- Photoenzymatic Synthesis of α-Tertiary Amines by Engineered Flavin-Dependent "ene"-Reductases
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α-Tertiary amines are a common motif in pharmaceutically important molecules but are challenging to prepare using asymmetric catalysis. Here, we demonstrate engineered flavin-dependent ‘ene'-reductases (EREDs) can catalyze radical additions into oximes to prepare this motif. Two different EREDs were evolved into competent catalysts for this transformation with high levels of stereoselectivity. Mechanistic studies indicate that the oxime contributes to the enzyme templated charge-transfer complex formed between the substrate and cofactor. These products can be further derivatized to prepare a variety of motifs, highlighting the versatility of ERED photoenzymatic catalysis for organic synthesis.
- Gao, Xin,Turek-Herman, Joshua R.,Choi, Young Joo,Cohen, Ryan D.,Hyster, Todd K.
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supporting information
p. 19643 - 19647
(2021/12/01)
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- Facile and efficient preparation of α-halomethyl ketones from α-diazo ketones catalyzed by iron(III) halides and silica gel
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An efficient and mild method for the synthesis of α-halomethyl ketones from α-diazo ketones was developed using ferric chloride or bromide as the halogen source and silica gel as the hydrogen source, with good to excellent yields.
- Shi, Xinxia,Zhang, Lingqiong,Yang, Pengfei,Sun, Han,Zhang, Yilan,Xie, Chunsong,Ou-yang, Zhen,Wang, Min
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supporting information
p. 1200 - 1203
(2018/03/08)
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- A Simple and Efficient Method for the Preparation of α-Halogenated Ketones Using Iron(III) Chloride and Iron(III) Bromide as Halogen Sources with Phenyliodonium Diacetate as Oxidant
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α-Halogenated ketones are both unique structure moieties existing in biologically natural products and valuable synthetic intermediates for the preparation of functional molecules. An efficient and scalable method for the preparation of α-halogenated ketone using iron (III) chloride and iron (III) bromide as halogen sources with phenyliodonium diacetate as oxidant has been developed, featuring mild reaction conditions, environmentally friendly reagents, and wide substrate scope. Notably, the three-step synthesis of drug prasugrel was achieved using this developed method as a key step with 30% yield on gram-scale. Additionally, the reaction mechanism involving chloride cation was proposed based on some preliminary control experiments. (Figure presented.).
- Tang, Shi-Zhong,Zhao, Wenshuang,Chen, Tao,Liu, Yang,Zhang, Xiao-Ming,Zhang, Fu-Min
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supporting information
p. 4177 - 4183
(2017/12/18)
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- Homologation of isocyanates with lithium carbenoids: A straightforward access to α-halomethyl- and α,α-dihalomethylamides
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Treatment of widely available isocyanates with monohalolithium and dihalolithium carbenoids provides a valuable protocol for the one-pot preparation of α-halo- and α,α-dihaloacetamide derivatives. While monohalolithium carbenoids can be prepared by a smoo
- Pace, Vittorio,Castoldi, Laura,Mamuye, Ashenafi Damtew,Holzer, Wolfgang
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p. 2897 - 2909
(2015/01/16)
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- Continuous flow generation and reactions of anhydrous diazomethane using a teflon AF-2400 tube-in-tube reactor
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A continuous process for generation, separation, and reactions of anhydrous diazomethane in a tube-in-tube reactor was developed. The inner tube of the reactor is made of hydrophobic, gas-permeable Teflon AF-2400. The diazomethane is formed in the inner tube and then diffuses through the permeable membrane into the outer chamber and subsequently reacts in the solution carried within. This technique allows safe and scalable reactions with dry diazomethane to be performed on a laboratory scale.
- Mastronardi, Federica,Gutmann, Bernhard,Oliver Kappe
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supporting information
p. 5590 - 5593
(2013/11/19)
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- Addition of lithium carbenoids to isocyanates: A direct access to synthetically useful N-substituted 2-haloacetamides
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The addition of lithium carbenoids to isocyanates provides a versatile access to N-substituted 2-haloacetamides: the reaction tolerates the presence of variously functionalized substituents on the nitrogen atom, including sterically demanding ones and reactive halogens. No erosion of the enantiopurity was observed in the case of optically active isocyanates. One of the substrates prepared has been employed in Charette's type chemoselective addition of a Grignard reagent to access an α-chloroketone.
