Journal of the American Chemical Society 2009-03-25

Synthesis of (-)-PNU-286607 by asymmetric cyclization of alkylidene barbiturates.

J Craig Ruble, Alexander R Hurd, Timothy A Johnson, Debra A Sherry, Michael R Barbachyn, Peter L Toogood, Gordon L Bundy, David R Graber, Gregg M Kamilar

Index: J. Am. Chem. Soc. 131(11) , 3991-7, (2009)

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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.