To increase polarity in the spiroazetidine-piperidine series (1) for the ghrelin inverse agonist program, introduction of heteroatoms and bicyclic heteroarylacetamides in place of phenylacetamides were designed. Using readily available haloheteroaryls under transition metal catalyzed coupling conditions with either t-butyl cyanoacetate followed by hydrolysis and decarboxylation or with ethyl acetoacetate followed by insitu deacylation by ethanolysis to afford the carboxylic acid for amidation. The 5,5- and 5,6-heterobicyclic compounds were prepared from the corresponding heteroarylamines and bromoacetoacetates via a base-mediated condensation. Herein we discuss these diverse approaches to access the polar heteroarylacetic acids. 

Synthesis of diverse polar bicyclic heteroarylacetic acid side chains for the ghrelin inverse agonist program

244th National Meeting (2012)

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