The commonly used inhalant anesthetics halothane, enflurane, and isoflurane each contain a single chiral carbon atom and hence each exists as a 50/50 (racemic) mixture of enantiomers; all are administered clinically in racemic form. In fact, nothing is known about either the anesthetic activity or the toxicity of the pure enantiomers of these agents. Recent developments in anesthesia research suggest that specific, active site binding of anesthetic agents with membrane-bound proteins may play a role in the mechanism of anesthetic action. Direct interaction with enzyme binding sites is usually highly sensitive to substrate stereostructure. Thus, evaluation of the relative activity and toxicity of the enantiomers of commonly used inhalant anesthetics is of clinical, as well as theoretical, importance. We propose to develop synthetic methodology to provide each of the enantiomers of halothane, enflurane, and isoflurane in optically pure form, and in sufficient quantities for in vitro evaluation. A recently described firefly luciferase assay will be used in our initial study. Our synthetic approaches to halothane, enflurane, and isoflurane will utilize either resolution techniques, or synthetic reactions which proceed with optical induction.
