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DOI: 10.1055/s-2008-1042753
Synthesis of Piperidinones from β-Amino Acids by Petasis Methylenation
Contributor(s):Victor Snieckus, Jignesh J. PatelUniversity of Glasgow, UK
β-Amino Acids to Piperidinones by Petasis Methylenation and Acid-Induced Cyclization
J. Org. Chem. 2007, 72: 10287-10290
Publication History
Publication Date:
21 February 2008 (online)
Key words
piperidinones - β-amino acids - Petasis methylenation - microwave
Significance
The authors describe a diastereoselective synthesis of 2,6-disubstituted piperidinones from substituted imines of β-amino acids via a nitrogen analogue of the Petasis-Ferrier rearrangement. Microwave-assisted Petasis methylenation followed by acid-catalyzed cyclization were the key steps in the synthesis. After methylenation, which is accelerated by microwave conditions, the precipitated titanium residue was removed by filtration and the crude residue was subjected to cyclization. The unusual combination of the polar solvent DMSO with the Lewis acid Al(i-Bu)3 for the cyclization works very well for electron-rich imines and ketone-derived imines, rather than the use of a protic acid.
Comment
New stereocontrolled syntheses of piperidines are of great interest due to the fact that they are potential drug candidates (B. E. Evans et al. J. Med. Chem. 1988, 31, 2235) and alkaloids (J. W. Dale, H. M. Garrafo, T. F. Spande Alkaloids: Chem. Biol. Perspect. 1999, 13, 2). The synthesis reported here starts from racemic β-amino acids, but a synthesis of enantiopure piperidinones from enantiopure β-amino esters may be feasible and would be of greater interest. In most cases the 2,6-syn diastereomer of the piperidinones was observed.