Synthesis and reactivity of bicycles derived from tartaric acid and alpha-amino acids: A novel class of conformationally constrained dipeptide isosteres based upon enantiopure 3-aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylicacid

3-Aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acids (named BTAa) derived from (R,R), (S,S)-, or meso-tartaric acid and natural (L), unnatural (D), or unusual alpha-amino acids are described as conformationally constrained dipeptide isosteres. The general strategy developed for their preparation h as required the transformation of the amino acids into the corresponding N- benzylamino alcohols, followed by the PyBroP-promoted condensation with the monomethyl ester of the suitable 2,3-di-O-isopropylidenetartaric acid. Oxi dation of the hydroxy group to aldheyde and subsequent acid-catalyzed trans -acetalization with the two hydroxy groups of the tartaric acid moiety prov ided 3-aza-2-oxo-6,8-dioxabicyclo [3.2.1] octane-7-carboxylic acid methyl e sters [named BTAa(O)] in good yield and, in most cases, as single enantiopu re diastereoisomers. This strategy has been applied to the preparation of B TAa(O) starting from (R,R)-, (S,S)-, or meso-tartaric acid and glycine, L- and D-phenylalanine, L- and D-alanine, and (+/-)-phenylglycine. In the case s of glycine, L- and D-phenylalanine, and L- and D-alanine, the selective r eduction by BH3. DMS of the amide group succeeding to the cyclization step, or the reduction of both amide and ester functions followed by reoxidation of the hydroxy to carboxylic group, provided in good yield the 3-aza-3-ben zyl-6,8-dioxabicyclo[3.2.1]-octane-7-carboxylic acids (or their methyl este r) BTAa, having the side chain of the amino acid precursors at position 4. The stability and rigidity of the bicyclic skeleton, the complete control o f all the stereocenters, the possibility of introducing the side chains of L- or D-amino acids, and the demonstrated compatibility with the conditions required for solid-phase peptide synthesis make the BTAa compounds potenti al dipeptide isosteres useful for the synthesis of modified peptides.