Model Studies toward the Synthesis of Dihydropyrimidinyl and Pyridyl α-Amino Acids via Three-Component Biginelli and Hantzsch Cyclocondensations

A novel and versatile strategy for the synthesis of heterocyclic α-amino acids has been described.
The use of components (aldehyde or β-ketoester) bearing a masked glycinyl moiety in Biginelli and
Hantzsch cyclocondensations allowed access to the 4-dihydropyrimidinyl-α-glycines, 4-dihydropyrimidinyl-α-alanines, 4-pyridyl-α-alanines, and 2-pyridyl-α-alanines classes. Dihydropyrimidinyl-amino acids were obtained as a mixture of diastereoisomers due to the formation of the stereocenter
at C4 of the dihydropyrimidinone ring. Individual stereoisomers were isolated as pure compounds
and their structures were assigned with the aid of X-ray crystallography and chiroptical properties.
The enantiomeric purity of a representative selection of the above amino acids was greater than
96% as verified by derivatization to the corresponding Mosher's amides and subsequent 1H and
19F NMR spectroscopy. Incorporation of the 4-pyridyl-α-alanine derivative into a peptide chain is
also described.