Stereocontrolled synthesis of piperidine-condensed tricyclic carbapenems (5-azatrinems) and their antibacterial activities.
Stereocontrolled synthesis of tricyclic carbapenem (5-azatrinem) derivatives 4, in which a piperidine ring is condensed to the carbapenem skeleton, was achieved. The pivotal tricyclic intermediate 2, allyl (8S,9R,10S)-5-(tert-butoxycarbonyl)-10-(R)-1-(tert-butyldimethylsilyl oxy)ethyl]-11-oxo-1,5-diazatricyclo[7.2.0.0(3,8)]undec-2- ene-2-carboxylate, was synthesized starting from an acetoxyazetidinone chiron 6 in a practical manner based on a C-C bond formation reaction between 6 and piperidinone-ester 5, palladium-catalyzed de(allyloxy)carbonylation of 7b and Wittig-type cyclization via an oxalimide 9. Selective deprotection of the N-Boc group of 2 was found to proceed smoothly by treatment with trimethylsilyl trifluoromethanesulfonate and 2,6-lutidine to give the amino compound 3, whose functionalization on the nitrogen atom to derivatives 10 followed by deprotection led to various 5-azatrinem acids 4. These compounds showed potent in vitro activities against gram-positive and gram-negative bacteria.
Mori
M
M
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. morimk@shina.sankyo.co.jp
Somada
A
A
Oida
S
S
D000818:Animals; D001419:Bacteria / Q000187:drug effects; D001711:Biotransformation; D015780:Carbapenems / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007202:Indicators and Reagents; D051379:Mice; D008826:Microbial Sensitivity Tests; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D015780:Carbapenems; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D010880:Piperidines