• Reactivity and selective protection/deprotection of five OH groups
  • Sensitivity of macrolides towards basic and acidic conditions (epimerisation on C-2, lactone opening, sugar cleavage)
  • No chromophore – difficult to monitor reaction progress (LC-MS and TLC with H2SO4)
  • Complex purification of final products (precipitation, acid/base extraction, solid-phase extraction)

Introducing substituents at position 2’ of azithromycin

  • Without protection: mixture of products (reaction proceeded on 2’-OH, 4’’-OH and 11-OH)
  • With protection:

Challenge at step 3

  • hydrolysis in MeOH at RT – two products (11,12-orthoamide and 11,12-orthoester)
  • 45°C – only 11,12-orthoester (used for scale-up)

Challenge at step 5

  • acetylation of 11-OH due to protecting group cleavage
  • acetylation of 1° amine – avoided with neutralization


  • An inventive protecting group strategy allowed regioselective alkylation at position 2′-OH
  • 100 g scale
  • Overall yield 5 % / 7 steps
  • No column chromatography
  • Low cost: 1g < $10