60th Annual Report on Research 2015

This grant period has allowed for the further development of a method to prepare thiohydroxamic and thiohydroximic acids and utilize them in several new bond forming reactions.  Importantly, the funds have allowed for the professional development of the PI by allowing for travel to national meetings to discuss the results obtained in his grant (Heterocycles Gordon Conference) and have provided the lead graduate student with a full stipend and a similar opportunity for travel.  This second year of PRF funding has allowed us to build upon our initial successes in N-O bond insertion/amination chemistry to now generate unusual oxathiazoles in high yields from our thiohydroximic acid building blocks.  This work is now being extended to other classes of heterocycles. 

Heterocycles are key components of bioactive natural products, materials for energy transport and storage, ligands for catalysis, and countless other applications where small organic molecules are employed. Consequently, rapid, selective, and efficient synthetic approaches to heterocycles are highly sought after. New methods for bond formation in organic synthesis are empowering tools since they provide alternate, and often improved, approaches to existing and novel high-value targets.  Countless methods for the preparation of heterocycles have been developed, rendering the synthesis of many simple structures straightforward. More complex heterocyclic scaffolds require significantly more synthetic overhead to prepare, particularly those bearing quaternary stereocenters, and remain a bottleneck in many synthetic efforts.

 1,4,2-oxathiazoles are a unusual heterocycle, largely since the current approach to their synthesis is via a [3+2] cycloaddition approach of thioaldehydes and thioketones.  Since these starting materials are not stable, very few oxathiazoles exist in the literature.  A general method to access a wide variety of 1,4,2-oxathiazoles from readily available starting material would therefore be useful and provide an additional heterocyclic scaddold. We were able to able to access 1,4,2-oxathiazoles with a variety of alkyl, aryl and heteroaryl substituents on both the thiohydroximic acid and activating fragments and the reaction has been demonstrated on gram-scale (Scheme 1).   A simple alkyl group does not provide enough activation (allyl or aryl group is required), rendering S-alkyl thiohydroximic acids unreactive; however, the cyclopropyl substituent activates the thiohydroximic acids enough to participate in the reaction and provides the corresponding 5-cyclopropyl-1,4,2-oxathiazole (Scheme 1). We were also able to synthesize in one step and 71% yield the 1,4,2-oxathiazole analog of an 1,2,4-oxadiazole.  This result highlights the scalability and utility of this chemistry. 

Scheme 1.  Substrate scope for oxathiazole formation. 

During this second funding period of this grant we have aggressively pursued approaches to enable the rapid and scalable preparation of valuable heterocycles.   We have now prepared two additional manuscripts from this funding period (one accepted in OL and one submitted to Synlett). 

In the last funding year (extension year) we plan to expand the types of heterocycles that are accessible from our developed reactions.  Taken together these efforts will enable access to value added materials and expand the chemical space of heterocyclic chemistry.  Finally, these efforts will enable the career development of the PI, and a talented graduate student, at an essential point of both scientific and professional development.