{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/124681"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/124681","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Stereospecific Csp3 cross-coupling for modular polyketide synthesis","abstract":"Iterative cross-coupling represents a simple strategy for the synthesis of functional molecules that is inherently automatable. However, an important limitation to this platform is an inability to generate Csp3-rich, stereochemically complex molecules due to challenges in the coupling of alkyl groups using Suzuki-Miyaura cross-coupling reactions. Here, I show that stereospecific palladium-catalyzed cross-coupling reactions of secondary alkyl organoboron nucleophiles can be leveraged to access the alpha-methyl-beta-hydroxyl motif that is ubiquitous amongst polyketide and other natural products. To achieve this objective, a novel class of activated beta-aryloxysilyl pinacol boronic ester nucleophiles were designed and shown to undergo highly stereospecific cross-coupling with aryl halides even when containing one of the most sterically hindered transmetalating carbons reported to date. While highly stereospecific, this reaction maintained a limitation that it was unproductive with unactivated vinyl halide electrophiles, representing a cold start problem where testing of a variety of coupling conditions provided no reaction yield. To overcome this and develop a general blueprint for rationally approaching cold start problems, a new reaction discovery strategy called directed coevolution of chemicals was developed, enabling the discovery of conditions amenable to the coupling of unactivated vinyl halides and other representative polyketide-extracted electrophiles. Finally, after showing that building block structure and reaction conditions can be evolved to uncover novel reactivity of secondary alkyl boronates, I showed that the structure of the boryl ligand is an important dial that can be tuned to modify reactivity of the alpha-boryl carbon atom. Together, this work represents an important advancement towards simplifying the synthesis of complex molecules thereby accelerating the exploration and discovery of new societally impactful functions.","abstract_html":"Iterative cross-coupling represents a simple strategy for the synthesis of functional molecules that is inherently automatable. However, an important limitation to this platform is an inability to generate Csp3-rich, stereochemically complex molecules due to challenges in the coupling of alkyl groups using Suzuki-Miyaura cross-coupling reactions. Here, I show that stereospecific palladium-catalyzed cross-coupling reactions of secondary alkyl organoboron nucleophiles can be leveraged to access the alpha-methyl-beta-hydroxyl motif that is ubiquitous amongst polyketide and other natural products. To achieve this objective, a novel class of activated beta-aryloxysilyl pinacol boronic ester nucleophiles were designed and shown to undergo highly stereospecific cross-coupling with aryl halides even when containing one of the most sterically hindered transmetalating carbons reported to date. While highly stereospecific, this reaction maintained a limitation that it was unproductive with unactivated vinyl halide electrophiles, representing a cold start problem where testing of a variety of coupling conditions provided no reaction yield. To overcome this and develop a general blueprint for rationally approaching cold start problems, a new reaction discovery strategy called directed coevolution of chemicals was developed, enabling the discovery of conditions amenable to the coupling of unactivated vinyl halides and other representative polyketide-extracted electrophiles. Finally, after showing that building block structure and reaction conditions can be evolved to uncover novel reactivity of secondary alkyl boronates, I showed that the structure of the boryl ligand is an important dial that can be tuned to modify reactivity of the alpha-boryl carbon atom. Together, this work represents an important advancement towards simplifying the synthesis of complex molecules thereby accelerating the exploration and discovery of new societally impactful functions.","abstract_has_math":false,"creators":["LaPorte, Antonio Joseph"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Burke, Martin D","Denmark, Scott E","Sarlah, David","Olshansky, Lisa"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-05","date_published":"2024-05","updated_at":"2026-07-22T22:25:02Z","subjects":["Cross-coupling","Palladium","Csp3","Modular","Synthesis","Polyketide","Natural","Products","Suzuki","Miyaura","Radical","Bromination","Led","Nmr"],"languages":["eng","en"],"rights":["Copyright 2024 Antonio LaPorte"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/124681","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Burke, Martin D","Denmark, Scott E","Sarlah, David","Olshansky, Lisa"]},{"key":"dc:creator","label":"Author","values":["LaPorte, Antonio Joseph"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-05","2024-04-25"]},{"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":["Cross-coupling","Palladium","Csp3","Modular","Synthesis","Polyketide","Natural","Products","Suzuki","Miyaura","Radical","Bromination","Led","Nmr"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng","en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2024 Antonio LaPorte"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/124681"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Iterative