Synthesis and antibacterial activity of 2α-functionalized 1β-methylcarbapenems related to KR-21012

The 2α-functionalized 1β-methylcarbapenems 3 were synthesized from the 2-formyl 1β-methylcarbapenem intermediate 5. The best compound in the series of 2α-(hydroxy)alkylcarbapenems, KR-21012, displayed well balanced in vitro and in vivo activity as a parent compound of oral carbapenem. Scheme 1. Reagents and reaction conditions; (i) MnO2, CH2Cl2, reflux (70%); (ii) RMgX or RLi, THF or Et2O (50–75%); (iii) KF, n-Bu4NBr, →KF, n-Bu4NBr, AcOH, THF (80%); (iv) Pd(PPh3)4, SHE, THF (62%).