{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/105887"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/105887","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"New horizons of aliphatic C—H amination and hydroxylation reactions with manganese catalysis","abstract":"Functionalized aliphatic C(sp3)–H scaffolds are being increasingly incorporated into small molecule pharmaceutical molecules to gain access to novel chemical space and bioactivities. Given the ubiquitous of C—H bonds and their inertness toward a wide range of reaction conditions, late-stage aliphatic C—H functionalizations afford unique opportunities to quickly diversify complex bioactive molecules and access novel heterocyclic substitution patterns on the aliphatic core structures. Although methods with preparative yields and site-selectivities for aliphatic C—H functionalization are emerging, a significant challenge remained with an apparent inverse correlation between reactivity and chemoselectivity: catalysts that are highly reactive to strong aliphatic C—H bonds usually lacks chemoselectivity for -functionalities (aromatics and olefins). My doctoral research in the White group has focused on developing novel manganese catalysts for C—H amination and C—H hydroxylation reactions with unprecedented amalgamation of high reactivity with strong C—H bonds (2º and even 1º) while maintaining high chemoselectivity for aromatic -functionalities. These new catalysts afford opportunities to fully realize the potential of using late-stage aliphatic C—H functionalizations in drug discovery processes. The first chapter of this dissertation discussed the discovery of a novel manganese catalyst, Mn[tBuPc], for intramolecular C—H aminations. Mn[tBuPc] showcase as an outliner of the inverse correlation between reactivity and chemoselectivity traditionally shown in metallonitrene mediated intramolecular C—H aminations. Collectively in this project, we demonstrated Mn[tBuPc] is uniquely effective to aminate all types of C(sp3)–H bonds intramolecularly while maintaining chemoselectivity for the olefin -functionality. Particularly, I demonstrated Mn[tBuPc] capable to preparatively aminate a wide range of benzylic C—H bonds of aromatic and medicinally important heteroaromatic substrates. Impressively, even strongest 1º C—H bonds can be preparatively aminated with Mn[tBuPc] in simple and complex molecules settings with perfect site-selectivity. Mechanistic studies suggest the Mn[tBuPc] catalyst transfers the bounded nitrene to C—H bonds via a stepwise C—H abstraction/ fast rebound pathway with attenuated radical character on the metallonitrene compared to the iron catalyst. Late-stage C—H amination and sequential C—H hydroxylation/ C—H amination were demonstrated to quickly install heteroatomic functionalities (O and N) onto the aliphatic core of complex natural products. The second chapter of this dissertation described the discovery of a novel manganese catalyst Mn(CF3-PDP), that for the first time enabled highly reactive methylene C—H oxidation with high chemoselectivity tolerating a wide range of oxidatively labile aromatic functionalities via a synergetic effect between catalyst design and chloroacetic acid additive. A total of 50 aromatic substrates housing medicinally important halogen, oxygen, nitrogen, heteroaromatic and biaryl moieties were demonstrated with Mn(CF3-PDP) to afford preparative yields for 2º oxidation products. Late-stage oxidative derivatization on four aromatic pharmaceutical molecule scaffolds were shown with Mn(CF3-PDP), including a sequential 2º benzylic/remote 2º C—H hydroxylations on an ethinylestradiol derivative where other oxidant only oxidize the doubly activated tertiary benzylic site. Mn(CF3-PDP) was also demonstrated to potentially serve as a general approach to rapidly access and identify drug metabolites (piragliatin) from advanced synthetic intermediates. Additionally, the high chemoselectivity observed in 2º C—H oxidation with Mn(CF3-PDP) can be maintained in the 3º C—H oxidation of substrates housing a range of pharmaceutically important substitutions on aromatic rings with Mn(PDP) catalyst.","abstract_html":"Functionalized aliphatic C(sp3)–H scaffolds are being increasingly incorporated into small molecule pharmaceutical molecules to gain access to novel chemical space and bioactivities. Given the ubiquitous of C—H bonds and their inertness toward a wide range of reaction conditions, late-stage