Stereoselective alkylation of N-Boc-2-pyrrolidinones and N-Boc-2-piperidinones. Synthesis and characterization of disubstituted lactams

Abstract

Alkylation of enolates of monosubstituted N-Boc lactams 4–6 afforded trans-disubstituted lactams as the major isomer. In the pyrrolidinone series, 1,3-induction seems to be ruled by steric interactions and the diastereoselection is low for the alkylation of enolates with small substituents at C-5 (e.g., Me) and methyl iodide. The trans selectivity improves with bulkier substituents at C-2 and/or bulkier electrophiles. The formation of 3,6- trans-disubstituted piperidinones benefits from the axial orientation of the substituent at C-2 due to the A 1,3 strain with the N-Boc group and excellent trans preference is observed even in the alkylation of the lithium enolate of N-Boc-6-methyl piperidinone with methyl iodide.