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Synthesis of (-)-PNU-286607 by asymmetric cyclization of alkylidene barbiturates
J Craig Ruble1, Alexander R Hurd, Timothy A Johnson
1Infectious Diseases Medicinal Chemistry, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, Michigan 49001, USA.
Abstract:
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.
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