Synthese of key intermediates to 1β-methylcarbapenem antibiotics

Abstract

A highly enantioselective synthesis of the key intermediate 8 of 1β-methylcarbapenem antibiotics was accomplished. The retrosynthetic strategy was focused on setting four contiguous chiral centers in the bicyclic isoxazolidine 169, followed by selective N-O bond cleavage and ultimate cyclization to construct the β-lactam ring. The key features of the scheme include the intramolecular 1,3-dipolar cycloaddition of nitrone to a bicyclic isoxazolidine with complete control of stereocenters and β-lactam formation from the β-amino acid 206b with trifluoroacetic anhydride in the presence of triethylamine. The substrate for the 1,3-dipolar cycloaddition, trans-lactol 164a, was prepared in 4 steps in three reaction pots starting from methyl (R)-3-iodo-2-methylpropionate in 76% overall yield. It was subjected to the nitrone formation with N-p-methoxybenzylhydroxylamine followed by the intramolecular 1,3-dipolar cycloaddition to provide the bicyclic isoxazolidine 169 as a single isomer with correct stereochemistry in 89% overall yield. Swern oxidation of 169, enol ether formation and oxidative cleavage followed by Wadsworth-Emmons olefination provided the conjugated ester 204a in 69% overall yield. Reductive N-O bond cleavage of 204a, β-lactam formation, debenzylation, TBS protection and oxidative cleavage in sequence afforded the desired azetidinone 8 in 74% overall yield from 204a. The direct formation of β-keto ester 181 from 209b, d, not via carboxylic acid 8, was attempted by palladium catalyzed oxidation. However, allyl ester 209b and p-methoxybenzyl ester 209d could not be converted into the desired β-keto esters. An alternative route to obtain the β-keto acid 232 from bicyclic ketone 184 was also intended. Ketone 184 was converted into 227b over 9 steps, of which the phenyl substituent was found to be resistant to oxidative degradation into carboxylic acid group.