cross-coupling represents a simple strategy for the synthesis of functional molecules that is inherently automatable. However, an important limitation to this platform is an inability to generate Csp3-rich, stereochemically complex molecules due to challenges in the coupling of alkyl groups using Suzuki-Miyaura cross-coupling reactions. Here, I show that stereospecific palladium-catalyzed cross-coupling reactions of secondary alkyl organoboron nucleophiles can be leveraged to access the alpha-methyl-beta-hydroxyl motif that is ubiquitous amongst polyketide and other natural products. To achieve this objective, a novel class of activated beta-aryloxysilyl pinacol boronic ester nucleophiles were designed and shown to undergo highly stereospecific cross-coupling with aryl halides even when containing one of the most sterically hindered transmetalating carbons reported to date. While highly stereospecific, this reaction maintained a limitation that it was unproductive with unactivated vinyl halide electrophiles, representing a cold start problem where testing of a variety of coupling conditions provided no reaction yield. To overcome this and develop a general blueprint for rationally approaching cold start problems, a new reaction discovery strategy called directed coevolution of chemicals was developed, enabling the discovery of conditions amenable to the coupling of unactivated vinyl halides and other representative polyketide-extracted electrophiles. Finally, after showing that building block structure and reaction conditions can be evolved to uncover novel reactivity of secondary alkyl boronates, I showed that the structure of the boryl ligand is an important dial that can be tuned to modify reactivity of the alpha-boryl carbon atom. Together, this work represents an important advancement towards simplifying the synthesis of complex molecules thereby accelerating the exploration and discovery of new societally impactful functions.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-05-01","The student, Antonio LaPorte, accepted the attached license on 2024-04-22 at 12:03.","The student, Antonio LaPorte, submitted this Dissertation for approval on 2024-04-22 at 12:24.","This Dissertation was approved for publication on 2024-04-25 at 16:04.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20533 on 2024-09-16 at 00:49:43"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Stereospecific Csp3 cross-coupling for modular polyketide synthesis"]}]}],"canonical_facts":{"dc:contributor":["Burke, Martin D","Denmark, Scott E","Sarlah, David","Olshansky, Lisa"],"dc:creator":["LaPorte, Antonio Joseph"],"dc:date":["2024-05","2024-04-25"],"dc:description":["Iterative cross-coupling represents a simple strategy for the synthesis of functional molecules that is inherently automatable. However, an important limitation to this platform is an inability to generate Csp3-rich, stereochemically complex molecules due to challenges in the coupling of alkyl groups using Suzuki-Miyaura cross-coupling reactions. Here, I show that stereospecific palladium-catalyzed cross-coupling reactions of secondary alkyl organoboron nucleophiles can be leveraged to access the alpha-methyl-beta-hydroxyl motif that is ubiquitous amongst polyketide and other natural products. To achieve this objective, a novel class of activated beta-aryloxysilyl pinacol boronic ester nucleophiles were designed and shown to undergo highly stereospecific cross-coupling with aryl halides even when containing one of the most sterically hindered transmetalating carbons reported to date. While highly stereospecific, this reaction maintained a limitation that it was unproductive with unactivated vinyl halide electrophiles, representing a cold start problem where testing of a variety of coupling conditions provided no reaction yield. To overcome this and develop a general blueprint for rationally approaching cold start problems, a new reaction discovery strategy called directed coevolution of chemicals was developed, enabling the discovery of conditions amenable to the coupling of unactivated vinyl halides and other representative polyketide-extracted electrophiles. Finally, after showing that building block structure and reaction conditions can be evolved to uncover novel reactivity of secondary alkyl boronates, I showed that the structure of the boryl ligand is an important dial that can be tuned to modify reactivity of the alpha-boryl carbon atom. Together, this work represents an important advancement towards simplifying the synthesis of complex molecules thereby accelerating the exploration and discovery of new societally impactful functions.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-05-01","The student, Antonio LaPorte, accepted the attached license on 2024-04-22 at 12:03.","The student, Antonio LaPorte, submitted this Dissertation for approval on 2024-04-22 at 12:24.","This Dissertation was approved for publication on 2024-04-25 at 16:04.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20533 on 2024-09-16 at 00:49:43"],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/124681"],"dc:language":["eng","en"],"dc:rights":["Copyright 2024 Antonio LaPorte"],"dc:subject":["Cross-coupling","Palladium","Csp3","Modular","Synthesis","Polyketide","Natural","Products","Suzuki","Miyaura","Radical","Bromination","Led","Nmr"],"dc:title":["Stereospecific Csp3 cross-coupling for modular polyketide synthesis"],"dc:type":["Text"],"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"}