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.
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.