Synthesis of (-)-PNU-286607 by asymmetric cyclization of alkylidene barbiturates.
PNU-286607 is the first member of a promising, novel class of antibacterial agents that act by inhibiting bacterial DNA gyrase, a target of clinical significance. Importantly, PNU-286607 displays little cross-resistance with marketed antibacterial agents and is active against methicillin-resistant staphylococcus aureus (MRSA) and fluoroquinoline-resistant bacterial strains. Despite the apparent stereochemical complexity of this unique spirocyclic barbituric acid compound, the racemic core is accessible by a two-step route employing a relatively obscure rearrangement of vinyl anilines, known in the literature as the "tert-amino effect." After a full investigation of the stereochemical course of the racemic reaction, starting with the meso cis-dimethylmorpholine, a practical asymmetric variant of this process was developed.
Ruble
J Craig
JC
Infectious Diseases Medicinal Chemistry, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, Michigan 49001, USA.
Hurd
Alexander R
AR
Johnson
Timothy A
TA
Sherry
Debra A
DA
Barbachyn
Michael R
MR
Toogood
Peter L
PL
Bundy
Gordon L
GL
Graber
David R
DR
Kamilar
Gregg M
GM
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001463:Barbiturates / Q000737:chemistry* / Q000494:pharmacology*; D003500:Cyclization; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001463:Barbiturates; D024841:Fluoroquinolones; D006576:Heterocyclic Compounds, 4 or More Rings; C541225:PNU-286607; D013141:Spiro Compounds; D059005:Topoisomerase II Inhibitors