Challenging Macrolide Chemistry

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)

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

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