Aminoglycoside Antibiotics – Fortamine Aglyca Total Synthesis, Optical Resolution, Chemical Modifications

Starting from the dianhydro‐ epi ‐inositol 10 (available ultimately from benzene) an expedient total synthesis of enantiomerically pure (+)/(−)‐de‐ O ‐methylfortamines (derivatives) has been developed. Key steps are the regiospecific epoxide openings which occur intramolecularly in the diepoxybis(urethane) 11 and intermolecularly by (+)‐1‐phenylthylamine in the epoxyurethanes rac ‐ 13 . The diastereomeric adducts ( 30, 32 ) are quantitatively separated by crystallization/chromatogrphy. Following hydrogenation, natural and nonnatural cis ‐1,4‐inosadiamines are obtained optically pure [e.g. fortamine (−)‐ 1 , ent ‐fortamine (+)‐ 1 , 3‐ O ‐demethylfortamine (−)‐ 38 , ent ‐3‐ O ‐demethylfortamine (+)‐ 38 ]. This approach, which was optimized by numerous model reactions, allows wide chemical modifications and leads among others to 3‐ O ‐demethylfortamine and ent ‐fortamine derivatives in which only the (6)4‐OH‐group, the one to be glycosidated, remains unprotected.