Synthesis of the Cyclic Hexapeptide Echinocandin D. New Approaches to the Asymmetric Synthesis of ,&Hydroxy a-Amino Acids

Derivatives of the two unusual 8-hydroxy amino acids in echinocandin D (1) have been synthesized by employing asymmetric glycine enolate aldol methodology. The N-Boc,O-benzyl derivative of (2S,3R)-3-hydroxyhomotyrosine (Hht) (2) and the methyl ester of (2.9,3S,4.9)-3-hydroxy-4-methylproline (Hmp) (3) have been synthesized in four steps each from (isothiocyanoacety1)oxazolidinone 4 and (bromoacety1)oxazolidinone 10, respectively. In both syntheses, asymmetric aldol addition reactions have been employed to establish the absolute stereochemical relationships at both hydroxyl and nitrogen-bearing asymmetric centers. In conjunction with the synthesis of Hmp (3) a new approach to the construction of nitrogen heterocycles via the intramolecular cycloalkylation of olefinic azides has been presented. Each of these amino acids has been integrated into a synthesis of echinocandin D. Echinocandin D (l), isolated from Aspergillus ruglosus, is a member of a family of lipopeptides possessing high antifungal activity.] This structure is unusual in that five of the six amino acids in this cyclic hexapeptide are hydroxylated. In addition to two threonine moieties and a 4-hydroxyproline, echinocandin D contains two rare P-hydroxy amino acids, (2S,3R)-3-hydroxyhomotyrosine (Hht) (2) and (2S,3S,4S)-3-hydroxy-4-methylproline (Hmp) (3). Both of these entities have recently been