2026-09-20T22:47:34Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/124681 2026-01-14 col_2142_5131 col_2142_14789 com_2142_5130 com_2142_14788 com_2142_8903

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. Text eng https://hdl.handle.net/2142/124681 Copyright 2024 Antonio LaPorte Burke, Martin D Burke, Martin D Denmark, Scott E Sarlah, David Olshansky, Lisa 2024-05 application/pdf en text 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 Stereospecific Csp3 cross-coupling for modular polyketide synthesis LaPorte, Antonio Joseph 2024-04-25 Cross-coupling Palladium Csp3 Modular Synthesis Polyketide Natural Products Suzuki Miyaura Radical Bromination Led Nmr Ph.D. Dissertation Chemistry University of Illinois at Urbana-Champaign Chemistry