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.