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Total synthesis of 7-Epi-FR 66979 and 7-Epi-FR 900482
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Pan, Weidong. Total synthesis of 7-Epi-FR 66979 and 7-Epi-FR 900482. Retrieved from https://doi.org/doi:10.7282/T3RR1Z9H

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TitleTotal synthesis of 7-Epi-FR 66979 and 7-Epi-FR 900482
NamePan, Weidong (author); Jimenez, Leslie (chair); Knapp, Spencer (internal member); Jones, Roger A (internal member); Ronald, Doll (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2010
Other Date2010 (degree)
SubjectChemistry and Chemical Biology, Streptomyces--Synthesis, Antibiotics--Synthesis
Extentxvi, 172 p. : ill.
DescriptionThe 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.
NotePh.D.
NoteIncludes abstract
NoteVita
NoteIncludes bibliographical references
Noteby Weidong Pan
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3RR1Z9H
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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