{"id":{"repo_id":"ghent","oai_identifier":"oai:archive.ugent.be:8561326"},"canonical_url":"https://search.dev.ndltd.org/etd/ghent/oai:archive.ugent.be:8561326","repository":{"repo_id":"ghent","name":"Ghent University","base_url":"https://biblio.ugent.be/oai"},"display":{"title":"Synthesis of 4-(trifluoromethyl)azetidin-2-one building blocks and their transformation into novel CF3-substituted amines and heterocyclic systems","abstract":"In light of the versatile synthetic potential of β-lactams on the one hand and the beneficial impact of fluorine on biological properties on the other hand, β-lactams bearing a trifluoromethyl group comprise interesting entities for the construction of novel targets with promising bioactivities. In this PhD thesis, the preparation and deployment of 4-trifluoromethyl-β-lactams as new building blocks toward a diverse set of functionalized CF3-amines and CF3-azaheterocycles was investigated. In particular, 3-benzyloxy-4-trifluoromethyl-β-lactams were conveniently synthesized as a first new class of building blocks. The aptitude of these systems with respect to ring-opening reactions was explored to enable an entry to functionalized aminopropane systems by either direct reductive β-lactam ring opening or initial carbonyl removal to azetidine intermediates, followed by ring opening. In addition, hydrogenolysis of the benzylether fragment in 3-benzyloxy-4-trifluoromethyl-β-lactams resulted in the formation of 3-hydroxy-4-trifluoromethyl-β-lactams as a second class of new building blocks. The latter alcohols enabled the construction of CF3-containing ring-rearranged products, including aziridines through a ring-contraction protocol via 3-chloro-β-lactam intermediates and dioxan-2-ones via initial O-allylation. Furthermore, alcohol oxidation gave rise to 3-oxo-4-trifluoromethyl-β-lactams as a third class of new building blocks. Attempts to form and trap the corresponding 2,3-dioxoazetidin-4-yl anions unexpectedly resulted in ring opening through C3-C4 bond fission, culminating in 2-[(2,2-difluorovinyl)amino]-2-oxoacetate products. This peculiar mechanism was investigated in depth, both experimentally and computationally. Finally, an addition/elimination sequence applied to 3-oxo-4-trifluoromethyl-β-lactams afforded 3-methylene-4-trifluoromethyl-β-lactams as a fourth class of new building blocks, which were shown to be eligible substrates for Michael additions, electrophilic additions and cycloadditions en route to a variety of stereodefined mono- and spirocyclic 4-CF3-β-lactams.","abstract_html":"In light of the versatile synthetic potential of β-lactams on the one hand and the beneficial impact of fluorine on biological properties on the other hand, β-lactams bearing a trifluoromethyl group comprise interesting entities for the construction of novel targets with promising bioactivities. In this PhD thesis, the preparation and deployment of 4-trifluoromethyl-β-lactams as new building blocks toward a diverse set of functionalized CF3-amines and CF3-azaheterocycles was investigated. In particular, 3-benzyloxy-4-trifluoromethyl-β-lactams were conveniently synthesized as a first new class of building blocks. The aptitude of these systems with respect to ring-opening reactions was explored to enable an entry to functionalized aminopropane systems by either direct reductive β-lactam ring opening or initial carbonyl removal to azetidine intermediates, followed by ring opening. In addition, hydrogenolysis of the benzylether fragment in 3-benzyloxy-4-trifluoromethyl-β-lactams resulted in the formation of 3-hydroxy-4-trifluoromethyl-β-lactams as a second class of new building blocks. The latter alcohols enabled the construction of CF3-containing ring-rearranged products, including aziridines through a ring-contraction protocol via 3-chloro-β-lactam intermediates and dioxan-2-ones via initial O-allylation. Furthermore, alcohol oxidation gave rise to 3-oxo-4-trifluoromethyl-β-lactams as a third class of new building blocks. Attempts to form and trap the corresponding 2,3-dioxoazetidin-4-yl anions unexpectedly resulted in ring opening through C3-C4 bond fission, culminating in 2-[(2,2-difluorovinyl)amino]-2-oxoacetate products. This peculiar mechanism was investigated in depth, both experimentally and computationally. Finally, an addition/elimination sequence applied to 3-oxo-4-trifluoromethyl-β-lactams afforded 3-methylene-4-trifluoromethyl-β-lactams as a fourth class of new building blocks, which were shown to be eligible substrates for Michael additions, electrophilic additions and cycloadditions en route to a variety of stereodefined mono- and spirocyclic 4-CF3-β-lactams.","abstract_has_math":false,"creators":["Dao Thi, Hang"],"institution":"Ghent University. Faculty of Bioscience Engineering","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["D'hooghe, Matthias","Nguyen, Tuyen Van"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018","date_published":"2018","updated_at":"2026-07-24T02:23:05Z","subjects":["Chemistry"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["https://biblio.ugent.be/publication/8561326","https://biblio.ugent.be/publication/8561326/file/8561327"],"render_values":[{"text":"https://biblio.ugent.be/publication/8561326","href":"https://biblio.ugent.be/publication/8561326","code":true},{"text":"https://biblio.ugent.be/publication/8561326/file/8561327","href":"https://biblio.ugent.be/publication/8561326/file/8561327","code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/1854/LU-8561326","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["D'hooghe, Matthias","Nguyen, Tuyen Van"]},{"key":"dc:creator","label":"Author","values":["Dao Thi, Hang"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018"]},{"key":"dc:publisher","label":"Institution","values":["Ghent University. 