59th Annual Report on Research 2014

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 (ACS Meeting).  The results that we have obtained have also fostered the development of two other projects, which are advancing to a stage that they will be ready to submit for additional external funding.  In these ways the first year of the PRF grant has allowed for significant personal and scientific advances in our research group.

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.

     Thiazolines are a class of heterocycles common in posttranslationally modified peptide natural products, serve as ligands for many catalytic reactions, and are an increasingly popular tool for biological imaging.  Since thiazolines represent the core component of many synthetic targets, rapid access to these heterocycles enables the streamlined synthesis of valuable molecules.  Traditionally, thiazolines are prepared from b-amino thiols or b-amino alcohols through a cyclization/dehydration sequence. These dehydrative approaches are facile and synthetically efficient and provide a solution to simple thiazoline synthesis; however, the synthesis of substituted chiral b-amino alcohols or thiols can often be lengthy and low yielding, particularly in the case of quaternary amino derivatives or when the amino acid precursors are unnatural.  Additionally, current methods force a synthetic sequence to adapt to these preformed chiral starting materials and do not allow for facile diversification of these molecular scaffolds.

During the initial funding period of this grant we have aggressively pursued approaches to enable the rapid and scalable preparation of valuable heterocycles.   In our first publication from this grant, and our initial explorations in this general research area, we developed a facile and scalable approach to thiohydroxamic and thiohydroximic acids (Figure 1).  This method was unique in the literature and was readily useful for the conversion of bulk materials to value added reagents bearing reactive handles for further functionalization. 

With these thiohydroxamic acids in hand we have explored a variety of transformations to harness their potential as synthetic reagents.  During this process we discovered the copper-catalyzed aminobromination reaction to generate unnatural thiazolines that are difficult to prepare via existing technology.  As shown in Figure 2, a variety of complex thiazolines can be prepared in high yields utilizing this reaction and the reaction proceeds with good selectivity. 

In the next funding year we plan to leverage our successful reactions to develop approaches to other heterocyclic scaffolds and work to develop asymmetric versions of our already reported processes.  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.