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Claudia Holec, Ute Hartrampf, Katharina Neufeld, Joerg Pietruszka
Cytochrome P450 BM3 monooxygenases are able to catalyze the regio- and stereoselective oxygenation of a broad range of substrates with promising potential for synthetic applications. To study the ability of P450 BM3 variants for the stereoselective benzylic hydroxylation of 2-alkylated benzoic acid esters, the biotransformation of methyl 2-ethylbenzoate was investigated resulting in both enantiomeric forms of 3-methylphthalide. In case of methyl 2-propylbenzoate as a substrate the regioselectivity of the reaction was shifted towards -hydroxylation resulting in the synthesis of enantioenriched (R)- and (S)-configured 3-methylisochroman-1-one...
January 20, 2017: Chembiochem: a European Journal of Chemical Biology
Nathalie Nett, Sabine Duewel, Alexandra Annelis Richter, Sabrina Hoebenreich
Every year numerous protein engineering and directed evolution studies are published, increasing the knowledge which could be used by protein engineers. Here we test a protein engineering strategy that allows quick access to improved biocatalysts with very little screening effort. Conceptually it is assumed that engineered residues, previously identified by rational and random methods, induce similar improvements when transferred to family members. Applied to ene-reductases from the Old Yellow Enzyme family (OYE), the newly created variants were tested with three compounds revealing more stereocomplementary OYE pairs with potent turnover frequencies (up to 660 h-1) and excellent stereoselectivities (up to >99%)...
January 20, 2017: Chembiochem: a European Journal of Chemical Biology
Yandong Lu, Haosen Yuan, Shijie Zhou, Tuoping Luo
The first asymmetric total synthesis of (-)-hibiscone C and a concise synthesis of ergot alkaloid lysergine are described. Both syntheses were achieved using the radical cyclization/fragmentation strategy. This cascade reaction enabled the application of the strained bicycle as a synthon for the synthesis of highly substituted decalins in an efficient and stereoselective manner.
January 20, 2017: Organic Letters
Tonia S Ahmed, Robert H Grubbs
Ruthenium-based olefin metathesis catalysts bearing dithiolate ligands have been recently employed to generate olefins with high E-selectivity (>99% E) but have been limited by low to moderate yields. In this report, (1)H NMR studies reveal that a major contributing factor to this low activity is the extremely low initiation rates of these catalysts with trans olefins. Introducing a 2-isopropoxy-3-phenylbenzylidene ligand in place of the conventional 2-isopropoxybenzylidene ligand resulted in catalysts that initiate rapidly under reaction conditions...
January 20, 2017: Journal of the American Chemical Society
Vinayak Agarwal, Zachary D Miles, Jaclyn M Winter, Alessandra S Eustáquio, Abrahim A El Gamal, Bradley S Moore
Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of chemical structures. Accordingly, a diverse collection of enzyme catalysts to install and remove halogens from organic scaffolds has evolved in nature. Accounting for the different chemical properties of the four halogen atoms (fluorine, chlorine, bromine, and iodine) and the diversity and chemical reactivity of their organic substrates, enzymes performing biosynthetic and degradative halogenation chemistry utilize numerous mechanistic strategies involving oxidation, reduction, and substitution...
January 20, 2017: Chemical Reviews
Dipendu Das, Tushar Kanti Chakraborty
Diastereoselective approaches toward the synthesis of a marine-derived sesquiterpenoid fungal metabolite, asperaculin A, are delineated, combining step economy and simplicity. Two distinct lactonization sequences from a common intermediate led to the first synthesis of 9-deoxyasperaculin A, a novel dioxa[]fenestrane, in 14 steps (16% overall yield) and 16 steps (18% overall yield), respectively. [2,3]-Wittig-Still rearrangement and Ti(III)-mediated epoxide opening-cyclization were employed as some of the key steps for the stereoselective generation of the vicinal all-carbon quaternary centers of the target molecule...
January 20, 2017: Organic Letters
Theo Peschke, Kersten S Rabe, Christof M Niemeyer
We herein describe the engineering of E. coli strains that display orthogonal tags for immobilization on their surface and overexpress a functional heterologous "protein content" in their cytosol at the same time. Using the outer membrane protein Lpp-ompA, cell-surface display of the streptavidin-binding peptide, the SpyTag/SpyCatcher system, or a HaloTag variant allowed us to generate bacterial strains that can selectively bind to solid substrates, as demonstrated with magnetic microbeads. The simultaneous cytosolic expression of functional content was demonstrated for fluorescent proteins or stereoselective ketoreductase enzymes...