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In this PhD thesis, the preparation and deployment of 4-trifluoromethyl-β-lactams as new building blocks toward a diverse set of functionalized CF3-amines and CF3-azaheterocycles was investigated. In particular, 3-benzyloxy-4-trifluoromethyl-β-lactams were conveniently synthesized as a first new class of building blocks. The aptitude of these systems with respect to ring-opening reactions was explored to enable an entry to functionalized aminopropane systems by either direct reductive β-lactam ring opening or initial carbonyl removal to azetidine intermediates, followed by ring opening. In addition, hydrogenolysis of the benzylether fragment in 3-benzyloxy-4-trifluoromethyl-β-lactams resulted in the formation of 3-hydroxy-4-trifluoromethyl-β-lactams as a second class of new building blocks. The latter alcohols enabled the construction of CF3-containing ring-rearranged products, including aziridines through a ring-contraction protocol via 3-chloro-β-lactam intermediates and dioxan-2-ones via initial O-allylation. Furthermore, alcohol oxidation gave rise to 3-oxo-4-trifluoromethyl-β-lactams as a third class of new building blocks. Attempts to form and trap the corresponding 2,3-dioxoazetidin-4-yl anions unexpectedly resulted in ring opening through C3-C4 bond fission, culminating in 2-[(2,2-difluorovinyl)amino]-2-oxoacetate products. This peculiar mechanism was investigated in depth, both experimentally and computationally. Finally, an addition/elimination sequence applied to 3-oxo-4-trifluoromethyl-β-lactams afforded 3-methylene-4-trifluoromethyl-β-lactams as a fourth class of new building blocks, which were shown to be eligible substrates for Michael additions, electrophilic additions and cycloadditions en route to a variety of stereodefined mono- and spirocyclic 4-CF3-β-lactams."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Synthesis of 4-(trifluoromethyl)azetidin-2-one building blocks and their transformation into novel CF3-substituted amines and heterocyclic systems"]}]}],"canonical_facts":{"dc:contributor":["D'hooghe, Matthias","Nguyen, Tuyen Van"],"dc:creator":["Dao Thi, Hang"],"dc:date":["2018"],"dc:description":["In light of the versatile synthetic potential of β-lactams on the one hand and the beneficial impact of fluorine on biological properties on the other hand, β-lactams bearing a trifluoromethyl group comprise interesting entities for the construction of novel targets with promising bioactivities. In this PhD thesis, the preparation and deployment of 4-trifluoromethyl-β-lactams as new building blocks toward a diverse set of functionalized CF3-amines and CF3-azaheterocycles was investigated. In particular, 3-benzyloxy-4-trifluoromethyl-β-lactams were conveniently synthesized as a first new class of building blocks. The aptitude of these systems with respect to ring-opening reactions was explored to enable an entry to functionalized aminopropane systems by either direct reductive β-lactam ring opening or initial carbonyl removal to azetidine intermediates, followed by ring opening. In addition, hydrogenolysis of the benzylether fragment in 3-benzyloxy-4-trifluoromethyl-β-lactams resulted in the formation of 3-hydroxy-4-trifluoromethyl-β-lactams as a second class of new building blocks. The latter alcohols enabled the construction of CF3-containing ring-rearranged products, including aziridines through a ring-contraction protocol via 3-chloro-β-lactam intermediates and dioxan-2-ones via initial O-allylation. Furthermore, alcohol oxidation gave rise to 3-oxo-4-trifluoromethyl-β-lactams as a third class of new building blocks. Attempts to form and trap the corresponding 2,3-dioxoazetidin-4-yl anions unexpectedly resulted in ring opening through C3-C4 bond fission, culminating in 2-[(2,2-difluorovinyl)amino]-2-oxoacetate products. This peculiar mechanism was investigated in depth, both experimentally and computationally. Finally, an addition/elimination sequence applied to 3-oxo-4-trifluoromethyl-β-lactams afforded 3-methylene-4-trifluoromethyl-β-lactams as a fourth class of new building blocks, which were shown to be eligible substrates for Michael additions, electrophilic additions and cycloadditions en route to a variety of stereodefined mono- and spirocyclic 4-CF3-β-lactams."],"dc:format":["application/pdf"],"dc:identifier":["https://biblio.ugent.be/publication/8561326","http://hdl.handle.net/1854/LU-8561326","https://biblio.ugent.be/publication/8561326/file/8561327"],"dc:language":["eng"],"dc:publisher":["Ghent University. Faculty of Bioscience Engineering"],"dc:rights":["info:eu-repo/semantics/openAccess"],"dc:subject":["Chemistry"],"dc:title":["Synthesis of 4-(trifluoromethyl)azetidin-2-one building blocks and their transformation into novel CF3-substituted amines and heterocyclic systems"],"dc:type":["dissertation","info:eu-repo/semantics/doctoralThesis","info:eu-repo/semantics/publishedVersion"]},"updated_at":"2026-07-24T02:23:05Z"}