Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals

https://science.sciencemag.org/content/sci/early/2010/06/17/science.1188934.full.pdf

Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture

ConspectusThe hydrogenation of alkenes is one of the most impactful reactions catalyzed by homogeneous transition metal complexes finding application in the pharmaceutical, agrochemical, and commodity chemical industries. For decades, catalyst technology has relied on precious metal catalysts supported by strong field ligands to enable highly predictable two-electron redox chemistry that constitutes key bond breaking and forming steps during turnover. Alternative catalysts based on earth abundant transition metals such as iron and cobalt not only offer potential environmental and economic advantages but also provide an opportunity to explore catalysis in a new chemical space. The kinetically and thermodynamically accessible oxidation and spin states may enable new mechanistic pathways, unique substrate scope, or altogether new reactivity. This Account describes my group’s efforts over the past decade to develop iron and cobalt catalysts for alkene hydrogenation. Particular emphasis is devoted to the inter...

Iron- and Cobalt-Catalyzed Alkene Hydrogenation: Catalysis with Both Redox-Active and Strong Field Ligands

Catalysis has become increasingly important for the pharmaceutical industry Catalysis is a critical technology that enables economical and environmentally-sound manufacturing processes The development of a viable catalytic process for industrial scales is a complex task that requires the collaboration of multiple disciplines In this article, a number of selected, noteworthy industrial examples are discussed to showcase the catalytic technologies that have been successfully practiced on large scales for active pharmaceutical ingredient (API) synthesis, involving transition metal catalysis, biocatalysis and organocatalysis In addition, several examples of potential and future catalytic transformations are included which can be utilized in pharmaceutical industry in large-scale operational settings

The Growing Impact of Catalysis in the Pharmaceutical Industry

Large-Scale Carbonyl Reductions in the Pharmaceutical Industry

Identification on catalytic sites of heterogeneous catalysts at atomic level is important to understand catalytic mechanism Surface engineering on defects of metal oxides can construct new active sites and regulate catalytic activity and selectivity Here we outline the strategy by controlling surface defects of nanoceria to create the solid frustrated Lewis pair (FLP) metal oxide for efficient hydrogenation of alkenes and alkynes Porous nanorods of ceria (PN-CeO2) with a high concentration of surface defects construct new Lewis acidic sites by two adjacent surface Ce3+ The neighbouring surface lattice oxygen as Lewis base and constructed Lewis acid create solid FLP site due to the rigid lattice of ceria, which can easily dissociate H-H bond with low activation energy of 017 eV

/pdf/solid-frustrated-lewis-pair-catalysts-constructed-by-7wlgacv4r4.pdf

Solid frustrated-Lewis-pair catalysts constructed by regulations on surface defects of porous nanorods of CeO 2

This Account provides an overview of our activities in the area of asymmetric hydrogenation over the last 12 years. We discuss the manufacture of metal-containing precatalysts and their use in asymmetric hydrogenation processes. Many of the metal complexes have been made on a multikilogram scale for our own use and also provided to our customers. In addition, we review some of the applications that we have developed for our asymmetric hydrogenation catalysts, many of which have been operated on commercial scales. This all underlines that asymmetric hydrogenation is a mature technology that has been adopted for use in the pharmaceutical and fine-chemical industries.

Industrial-scale synthesis and applications of asymmetric hydrogenation catalysts.

Industrial-Scale Synthesis and Applications of Asymmetric Hydrogenation Catalysts

The Application of DuPHOS Rhodium(I) Catalysts for Commercial Scale Asymmetric Hydrogenation

/pdf/biochemical-characterization-of-a-cyanobactin-arginine-n-26kevjuy.pdf

Biochemical characterization of a cyanobactin arginine-N-prenylase from the autumnalamide biosynthetic pathway

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Industrial-scale synthesis and applications of asymmetric hydrogenation catalysts.

Industrial-Scale Synthesis and Applications of Asymmetric Hydrogenation Catalysts

The Application of DuPHOS Rhodium(I) Catalysts for Commercial Scale Asymmetric Hydrogenation

Biochemical characterization of a cyanobactin arginine-N-prenylase from the autumnalamide biosynthetic pathway