University of Illinois Urbana-Champaign

Stereospecific Csp3 cross-coupling for modular polyketide synthesis

LaPorte, Antonio Joseph

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https://hdl.handle.net/2142/124681

Description

Title
Stereospecific Csp3 cross-coupling for modular polyketide synthesis
Author(s)
LaPorte, Antonio Joseph
Issue Date
2024-04-25
Director of Research (if dissertation) or Advisor (if thesis)
Burke, Martin D
Doctoral Committee Chair(s)
Burke, Martin D
Committee Member(s)
  • Denmark, Scott E
  • Sarlah, David
  • Olshansky, Lisa
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
  • cross-coupling
  • palladium
  • csp3
  • modular
  • synthesis
  • polyketide
  • natural
  • products
  • suzuki
  • miyaura
  • radical
  • bromination
  • LED
  • NMR
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.
Graduation Semester
2024-05
Type of Resource
Thesis
Copyright and License Information
Copyright 2024 Antonio LaPorte

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