Stereospecific Csp3Suzuki-Miyaura Cross-Coupling That Evades β-Oxygen Elimination

Antonio J. Laporte, Yao Shi, Jason E. Hein, Martin D. Burke

Research output: Contribution to journalArticlepeer-review

Abstract

Stereospecific Csp3 Suzuki-Miyaura cross-coupling could transform stereochemically complex small molecule synthesis into a simple and broadly accessible process. However, most current methods are not compatible with complex building blocks that represent densely packed, multistereogenic center-containing motifs commonly found in natural products and other complex targets. Here, we report a method that enables the α-methyl-β-hydroxyl motif, which is found in >18 »000 natural products as well as other Csp3-rich organic fragments, to be embedded within stereochemically defined secondary alkyl boronic ester building blocks that are readily cross-coupled in a stereospecific manner. The steric effect-mediated decrease in reactivity toward transmetalation and deleterious side reactions associated with the cross-coupling of β-oxygen-containing Csp3 boronic esters are concomitantly addressed using β-aryloxysilyl groups as dual-purpose transmetalation-promoting groups and stable β-oxygen surrogates. Mechanistic studies including real-time HPLC analysis show that a five-membered pinacol siloxaborolate generated in situ is then hydrolyzed to a dihydroxysiloxaborolate that acts as an activated transmetalation partner in a stereospecific process that proceeds with retention of configuration.

Original languageEnglish (US)
Pages (from-to)10905-10912
Number of pages8
JournalACS Catalysis
DOIs
StatePublished - Sep 2 2022

Keywords

  • Csp3
  • Suzuki-Miyaura
  • alkyl
  • cross-coupling
  • palladium
  • siloxaborolate
  • stereospecific

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry

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