Strategic Applications of Pinacolato Allylboron Reagents: New Reactions in Enantioselective Allyl-Allyl Cross-Coupling and Allylboration to Form New Carbon-Heteroatom Bonds

Thesis advisor: James P. MorkenDetailed within this dissertation are three new reactions involving allylboron reagents. Chapter 1 describes the development of Pd-catalyzed allyl-allyl cross-coupling for the preparation of enantioenriched all-carbon quaternary stereogenic centers. This methodology represents a novel approach to a significant challenge for synthetic chemists. Subsequently, an allyl-allyl cross-coupling is described which generates functionally differentiated 1,5-dienes. Such structures allow for several chemoselective manipulations, which add a significant practical note to this cross-coupling methodology. Chapter 2 details the development of the allylboration of nitrosobenzene with (Z)-crotylboronate derivatives, which results in the formation of branched allylic alcohols. This methodology provides a regioselective complement to standard boron oxidation conditions.Thesis (PhD) — Boston College, 2012.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Chemistry

Catalytic Enantioselective Allyl–Allyl Cross-Coupling with a Borylated Allylboronate

Catalytic enantioselective allyl–allyl cross-coupling of a borylated allylboronate reagent gives versatile borylated chiral 1,5-hexadienes. These compounds may be manipulated in a number of useful ways to give functionalized chiral building blocks for asymmetric synthesis

Synthesis of Pyrazoles from 1,3-Diols via Hydrogen Transfer Catalysis

1,3-Diols engage in ruthenium-catalyzed hydrogen transfer in the presence of alkyl hydrazines to provide 1,4-disubstituted pyrazoles. Regioselective synthesis of unsymmetrical pyrazoles from β-hydroxy ketones is also described

Synthetic Approaches to the New Drugs Approved during 2015

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 29 new chemical entities (NCEs) that were approved for the first time in 2015

Selectivity Determination of a Small Molecule Chemical Probe Using Protein Microarray and Affinity Capture Techniques

Small molecule selectivity is an essential component of candidate drug selection and target validation. New technologies are required to better understand off-target effects, with particular emphasis needed on broad protein profiling. Here, we describe the use of a tritiated chemical probe and a 9000 human protein microarray to discern the binding selectivity of an inhibitor of the mRNA decapping scavenger enzyme DcpS. An immobilized m⁷GTP resin was also used to assess the selectivity of a DcpS inhibitor against mRNA cap-associated proteins in whole cell extracts. These studies confirm the exquisite selectivity of diaminoquinazoline DcpS inhibitors, and highlight the utility of relatively simple protein microarray and affinity enrichment technologies in drug discovery and chemical biology

Covalent Enzyme Inhibition through Fluorosulfate Modification of a Noncatalytic Serine Residue

Irreversible enzyme inhibitors and covalent chemical biology probes often utilize the reaction of a protein cysteine residue with an appropriately positioned electrophile (<i>e.g.</i>, acrylamide) on the ligand template. However, cysteine residues are not always available for site-specific protein labeling, and therefore new approaches are needed to expand the toolkit of appropriate electrophiles (“warheads”) that target alternative amino acids. We previously described the rational targeting of tyrosine residues in the active site of a protein (the mRNA decapping scavenger enzyme, DcpS) using inhibitors armed with a sulfonyl fluoride electrophile. These inhibitors subsequently enabled the development of clickable probe technology to measure drug-target occupancy in live cells. Here we describe a fluorosulfate-containing inhibitor (aryl fluorosulfate probe (FS-p1)) with excellent chemical and metabolic stability that reacts selectively with a noncatalytic serine residue in the same active site of DcpS as confirmed by peptide mapping experiments. Our results suggest that noncatalytic serine targeting using fluorosulfate electrophilic warheads could be a suitable strategy for the development of covalent inhibitor drugs and chemical probes