The Many Roles for Fluorine in Medicinal Chemistry

Over the past ten years, scientific and technological advances have established biocatalysis as a practical and environmentally friendly alternative to traditional metallo- and organocatalysis in chemical synthesis, both in the laboratory and on an industrial scale. Key advances in DNA sequencing and gene synthesis are at the base of tremendous progress in tailoring biocatalysts by protein engineering and design, and the ability to reorganize enzymes into new biosynthetic pathways. To highlight these achievements, here we discuss applications of protein-engineered biocatalysts ranging from commodity chemicals to advanced pharmaceutical intermediates that use enzyme catalysis as a key step.

Engineering the third wave of biocatalysis

Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024

Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas

Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals.

Iron Catalysis in Organic Synthesis

Considerable effort has been spent to develop efficient, catalytic methods for the preparation of enantiomerically pure chiral amines as pharmaceutical building blocks. Biocatalytic approaches have largely relied on kinetic resolution of racemic amines using lipases. In some instances, in situ racemization of the unreactive enantiomer has permitted dynamic kinetic resolutions to be performed. Racemic amines can also be deracemized using an amine oxidase combined with a nonselective reducing agent. The emergence of transaminases, which catalyze the direct amination of prochiral ketones, has provided an attractive alternative option for the synthesis chiral amines. Tufvesson et al. have published an excellent review of the process challenges encountered when using transaminases for the synthesis of chiral amines. We previously reported on the creation of an active and stable R-selective amine transaminase for the synthesis of sitagliptin by using a combination of modeling and directed evolution (Scheme 1). A limitation of the protocol in its current

Development of an Immobilized Transaminase Capable of Operating in Organic Solvent

The invention encompasses the novel compound of formula (I) useful in the treatment of cyclooxygenase-2 mediated diseases. The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of formula (I). ##STR1##

3,4-Diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to cox-2 inhibitors

F the purposes of this thematic issue of Chemical Reviews, we define biocatalysis as the use of enzymes in their purified form, as part of a cell lysate, or whole cells, to convert a molecular substrate, particularly a substrate not known to be transformed by that enzyme in natural systems, into a product. Louis Pasteur provided the first example of modern biocatalysis in 1858 by demonstrating the resolution of racemic tartaric acid through fermentation with a variety of microorganisms, including the common mold Penicillium glaucum. In these experiments, (+)-tartaric acid was consumed much faster than (−)-tartaric acid, allowing for isolation of the latter. Towards the end of the 19th century, Emil Fischer proposed the “lock and key” model for enzyme catalysis, and Buchner demonstrated that cell-free extracts were capable of catalyzing fermentation processes. These seminal developments would lead to a rapidly expanding number of applications of biocatalysis in the 20th century, including many important industrial examples. This growth has been driven by an array of factors. Enzymes can be thought of as renewable catalysts. Unlike metal based alternatives that rely on mining and harsh, energy intensive processing, biocatalysts are biodegradable and easily replaced through inexpensive and environmentally benign fermentation processes. The minimal environmental and economic burden posed by enzymes is further diminished by the potential to engineer even more active variants than can be found in nature, to optimize expression efficiencies and fermentation yields, and to immobilize and reuse these powerful catalysts. The following are just a few of the many examples of how enzymes are improving industrial chemical processing. Nitrile hydratases have now supplanted an earlier Cu based method for converting acrylonitrile to acrylamide, the monomer used to prepare polyacrylamide. This process is now conducted on tens of thousands of metric tons per year. Likewise, conventional bleaching processes in the textile industry, which previously used Cl2 or NaOCl, can now be carried out with the more benign H2O2. 5 This switch was initially hampered by the fact that residual peroxide was detrimental to subsequent dying processes. This issue is obviated by the use of peroxidases which quantitatively convert residual H2O2 to molecular oxygen and water, allowing for more economical and environmentally friendly processing. Another nitrile hydratase application involves the regioselective partial hydrolysis of adiponitrile to form 5-cyanovaleramide, which serves as a starting material for the Dupont herbicide azafenidin (Milestone). Some of the most powerful examples of biocatalytic applications exploit the chiral nature of these catalysts. In fact, the R and S nomenclature commonly used to define the orientation of substituents of a chiral center as popularized by Prelog and others was first described in the context of the products formed by the reduction of prochiral ketones by alcohol dehydrogenases (ADHs). While the majority of natural organisms express ADHs providing the S enantiomer, a number ADHs are now available both from natural sources as well as engineered variants which provide the so called antiPrelog or R enantiomers of these important chiral synthons. Beginning in the late 1970s with pioneering work of Michael Smith and later amplified by contributions from Pim Stemmer and Frances Arnold, microbiologists began developing techniques that enabled directed evolution of enzymes. This approach has been used to produce engineered or customized enzymes that are tailored to unnatural substrates and reaction conditions far removed from those found in natural systems. In a seminal 1993 paper by Frances Arnold, for example, it was demonstrated that subtilisin E could be engineered through successive rounds of random mutagenesis to be increasingly tolerant of dimethylformamide (DMF) as an organic cosolvent, with one variant being 256 times more active in 65% DMF versus wild-type. In addition to addressing cosolvent stability deficiencies commonly seen with wild-type enzymes, an array of genetic engineering techniques have been employed to address acceptance of unnatural substrates, to deliver complimentary stereoselectivity, to address substrate, product, or co-factor inhibition issues, and to improve thermal stability or pH stability. The widespread adoption of modern protein engineering has led to a number of remarkable applications. Substrates which are dramatically distinct from natural ligands are now able to be transformed with efficiencies suitable for industrial applications. An early example of this was the development of a ketoreductase (CDX-026) capable of reducing the large, hydrophobic ketone substrate 1 to yield alcohol 2, which serves as a precursor to montelukast, widely used to treat asthma and seasonal rhinitis (Scheme 1). A Baeyer Villeger Monooxygenase has also been engineered to enantioselectively oxidize sulfide 3 to provide esomeprazole 4, used to treat acid reflux (Scheme 2). Transaminases have also become widely recognized as a platform for preparing chiral amines from prochiral ketones. One particularly noteworthy application is in the production of sitagliptin 6, a DPP4 inhibitor used for the treatment of type II diabetes. While no detectable activity could initially be established for the sitagliptin ketone 5, initial rounds of evolution using a truncated analogue enabled measurable conversion of the ketone of interest, ultimately leading to the development of a biocatalyst with activity suitable for commercial manufacturing (Scheme 3). Another interesting example is the engineering of carbonic anhydrase. While the substrate in this instance (CO2) is its native ligand and is very simple, the work is noteworthy for the severity of the conditions which the enzyme was engineered to sustain (107 °C, pH > 10). More recently, protein systems have even been engineered to deliver chemical reactions such as enantioselective cyclopropanations, silylations, and borylation reactions which are unprecedented in nature.

Introduction: Biocatalysis in Industry.

Cycloaddition de cyanocetenes (t-butylcyanocetene, chlorocyanocetene et hexynylcyanocetene) aux imines du titre. Influence de la taille et du degre d'insaturation des substituants de l'imine sur la stereo- et la periselectivite des cycloadditions

Greg Hughes

Papers

Development of an Immobilized Transaminase Capable of Operating in Organic Solvent

3,4-Diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to cox-2 inhibitors

Introduction: Biocatalysis in Industry.

Cycloadditions of cyanoketenes to cinnamylidenamines and benzylidenamines. Synthetic scope, stereochemistry, and mechanism

Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist