Abstract
Mucin-type glycopeptides and glycoproteins are the most prevalent type of O-linked glycosylation in eukaryotes. Many forms of cancer aberrantly express mucin-type glycopeptides and glycoproteins such as Tn-antigens and MUC1. These glycoconjugates have been extensively explored as viable biomarkers and therapeutic targets for CAR-T cell therapy and cancer vaccines. Due to the specific and selective nature of these therapies, a homogenous source of mucin-type glycopeptides and glycoproteins is required. Homogenous isolation of these compounds from natural sources is difficult due to their ubiquitous and complex expression across most epithelial cells. This positions chemical and enzymatic synthetic methods as powerful tools to access homogenous samples of mucin-type glycopeptides and glycoproteins. Mucin-type glycopeptides and glycoproteins are linked through a serine or threonine residue to a N-acetylgalactosamine glycan in a 1,2-cis-ɑ manner. Through this common motif, 8 oligosaccharide core structures are derived that confer functionality. Previous synthetic methods have utilized chemoenzymatic approaches to synthesize and diversify these glycans with most glycosylations performed via Lewis-acid assisted activation. These established methods are inefficient as they do not guarantee complete stereochemical control and require stoichiometric amounts of reagents. Our group has developed several highly stereoselective iron-catalyzed glycosylation reactions. These reactions can achieve high stereoselectivity in excellent yield across a wide range of donor and acceptor combinations. Through the application of our iron-catalyzed glycosylations, a rapid and highly stereoselective synthesis of mucin-type core structures 1 and 2 was achieved.