Paul G. Bulger

Recent advances in biomimetic natural product synthesis

This review highlights some of the most elegant and instructive biomimetic syntheses of natural products over the last few years, providing an updated overview of this area of research.

CRTH2 Antagonist MK-7246: A Synthetic Evolution from Discovery through Development

In this paper, we report the development of different synthetic routes to MK-7246 (1) designed by the Process Chemistry group. The syntheses were initially designed as an enabling tool for Medicinal Chemistry colleagues in order to rapidly explore structure-activity relationships (SAR) and to procure the first milligrams of diverse target molecules for in vitro evaluation. The initial aziridine opening/cyclodehydration strategy was also directly amenable to the first GMP deliveries of MK-7246 (1), streamlining the transition from milligram to kilogram-scale production needed to support early preclinical and clinical evaluation of this compound. Subsequently a more scalable and cost-effective manufacturing route to MK-7246 (1) was engineered. Highlights of the manufacturing route include an Ir-catalyzed intramolecular N-H insertion of sulfoxonium ylide 41 and conversion of ketone 32 to amine 31 in a single step with excellent enantioselectivity through a transaminase process. Reactions such as these illustrate the enabling impact and efficiency gains that innovative developments in chemo- and biocatalysis can have on the synthesis of pharmaceutically relevant target molecules.

An investigation into the alkylation of 1,2,4-triazole

Abstract The alkylation of 1,2,4-triazole with 4-nitrobenzyl halides and a variety of bases afforded the 1- and 4-alkylated isomers with a consistent regioselectivity of 90:10. Previously reported regiospecific alkylations of 1,2,4-triazole were re-examined and the quoted isomer ratios were shown to depend on the isolation procedure. The use of DBU as base in the alkylation of 1,2,4-triazole allows for a convenient and high yielding synthesis of 1-substituted-1,2,4-triazoles.

A cascade approach to cyclic aminonitrones: reaction discovery, mechanism, and scope.

Treatment of omega-epoxynitriles with hydroxylamine affords cyclic aminonitrones in a single step and with high stereoselectivity. The scope of this novel transformation was explored in a series of examples. The aminonitrone products were shown to be useful substrates for further selective elaboration.

A high-yielding method for the preparation of isoxazolopyridin-3-amine derivatives

A highly efficient and green method has been developed for the rapid preparation of highly functionalized isoxazolopyridin-3-amine derivatives in excellent yields. This process has a broad substrate scope, is operationally simple, and generally requires no chromatographic purification. In addition, the process is scalable and significantly greener than current alternatives with a PMI of 18 and water as the reaction solvent.