Total Syntheses of the Thiopeptides Amythiamicin C and D

The thiopeptides amythiamicin C and D were synthesized by employing amide bond formation, a Stille cross‐coupling reaction, and two Negishi cross‐coupling reactions as key transformations. The central 2,3,6‐trisubstituted pyridine ring of the target compounds was introduced as a 2,6‐dibromo‐3‐iodopyridine, which was selectively metalated at the 3‐position and connected to the complete Southern fragment of the amythiamicins by a Negishi cross‐coupling. For the synthesis of amythiamicin C, this step was followed by a Negishi cross‐coupling at C‐6 of the pyridine core. Subsequent attachment of the Eastern fragment was achieved by amide bond formation and macrolactam ring closure by a Stille cross‐coupling at C‐2. The Eastern bithiazole fragment of the amythiamins was constructed also by regioselective metalation and cross‐coupling reactions. The pivotal step involved the diastereoselective addition of 4‐bromothiazole‐2‐magnesium bromide to a chiral sulfinyl imine. For the synthesis of amythiamicin D, the order of cross‐coupling at C‐6, amide bond formation, and cross‐coupling at C‐2 was changed. The amide bond formation to the Eastern fragment was performed first and it was subsequently attempted to close the macrolactam by an intramolecular regioselective Stille cross‐coupling at C‐2. Despite the low regioselectivity of this reaction it paved the way to the immediate completion of the amythiamicin D synthesis when followed by a Negishi cross‐coupling at C‐6 with 2‐zincated methyl thiazole‐5‐carboxylate.