The design of a novel nucleoside scaffold that exhibits an all-carbon quaternary center is reported. This allows for both α- and β-anomers of a given 2'-deoxy-2',2'-difluoro nucleoside analog (NA) to have potential biological activity. Using an intramolecular atom-transfer reaction, an all-carbon quaternary center was obtained without the use of heavy metals and/or harsh conditions. The chemistry developed is efficient, easily scalable and leads to novel libraries of molecules.

Reported herein is the synthesis of sialyl LewisX analogues bearing a trans-bicyclo­[4.4.0] dioxadecane-modified 3-O,4-C-fused galactopyranoside scaffold that locks the carboxylate pharmacophore in either the axial or equatorial position. This novel series of bicyclic galactopyranosides are prepared through a stereocontrolled intramolecular cyclization reaction that has been evaluated both experimentally and by density functional theory calculations. The cyclization precursors are obtained from β-d-galactose pentaacetate in a nine-step sequence featuring a highly diastereoselective equatorial alkynylation and Cu­(I) catalyzed formation of the acetylenic α-ketoester moiety. Preliminary biological evaluations indicate improved activity as P-selectin antagonists for the axially configured analogues as compared to their equatorial counterparts.

A key missing tool in the chemist's toolbox is an effective biocatalyst for macrocyclization. Macrocycles limit the conformational flexibility of small molecules, often improving their ability to bind selectively and with high affinity to a target, making them a privileged structure in drug discovery. Macrocyclic natural product biosynthesis offers an obvious starting point for biocatalyst discovery via the native macrocycle forming biosynthetic mechanism. Herein we demonstrate that the thioesterase domains (TEs) responsible for macrocyclization of resorcylic acid lactones are promising catalysts for the chemoenzymatic synthesis of 12- to 18-member ring macrolactones and macrolactams. The TE domains responsible for zearalenone and radicicol biosynthesis successfully generate resorcylate-like 12- to 18-member macrolactones and a 14-member macrolactam. In addition these enzymes can also macrolactonize a non-resorcylate containing depsipeptide, suggesting they are versatile biocatalysts. Simple saturated omega-hydroxy acyl chains are not macrocyclized, nor are the alpha-beta unsaturated derivatives, clearly outlining the scope of the substrate tolerance. These data dramatically expand our understanding of substrate tolerance of these enzymes and are consistent with our understanding of the role of TEs in iterative polyketide biosynthesis. In addition this work shows these TEs to be the most substrate tolerant polyketide macrocyclizing enzymes known, accessing resorcylate lactone and lactams as well as cyclicdepsipeptides, which are highly biologically relevant frameworks.

Over 50 years ago, Jencks and Gilchrist showed that formaldehyde catalyses the hydrolysis of phosphoramidate through electrophilic activation, induced by covalent attachment to its nitrogen atom. Given our interest in the use of aldehydes as catalysts, this work was revisited to identify a superior catalyst, o-phthalaldehyde, which facilitates hydrolyses of various organophosphorus compounds bearing P([double bond, length as m-dash]O)-NH subunits under mild conditions. Interestingly, chemoselective hydrolysis of the P([double bond, length as m-dash]O)-N bonds could be accomplished in the presence of P([double bond, length as m-dash]O)-OR bonds.