January 20, 2017: Angewandte Chemie
Jan M Klenk, Bernd A Nebel, Joanne L Porter, Justyna K Kulig, Shaneela A Hussain, Sven M Richter, Michele Tavanti, Nicholas J Turner, Martin A Hayes, Bernhard Hauer, Sabine L Flitsch
P450 monooxygenases are able to catalyse the highly regio- and stereoselective oxidations of many organic molecules. However, the scale-up of such bio-oxidations remains challenging due to the often-low activity, level of expression and stability of P450 biocatalysts. Despite these challenges they are increasingly desirable as recombinant biocatalysts, particularly for the production of drug metabolites. Diclofenac is a widely used anti-inflammatory drug that is persistent in the environment along with the 4'- and 5-hydroxy metabolites...
January 18, 2017: Biotechnology Journal
Fu-Min Liao, Zhong-Yan Cao, Jin-Sheng Yu, Jian Zhou
We report a highly stereoselective synthesis of all-carbon or fluorinated tetrasubstituted alkenes from diazo reagents and fluorinated enol silyl ethers, using C-F bond as a synthetic handle. Cationic Au(I) catalysis plays a key role in this reaction. Remarkable fluorine effects on the reactivity and selectivity was also observed.
January 18, 2017: Angewandte Chemie
Tao Yang, Masahiro Ehara
The reaction mechanism and origins of ligand-controlled selectivity, regioselectivity, and stereoselectivity of Ni-catalyzed (2 + 2 + 2) cycloadditions and alkenylative cyclizations of 1,6-ene-allenes and alkenes were studied by using density functional theory. The catalytic cycle involves intermolecular oxidative coupling and intramolecular concerted 1,4-addition step to afford a stable metallacycloheptane intermediate; these steps determine both the regioselectivity and stereoselectivity. Subsequent C-C reductive elimination leads to the cyclohexane product, whereas the β-hydride elimination leads to the trans-diene product...
January 17, 2017: Journal of Organic Chemistry
Elisabetta Brenna, Michele Crotti, Francesco Gilberto Gatti, Ludovico Marinoni, Daniela Monti, Sara Quaiato
Enantiopure 2-methyl-3-substituted tetrahydrofurans are key precursors of several biologically active products (drugs, flavors and agrochemicals). Thus, a stereocontrolled and efficient methodology for the obtainment of these synthons is highly desirable. We exploited a two-steps multienzymatic stereoselective cascade reduction of α-bromo-α,β-unsaturated ketones to give the corresponding bromohydrins in good yields, with high ee and de values. The cascade process is catalyzed by an ene-reductase and an alcohol dehydrogenase...
January 17, 2017: Journal of Organic Chemistry
Zhao Li, David S Hage
The interactions of drugs with serum proteins are often stereoselective and can affect the distribution, activity, toxicity and rate of excretion of these drugs in the body. A number of approaches based on affinity chromatography, and particularly high-performance affinity chromatography (HPAC), have been used as tools to study these interactions. This review describes the general principles of affinity chromatography and HPAC as related to their use in drug binding studies. The types of serum agents that have been examined with these methods are also discussed, including human serum albumin, α1-acid glycoprotein, and lipoproteins...
January 11, 2017: Journal of Pharmaceutical and Biomedical Analysis
Takahiro Kawamata, Masanori Nagatomo, Masayuki Inoue
Zaragozic acid C (1) was isolated as a potent squalene synthase inhibitor. The 2,8-dioxabicyclo[3.2.1]octane core of 1 is decorated with the three hydroxycarbonyl (C3,4,5), two hydroxy (C4,7), one acyloxy (C6), and one alkyl (C1) groups. Installation of the contiguous C4- and C5-fully-substituted carbons presents a formidable synthetic challenge. Our approach to addressing this problem utilized a two-step photochemical C(sp3)-H acylation. Persilylated D-gluconolactone 4 was derivatized into 3 with the 1,2-diketone moiety at the C5-tetrasubstituted center...
