Biocatalytic oxidation of alcohols using galactose oxidase and a manganese(<scp>iii</scp>) activator for the synthesis of islatravir

Manganese(iii) acetate activates galactose oxidase (GOase), a Cu-dependent metalloenzyme that catalyzes the oxidation of alcohols to aldehydes.</p

Driving Aspirational Process Mass Intensity Using Simple Structure-Based Prediction

An important metric for gauging the impact that a synthetic route has on chemical resources, cost, and sustainability is process mass intensity (PMI). Calculating the overall PMI or step-PMI for a given synthesis from a process description is more and more common across the pharmaceutical industry, especially in process chemistry departments. As with other pharmaceutical companies, our company has established a strong track record of delivering on our Corporate Sustainability goals, being recognized with eight EPA Green Chemistry Challenge Awards in the last 15 years, and we show how these routes help define aspirational PMI targets. While green chemistry principles help in optimizing PMI and developing more sustainable processes, a key challenge for the field is defining what a “good” PMI for a molecule looks like given its structure alone. An existing tool that chemists have at their disposal to predict PMI requires the synthetic route be provided or proposed (e.g., via retrosynthetic analysis) which then enables practitioners to compare predicted PMIs between routes. We have developed SMART-PMI (in-Silico MSD Aspirational Research Tool) to complement existing tools by predicting PMI from molecular structure alone. Using only a 2D chemical structure, we can generate a predicted SMART-PMI from a measure of molecular complexity and molecular weight. We show how these predictions correlate with historical PMI data from our company’s clinical and commercial portfolio of processes. From this SMART-PMI prediction, we have established target ranges which we termed “Successful”, “World Class”, and “Aspirational” PMI. The goal of this range is to set the floor for what is a “good” PMI for a given molecule and provide ambitious targets to drive innovative green chemistry. Using this model, chemists can develop synthetic strategies that make the biggest impact on PMI. As innovation in chemistry and processes leads to better and better PMIs, in turn, this data can drive ever more aggressive targets for the model. The potential of SMART-PMI, in combination with other existing PMI tools, to set industry-wide aspirational PMI targets is discussed

Development of a Biocatalytic Aerobic Oxidation for the Manufacturing Route to Islatravir

Biocatalytic oxidations have the potential to address many synthetic chemistry challenges, enabling the selective synthesis of chiral intermediates such as carbonyl compounds, alcohols, or amines. The use of oxygen-dependent enzymes can dramatically reduce the environmental footprint of redox transformations at manufacturing scale. Here, as part of the biocatalytic cascade to an anti-HIV investigational drug islatravir 1, we describe the development of an aerobic oxidation process delivering (R)-ethynylglyceraldehyde 3-phosphate 3 using an evolved galactose oxidase enzyme. Integrated enzyme and reaction engineering were critical for achieving a robust, high-yielding oxidation performed at pilot plant scale (>20 kg, 90% yield)

Design of an in vitro biocatalytic cascade for the manufacture of islatravir

Maximal efficiency from enzyme cascades Enzymes are highly selective catalysts that can be useful for specific transformations in organic synthesis. Huffman et al. combined designer enzymes in a multistep cascade reaction (see the Perspective by O'Reilly and Ryan). The approach eliminates purification steps, recycles expensive cofactors, and couples favorable and unfavorable reactions. With the target molecule islatravir, an experimental HIV drug, they optimized five enzymes by directed evolution to be compatible with unnatural substrates and stable in the reaction conditions. Stereochemical purity was amplified at every enzymatic step, and the final synthesis was both atom economical and efficient. Science , this issue p. 1255 ; see also p. 1199 </jats:p