Synthesis of CC-1065/duocarmycin analogs

Details Synthesis of CC-1065/duocarmycin analogs Synthesis of CC-1065/duocarmycin analogs

2000-07-10

2001-10-30

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S084000, C546S170000

Reexamination Certificate

active

06310209

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a method for the synthesis of the dihydroindole C-ring found in CC-1065/duocarmycin analogs. More particularly, the invention comprises the 5-exo-trig radical cyclization of an aryl halide onto a tethered vinyl chloride forming the dihydroindole C-ring with chlorine installed as a suitable leaving group for subsequent cyclopropane spirocyclization. The versatility of this approach is examined in the context of six CC-1065/duocarmycin analogs previously synthesized in this laboratory.
BACKGROUND
CC-1065 (1; Chidester et al.
J. Am. Chem. Soc.
1981, 1-3, 7629) and the duocarmycins 2 (Ichimura et al.
J. Antibiot.
1990, 43, 1037) and 3 (Takahashi et al.
J. Antibiot.
1988, 41, 1915; Yasuzawa et al.
Chem. Pharm. Bull.
1995, 43, 378) are the parent members of a potent class of antitumor antibiotics that derive their biological properties through reversible, sequence selective alkylation of DNA (For a review of mechanistic aspects see: Boger, et al.
Angew. Chem., Int. Ed. Engl.
1996, 35, 230).
Since their disclosure, synthetic efforts have focused on the natural products as well as a great number of rationally designed analogs (For a review of synthetic efforts see: Boger et al.
Chem. Rev.,
1997, 97, 787). These analogs have served define the fundamental principles underlying the relationships between structure, chemical reactivity and biological properties within this family, and have advanced the understanding of the origin of sequence selectivity and the catalysis of the DNA alkylation reaction by 1-3 (Boger et al.
J. Am. Chem. Soc.
1997, 119, 4977; Boger et al.
J. Am. Chem. Soc.
1997, 119, 4987; Boger et al.
Biorg. Med. Chem.
1997, 5, 263; Warpehoski et al.
J. Am. Chem. Soc.
1994, 116, 7573; Warpehoski et al.
J. Am. Chem. Soc.
1995, 117, 2951).
Common synthetic routes to many of the duocarmycin and CC-1065 analogs incorporate the same transformation via a four step procedure highlighted by an in-situ trap of a primary radical with TEMPO (TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy free radical) followed by its reductive removal and conversion to the chloride as depicted for the synthesis of CBI (Boger et al.
J. Org. Chem.
1995, 60, 1271) as illustrated in FIG.
4
.
It would be beneficial to have a more direct and higher yielding transformation to obtain the dihydroindole C-ring found in CC-1065/duocarmycin analogs. What is needed, therefore, is an efficient and general method for the synthesis of the dihydroindole C-ring found in CC-1065/duocarmycin analogs with less steps than the standard four step TEMPO procedure as described above.
SUMMARY OF THE INVENTION
One aspect of the invention is directed to a 2 step synthesis of the dihydroindole C-ring found in CC-1065/duocarmycin analog. An aryl halide is alkylated with 1,3-dichloropropene and a catalytic amount of n-tetrabutylammonium iodide for forming a vinyl chloride. The vinyl chloride is then cyclized under conditions using tribuytyl tin hydride, catalytic AIBN and toluene as the solvent for forming the dihydroindole C-ring of the CC-1065/duocarmycin analog.
Another aspect of the invention is directed to the following compounds:


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