Total Synthesis of Oligomeric Cyclotryptamine Alkaloids
I. Total Synthesis and Stereochemical Assignment of (–)-Psychotridine We report the first enantioselective total synthesis and stereochemical assignment of (–)-psychotridine. The application of our diazene-directed assembly of enantiomerically enriched cyclotryptamines afforded a highly convergen...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2023
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| Online Access: | https://hdl.handle.net/1721.1/150563 |
| _version_ | 1826204738078638080 |
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| author | Scott, Tony Z. |
| author2 | Movassaghi, Mohammad |
| author_facet | Movassaghi, Mohammad Scott, Tony Z. |
| author_sort | Scott, Tony Z. |
| collection | MIT |
| description | I. Total Synthesis and Stereochemical Assignment of (–)-Psychotridine
We report the first enantioselective total synthesis and stereochemical assignment of (–)-psychotridine. The application of our diazene-directed assembly of enantiomerically enriched cyclotryptamines afforded a highly convergent synthesis of the pentameric alkaloid, allowing its detailed structural assignment. Highlights of the synthesis include the introduction of four quaternary stereocenters with complete stereochemical control in a single step via the photoextrusion of three molecules of dinitrogen from an advanced intermediate and metal-catalyzed C–H amination reactions in challenging settings.
II. Iterative, Diazene-Directed Total Synthesis of (+)-Quadrigemine H, (+)-Isopsychotridine C, (+)-Oleoidine, and (+)-Caledonine
We describe the unified enantioselective total synthesis of the polycyclotryptamine natural products (+)-quadrigemine H, (+)-isopsychotridine C, (+)-oleoidine, and (+)-caledonine. Our bioinspired synthesis leverages the modular, diazene-directed assembly of whole cyclotryptmines to iteratively introduce C3a−C7' quaternary linkages on an advanced heterodimeric intermediate with full stereochemical control at each quaternary linkage. We developed a strategy for iterative aryl-alkyl diazene synthesis using increasingly complex oligomeric hydrazide nucleophiles and bifunctional cyclotryptamines bearing a C3a leaving group and a pendant C7 pronucleophile. The utility of our method is demonstrated by the first total synthesis of heptamer (+)-caledonine and hexamer (+)-oleoidine. Additionally, enabled by our fully stereoselective total synthesis and acquisition of expanded characterization data, we provide the first complete stereochemical assignment of pentamer (+)-isopsychotridine C and confirm that tetramer (+)-quadrigemine H is identical to the alkaloid called (+)-quadrigemine I. |
| first_indexed | 2024-09-23T13:00:36Z |
| format | Thesis |
| id | mit-1721.1/150563 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:00:36Z |
| publishDate | 2023 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1505632023-04-26T03:25:13Z Total Synthesis of Oligomeric Cyclotryptamine Alkaloids Scott, Tony Z. Movassaghi, Mohammad Massachusetts Institute of Technology. Department of Chemistry I. Total Synthesis and Stereochemical Assignment of (–)-Psychotridine We report the first enantioselective total synthesis and stereochemical assignment of (–)-psychotridine. The application of our diazene-directed assembly of enantiomerically enriched cyclotryptamines afforded a highly convergent synthesis of the pentameric alkaloid, allowing its detailed structural assignment. Highlights of the synthesis include the introduction of four quaternary stereocenters with complete stereochemical control in a single step via the photoextrusion of three molecules of dinitrogen from an advanced intermediate and metal-catalyzed C–H amination reactions in challenging settings. II. Iterative, Diazene-Directed Total Synthesis of (+)-Quadrigemine H, (+)-Isopsychotridine C, (+)-Oleoidine, and (+)-Caledonine We describe the unified enantioselective total synthesis of the polycyclotryptamine natural products (+)-quadrigemine H, (+)-isopsychotridine C, (+)-oleoidine, and (+)-caledonine. Our bioinspired synthesis leverages the modular, diazene-directed assembly of whole cyclotryptmines to iteratively introduce C3a−C7' quaternary linkages on an advanced heterodimeric intermediate with full stereochemical control at each quaternary linkage. We developed a strategy for iterative aryl-alkyl diazene synthesis using increasingly complex oligomeric hydrazide nucleophiles and bifunctional cyclotryptamines bearing a C3a leaving group and a pendant C7 pronucleophile. The utility of our method is demonstrated by the first total synthesis of heptamer (+)-caledonine and hexamer (+)-oleoidine. Additionally, enabled by our fully stereoselective total synthesis and acquisition of expanded characterization data, we provide the first complete stereochemical assignment of pentamer (+)-isopsychotridine C and confirm that tetramer (+)-quadrigemine H is identical to the alkaloid called (+)-quadrigemine I. Ph.D. 2023-04-25T14:22:02Z 2023-04-25T14:22:02Z 2023-02 2023-04-05T18:52:52.827Z Thesis https://hdl.handle.net/1721.1/150563 In Copyright - Educational Use Permitted Copyright MIT http://rightsstatements.org/page/InC-EDU/1.0/ application/pdf Massachusetts Institute of Technology |
| spellingShingle | Scott, Tony Z. Total Synthesis of Oligomeric Cyclotryptamine Alkaloids |
| title | Total Synthesis of Oligomeric Cyclotryptamine Alkaloids |
| title_full | Total Synthesis of Oligomeric Cyclotryptamine Alkaloids |
| title_fullStr | Total Synthesis of Oligomeric Cyclotryptamine Alkaloids |
| title_full_unstemmed | Total Synthesis of Oligomeric Cyclotryptamine Alkaloids |
| title_short | Total Synthesis of Oligomeric Cyclotryptamine Alkaloids |
| title_sort | total synthesis of oligomeric cyclotryptamine alkaloids |
| url | https://hdl.handle.net/1721.1/150563 |
| work_keys_str_mv | AT scotttonyz totalsynthesisofoligomericcyclotryptaminealkaloids |