{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/125754"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/125754","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Total synthesis of bioactive natural products: Darobactin A and nimbolide","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","abstract_has_math":false,"creators":["Ryffel, David"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Sarlah, David","White, M Christina","Burke, Martin D","Mitchell, Douglas A"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-08","date_published":"2024-08","updated_at":"2026-07-22T22:25:02Z","subjects":["Total Synthesis","Bioactive Compounds"],"languages":["en","eng"],"rights":["Copyright 2024 David Ryffel"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/125754","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Sarlah, David","White, M Christina","Burke, Martin D","Mitchell, Douglas A"]},{"key":"dc:creator","label":"Author","values":["Ryffel, David"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-08","2024-06-26"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Total Synthesis","Bioactive Compounds"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2024 David Ryffel"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/125754"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","The student, David Ryffel, accepted the attached license on 2024-06-15 at 13:19.","The student, David Ryffel, submitted this Dissertation for approval on 2024-06-15 at 13:24.","This Dissertation was approved for publication on 2024-06-26 at 16:05.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20841 on 2025-02-04 at 21:24:59","Natural products are important to the field of organic chemistry because they represent some of the most difficult synthetic challenges that face the field. Historically, many widely utilized reactions have been developed in the proving ground of total synthesis. Furthermore, many leaders of the field have been trained in laboratories that engage in total synthesis. Still, total synthesis remains relevant in the modern era of organic chemistry as increasingly complex natural products are isolated in even lower isolation yields. Additionally, these molecules oftentimes demonstrate unprecedented biological activities. To best capitalize on these unique structures, we must develop synthetic routes to these molecules while at the same time continuing to expand what is possible in the field of reaction discovery. The first chapter of this document describes the development of a synthetic route towards darobactin A, a recently discovered Gram-negative antibiotic. Our collaborative efforts towards darobactin A led to the development of novel approaches to unnatural amino acid derivatives and a halogen selective Larock macrocyclization. Furthermore, we found that the order of forming the two indole-containing macrocycles was crucial to delivering the desired atropisomer of the eastern macrocycle. Finally, a one-pot deprotection protocol was implemented to complete the first total synthesis of darobactin A in 16 steps longest linear sequence. The second chapter of this document describes the development of a synthetic route towards nimbolide, a potent anticancer agent. As part of these investigations, we have developed a palladium-mediated borylative Heck reaction to quickly access both diastereomers of a trans-decalin system that contains oxidation at the C4-position (nimbolide numbering). Selective oxidative manipulations were employed to avoid decarboxylation and provide a handle for introduction of the ester fragment on the B-ring. Finally, etherification, reductive cyclization, and lactonization will afford the natural product in a concise sequence."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Total synthesis of bioactive natural products: Darobactin A and nimbolide"]}]}],"canonical_facts":{"dc:contributor":["Sarlah, David","White, M Christina","Burke, Martin D","Mitchell, Douglas A"],"dc:creator":["Ryffel, David"],"dc:date":["2024-08","2024-06-26"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","The student, David Ryffel, accepted the attached license on 2024-06-15 at 13:19.","The student, David Ryffel, submitted this Dissertation for approval on 2024-06-15 at 13:24.","This Dissertation was approved for publication on 2024-06-26 at 16:05.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20841 on 2025-02-04 at 21:24:59","Natural products are important to the field of organic chemistry because they represent some of the most difficult synthetic challenges that face the field. Historically, many widely utilized reactions have been developed in the proving ground of total synthesis. Furthermore, many leaders of the field have been trained in laboratories that engage in total synthesis. Still, total synthesis remains relevant in the modern era of organic chemistry as increasingly complex natural products are isolated in even lower isolation yields. Additionally, these molecules oftentimes demonstrate unprecedented biological activities. To best capitalize on these unique structures, we must develop synthetic routes to these molecules while at the same time continuing to expand what is possible in the field of reaction discovery. The first chapter of this document describes the development of a synthetic route towards darobactin A, a recently discovered Gram-negative antibiotic. Our collaborative efforts towards darobactin A led to the development of novel approaches to unnatural amino acid derivatives and a halogen selective Larock macrocyclization. Furthermore, we found that the order of forming the two indole-containing macrocycles was crucial to delivering the desired atropisomer of the eastern macrocycle. Finally, a one-pot deprotection protocol was implemented to complete the first total synthesis of darobactin A in 16 steps longest linear sequence. The second chapter of this document describes the development of a synthetic route towards nimbolide, a potent anticancer agent. As part of these investigations, we have developed a palladium-mediated borylative Heck reaction to quickly access both diastereomers of a trans-decalin system that contains oxidation at the C4-position (nimbolide numbering). Selective oxidative manipulations were employed to avoid decarboxylation and provide a handle for introduction of the ester fragment on the B-ring. Finally, etherification, reductive cyclization, and lactonization will afford the natural product in a concise sequence."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/125754"],"dc:language":["en","eng"],"dc:rights":["Copyright 2024 David Ryffel"],"dc:subject":["Total Synthesis","Bioactive Compounds"],"dc:title":["Total synthesis of bioactive natural products: Darobactin A and nimbolide"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:02Z"}