Stereoselective waste minimization

Methods for lactone synthesis by transition metal catalysis involving C—O formation developed over the past 50 years have demonstrated much promise. Indeed, lactones have inspired the discovery of new organometallic transformations, design of metal catalysts, and detailed understanding of reaction mechanisms. Issues of waste minimization and stereoselectivity have been addressed. Future developments for chiral lactone synthesis will likely focus on establishing efficient transformations with broad scope and application in complex molecule total synthesis, especially in regards to macrolactonization where entropic costs often plague intramolecular reactivity with undesired intermolecular reactions. 

Carrying out the benzhydrylpiperazine formation via nucleophilic displacement as depicted in Scheme 2 using the enantiopure (—)-(2R,5S)-l -allyl-2,5-dimethylpiperazine provides two stereoisomers, epimeric at the benz-hydryl position. These epimers are separable by common chromatographic techniques (although these are sometimes difficult separations), and the absolute stereochemistry of the products has been proven via x-ray crystallography [19,23,40,41]. For large-scale preparation, a stereoselective approach to the final products is preferred to minimize waste and reduce costs. Two distinct stereoselective routes to benzhydrylpiperazines have been described. 

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