Stereospecific Csp3 cross-coupling for modular polyketide synthesis

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• LaPorte, Antonio Joseph

Contributors dc:contributor

• Burke, Martin D
• Denmark, Scott E
• Sarlah, David
• Olshansky, Lisa

• Cross-coupling
• Palladium
• Csp3
• Modular
• Synthesis
• Polyketide
• Natural
• Products
• Suzuki
• Miyaura
• Radical
• Bromination
• Led
• Nmr

Statement dc:rights

• Copyright 2024 Antonio LaPorte

Language dc:language

eng, en

Handle dc:identifier

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

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/124681