{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/109682"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/109682","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"Mechanistic investigation of the interrupted Bischler-Napieralski reaction and its application to the total synthesis of the aspidosperma alkaloids","abstract":"I. Direct Observation of Intermediates Involved in the Interruption of the Bischler- Napieralski Reaction. The first mechanistic investigation of electrophilic amide activation of [alpha], [alpha]-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in our interrupted Bischler-Napieralski based synthetic strategy to the aspidosperma alkaloids is described. Importantly, when considering base additives during electrophilic amide activation, more hindered c-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation. II. Total Synthesis of (+)-Fendleridine, (+)-Acetylaspidoalbidine, and (+)-Limaspermidine. An Tf2O-mediated electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provides access to the hexacyclic C19-hemiaminal ether alkaloids (+)- fendleridine, (+)-acetylaspidoalbidine, and (+)-limaspermidine. A highly effective enzymatic resolution of a non-[beta]-branched primary alcohol (E=22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. III. Development of an Ortho-Acetoxylation of Indoline Amides and its Application to the Total Synthesis of (+)-Haplocidine and (+)-Haplocine. The first total syntheses of (+)-haplocidine and its NI-amide congener (+)-haplocine is described. The concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide directed ortho-acetoxylation of indoline amides enabled the implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions.","abstract_html":"I. Direct Observation of Intermediates Involved in the Interruption of the Bischler- Napieralski Reaction. The first mechanistic investigation of electrophilic amide activation of [alpha], [alpha]-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in our interrupted Bischler-Napieralski based synthetic strategy to the aspidosperma alkaloids is described. Importantly, when considering base additives during electrophilic amide activation, more hindered c-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation. II. Total Synthesis of (+)-Fendleridine, (+)-Acetylaspidoalbidine, and (+)-Limaspermidine. An Tf2O-mediated electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provides access to the hexacyclic C19-hemiaminal ether alkaloids (+)- fendleridine, (+)-acetylaspidoalbidine, and (+)-limaspermidine. A highly effective enzymatic resolution of a non-[beta]-branched primary alcohol (E=22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. III. Development of an Ortho-Acetoxylation of Indoline Amides and its Application to the Total Synthesis of (+)-Haplocidine and (+)-Haplocine. The first total syntheses of (+)-haplocidine and its NI-amide congener (+)-haplocine is described. The concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide directed ortho-acetoxylation of indoline amides enabled the implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions.","abstract_has_math":false,"creators":["White, Kolby Lyn"],"institution":"Massachusetts Institute of Technology","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. Department of Chemistry.","school":null,"contributors":[],"advisors":["Mohammad Movassaghi."],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017","date_published":"2017","updated_at":"2026-07-22T22:22:06Z","subjects":["Chemistry."],"languages":["eng"],"rights":["MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission."],"rights_urls":["http://dspace.mit.edu/handle/1721.1/7582"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1721.1/109682","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Mohammad Movassaghi."]},{"key":"dc:contributor.department","label":"Department","values":["Massachusetts Institute of Technology. Department of Chemistry."]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Massachusetts Institute of Technology. Department of Chemistry."]},{"key":"dc:creator","label":"Author","values":["White, Kolby Lyn"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2017-06-06T19:25:11Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2017-06-06T19:25:11Z"]},{"key":"dc:date.issued","label":"Date","values":["2017"]},{"key":"dc:publisher","label":"Institution","values":["Massachusetts Institute of Technology"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Chemistry."]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission."]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://dspace.mit.edu/handle/1721.1/7582"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1721.1/109682"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2017.","Vita. Scanning issues: Page 114 contains text that has been cropped/deleted from the right-side page margin. Appendix B section contains several graph pages with faint/illegible images. Cataloged from PDF version of thesis.","Includes bibliographical references."]},{"key":"dc:description.abstract","label":"Abstract","values":["I. Direct Observation of Intermediates Involved in the Interruption of the Bischler- Napieralski Reaction. The first mechanistic investigation of electrophilic amide activation of [alpha], [alpha]-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in our interrupted Bischler-Napieralski based synthetic strategy to the aspidosperma alkaloids is described. Importantly, when considering base additives during electrophilic amide activation, more hindered c-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation. II. Total Synthesis of (+)-Fendleridine, (+)-Acetylaspidoalbidine, and (+)-Limaspermidine. An Tf2O-mediated electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provides access to the hexacyclic C19-hemiaminal ether alkaloids (+)- fendleridine, (+)-acetylaspidoalbidine, and (+)-limaspermidine. A highly effective enzymatic resolution of a non-[beta]-branched primary alcohol (E=22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. III. Development of an Ortho-Acetoxylation of Indoline Amides and its Application to the Total Synthesis of (+)-Haplocidine and (+)-Haplocine. The first total syntheses of (+)-haplocidine and its NI-amide congener (+)-haplocine is described. The concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide directed ortho-acetoxylation of indoline amides enabled the implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph. D. in Organic Chemistry"]},{"key":"dc:title","label":"Title","values":["Mechanistic investigation of the interrupted Bischler-Napieralski reaction and its application to the total synthesis of the aspidosperma alkaloids"]}]}],"canonical_facts":{"dc:contributor.advisor":["Mohammad Movassaghi."],"dc:contributor.department":["Massachusetts Institute of Technology. Department of Chemistry."],"dc:contributor.other":["Massachusetts Institute of Technology. Department of Chemistry."],"dc:creator":["White, Kolby Lyn"],"dc:date.accessioned":["2017-06-06T19:25:11Z"],"dc:date.available":["2017-06-06T19:25:11Z"],"dc:date.issued":["2017"],"dc:description":["Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2017.","Vita. Scanning issues: Page 114 contains text that has been cropped/deleted from the right-side page margin. Appendix B section contains several graph pages with faint/illegible images. Cataloged from PDF version of thesis.","Includes bibliographical references."],"dc:description.abstract":["I. Direct Observation of Intermediates Involved in the Interruption of the Bischler- Napieralski Reaction. The first mechanistic investigation of electrophilic amide activation of [alpha], [alpha]-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in our interrupted Bischler-Napieralski based synthetic strategy to the aspidosperma alkaloids is described. Importantly, when considering base additives during electrophilic amide activation, more hindered c-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation. II. Total Synthesis of (+)-Fendleridine, (+)-Acetylaspidoalbidine, and (+)-Limaspermidine. An Tf2O-mediated electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provides access to the hexacyclic C19-hemiaminal ether alkaloids (+)- fendleridine, (+)-acetylaspidoalbidine, and (+)-limaspermidine. A highly effective enzymatic resolution of a non-[beta]-branched primary alcohol (E=22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. III. Development of an Ortho-Acetoxylation of Indoline Amides and its Application to the Total Synthesis of (+)-Haplocidine and (+)-Haplocine. The first total syntheses of (+)-haplocidine and its NI-amide congener (+)-haplocine is described. The concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide directed ortho-acetoxylation of indoline amides enabled the implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions."],"dc:description.degree":["Ph. D. in Organic Chemistry"],"dc:identifier.uri":["http://hdl.handle.net/1721.1/109682"],"dc:language.iso":["eng"],"dc:publisher":["Massachusetts Institute of Technology"],"dc:rights":["MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission."],"dc:rights.uri":["http://dspace.mit.edu/handle/1721.1/7582"],"dc:subject":["Chemistry."],"dc:title":["Mechanistic investigation of the interrupted Bischler-Napieralski reaction and its application to the total synthesis of the aspidosperma alkaloids"],"dc:type":["Thesis"]},"updated_at":"2026-07-22T22:22:06Z"}