Andrew Brunskill

A multifunctional catalyst that stereoselectively assembles prodrugs

Getting phosphorus into healthy shape ProTide therapeutics play a trick on the body, getting nucleoside analogs where they need to be by decorating them with unnatural phosphoramidates in place of ordinary phosphates. These compounds pose an unusual synthetic challenge because their configuration must be controlled at phosphorus; most methods have been refined to manipulate the geometry of carbon. DiRocco et al. report a metal-free, small-molecule catalyst that attains high selectivity for nucleoside phosphoramidation by activating both reaction partners. Kinetic studies with an early prototype revealed a double role for the catalyst that inspired the rational design of a more active and selective dimeric structure. Science, this issue p. 426 A doubly activating catalyst efficiently forms key phosphorus-based chiral centers inherent to ProTide therapeutics. The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.

The Discovery of Quinoxaline-Based Metathesis Catalysts from Synthesis of Grazoprevir (MK-5172)

Olefin metathesis (OM) is a reliable and practical synthetic methodology for challenging carbon-carbon bond formations. While existing catalysts can effect many of these transformations, the synthesis and development of new catalysts is essential to increase the application breadth of OM and to achieve improved catalyst activity. The unexpected initial discovery of a novel olefin metathesis catalyst derived from synthetic efforts toward the HCV therapeutic agent grazoprevir (MK-5172) is described. This initial finding has evolved into a class of tunable, shelf-stable ruthenium OM catalysts that are easily prepared and exhibit unique catalytic activity.

Characterization of a Unique Co-crystal of the BACE1 Inhibitor Verubecestat and a Reaction Intermediate: Implications for the Development of a Commercial Manufacturing Process

Verubecestat is an inhibitor of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) that is currently under clinical evaluation for the treatment of prodromal Alzheimer’s disease. This article describes the characterization of a co-crystal composed of a HBr salt of verubecestat and a HBr salt of a reaction intermediate as the components. This unique co-crystal was formed during production of a multikilogram batch of verubecestat. The impact of this observation is discussed, followed by the description of a modified procedure that served to prevent the formation of this highly unusual crystalline material.

Promotion of a Ti-Mediated Mannich Reaction by a Proton Source

Low temperature NMR studies revealed that a diastereoselective Mannich reaction between a phenyl oxazolidone-derived titanium enolate and an aromatic aldimine was found to occur only after introduction of a proton source. While various protic additives could be used to promote the transformation, the best results were obtained using AcOH to afford the corresponding Mannich products in high diastereoselectivities and yields.