,b   Schultz, Richard M ^a   Soose, Daniel J ^a   Spees, Michael M ^a  

^a ELI LILLY AND COMPANY   (United States)

^b ABBOTT LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC ANTIBIOTIC; OXADUOCARMYCIN; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER; CYCLIZATION; CYTOTOXICITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; ISOMERISM; LUNG CARCINOMA;

EID: 0031467660     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo971880b     Document Type: Article

References (74)

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43. Seco-(+)-duocarmycin SA exhibits cytotoxic activity as well as a DNA alkylating selectivity and efficiency identical with those of (+)-duocarmycin SA: see ref 8a.
44. ent-(-)-Duocarmycin SA alkylates DNA but only at concentrations approximately 10× that required for (+)-duocarmycin SA. Consequently, the natural enantiomer is 10× more effective than the unnatural enantiomer: see ref 5e.
45. To our knowledge, the intramolecular addition of carbon radicals to vinyl chlorides has not been reported; however, vinyl fluorides are known to be suitable radical acceptors: (a) Morikawa, T.; Uchida, J.; Hasegawa, Y.; Taguchi, T. Chem. Pharm. Bull. 1991, 39, 2464. (b) Morikawa, T.; Uchida, J.; Imoto, K.; Taguchi, T. J. Fluorine Chem. 1992, 58, 119. (c) Dolbier, W. R., Jr.; Rong, X. X. Tetrahedron Lett. 1996, 37, 5321. The corresponding intermolecular reactions with vinyl chlorides and vinyl fluorides are well-documented: (d) Low, H. C.; Tedder, J. M.; Walton, J. C. J. Chem. Soc., Faraday Trans. 1976, 72, 1707. (e) Henning, R.; Urbach, H. Tetrahedron Lett. 1983, 24, 5343. (f) Giese, B.; Gonzalez-Gomez, J. A.; Witzel, T. Angew. Chem., Int. Ed. Engl. 1984, 23, 69.
46. To our knowledge, the intramolecular addition of carbon radicals to vinyl chlorides has not been reported; however, vinyl fluorides are known to be suitable radical acceptors: (a) Morikawa, T.; Uchida, J.; Hasegawa, Y.; Taguchi, T. Chem. Pharm. Bull. 1991, 39, 2464. (b) Morikawa, T.; Uchida, J.; Imoto, K.; Taguchi, T. J. Fluorine Chem. 1992, 58, 119. (c) Dolbier, W. R., Jr.; Rong, X. X. Tetrahedron Lett. 1996, 37, 5321. The corresponding intermolecular reactions with vinyl chlorides and vinyl fluorides are well-documented: (d) Low, H. C.; Tedder, J. M.; Walton, J. C. J. Chem. Soc., Faraday Trans. 1976, 72, 1707. (e) Henning, R.; Urbach, H. Tetrahedron Lett. 1983, 24, 5343. (f) Giese, B.; Gonzalez-Gomez, J. A.; Witzel, T. Angew. Chem., Int. Ed. Engl. 1984, 23, 69.
47. To our knowledge, the intramolecular addition of carbon radicals to vinyl chlorides has not been reported; however, vinyl fluorides are known to be suitable radical acceptors: (a) Morikawa, T.; Uchida, J.; Hasegawa, Y.; Taguchi, T. Chem. Pharm. Bull. 1991, 39, 2464. (b) Morikawa, T.; Uchida, J.; Imoto, K.; Taguchi, T. J. Fluorine Chem. 1992, 58, 119. (c) Dolbier, W. R., Jr.; Rong, X. X. Tetrahedron Lett. 1996, 37, 5321. The corresponding intermolecular reactions with vinyl chlorides and vinyl fluorides are well-documented: (d) Low, H. C.; Tedder, J. M.; Walton, J. C. J. Chem. Soc., Faraday Trans. 1976, 72, 1707. (e) Henning, R.; Urbach, H. Tetrahedron Lett. 1983, 24, 5343. (f) Giese, B.; Gonzalez-Gomez, J. A.; Witzel, T. Angew. Chem., Int. Ed. Engl. 1984, 23, 69.
