Studies toward the synthesis of antitumor antibiotics FR-900482 and FR-66979 /
The antitumor antibiotic FR-900482 (1) and FR-66979 (2) were isolated from Streptomyces sandaensis from Fujisawa Pharmaceutical Co. (Japan). FR-900482 (1) and FR-66979 (2) showed potent antitumor activity. This cytotoxicity is apparently related to their ability to induce DNA-DNA and DNA-protein c...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1996.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=743266761&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | The antitumor antibiotic FR-900482 (1) and FR-66979 (2) were isolated from Streptomyces sandaensis from Fujisawa Pharmaceutical Co. (Japan). FR-900482 (1) and FR-66979 (2) showed potent antitumor activity. This cytotoxicity is apparently related to their ability to induce DNA-DNA and DNA-protein cross-links. This dissertation describes the development of a general strategy for the enantioselective synthesis of 1 and 2. One of the key elements of this approach is the formal oxidative ring expansion of an appropriately substituted mitosene ring system to the target heterocycle. The enantioselective synthesis of the mitosene ring system 3 then constitutes the major synthetic obstacles. In Chapter 11 of this dissertation an enantioselective approach to 1,2-disubstituted mitosene heterocycles is investigated. Specifically, the synthesis and intramolecular cyclization of diazo esters (4) are described. Following oxidation of the primary cyclization product, mitosene 5 was obtained in high yield. Asymmetric versions of the cyclization were examined using chiral copper(l) and chiral rhodium(II) catalysts under various conditions. The selectivity of the cyclizations was primarily effected by the catalyst and solvents . Surprisingly, copper(l) catalysts were found to be superior to rhodium(II) catalysts in inducing asymmetry. Finally, it was found that the choice of solvent had a dramatic effect on the overall enantioselectivity of the cyclization-oxidation process. In chapter III a synthetic approach to FR-900482 (1) and FR-66979 (2) is described. After investigating a series of substrates to effect the diazo transfer-cyclization sequence, it was determined that ketone 6 met the structure requirements to execute these two transformations and ultimately led to the production of mitosene 7. Unfortunately, the overall enantioselectivity of the process was poor in comparison to that obtained from diazo esters (4) investigated in chapter II. The oxidative ring expansion of 7 to dihydrobenzoxazine 8 is also described. |
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| Item Description: | Vita. "Major Subject: Chemistry". In title, numerals are used. |
| Physical Description: | xix, 259 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilms Inc. |
| Bibliography: | Includes bibliographical references. |