Synthesis of (2S,3R)-3-Amino-2-hydroxy-5-methylhexanoic Acid Derivatives. Application to the Synthesis of Amastatin, an Inhibitor of Aminopeptidases

Article abstract of DOI:10.1021/jo01300a004

Methods are reported for the synthesis of optically pure derivatives of (2S,3R)-3-amino-2-hydroxy-5-methylhexanoic acid. <(Benzyloxy)carbonyl>-D-leucine methyl ester was reduced in 95percent yield with diisobutylaluminum hydride to the aldehyde which was converted via the cyanohydrin to (2RS,3R)-3-amino-2-hydroxy-5-methylhexanoic acid (AHMHA).The mixture of diastereomers was converted to the corresponding Boc-AHMHA methyl ester derivatives and separated by chromatography over silica gel.The optical purity of the diastereomers at C-3 was established by converting each to diastereomeric Boc-AHMHA-Leu-OMe and separating these dipeptides by chromatography.Pure (2S,3R)-Boc-AHMHA was coupled with valyl-valyl-aspartic acid dibenzyl ester by using dicyclohexylcarbodiimide/ 1-hydroxybenzotriazole in 63percent yield.The Boc group was removed by using trifluoroacetid acid, and the benzyl groups were removed by hydrogenolysis.The product, (2S,3R)-AHMHA-L-Val-L-Val-L-Asp, amastatin, was found to be identical with the natural product.