aliphatic C—H functionalizations afford unique opportunities to quickly diversify complex bioactive molecules and access novel heterocyclic substitution patterns on the aliphatic core structures. Although methods with preparative yields and site-selectivities for aliphatic C—H functionalization are emerging, a significant challenge remained with an apparent inverse correlation between reactivity and chemoselectivity: catalysts that are highly reactive to strong aliphatic C—H bonds usually lacks chemoselectivity for -functionalities (aromatics and olefins). My doctoral research in the White group has focused on developing novel manganese catalysts for C—H amination and C—H hydroxylation reactions with unprecedented amalgamation of high reactivity with strong C—H bonds (2º and even 1º) while maintaining high chemoselectivity for aromatic -functionalities. These new catalysts afford opportunities to fully realize the potential of using late-stage aliphatic C—H functionalizations in drug discovery processes. The first chapter of this dissertation discussed the discovery of a novel manganese catalyst, Mn[tBuPc], for intramolecular C—H aminations. Mn[tBuPc] showcase as an outliner of the inverse correlation between reactivity and chemoselectivity traditionally shown in metallonitrene mediated intramolecular C—H aminations. Collectively in this project, we demonstrated Mn[tBuPc] is uniquely effective to aminate all types of C(sp3)–H bonds intramolecularly while maintaining chemoselectivity for the olefin -functionality. Particularly, I demonstrated Mn[tBuPc] capable to preparatively aminate a wide range of benzylic C—H bonds of aromatic and medicinally important heteroaromatic substrates. Impressively, even strongest 1º C—H bonds can be preparatively aminated with Mn[tBuPc] in simple and complex molecules settings with perfect site-selectivity. Mechanistic studies suggest the Mn[tBuPc] catalyst transfers the bounded nitrene to C—H bonds via a stepwise C—H abstraction/ fast rebound pathway with attenuated radical character on the metallonitrene compared to the iron catalyst. Late-stage C—H amination and sequential C—H hydroxylation/ C—H amination were demonstrated to quickly install heteroatomic functionalities (O and N) onto the aliphatic core of complex natural products. The second chapter of this dissertation described the discovery of a novel manganese catalyst Mn(CF3-PDP), that for the first time enabled highly reactive methylene C—H oxidation with high chemoselectivity tolerating a wide range of oxidatively labile aromatic functionalities via a synergetic effect between catalyst design and chloroacetic acid additive. A total of 50 aromatic substrates housing medicinally important halogen, oxygen, nitrogen, heteroaromatic and biaryl moieties were demonstrated with Mn(CF3-PDP) to afford preparative yields for 2º oxidation products. Late-stage oxidative derivatization on four aromatic pharmaceutical molecule scaffolds were shown with Mn(CF3-PDP), including a sequential 2º benzylic/remote 2º C—H hydroxylations on an ethinylestradiol derivative where other oxidant only oxidize the doubly activated tertiary benzylic site. Mn(CF3-PDP) was also demonstrated to potentially serve as a general approach to rapidly access and identify drug metabolites (piragliatin) from advanced synthetic intermediates. Additionally, the high chemoselectivity observed in 2º C—H oxidation with Mn(CF3-PDP) can be maintained in the 3º C—H oxidation of substrates housing a range of pharmaceutically important substitutions on aromatic rings with Mn(PDP) catalyst.","abstract_has_math":false,"creators":["Zhao, Jinpeng"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["White, Maria C","Denmark, Scott E","Hergenrother, Paul J","Nuzzo, Ralph G"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-11-26T20:58:35Z","date_published":"2019-11-26T20:58:35Z","updated_at":"2026-07-22T22:24:45Z","subjects":["C—H functionalization","Manganese catalysts","synthetic methodology"],"languages":["en"],"rights":["Copyright 2019 Jinpeng Zhao"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/105887","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["White, Maria C","Denmark, Scott E","Hergenrother, Paul J","Nuzzo, Ralph G"]},{"key":"dc:creator","label":"Author","values":["Zhao, Jinpeng"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019-11-26T20:58:35Z","2021-11-27T10:15:16Z","2019-07-02","2019-08"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"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":["C—H