A novel and efficient synthesis of the key intermediate of 1β-methylcarbapenem antibiotics employing [ 2+2 ]-cycloaddition reaction of diketene with a chiral imine

The key intermediate (2) of 1β-methylcarbapenems was efficiently synthesized from (S)-methyl 3-hydroxy-2-methyl-propionate ((S)-5) in ten steps and 30 % overall yield. Thus, (S)-3-benzyloxy-2-methylpropanal readily obtainable from (S)-5, was condensed with di-p-anisylmethylamine to afford the chiral imine. The [2+2]-cycloaddition reaction of diketene with the imine was found to proceed in a highly diastereoselective manner, giving the desired 3,4-trans-3-acetyl-β-lactam (max. diastereoselectivity 11-15:1). This was readily elaborated to 2 by five sequential operations.