Total synthesis is very well known to provide access to many biologically significant molecules. Generally, an individual total synthesis focuses on one target compound or class of compounds at a time. If found to be biologically relevant, derivatives from this final compound(s) can be constructed. It has been traditionally shown that these derivatives will possess similar biological properties to the natural product synthesized. Relevant SAR studies of the individual compound and said derivative(s) lack a wide application to various biological targets/diseases; therefore, greatly limiting their therapeutic scope for potential discovery of new drug lead scaffolds. To this end, our lab is focusing on a new direction/application of total synthesis as the means of accessing new classes of screening library compounds and complex scaffolds for synthetic endeavors. Through divergent total synthesis these libraries and complex scaffolds will be assembled through synthetic manipulation of scalable and stable intermediates accessed in total synthesis campaigns. In this, a variety of molecular frameworks with entirely independent biological properties to each other will be accessed that will allow for broader application scopes into new drug lead scaffold development. For this we have selected brocazine F & G, a thiodiketopiperazine (TDKP) family of natural products with remarkable anti-cancer and anti-bacteria properties as our “proof-of-concept” into this small molecule construction approach. As a part of model studies directed towards the synthesis of this natural product, we have successfully constructed the initial diketopiperazine (DKP) ring system. Current efforts are aimed at synthesizing the di-thio bond to access the TDKP ring system and utilizing the intermediates of this synthesis to construct libraries of molecules via various chemical transformations. To be presented is the current state of the total synthesis of brocazine F, efforts towards new classes of screening compounds, and applications of the libraries accessed into studying molecular transport across complex molecular barriers.

Brocazine F&G: Total synthesis efforts and small molecule construction for investigations into molecular transport about complex barriers

254th National Meeting (2017)

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