January 16, 2017: Journal of the American Chemical Society
Fei Li, Karyn D Howard, Michael J Myers
OBJECTIVES: P-glycoprotein (P-gp) is responsible for the efflux of a broad variety of human and veterinary drugs. Canine P-gp polymorphisms alter drug disposition and toxicity, but their impact on the disposition of enantiomeric drugs is unknown. Using fexofenadine as a model compound, we developed and validated HPLC-fluorescence methods to determine the effect of P-gp on the disposition of fexofenadine and its enantiomers. METHODS: A chiral CD-Ph column was used for the separation of (R) and (S)-fexofenadine...
January 16, 2017: Journal of Pharmacy and Pharmacology
Atanu Bhaumik, Ram Subhawan Verma, Bhoopendra Tiwari
A one-pot, stereoselective construction of 2,3-dihydroxy-2,3-diaryltetrahydrofurans has been achieved via N-heterocyclic carbene (NHC)/base-mediated domino reactions of aldehydes and vinyl selenone. The products containing two contiguous quaternary hydroxyl functionalities among the three stereocenters are obtained advantageously as either acetals or ketals through the formation of five new chemical bonds in a single operation. This report constitutes an altogether different reactivity of vinyl selenone in comparison with the corresponding sulfones and phosphonates under NHC/base-mediated reactions...
January 12, 2017: Organic Letters
Yu-Guo Zheng, Huan-Huan Yin, Dao-Fu Yu, Xiang Chen, Xiao-Ling Tang, Xiao-Jian Zhang, Ya-Ping Xue, Ya-Jun Wang, Zhi-Qiang Liu
Alcohol dehydrogenases (ADHs), which belong to the oxidoreductase superfamily, catalyze the interconversion between alcohols and aldehydes or ketones with high stereoselectivity under mild conditions. ADHs are widely employed as biocatalysts for the dynamic kinetic resolution of racemic substrates and for the preparation of enantiomerically pure chemicals. This review provides an overview of biotechnological applications for ADHs in the production of chiral pharmaceuticals and fine chemicals.
February 2017: Applied Microbiology and Biotechnology
Yukiho Sakaguchi, Shigeyuki Yamada, Tsutomu Konno, Tomohiro Agou, Toshio Kubota
Highly regio- and stereoselective transformation of commercially available 4-bromo-3,3,4,4-tetrafluoro-1-butene into multisubstituted alkenes having a tetrafluoroethylene fragment through Heck reaction and/or Suzuki-Miyaura cross coupling reaction was established. Thus obtained alkenes underwent a smooth reductive coupling reaction with aldehydes under the influence of MeLi/LiBr-free, affording structurally unprecedented fluorinated materials.
January 10, 2017: Journal of Organic Chemistry
Xiao Shen, Thach T Nguyen, Ming Joo Koh, Dongmin Xu, Alexander W H Speed, Richard R Schrock, Amir H Hoveyda
Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation)...
January 19, 2017: Nature
Marta Meazza, Fernando Tur, Niels Hammer, Karl Anker Jørgensen
A novel alkyl functionalization of unactivated alkyl quinolines has been developed combining InCl3 activation with organocatalytic activation of α,β-unsaturated aldehydes in a synergistic fashion. The reaction proceeds in a highly stereoselective manner as a sequence involving two consecutive synergistic catalytic cycles (Lewis acid- and iminium ion-catalyzed) and requires neither pre-activated alkyl quinoline substrates with electron-withdrawing substituents nor highly activated electrophiles. The reaction provides selectively double- or mono-addition products in good yields and high to excellent stereoselectivities...
January 9, 2017: Angewandte Chemie
Dirk Alpers, Malte Gallhof, Julian Witt, Frank Hoffmann, Malte Brasholz
A stereoselective synthesis of functionalized hexahydrocarbazoles was developed based on an unprecedented photoredox-induced dearomative radical (4+2)-cyclization/1,4-addition cascade between 3-(2-iodoethyl)indoles and acceptor-substituted alkenes. The title reaction simultaneously generates three C-C bonds and one C-H bond, along with three contiguous stereogenic centers. The hexahydro-1H-carbazole products are highly valuable intermediates for the synthesis of novel antibiotics, as well as unnatural ring homologues of polycyclic indoline alkaloids...
January 9, 2017: Angewandte Chemie
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