Catalysis has provided chemists with powerful methods to synthesize structurally interesting and biologically active compounds that can be used as effective therapeutics. Methods that generate structurally complex compounds from simple and readily available starting materials allow chemists to synthesize various analogs of compounds, and the biological activity of these compounds can often be tuned by making subtle structural changes. The goal of this project is to develop a highly efficient, asymmetric synthesis of thiazolines and oxazolines, which are common heterocyclic structures found in biologically active compounds. Currently, the syntheses of chiral thiazolines and oxazolines rely on enantiopure starting materials such as amino thiols and amino acids. The availability of enantiopure starting materials limits the number of analogs of these heterocycles that can be made efficiently. We will develop methods that use readily accessible achiral starting materials (amides, thioamides and alkynoates) and induce chirality using readily available chiral phosphines. The phosphine-catalyzed synthesis of thiazolines starting from thioamides and alkynoates is known, but there has been no description of an asymmetric synthesis of thiazolines using this chemistry. The phosphine is bound to the alkynoate throughout the catalytic cycle, so with the correct choice of phosphine, it will be possible to develop an asymmetric synthesis of thiazolines. We will also develop a method that couples amides and alkynoates to yield oxazolines using phosphine-catalysis. The initial oxazoline method will be developed with achiral phosphines to establish the scope, and then chiral phosphines will be investigated to develop an asymmetric process. There are no known examples of this catalytic reaction in the literature, but analysis of the mechanism suggest that this transformation is possible. This method would provide chemists with a route to enantiopure oxazolines from achiral starting materials.
Synthetic chemistry has provided efficient routes to Pharmaceuticals that allow for the treatment of many diseases and infections that, at one time, decreased quality of life. It is important to further develop and create methodologies that allow for the facile and rapid synthesis of biologically important structural motifs that are commonly seen in effective Pharmaceuticals and isolated natural products. Development of an asymmetric catalytic method for the synthesis of thiazolines and oxazolines would allow rapid entry into these biologically relevant classes of heterocycles.
| Lee, Sarah Yunmi; Murphy, Jaclyn M; Ukai, Atsushi et al. (2012) Nonenzymatic dynamic kinetic resolution of secondary alcohols via enantioselective acylation: synthetic and mechanistic studies. J Am Chem Soc 134:15149-53 |