48. To our knowledge, the intramolecular addition of carbon radicals to vinyl chlorides has not been reported; however, vinyl fluorides are known to be suitable radical acceptors: (a) Morikawa, T.; Uchida, J.; Hasegawa, Y.; Taguchi, T. Chem. Pharm. Bull. 1991, 39, 2464. (b) Morikawa, T.; Uchida, J.; Imoto, K.; Taguchi, T. J. Fluorine Chem. 1992, 58, 119. (c) Dolbier, W. R., Jr.; Rong, X. X. Tetrahedron Lett. 1996, 37, 5321. The corresponding intermolecular reactions with vinyl chlorides and vinyl fluorides are well-documented: (d) Low, H. C.; Tedder, J. M.; Walton, J. C. J. Chem. Soc., Faraday Trans. 1976, 72, 1707. (e) Henning, R.; Urbach, H. Tetrahedron Lett. 1983, 24, 5343. (f) Giese, B.; Gonzalez-Gomez, J. A.; Witzel, T. Angew. Chem., Int. Ed. Engl. 1984, 23, 69.
49. To our knowledge, the intramolecular addition of carbon radicals to vinyl chlorides has not been reported; however, vinyl fluorides are known to be suitable radical acceptors: (a) Morikawa, T.; Uchida, J.; Hasegawa, Y.; Taguchi, T. Chem. Pharm. Bull. 1991, 39, 2464. (b) Morikawa, T.; Uchida, J.; Imoto, K.; Taguchi, T. J. Fluorine Chem. 1992, 58, 119. (c) Dolbier, W. R., Jr.; Rong, X. X. Tetrahedron Lett. 1996, 37, 5321. The corresponding intermolecular reactions with vinyl chlorides and vinyl fluorides are well-documented: (d) Low, H. C.; Tedder, J. M.; Walton, J. C. J. Chem. Soc., Faraday Trans. 1976, 72, 1707. (e) Henning, R.; Urbach, H. Tetrahedron Lett. 1983, 24, 5343. (f) Giese, B.; Gonzalez-Gomez, J. A.; Witzel, T. Angew. Chem., Int. Ed. Engl. 1984, 23, 69.
50. To our knowledge, the intramolecular addition of carbon radicals to vinyl chlorides has not been reported; however, vinyl fluorides are known to be suitable radical acceptors: (a) Morikawa, T.; Uchida, J.; Hasegawa, Y.; Taguchi, T. Chem. Pharm. Bull. 1991, 39, 2464. (b) Morikawa, T.; Uchida, J.; Imoto, K.; Taguchi, T. J. Fluorine Chem. 1992, 58, 119. (c) Dolbier, W. R., Jr.; Rong, X. X. Tetrahedron Lett. 1996, 37, 5321. The corresponding intermolecular reactions with vinyl chlorides and vinyl fluorides are well-documented: (d) Low, H. C.; Tedder, J. M.; Walton, J. C. J. Chem. Soc., Faraday Trans. 1976, 72, 1707. (e) Henning, R.; Urbach, H. Tetrahedron Lett. 1983, 24, 5343. (f) Giese, B.; Gonzalez-Gomez, J. A.; Witzel, T. Angew. Chem., Int. Ed. Engl. 1984, 23, 69.
51. Review: Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A. Chem. Rev. (Washington, D.C.) 1997, 97, 787.
52. This approach provides a useful improvement to established synthetic approaches to such agents: (a) 5-exo-dig aryl radical cyclization: Boger, D. L.; Ishizaki, T.; Wysocki, R. J., Jr.; Munk, S. A.; Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1989, 111, 6461. Boger, D. L.; Ishizaki, T.; Kitos, P. A.; Suntornwat, O. J. Org. Chem. Soc. 1990, 55, 5823. (b) 5-exo-trig aryl radical-alkene cyclization (functionalized alkene): Boger, D. L.; Yun, W.; Teegarden, B. R. J. Org. Chem. Soc. 1992, 57, 2873. (c) Boger, D. L.; Mckie, J. A. J. Org. Chem. 1995, 60, 1271.
53. This approach provides a useful improvement to established synthetic approaches to such agents: (a) 5-exo-dig aryl radical cyclization: Boger, D. L.; Ishizaki, T.; Wysocki, R. J., Jr.; Munk, S. A.; Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1989, 111, 6461. Boger, D. L.; Ishizaki, T.; Kitos, P. A.; Suntornwat, O. J. Org. Chem. Soc. 1990, 55, 5823. (b) 5-exo-trig aryl radical-alkene cyclization (functionalized alkene): Boger, D. L.; Yun, W.; Teegarden, B. R. J. Org. Chem. Soc. 1992, 57, 2873. (c) Boger, D. L.; Mckie, J. A. J. Org. Chem. 1995, 60, 1271.