functionalization","Manganese catalysts","synthetic methodology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2019 Jinpeng Zhao"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/105887"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Functionalized aliphatic C(sp3)–H scaffolds are being increasingly incorporated into small molecule pharmaceutical molecules to gain access to novel chemical space and bioactivities. Given the ubiquitous of C—H bonds and their inertness toward a wide range of reaction conditions, late-stage aliphatic C—H functionalizations afford unique opportunities to quickly diversify complex bioactive molecules and access novel heterocyclic substitution patterns on the aliphatic core structures. Although methods with preparative yields and site-selectivities for aliphatic C—H functionalization are emerging, a significant challenge remained with an apparent inverse correlation between reactivity and chemoselectivity: catalysts that are highly reactive to strong aliphatic C—H bonds usually lacks chemoselectivity for -functionalities (aromatics and olefins). My doctoral research in the White group has focused on developing novel manganese catalysts for C—H amination and C—H hydroxylation reactions with unprecedented amalgamation of high reactivity with strong C—H bonds (2º and even 1º) while maintaining high chemoselectivity for aromatic -functionalities. These new catalysts afford opportunities to fully realize the potential of using late-stage aliphatic C—H functionalizations in drug discovery processes. The first chapter of this dissertation discussed the discovery of a novel manganese catalyst, Mn[tBuPc], for intramolecular C—H aminations. Mn[tBuPc] showcase as an outliner of the inverse correlation between reactivity and chemoselectivity traditionally shown in metallonitrene mediated intramolecular C—H aminations. Collectively in this project, we demonstrated Mn[tBuPc] is uniquely effective to aminate all types of C(sp3)–H bonds intramolecularly while maintaining chemoselectivity for the olefin -functionality. Particularly, I demonstrated Mn[tBuPc] capable to preparatively aminate a wide range of benzylic C—H bonds of aromatic and medicinally important heteroaromatic substrates. Impressively, even strongest 1º C—H bonds can be preparatively aminated with Mn[tBuPc] in simple and complex molecules settings with perfect site-selectivity. Mechanistic studies suggest the Mn[tBuPc] catalyst transfers the bounded nitrene to C—H bonds via a stepwise C—H abstraction/ fast rebound pathway with attenuated radical character on the metallonitrene compared to the iron catalyst. Late-stage C—H amination and sequential C—H hydroxylation/ C—H amination were demonstrated to quickly install heteroatomic functionalities (O and N) onto the aliphatic core of complex natural products. The second chapter of this dissertation described the discovery of a novel manganese catalyst Mn(CF3-PDP), that for the first time enabled highly reactive methylene C—H oxidation with high chemoselectivity tolerating a wide range of oxidatively labile aromatic functionalities via a synergetic effect between catalyst design and chloroacetic acid additive. A total of 50 aromatic substrates housing medicinally important halogen, oxygen, nitrogen, heteroaromatic and biaryl moieties were demonstrated with Mn(CF3-PDP) to afford preparative yields for 2º oxidation products. Late-stage oxidative derivatization on four aromatic pharmaceutical molecule scaffolds were shown with Mn(CF3-PDP), including a sequential 2º benzylic/remote 2º C—H hydroxylations on an ethinylestradiol derivative where other oxidant only oxidize the doubly activated tertiary benzylic site. Mn(CF3-PDP) was also demonstrated to potentially serve as a general approach to rapidly access and identify drug metabolites (piragliatin) from advanced synthetic intermediates. Additionally, the high chemoselectivity observed in 2º C—H oxidation with Mn(CF3-PDP) can be maintained in the 3º C—H oxidation of substrates housing a range of pharmaceutically important substitutions on aromatic rings with Mn(PDP) catalyst.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2021-08-01","The student, Jinpeng Zhao, accepted the attached license on 2019-07-01 at 08:23.","The student, Jinpeng Zhao, submitted this Dissertation for approval on 2019-07-01 at 08:37.","This Dissertation was approved for publication on 2019-07-02 at 13:54.","DSpace SAF Submission Ingestion Package generated from Vireo submission #14115 on 2019-11-26 at 14:00:41","Made available in DSpace on 2019-11-26T20:58:35Z (GMT). 