Advances in high-throughput screening and in chemical biology have encouraged the creation of ever-expanding libraries of small molecules.  In order to explore new molecular structures and study their relationship with relevant biological targets, recent efforts have focused toward diversity-oriented synthesis (DOS).  The goal of such strategy is the design of molecules with richer structural features, such as a larger number of sp3-hybridized carbons, the introduction of stereocenters and of polycyclic frameworks.  Another evolving strategy in molecular design is the mimicry of biomolecules, starting with one or more of their basic building blocks such as amino acids, nucleic acids, lipids, and carbohydrates.  The automated synthesis laboratory (ASL) at Lilly research laboratories is designed to increase turnover between successive rounds of synthetic chemistry and of biological testing.  Thus, small focused libraries that are generated using the ASL can be more rapidly optimized, following their biological and pharmacological evaluation.  A small library of C-glycosides was prepared from the Lewis acid-catalyzed cycloaddition between peracetylated �-galactosylmethylnitrile and several hydrazonyl chlorides.  Treatment of benzoic acid analogues and of hydrazide analogues using T3P in ethyl acetate led to a series of hydrazides which were then converted into the corresponding hydrazonyl chloride using polymer-supported triphenylphosphine and carbon tetrachloride in acetonitrile.  Following the validation of the synthetic sequence leading to this library of C-glycosides, the experimental procedures were optimized for the robotic suite, including the use of polymer-supported reagents, and minimizing workup procedures through the use of SPE techniques.

Synthesis of a library of <i>C</i>-glycosides using the automated synthesis laboratory (ASL)

246th National Meeting (2013)

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Synthesis of a library of C-glycosides using the automated synthesis laboratory (ASL)