Divergent Solid‐Phase Synthesis and Biological Evaluation of Yaku'amide B and Its Seven E/Z Isomers

Yaku′amide B (1) inhibits cancer cell growth through a unique mechanism of action. Compound 1 binds to mitochondrial FoF1‐ATP synthase, inhibits ATP production, and enhances ATP hydrolysis. The presence of one (E)‐ and two (Z)‐α,β‐dehydroisoleucines (ΔIle) in the linear 13‐mer sequence is the most unusual structural feature of 1. To uncover the biological importance of these residues, we synthesized 1 and its seven E/Z isomers 2–8 by devising a new divergent solid‐phase strategy. Both the (E)‐ and (Z)‐ΔIle residues were stereoselectively constructed by traceless Staudinger ligation on resin to ultimately deliver 1–8. All isomers 2–8 displayed effects on the inhibition of cell growth and ATP production, and enhanced ATP hydrolysis, thus indicating that 2–8 share the same mode of action as 1. The least potent isomer, 8, was isomeric at three ΔIle residues of the most potent 1. These findings together indicate that the E/Z stereochemistry of the three ΔIle residues controls the magnitude of the biological functions of 1. The importance of ΔIle: Yaku′amide B (1) displays potent antiproliferative activity against cancer cells and possesses unusual (E)‐ and (Z)‐α,β‐dehydroisoleucines (ΔIle) in its linear 13‐mer sequence. We stereoselectively constructed 1 and its seven (E)/(Z)‐ΔIle isomers 2–8 by devising a new divergent solid‐phase strategy and revealed that the E/Z stereochemistry affects the biological activities.