Synthetic studies of FR900482: Promising method to construct the bicyclic hydroxylamine hemi-ketal ring system

✍ Scribed by Nobuyoshi Yasuda; Robert M. Williams

• Book ID: 104229407
• Publisher: Elsevier Science
• Year: 1989
• Tongue: French
• Weight: 237 KB
• Volume: 30
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(00)99254-2

✦ Synopsis

Intramolecular reductive amination is utilized as a key &membered ring-forming cyclization reaction to construct the novel bicyclic hydroxylamine hemi-ketal ring system of FR900482.

The recently discovered anti-tumor antibiotic FR-900482 (1) was obtained from the fermentation harvest of Streptomyces sandaensis No. 6897 at Fujisawa Pharmaceutical Co. in Japan.2 The derived triacetate, FK973 (2) has shown very promising activity3 against various transplanted murine and human tumors. These substances are structurally related to mitomycin C but lack the quinone moiety and contain the novel hydroxylamine hemi-ketal. FK973 has been shown4 to form DNA-DNA cross-links and DNA-protein cross-links in L1210 cells; unlike the mitomycins and other quinone anti-tumor antibiotics, FK973 does not cause oxidative scission of single-strand DNA. Furthermore, FK973 is ca three-fold more potent than mitomycin C and has significantly lower toxicity. Syntheses of these novel structures or approaches to the unique dihydrobenzoxazine ring system have not yet appeared. In this paper, we wish to detail the first successful construction of the unique central bicyclic hydroxylamine hemi-ketal ring system of these medicinally significant substances.