Total synthesis of avermectins. II: Enantioselective synthesis of the C10-C25 northern fragment and final steps for the construction of the 22,23-dihydroavermectin Bib aglycone

The total synthesis of the aglycone of 22,23-dihydroavermectin B1b involves a retrosynthetic two building-blocks approach. A Stille Pd(0) catalyzed cross-coupling reaction is carried out between a northern C10-C25 E-vinylstannane and a southern C1-C9 vinyl iodide. The final steps include successive removal of the carboxyl β-(trimethylsilyl)ethyl protecting group of the intermediate secoester, macrolactonization under Yonemitsu's conditions and removal of the 5-O-TBS protecting group. These last steps have been carried out with the aid of a relay study from commercial Ivermectin; a macrolactone opening reaction of the aglycone in the presence of Ti(O i Pr) 4 has been developed where the crucial Δ 3,4 double bond as well as the configuration at C-2 were totally preserved.