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Total synthesis of 7-Epi-FR 66979 and 7-Epi-FR 900482
Descriptive
TypeOfResource
Text
TitleInfo
(ID = T-1)
Title
Total synthesis of 7-Epi-FR 66979 and 7-Epi-FR 900482
Identifier
ETD_2636
Identifier
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http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000053410
Language
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eng
Genre
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theses
Subject
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(authority = RUETD)
Topic
Chemistry and Chemical Biology
Subject
(ID = SBJ-2);
(authority = ETD-LCSH)
Topic
Streptomyces--Synthesis
Subject
(ID = SBJ-3);
(authority = ETD-LCSH)
Topic
Antibiotics--Synthesis
Abstract
(type = abstract)
The completion of the total synthesis of 7-Epi-FR 66979 and 7-Epi-FR 900482 is presented in this thesis. The natural product FR 66979 and FR 900482 were isolated by the Fujisawa Pharmaceutical Corporation from Streptomyces sandaensis. They are antibiotics with potent antitumor activity. The first stage of the total synthesis is to make indole ester. For the preparation of the precursor of the indole ester, the commercial available starting material 3-hydroxymethylphenol was converted to benzyl aldehyde by using the reagents paraformaldehyde and lewis catalyst SnCl4 after the selective protection of hydroxymethyl group. After the phenol had been protected, this benzyl aldehyde precursor was transformed to indole ester by the Hemetsberger-Knittel reaction in 61% yield. The second stage of the total synthesis is to make fully functionalized pyrroloindole. The indole ester was reduced by DIBAL and then was oxidized to indole aldehyde. The vinylsulfonium salt reacted with this indole aldehyde to form the tetracyclic oxirane, then subsequently treated by sodium azide in acetone-water to afford pyrroloindole in 74% yield. The third stage of the total synthesis is to synthesize the core ring system. The fully functionalized pyrroloindole was successfully oxidized by two equivalents of dimethydioxirane (DMDO) in acetone/water to give ring expanded hydroxylamine hemiketal ring system in 57% yield. The final stage of the total synthesis is to complete the total synthesis. One of the challenging steps is to prepare the hydroxylmethyl group on this core structure. With many studies, the hydrosilylation-oxidation was found to be a good method to make the hydroxymethyl group on this complex molecule. After converting the hydroxymethyl group to urethane and deprotection, 7-Epi-FR 66979 was successfully obtained. With a one step oxidation of 7-Epi-FR 66979, 7-Epi-FR 900482 was prepared. This total synthesis is the shortest and most efficient so far. Epi-FR 66979 is synthesized in 20 steps while epi-FR 900482 required 21 steps. The attempt of making the beta configuration of the hydroxymethyl group on the 7-position for FR 66979 and FR 900482 is also described in this thesis. The efforts included intramolecular hydrosilylation-oxidation, less hindered intermolecular hydrosilylation-oxidation, catalytic hydroboration-oxidation and Danishefsky's methods of the epoxidation and opening. Both less hindered intermolecular hydrosilylation-oxidation and Danishefsky's methods provided intermediate with beta configuration of hydroxymethyl, but the final product was not obtained. A less hindered intermolecular hydrosilylation-oxidation method will provide the best chance to get the natural product when additional more intermediates are prepared in the future.
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electronic resource
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xvi, 172 p. : ill.
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Note
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Ph.D.
Note
Includes abstract
Note
Vita
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Includes bibliographical references
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by Weidong Pan
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Pan
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Weidong
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1966-
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Weidong Pan
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Jimenez
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Leslie
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chair
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Advisory Committee
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Leslie Jimenez
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Knapp
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Spencer
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internal member
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Advisory Committee
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Spencer Knapp
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Jones
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Roger A
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Roger A Jones
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Ronald
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Doll
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Advisory Committee
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Doll Ronald
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Rutgers University
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Graduate School - New Brunswick
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school
OriginInfo
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2010
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2010
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xx
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Title
Rutgers University Electronic Theses and Dissertations
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ETD
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Title
Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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NjNbRU
Identifier
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doi:10.7282/T3RR1Z9H
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
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The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
RightsHolder
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Name
FamilyName
Pan
GivenName
Weidong
Role
Copyright Holder
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Type
Permission or license
DateTime
2010-04-15 14:41:16
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Weidong Pan
Affiliation
Rutgers University. Graduate School - New Brunswick
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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