Project Summary/Abstract
This proposal describes the use of fundamental chemical properties to alter the reactivity of reagents for
the synthesis of biomedically important compounds. The role of carbohydrates in biological systems cannot be
overstated and is of great interest to scientific research. Robust, practical, and general methods for glycosylation
reactions with predictable stereoselectivity will enable further research in the role of sugars in biological chemistry
and medicine. Despite recent advances, glycan synthesis remains a challenging endeavor largely reserved for
specialists in sugar chemistry, and a general, selective synthesis of 2-deoxy-ß-glycosides remains elusive.
Hydrogen-bond-donor catalysts will be used to alter the innate reactivity of 2-deoxy-a-phosphate donors for the
selective synthesis of 2-deoxy-ß-glycosides (K99). The synthesis relies on the in situ generation of a phosphate
ester glycosyl donor, and on the identification of a tailored organocatalyst to promote stereospecific
glycosylations by simultaneously activating the electrophile (the donor) and the nucleophile (the acceptor).
Developing a general method for the synthesis of 2-deoxy-ß-glycosides 1) provides a solution for the
glycosylation of sugars lacking the C2 functionality often used as a directing group via anchimeric assistance, 2)
enables further research on their role in biological chemistry and medicine, and 3) provides an alternative
strategy for the synthesis of biologically active natural products.
Secondly, the chemical properties of C–S bonds will be used for the synthesis of novel donor-acceptor
Stenhouse adducts, DASAs (R00). Though Stenhouse adducts were introduced in 2014, they are used in drug
delivery, dynamic phase transfer, polymers, liquid crystals, wavelength-selective photoswitching, and
chemosensing applications. Despite their promising applications, DASAs are currently limited by their structural
diversity. Only amine donors and two acceptors are generally used in DASA systems today. Novel adducts with
sulfur, phosphine, oxygen, or other heteroatom donors will expand the pool of applications and provide more
efficient compounds for known applications. The synthesis relies on using 2-thiophenecarboxaldehyde, an
economical starting material that will circumvent reactivity problems faced when using furfural. 2-
Thiophenecarboxaldehyde bears a weaker and longer C–S bond in place of the C–O bond responsible for the
inability to incorporate other donor functionality in DASAs when using furfural; thiophene derivatives also carry
less electron density on the carbon atoms, making it a perfect substrate for ring opening upon condensing an
acceptor molecule. If the C–S bond is not sufficiently weak, the polarizable sulfur will be activated using thiophilic
Lewis acids. Synthesizing novel Stenhouse adducts 1) provides additional DASAs to explore applications listed
above, 2) enables further research on the chemical properties of these new photoswitches, and 3) provides an
opportunity to develop additional applications.
