Preparation of chiral lactone from laevoglucosan; a key intermediate for synthesis of the spiroacetal moieties of the avermectins and milbemycins

Abstract

A synthesis of two diprotected (4S,6S)-4-hydroxy-6-hydroxymethyltetrahydropyran-2-ones has been developed from laevoglucosan. Reaction of these lactones with a substituted chiral lithium acetylide followed by hydrogenation and acid-catalysed cyclisation led to formation of the spiroacetal moiety of milbemycin β1 and β3. The acetylene was prepared by resolution of racemic material obtained from reaction of lithium acetylide and cis-butene epoxide. Alternatively a stereocontrolled synthesis was developed from (S)-methyl-3-hydroxy-2-methylpropionate which involved ‘chelation controlled’ addition of lithium dimethylcuprate to the corresponding tetrahydropyranyloxy aldehyde.