A stereochemical journey around spirocyclic glutamic acid analogs

Abstract

A practical divergent synthetic approach is reported for the library of regio- and stereoisomers of glutamic acid analogs built on the spiro[3.3]heptane scaffold. Formation of the spirocyclic scaffold was achieved starting from a common precursor – an O-silylated 2-(hydroxymethyl)cyclobutanone derivative. Its olefination required using the titanium-based Tebbe protocol since the standard Wittig reaction did not work with this particular substrate. The construction of the second cyclobutane ring of the spirocyclic system was achieved through either subsequent dichloroketene addition or Meinwald oxirane rearrangement as the key synthetic steps, depending on the substitution patterns in the target compounds (1,6- or 1,5-, respectively). Further modified Strecker reaction of the resulting racemic spirocyclic ketones with the Ellman's sulfinamide as a chiral auxiliary had low to moderate diastereoselectivity; nevertheless, all stereoisomers were isolated in pure form via chromatographic separation, and their absolute configuration was confirmed by X-ray crystallography. Members of the library were tested for the inhibitory activity against H. pylori glutamate racemase.