{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/301779"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/301779","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"A novel photocatalytic strategy for complex aliphatic amine synthesis and the total synthesis of alkaloids (−) FR901483 and (+)-TAN1251C","abstract":"Owing to their unique properties, the synthesis and functionalization of aliphatic amines plays a central role in the field of visible light photoredox chemistry. In this thesis, the development of a novel, visible light mediated process for the synthesis of complex aliphatic amines is described. The novel multicomponent reaction between secondary amines, aldehydes and electron-deficient olefins efficiently furnishes complex aliphatic tertiary amine products. Selective generation of an $\\alpha$-amino radical species is achieved via photocatalytic single electron reduction of in situ generated all-alkyl iminium ions. Under optimized reaction conditions, the photocatalytic olefin-hydroaminoalkylation procedure was shown to be compatible with a broad range of benzyl amine, aldehyde, and olefin substrates. A detailed study of the mechanism of the transformation is described, revealing an unusual 1,5-hydrogen atom transfer step and an unprecedented redox-relay of iminium ions. In further studies, the reaction scope was expanded to include non-benzylic amines and enamines, enabling the generation of synthetically valuable $\\alpha$-tertiary amines. $\\alpha$-Tertiary amines are a common feature in a number of bioactive natural products. Immunosuppressant ($-$)-FR901483 (1) and muscarinic antagonist ($+$)-TAN1251C (2) are biosynthetically related di-tyrosine-derived alkaloids, which have attracted significant attention from the synthetic community by virtue of their biological activity and the challenges posed by their architecturally complex structures. The development of a variant of the multicomponent photocatalytic olefin-hydroaminoalkylation approach to couple primary amines, ketones and olefins, and its use in total synthesis, is described. The novel transformation enabled the rapid, divergent total synthesis of both ($-$)-FR901483 and ($+$)-TAN1251C via a common spirolactam precursor. Finally, the reaction proved amenable to a number of primary amines and ketones, giving direct, modular access to a series of useful chiral spirolactam scaffolds.","abstract_html":"Owing to their unique properties, the synthesis and functionalization of aliphatic amines plays a central role in the field of visible light photoredox chemistry. In this thesis, the development of a novel, visible light mediated process for the synthesis of complex aliphatic amines is described. The novel multicomponent reaction between secondary amines, aldehydes and electron-deficient olefins efficiently furnishes complex aliphatic tertiary amine products. Selective generation of an <span class=\"etd-inline-math\">&alpha;</span>-amino radical species is achieved via photocatalytic single electron reduction of in situ generated all-alkyl iminium ions. Under optimized reaction conditions, the photocatalytic olefin-hydroaminoalkylation procedure was shown to be compatible with a broad range of benzyl amine, aldehyde, and olefin substrates. A detailed study of the mechanism of the transformation is described, revealing an unusual 1,5-hydrogen atom transfer step and an unprecedented redox-relay of iminium ions. In further studies, the reaction scope was expanded to include non-benzylic amines and enamines, enabling the generation of synthetically valuable <span class=\"etd-inline-math\">&alpha;</span>-tertiary amines. <span class=\"etd-inline-math\">&alpha;</span>-Tertiary amines are a common feature in a number of bioactive natural products. Immunosuppressant ($-$)-FR901483 (1) and muscarinic antagonist ($+$)-TAN1251C (2) are biosynthetically related di-tyrosine-derived alkaloids, which have attracted significant attention from the synthetic community by virtue of their biological activity and the challenges posed by their architecturally complex structures. The development of a variant of the multicomponent photocatalytic olefin-hydroaminoalkylation approach to couple primary amines, ketones and olefins, and its use in total synthesis, is described. The novel transformation enabled the rapid, divergent total synthesis of both ($-$)-FR901483 and ($+$)-TAN1251C via a common spirolactam precursor. Finally, the reaction proved amenable to a number of primary amines and ketones, giving direct, modular access to a series of useful chiral spirolactam scaffolds.","abstract_has_math":true,"creators":["Reich, Dominik"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Gaunt, Matthew J."],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-07-18","date_published":"2020-07-18","updated_at":"2026-07-22T22:24:24Z","subjects":["total synthesis","amine synthesis","photoredox catalysis"],"languages":["en"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f69b625d-c640-4dea-a269-d1e09d4dd20c/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.48852","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Gaunt, Matthew J."]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["AstraZeneca"]},{"key":"dc:creator","label":"Author","values":["Reich, Dominik"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2020-07-18"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/301779"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["total synthesis","amine synthesis","photoredox catalysis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f69b625d-c640-4dea-a269-d1e09d4dd20c/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.48852"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/852df437-a6da-4e70-8d82-ff435a055764/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Owing to their unique properties, the synthesis and functionalization of aliphatic amines plays a central role in the field of visible light photoredox chemistry. 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In further studies, the reaction scope was expanded to include non-benzylic amines and enamines, enabling the generation of synthetically valuable $\\alpha$-tertiary amines. $\\alpha$-Tertiary amines are a common feature in a number of bioactive natural products. Immunosuppressant ($-$)-FR901483 (1) and muscarinic antagonist ($+$)-TAN1251C (2) are biosynthetically related di-tyrosine-derived alkaloids, which have attracted significant attention from the synthetic community by virtue of their biological activity and the challenges posed by their architecturally complex structures. The development of a variant of the multicomponent photocatalytic olefin-hydroaminoalkylation approach to couple primary amines, ketones and olefins, and its use in total synthesis, is described. The novel transformation enabled the rapid, divergent total synthesis of both ($-$)-FR901483 and ($+$)-TAN1251C via a common spirolactam precursor. 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The novel multicomponent reaction between secondary amines, aldehydes and electron-deficient olefins efficiently furnishes complex aliphatic tertiary amine products. Selective generation of an $\\alpha$-amino radical species is achieved via photocatalytic single electron reduction of in situ generated all-alkyl iminium ions. Under optimized reaction conditions, the photocatalytic olefin-hydroaminoalkylation procedure was shown to be compatible with a broad range of benzyl amine, aldehyde, and olefin substrates. A detailed study of the mechanism of the transformation is described, revealing an unusual 1,5-hydrogen atom transfer step and an unprecedented redox-relay of iminium ions. In further studies, the reaction scope was expanded to include non-benzylic amines and enamines, enabling the generation of synthetically valuable $\\alpha$-tertiary amines. $\\alpha$-Tertiary amines are a common feature in a number of bioactive natural products. Immunosuppressant ($-$)-FR901483 (1) and muscarinic antagonist ($+$)-TAN1251C (2) are biosynthetically related di-tyrosine-derived alkaloids, which have attracted significant attention from the synthetic community by virtue of their biological activity and the challenges posed by their architecturally complex structures. The development of a variant of the multicomponent photocatalytic olefin-hydroaminoalkylation approach to couple primary amines, ketones and olefins, and its use in total synthesis, is described. The novel transformation enabled the rapid, divergent total synthesis of both ($-$)-FR901483 and ($+$)-TAN1251C via a common spirolactam precursor. 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