Total Synthesis of Verticillin A and Application of Diazene-Directed Fragment Assembly to the Synthesis of Heterodimeric Epidithiodiketopiperazine Derivatives
I. Total Synthesis of (+)-Verticillin A We report the first total synthesis of (+)-verticillin A, completed in 16 steps. Our initial strategy of late-stage sulfidation on a dimeric substrate produced an undesired diastereomer of ETP. We were able to access an ETP with the desired diastereoselectivit...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2024
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| Online Access: | https://hdl.handle.net/1721.1/157574 |
| _version_ | 1824458228245725184 |
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| author | Knauss, Walker |
| author2 | Movassaghi, Mohammad |
| author_facet | Movassaghi, Mohammad Knauss, Walker |
| author_sort | Knauss, Walker |
| collection | MIT |
| description | I. Total Synthesis of (+)-Verticillin A We report the first total synthesis of (+)-verticillin A, completed in 16 steps. Our initial strategy of late-stage sulfidation on a dimeric substrate produced an undesired diastereomer of ETP. We were able to access an ETP with the desired diastereoselectivity by effecting sulfidation on an epimerized, monomeric substrate. In order to install a disulfide with the desired facial selectivity, we developed a stepwise sequence involving stereoselective formation of a C15-benzhydryl disulfide followed by intramolecular sulfidation at C11. Because ETPs are unstable to carboncentered radicals and irradiation with UV light, we developed conditions to reduce the disulfide and protect the resulting thiols as alkylsulfides prior to cobalt reductive dimerization and photochemical desulfonylation. Finally, deprotection of the thiols and oxidation delivered the ETP natural product (+)-verticillin A.
II. Synthesis of Heterodimeric ETP Derivatives Using Diazene-Directed Fragment Assembly
We report the development of a novel route to heterodimeric ETP derivatives using diazenedirected fragment assembly. This is the first application of diazene-directed coupling to the synthesis of dimeric diketopiperazine alkaloids Our group’s initial route to heterodimeric ETP derivatives relied upon reductive cobalt dimerization, which produces a nearly statistical mixture of homo- and heterodimeric products. In contrast to the initial route, the diazene-based approach disclosed herein enables selective heterodimerization. To demonstrate the utility of heterodimeric ETP derivatives, we have synthesized an ETP-diazirine photoaffinity labelling probe, which we hope can be used to study the interactions of ETPs with cellular targets. |
| first_indexed | 2025-02-19T04:22:33Z |
| format | Thesis |
| id | mit-1721.1/157574 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2025-02-19T04:22:33Z |
| publishDate | 2024 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1575742024-11-19T14:38:43Z Total Synthesis of Verticillin A and Application of Diazene-Directed Fragment Assembly to the Synthesis of Heterodimeric Epidithiodiketopiperazine Derivatives Knauss, Walker Movassaghi, Mohammad Massachusetts Institute of Technology. Department of Chemistry I. Total Synthesis of (+)-Verticillin A We report the first total synthesis of (+)-verticillin A, completed in 16 steps. Our initial strategy of late-stage sulfidation on a dimeric substrate produced an undesired diastereomer of ETP. We were able to access an ETP with the desired diastereoselectivity by effecting sulfidation on an epimerized, monomeric substrate. In order to install a disulfide with the desired facial selectivity, we developed a stepwise sequence involving stereoselective formation of a C15-benzhydryl disulfide followed by intramolecular sulfidation at C11. Because ETPs are unstable to carboncentered radicals and irradiation with UV light, we developed conditions to reduce the disulfide and protect the resulting thiols as alkylsulfides prior to cobalt reductive dimerization and photochemical desulfonylation. Finally, deprotection of the thiols and oxidation delivered the ETP natural product (+)-verticillin A. II. Synthesis of Heterodimeric ETP Derivatives Using Diazene-Directed Fragment Assembly We report the development of a novel route to heterodimeric ETP derivatives using diazenedirected fragment assembly. This is the first application of diazene-directed coupling to the synthesis of dimeric diketopiperazine alkaloids Our group’s initial route to heterodimeric ETP derivatives relied upon reductive cobalt dimerization, which produces a nearly statistical mixture of homo- and heterodimeric products. In contrast to the initial route, the diazene-based approach disclosed herein enables selective heterodimerization. To demonstrate the utility of heterodimeric ETP derivatives, we have synthesized an ETP-diazirine photoaffinity labelling probe, which we hope can be used to study the interactions of ETPs with cellular targets. II. Synthesis of Heterodimeric ETP Derivatives Using Diazene-Directed Fragment Assembly We report the development of a novel route to heterodimeric ETP derivatives using diazenedirected fragment assembly. This is the first application of diazene-directed coupling to the synthesis of dimeric diketopiperazine alkaloids Our group’s initial route to heterodimeric ETP derivatives relied upon reductive cobalt dimerization, which produces a nearly statistical mixture of homo- and heterodimeric products. In contrast to the initial route, the diazene-based approach disclosed herein enables selective heterodimerization. To demonstrate the utility of heterodimeric ETP derivatives, we have synthesized an ETP-diazirine photoaffinity labelling probe, which we hope can be used to study the interactions of ETPs with cellular targets. Ph.D. 2024-11-18T19:11:49Z 2024-11-18T19:11:49Z 2024-09 2024-10-30T12:47:17.746Z Thesis https://hdl.handle.net/1721.1/157574 Attribution-ShareAlike 4.0 International (CC BY-SA 4.0) Copyright retained by author(s) https://creativecommons.org/licenses/by-sa/4.0/ application/pdf Massachusetts Institute of Technology |
| spellingShingle | Knauss, Walker Total Synthesis of Verticillin A and Application of Diazene-Directed Fragment Assembly to the Synthesis of Heterodimeric Epidithiodiketopiperazine Derivatives |
| title | Total Synthesis of Verticillin A and Application of Diazene-Directed Fragment Assembly to the Synthesis of Heterodimeric Epidithiodiketopiperazine Derivatives |
| title_full | Total Synthesis of Verticillin A and Application of Diazene-Directed Fragment Assembly to the Synthesis of Heterodimeric Epidithiodiketopiperazine Derivatives |
| title_fullStr | Total Synthesis of Verticillin A and Application of Diazene-Directed Fragment Assembly to the Synthesis of Heterodimeric Epidithiodiketopiperazine Derivatives |
| title_full_unstemmed | Total Synthesis of Verticillin A and Application of Diazene-Directed Fragment Assembly to the Synthesis of Heterodimeric Epidithiodiketopiperazine Derivatives |
| title_short | Total Synthesis of Verticillin A and Application of Diazene-Directed Fragment Assembly to the Synthesis of Heterodimeric Epidithiodiketopiperazine Derivatives |
| title_sort | total synthesis of verticillin a and application of diazene directed fragment assembly to the synthesis of heterodimeric epidithiodiketopiperazine derivatives |
| url | https://hdl.handle.net/1721.1/157574 |
| work_keys_str_mv | AT knausswalker totalsynthesisofverticillinaandapplicationofdiazenedirectedfragmentassemblytothesynthesisofheterodimericepidithiodiketopiperazinederivatives |