A Novel Telescoped Kilogram-Scale Process for Preparation of Obeticholic Acid

A novel scalable four-step process has been developed to improve the synthesis of obeticholic acid (OCA). The key step of this process was the isolation of the amide intermediate, which underwent hydrogenation, basic epimerization, ketone reduction, and amide hydrolysis in a one-pot procedure. The use of efficient single recrystallization for the final purification in this process made the corresponding work-up procedure more concise and environmentally friendly. A kilogram-scale production of OCA following this process could achieve over 70% yield with all impurities controlled below 0.10%.

A Pharmacophore-Based Approach to Demonstrating the Scope of Alcohol Dehydrogenases

<p>Barriers to the ready adoption of biocatalysis into asymmetric synthesis for early stage medicinal chemistry are addressed, using ketone reduction by alcohol dehydrogenase as a model reaction. An efficient substrate screening approach is used to show the wide substrate scope of commercial alcohol dehydrogenase enzymes, with a high tolerance to chemical groups employed in drug discovery (heterocycle, trifluoromethyl and nitrile/nitro groups) observed. We use our screening data to build a preliminary predictive pharmacophore-based screening tool using Forge software, with a precision of 0.67/1, demonstrating the potential for developing substrate screening tools for commercially available enzymes without publically available structures. We hope that this work, combined with our simple protocols for scaleable H₂-driven biocatalytic ketone reduction, will facilitate a culture shift towards adopting biocatalysis alongside traditional chemical catalytic methods.</p>

A Pharmacophore-Based Approach to Demonstrating the Scope of Alcohol Dehydrogenases

<p>Barriers to the ready adoption of biocatalysis into asymmetric synthesis for early stage medicinal chemistry are addressed, using ketone reduction by alcohol dehydrogenase as a model reaction. An efficient substrate screening approach is used to show the wide substrate scope of commercial alcohol dehydrogenase enzymes, with a high tolerance to chemical groups employed in drug discovery (heterocycle, trifluoromethyl and nitrile/nitro groups) observed. We use our screening data to build a preliminary predictive pharmacophore-based screening tool using Forge software, with a precision of 0.67/1, demonstrating the potential for developing substrate screening tools for commercially available enzymes without publically available structures. We hope that this work, combined with our simple protocols for scaleable H₂-driven biocatalytic ketone reduction, will facilitate a culture shift towards adopting biocatalysis alongside traditional chemical catalytic methods.</p>

A post-synthetically reduced borane-functionalised metal–organic framework with oxidation-inhibiting reactivity

Highly porous boron-loaded MOFs with novel auto-oxidation inhibiting reactivity are achieved via post-synthetic ketone reduction and alcohol reactions with H3B·THF.

Borohydride intermediates pave the way for magnesium-catalysed enantioselective ketone reduction

A magnesium precatalyst for the highly enantioselective hydro-boration of CO bonds is reported.