ABSTRACT
Carbohydrates are ubiquitous and play a vital role in many important biological processes. The development of
efficient and selective chemical methods for the synthesis of carbohydrates and glycoconjugates is necessary
to understand the specific roles of carbohydrates and for therapeutic development. The most prevalent
functionality in carbohydrates is the hydroxyl group. There are two fundamental challenges in carbohydrate
synthesis associated with the hydroxyl group: 1) site-selective functionalization of one hydroxyl in the presence
of many other seemingly identical hydroxyls, and 2) stereoselective glycosylation. One long-term goal of this
program is to develop methods to address these challenges and improve the efficiency and selectivity for
carbohydrate synthesis. In the next five years, we will develop methods that can site-selectively functionalize
hydroxyl groups, such as acylation, alkylation, and sulfation, in various minimally protected or unprotected
glycosides in a predictable and general manner. We will also develop methods that can site-selectively remove
protecting groups in carbohydrates. The directing groups that are site-selectively installed in carbohydrates will
also allow us to access various types of glycosidic linkages stereoselectively. These transformations can
significantly improve the efficiency and selectivity for the synthesis of carbohydrates.
The other long-term goal of this program is to prepare carbohydrates and glycocongates with novel biological
functions. Certain glycans on glycoproteins can be recognized by lysosome targeting receptors (LTRs), which
then transport the glycoproteins to the lysosome for degradation. To take advantage of this natural process,
lysosome targeting chimeras were recently reported for the degradation of disease-associated extracellular
proteins. These degraders are created by conjugating carbohydrate ligands of LTRs on the cell surface with
ligands that can bind to the extracellular protein targets. The receptor-ligand interaction then triggers the
internalization of the extracellular proteins through receptor-mediated endocytosis, which further induces the
degradation of the endogenous extracellular protein targets in the lysosome. This new strategy complements
existing targeted protein degradation methods, which largely focus on intracellular proteins. In the next five
years, we will develop a series of carbohydrate-based ligands for LTRs that can be used for the degradation of
various extracellular disease associated proteins.
During our previous studies, we recognized the enormous potential of transition metal catalysts and chiral
organocatalysts in carbohydrate synthesis and the unique utility of glycoconjugates in cell-type selective
targeted protein degradation. In the next five years, we will continue developing novel methods for the
synthesis of carbohydrates and glycoconjugates, studying their applications in targeted protein degradation,
and pioneering new research directions.