54. This approach provides a useful improvement to established synthetic approaches to such agents: (a) 5-exo-dig aryl radical cyclization: Boger, D. L.; Ishizaki, T.; Wysocki, R. J., Jr.; Munk, S. A.; Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1989, 111, 6461. Boger, D. L.; Ishizaki, T.; Kitos, P. A.; Suntornwat, O. J. Org. Chem. Soc. 1990, 55, 5823. (b) 5-exo-trig aryl radical-alkene cyclization (functionalized alkene): Boger, D. L.; Yun, W.; Teegarden, B. R. J. Org. Chem. Soc. 1992, 57, 2873. (c) Boger, D. L.; Mckie, J. A. J. Org. Chem. 1995, 60, 1271.
55. This approach provides a useful improvement to established synthetic approaches to such agents: (a) 5-exo-dig aryl radical cyclization: Boger, D. L.; Ishizaki, T.; Wysocki, R. J., Jr.; Munk, S. A.; Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1989, 111, 6461. Boger, D. L.; Ishizaki, T.; Kitos, P. A.; Suntornwat, O. J. Org. Chem. Soc. 1990, 55, 5823. (b) 5-exo-trig aryl radical-alkene cyclization (functionalized alkene): Boger, D. L.; Yun, W.; Teegarden, B. R. J. Org. Chem. Soc. 1992, 57, 2873. (c) Boger, D. L.; Mckie, J. A. J. Org. Chem. 1995, 60, 1271.
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63. An example of regiospecific homolysis of a C-Br bond in the presence of a C-Cl bond has been reported: Stork, G.; Mook, R. J. Am. Chem. Soc. 1983, 105, 3721.
64. (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
65. (b) Beckwith, A. J. L.; Schiesser, C. H. Tetrahedron 1985, 41, 3945.
66. The amine, derived from deprotection of 14, proved unstable and was unamenable to resolution through classical fractional recrystallization of diastereomeric salts. Covalent diastereomers, prepared by attachment of chiral agents to either the amine or phenol derivatives of 14, were not readily separable by chromatograhic means.
67. Effective separations on related agents have been previously achieved by direct shromatographic resolution on a ChiraCel OD column: (a) Boger, D. L.; Yu, W. J. Am. Chem. Soc. 1994, 116, 7996. (b) Boger, D. L.; Bollinger, B.; Johnson, D. S. Bioorg. Med. Chem. Lett. 1996, 6, 2207. (c) Boger, D. L. et al, J. Am. Chem. Soc. 1997, 119, 4977. See also ref 8a.
68. Effective separations on related agents have been previously achieved by direct shromatographic resolution on a ChiraCel OD column: (a) Boger, D. L.; Yu, W. J. Am. Chem. Soc. 1994, 116, 7996. (b) Boger, D. L.; Bollinger, B.; Johnson, D. S. Bioorg. Med. Chem. Lett. 1996, 6, 2207. (c) Boger, D. L. et al, J. Am. Chem. Soc. 1997, 119, 4977. See also ref 8a.
69. Effective separations on related agents have been previously achieved by direct shromatographic resolution on a ChiraCel OD column: (a) Boger, D. L.; Yu, W. J. Am. Chem. Soc. 1994, 116, 7996. (b) Boger, D. L.; Bollinger, B.; Johnson, D. S. Bioorg. Med. Chem. Lett. 1996, 6, 2207. (c) Boger, D. L. et al, J. Am. Chem. Soc. 1997, 119, 4977. See also ref 8a.
70. Boger, D. L.; Machiya, K. J. Am. Chem. Soc. 1992, 114, 10056.
71. (a) Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91. Bieg, T.; Szeja, W. Synthesis 1985, 76.
72. (a) Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91. Bieg, T.; Szeja, W. Synthesis 1985, 76.
73. The absolute configuration at C1 in analogue (+)-3a was assigned based on analogy of the biological activity with (+)-DSA (1).
74. Procedures are described in the experimental section. For T222 tumor cell line also see: ref 15; for CCRF-CEM and GC3/C1 tumor cell lines also see: Mosmann, T. J. Immunol. Meth. 1983, 65, 55-62.