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

• Published in: Journal of organic chemistry Vol. 68; no. 16; pp. 6172 - 6183
• Main Authors: Dondoni, Alessandro, Massi, Alessandro, Minghini, Erik, Sabbatini, Simona, Bertolasi, Valerio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.08.2003; Amer Chemical Soc
• Subjects: Amino Acids, Basic - chemical synthesis; Chemistry; Chemistry, Organic; Crystallography, X-Ray; Cyclization; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Indicators and Reagents; Magnetic Resonance Spectroscopy; Models, Chemical; Models, Molecular; Molecular Conformation; Organic chemistry; Oxidation-Reduction; Peptides - chemical synthesis; Physical Sciences; Preparations and properties; Pyridines - chemical synthesis; Pyrimidines - chemical synthesis; Science & Technology; Stereoisomerism; ANTIBIOTIC L-AZATYROSINE; GLYCOSYL ASPARAGINE; SIDE-CHAINS; EXPLOITATION; ANALOGS; CONFIGURATION; ACYL MIGRATION STRATEGY; ALKYNYL KETONES; CONJUGATE RADICAL-ADDITION; PEPTIDE; Stereoisomer; Condensation reaction; Nitrogen heterocycle; Fluorine 19; Lactam; Aniline derivatives; NMR spectrometry; Aldehyde; X ray diffraction; Pyridine derivatives; Hydrogen 1; Ester; α-Aminoacid; Cyclization; Enantiomer; Pyrimidine derivatives; Ketoester; Chemical synthesis
• DOI: 10.1021/jo0342830
• ISSN: 0022-3263

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.