Unravelling mechanistic features of organocatalysis with in situ modifications at the secondary sphere

Vasudevan Dhayalan, Santosh C. Gadekar, Zayed Alassad, Anat Milo

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Secondary-sphere interactions serve a fundamental role in controlling the reactivity and selectivity of organometallic and enzymatic catalysts. However, there is a dearth of studies that explicitly incorporate secondary-sphere modifiers into organocatalytic systems. In this work, we introduce an approach for the in situ systematic modification of organocatalysts in their secondary sphere through dynamic covalent binding under the reaction conditions. As a proof-of-concept, we applied boronic acids as secondary-sphere modifiers of N-heterocyclic carbenes that contained a hydroxy handle. The bound system formed in the reaction mixture catalysed the enantioselective benzoin condensations of a challenging substrate class that contains electron-withdrawing groups. Linear regression coupled with data visualization served to pinpoint the divergent origins of enantioselectivity for different substrates and decision tree algorithms served to formulate selection criteria for the appropriate secondary-sphere modifiers. The combination of this highly modular catalytic approach with machine-learning techniques provided mechanistic insights and guided the streamlined optimization process of a gram-scale reaction at low organocatalyst loading.

Original languageEnglish
Pages (from-to)543-551
Number of pages9
JournalNature Chemistry
Volume11
Issue number6
DOIs
StatePublished - 1 Jun 2019

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering

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