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Catalytic Synthesis of Alpha-Tetrasubstituted Homoallylamines and Their Use in the Construction of 1-Azaspirocyclic Scaffolds

  • Author(s): Nelson, Keegan Gregory
  • Advisor(s): Larsen, Catharine H
  • et al.
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Abstract

Alpha-tetrasubstituted amines are found in numerous natural products and drug therapies. Variants are typically accessed through multiple steps: synthesis and isolation of the appropriate ketimine followed by stoichiometric reaction with an organometallic reagent. The first direct three-component coupling of a ketone, amine, and allyl nucleophile proceeds efficiently under green, solvent-free conditions to provide the hindered amine building blocks in a single catalytic step.

The resultant alpha-tetrasubstituted homoallyl amines provide a streamlined synthetic platform for producing a wide variety of structurally complex small molecules, including spirocyclic ring systems. Conditions were developed to allow the terminal olefin of the homoallyl amines to undergo cross-metathesis in the presence of Grubbs’ catalysts. When the free amine of the product is protected via either allylation or acrylation, ring-closing metathesis provides either amine or amide ring systems while only requiring column chromatography for a single step in the sequence.

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This item is under embargo until May 14, 2021.