(693a) Data-Rich Development of a Novel Biocatalytic Aerobic Oxidation across Scales

Recent advances in the biocatalytic retrosynthetic toolbox have transformed the way Merck conceives of novel synthetic routes, particularly for drug candidates with significant structural similarity to naturally occurring biomolecules such as proteins, peptides and nucleosides. This is particularly evident in the ongoing development of the biocatalytic route to MK-8591, a nucleoside reverse transcriptase/translocation inhibitor (NRTTI) currently progressing through Phase II clinical trials, displaying great promise as a next-generation anti-HIV drug. Broadly speaking, this synthetic pathway represents a ground-breaking application of cascaded biocatalysis for the synthesis of a complex, clinically relevant small molecule compound.

Furthermore, the oxidation of alcohols to aldehydes represents key transformations in organic synthesis. Traditionally, many of these oxidation reactions have been carried out using stoichiometric amounts of transition metal-based oxidants while selective and green methods have remained largely underdeveloped. To surmount those obstacles, Merck has recently expanded its biocatalytic platform to include the copper-dependent galactose oxidases (GOases), which are highly efficient enzymes for the mild, regio- and stereoselective oxidation of a broad variety of primary and secondary alcohols, polyols and sugars. These enzymes are capable of catalytic oxidations in water, making direct use of the molecular oxygen from compressed air as the oxidant.

In this submission, we will showcase how collaborative efforts across Process Research and Development are contributing towards building deep, fundamental understanding of the oxidation of 2-ethynylglycerol, a key intermediate in the MK-8591 synthesis. We will highlight past and ongoing efforts centering on enzyme discovery and reaction engineering, underpinned by data-rich experimentation methods including; high-throughput experimentation and analysis, automation, and insitu reaction analysis using novel analytical tools. Furthermore, development of a robust process optimized for a commercially relevant synthetic chemistry reactor (vs. for example a more optimal bioreactor or fermentor) will be reviewed including demonstration across scales.