2026-09-21T02:05:17Zhttps://dspace.mit.edu/server/oai/requestoai:dspace.mit.edu:1721.1/823142026-06-16T18:17:14Zcom_1721.1_7582com_1721.1_7581col_1721.1_131022
Mohammad Movassaghi.
Kim, Justin, Ph. D. Massachusetts Institute of Technology
Massachusetts Institute of Technology. Department of Chemistry.
Massachusetts Institute of Technology. Department of Chemistry
2013-11-18T19:07:39Z
2013-11-18T19:07:39Z
2013
2013
http://hdl.handle.net/1721.1/82314
861613080
Thesis (Ph. D. in Organic Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.
Cataloged from PDF version of thesis. Vita.
Includes bibliographical references.
I. Total Synthesis of the (+)-12,12'-Dideoxyverticillin A The fungal metabolite (+)-12,12'-dideoxyverticillin A, a cytotoxic alkaloid isolated from a marine Penicillium sp., belongs to a fascinating family of densely functionalized, stereochemically complex, and intricate dimeric epidithiodiketopiperazine natural products. Although the dimeric epidithiodiketopiperazines have been known for nearly four decades, none has succumbed to total synthesis. We report a concise enantioselective total synthesis of (+)- 12,12'-dideoxyverticillin A via a strategy inspired by our biosynthetic hypothesis for this alkaloid. Highly stereo- and chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions, as well as a mild strategy for the introduction of the epidithiodiketopiperazine core in the final step, were developed to address this highly sensitive substructure. Our rapid functionalization of the advanced molecular framework aims to mimic plausible biosynthetic steps and offers an effective strategy for the chemical synthesis of other members of this family of alkaloids. II. General Approach to Epipolythiodiketopiperazine Alkaloids: Total Synthesis of (+)- Chaetocins A and C and (+)-12,12'-Dideoxychetracin A A highly stereoselective and systematic strategy for the introduction of polysulfides in the synthesis of epipolythiodiketopiperazine alkaloids is described. We report the first total synthesis of dimeric epitri- and epitetrathiodiketopiperazine alkaloids. III. Concise Total Synthesis and Stereochemical Revision of (+)-Naseseazines A and B: Regioselective Arylative Dimerization of Diketopiperazine Alkaloids Concise and enantioselective total syntheses of (+)-naseseazines A and B are described. Our regioselective and directed dimerization of diketopiperazines provides their critical C3-Csp2 linkages, an assembly with plausible biogenetic relevance. We have revised the absolute stereochemistry of (+)-naseseazines A and B. IV. Concise Total Synthesis of (+)-Bionectins A and C The concise and efficient total synthesis of (+)-bionectins A and C is described. Our approach to these natural products features a new and scalable method for erythro-[beta]-hydroxytryptophan amino acid synthesis, an intramolecular Friedel-Crafts reaction of a silyl-tethered indole, and a new mercaptan reagent for epipolythiodiketopiperazine (ETP) synthesis that can be unravelled under very mild conditions. In evaluating the impact of Cl 2-hydroxylation, we have identified a unique need for an intramolecular variant of our Friedel-Crafts indolylation chemistry. Several key discoveries including the first example of permanganate-mediated stereoinvertive hydroxylation of the a-stereocenters of diketopiperazines as well as the first example of a direct triketopiperazine synthesis from a parent cyclo-dipeptide are discussed. Finally, the synthesis of (+)-bionectin A and its unambiguous structural assignment through X-ray analysis provides motivation for the reevaluation of its original characterization data and assignment.
by Justin Kim.
Ph.D. in Organic Chemistry
615 p.
eng
Massachusetts Institute of Technology
M.I.T. theses are protected by
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http://dspace.mit.edu/handle/1721.1/7582
Chemistry.
Total synthesis of cyclotryptamine and diketopiperazine alkaloids
Thesis
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<Abstract>I. Total Synthesis of the (+)-12,12'-Dideoxyverticillin A The fungal metabolite (+)-12,12'-dideoxyverticillin A, a cytotoxic alkaloid isolated from a marine Penicillium sp., belongs to a fascinating family of densely functionalized, stereochemically complex, and intricate dimeric epidithiodiketopiperazine natural products. Although the dimeric epidithiodiketopiperazines have been known for nearly four decades, none has succumbed to total synthesis. We report a concise enantioselective total synthesis of (+)- 12,12'-dideoxyverticillin A via a strategy inspired by our biosynthetic hypothesis for this alkaloid. Highly stereo- and chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions, as well as a mild strategy for the introduction of the epidithiodiketopiperazine core in the final step, were developed to address this highly sensitive substructure. Our rapid functionalization of the advanced molecular framework aims to mimic plausible biosynthetic steps and offers an effective strategy for the chemical synthesis of other members of this family of alkaloids. II. General Approach to Epipolythiodiketopiperazine Alkaloids: Total Synthesis of (+)- Chaetocins A and C and (+)-12,12'-Dideoxychetracin A A highly stereoselective and systematic strategy for the introduction of polysulfides in the synthesis of epipolythiodiketopiperazine alkaloids is described. We report the first total synthesis of dimeric epitri- and epitetrathiodiketopiperazine alkaloids. III. Concise Total Synthesis and Stereochemical Revision of (+)-Naseseazines A and B: Regioselective Arylative Dimerization of Diketopiperazine Alkaloids Concise and enantioselective total syntheses of (+)-naseseazines A and B are described. Our regioselective and directed dimerization of diketopiperazines provides their critical C3-Csp2 linkages, an assembly with plausible biogenetic relevance. We have revised the absolute stereochemistry of (+)-naseseazines A and B. IV. Concise Total Synthesis of (+)-Bionectins A and C The concise and efficient total synthesis of (+)-bionectins A and C is described. Our approach to these natural products features a new and scalable method for erythro-[beta]-hydroxytryptophan amino acid synthesis, an intramolecular Friedel-Crafts reaction of a silyl-tethered indole, and a new mercaptan reagent for epipolythiodiketopiperazine (ETP) synthesis that can be unravelled under very mild conditions. In evaluating the impact of Cl 2-hydroxylation, we have identified a unique need for an intramolecular variant of our Friedel-Crafts indolylation chemistry. Several key discoveries including the first example of permanganate-mediated stereoinvertive hydroxylation of the a-stereocenters of diketopiperazines as well as the first example of a direct triketopiperazine synthesis from a parent cyclo-dipeptide are discussed. Finally, the synthesis of (+)-bionectin A and its unambiguous structural assignment through X-ray analysis provides motivation for the reevaluation of its original characterization data and assignment.</Abstract>
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