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Given the ubiquitous of C—H bonds and their inertness toward a wide range of reaction conditions, late-stage aliphatic C—H functionalizations afford unique opportunities to quickly diversify complex bioactive molecules and access novel heterocyclic substitution patterns on the aliphatic core structures. Although methods with preparative yields and site-selectivities for aliphatic C—H functionalization are emerging, a significant challenge remained with an apparent inverse correlation between reactivity and chemoselectivity: catalysts that are highly reactive to strong aliphatic C—H bonds usually lacks chemoselectivity for -functionalities (aromatics and olefins). My doctoral research in the White group has focused on developing novel manganese catalysts for C—H amination and C—H hydroxylation reactions with unprecedented amalgamation of high reactivity with strong C—H bonds (2º and even 1º) while maintaining high chemoselectivity for aromatic -functionalities. These new catalysts afford opportunities to fully realize the potential of using late-stage aliphatic C—H functionalizations in drug discovery processes. The first chapter of this dissertation discussed the discovery of a novel manganese catalyst, Mn[tBuPc], for intramolecular C—H aminations. Mn[tBuPc] showcase as an outliner of the inverse correlation between reactivity and chemoselectivity traditionally shown in metallonitrene mediated intramolecular C—H aminations. Collectively in this project, we demonstrated Mn[tBuPc] is uniquely effective to aminate all types of C(sp3)–H bonds intramolecularly while maintaining chemoselectivity for the olefin -functionality. Particularly, I demonstrated Mn[tBuPc] capable to preparatively aminate a wide range of benzylic C—H bonds of aromatic and medicinally important heteroaromatic substrates. Impressively, even strongest 1º C—H bonds can be preparatively aminated with Mn[tBuPc] in simple and complex molecules settings with perfect site-selectivity. Mechanistic studies suggest the Mn[tBuPc] catalyst transfers the bounded nitrene to C—H bonds via a stepwise C—H abstraction/ fast rebound pathway with attenuated radical character on the metallonitrene compared to the iron catalyst. Late-stage C—H amination and sequential C—H hydroxylation/ C—H amination were demonstrated to quickly install heteroatomic functionalities (O and N) onto the aliphatic core of complex natural products. The second chapter of this dissertation described the discovery of a novel manganese catalyst Mn(CF3-PDP), that for the first time enabled highly reactive methylene C—H oxidation with high chemoselectivity tolerating a wide range of oxidatively labile aromatic functionalities via a synergetic effect between catalyst design and chloroacetic acid additive. A total of 50 aromatic substrates housing medicinally important halogen, oxygen, nitrogen, heteroaromatic and biaryl moieties were demonstrated with Mn(CF3-PDP) to afford preparative yields for 2º oxidation products. Late-stage oxidative derivatization on four aromatic pharmaceutical molecule scaffolds were shown with Mn(CF3-PDP), including a sequential 2º benzylic/remote 2º C—H hydroxylations on an ethinylestradiol derivative where other oxidant only oxidize the doubly activated tertiary benzylic site. Mn(CF3-PDP) was also demonstrated to potentially serve as a general approach to rapidly access and identify drug metabolites (piragliatin) from advanced synthetic intermediates. Additionally, the high chemoselectivity observed in 2º C—H oxidation with Mn(CF3-PDP) can be maintained in the 3º C—H oxidation of substrates housing a range of pharmaceutically important substitutions on aromatic rings with Mn(PDP) catalyst.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2021-08-01","The student, Jinpeng Zhao, accepted the attached license on 2019-07-01 at 08:23.","The student, Jinpeng Zhao, submitted this Dissertation for approval on 2019-07-01 at 08:37.","This Dissertation was approved for publication on 2019-07-02 at 13:54.","DSpace SAF Submission Ingestion Package generated from Vireo submission #14115 on 2019-11-26 at 14:00:41","Made available in DSpace on 2019-11-26T20:58:35Z (GMT). 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