Oxygen, nitrogen and sulfur-containing stereocenters are prevalent in natural products and many of the most prescribed single-enantiomer pharmaceutical compounds. As a result, the development of catalytic asymmetric methodologies for carbon-heteroatom bond formations that show high selectivity and efficiency accompanied by low toxicity and sensitivity to air and moisture are important to health-related areas of organic chemistry ranging from synthesis and drug discovery to manufacturing of commercial drugs. Asymmetric anion-binding organocatalysts possess many of these characteristics, and their application towards O, N, or S-based anion- binding could provide entry into new asymmetric transformations. Unfortunately, current catalyst designs rely on acidic hydrogen-bonds for anion-binding, and will undergo deprotonation and decomposition with hard, basic anions. This proposal outlines the development and application of a new class of chiral disiloxane catalysts that seek to address this limitation. Unlike current catalysts, disiloxanes ar able to bind anions without hydrogen-bonds, which would allow them to greatly expand the scope of current anion-binding catalysts. As these molecules have never been used as catalysts, initial studies will seek to understand the steric and electronic factors of achiral disiloxanes necessary for anion-binding catalysis. These features will be considered in the design and synthesis of chiral disiloxane catalysts, which will seek to utilize silicon-centered chirality for high stereoinduction. Upon synthesis of these new catalysts, their application for reactions involving hard oxygen, nitrogen and sulfur anions will be considered. Their use in the asymmetric hetero-Michael addition to ?-unsaturated carbonyl compounds and nitro-olefins will produce motifs prevalent in biologically active molecules such as polyacetate and polyketide natural products, ?mino alcohols and thiols, and 1,2- diamines. Extension of the methodology to allow activity biomimetic of hydrolase enzymes will allow desymmetrizations and resolutions that can deliver ?ertiary ?mino acids and a host of other important structures. Together, the stability, facile synthesis, and wide potential application of these new disiloxane catalysts towards biologically active structures will allow them to find great use in the development and production of a wide range of therapeutic drugs that can improve human health.
The design and production of new small-molecule medicines often relies on a chemist's ability to select a specific structural orientation or 'chirality' of a molecule, which is typically accomplished with a catalyst that is also chiral. Organocatalysts are an important class of catalysts that are particularly well suited to the production of therapeutic drugs due to their low toxicity, high stability towards air and moisture, and facile synthesis from cheap and readily available starting materials. This proposal seeks to design a new type of silicon-based organocatalyst that will be able to deliver medicinally important compounds in a new and highly specific way that could find great use in the development and production of new compounds to fight cancer and other diseases.