- Pace, Vittorio,Castoldi, Laura,Holzer, Wolfgang
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p. 8383 - 8385
(2013/09/23)
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- β-fluoroamphetamines via the stereoselective synthesis of benzylic fluorides
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A range of substituted aryl epoxides undergo efficient ring-opening hydrofluorination upon treatment with 0.33 equiv of BF3-OEt 2 in CH2Cl2 at -20 -°C to give the corresponding syn-fluorohydrins, consistent with a mechanism involving a stereoselective SN1-type epoxide ring-opening process. The benzylic fluoride products of these reactions are valuable templates for further elaboration, as demonstrated by the preparation of a range of aryl-substituted β-fluoroamphetamines.
- Cresswell, Alexander J.,Davies, Stephen G.,Lee, James A.,Roberts, Paul M.,Russell, Angela J.,Thomson, James E.,Tyte, Melloney J.
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supporting information; experimental part
p. 2936 - 2939
(2010/09/10)
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- Methods and Compositions for Treatment of Scleritis and Related Disorders
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The present teachings relate to the field of anti-inflammatory substances and more particularly to compounds that are useful for the treatment of scleritis, a scleritis symptom, or a scleritis-related disorder. In one aspect, methods of treating scleritis, a scleritis symptom, or a scleritis-related disorder generally include administering to a subject a compound of Formula I: or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein W1, W2, R1, L, X, Y, Z, and n1 are defined as described herein.
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Page/Page column 29-30
(2008/12/05)
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- 2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H] quinoline-4-carboxylic acid (PSI-697): Identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists
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P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
- Kaila, Neelu,Janz, Kristin,Huang, Adrian,Moretto, Alessandro,DeBernardo, Silvano,Bedard, Patricia W.,Tam, Steve,Clerin, Valerie,Keith Jr., James C.,Tsao, Desirée H.H.,Sushkova, Natalia,Shaw, Gray D.,Camphausen, Raymond T.,Schaub, Robert G.,Wang, Qin
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- Non-racemic halohydrins via biocatalytic hydrogen-transfer reduction of halo-ketones and one-pot cascade reaction to enantiopure epoxides
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Biocatalytic hydrogen-transfer reduction of α-chloro-ketones furnished non-racemic chlorohydrins by employing either Rhodococcus ruber as lyophilized cell catalyst or an alcohol dehydrogenase preparation from Pseudomonas fluorescens DSM 50106 (PF-ADH). Fo
- Poessl, Tina M.,Kosjek, Birgit,Ellmer, Ursula,Gruber, Christian C.,Edegger, Klaus,Faber, Kurt,Hildebrandt, Petra,Bornscheuer, Uwe T.,Kroutil, Wolfgang
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p. 1827 - 1834
(2007/10/03)
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- Oximes and hydrazones that are useful in treating sexual dysfunction
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The present invention relates to oximes and hydrazones of formula (I) for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.
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Page/Page column 32
(2010/02/13)
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- Methods and compositions for selectin inhibition
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The present invention relates to the field of anti-inflammatory substances, and more particularly to novel compounds that act as antagonists of the mammalian adhesion proteins known as selectins. In some embodiments, methods for treating selectin mediated disorders are provided which include administration of compound of Formula I: wherein the constituent variables are defined herein.
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Page/Page column 30
(2008/06/13)
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- Quinuclidine compounds and drugs containing the same as the active ingredient
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The present invention provides an excellent squalene synthesizing enzyme inhibitor. Specifically, it provides a compound (I) represented by the following formula, a salt thereof or a hydrate of them. In which R1 represents (1) hydrogen atom or (2) hydroxyl group; HAr represents an aromatic heterocycle which may be substituted with 1 to 3 groups; Ar represents an optionally substituted aromatic ring; W represents a chain represented by (1) —CH2—CH2— which may be substituted, (2) —CH=CH— which may be substituted, (3) —C≡C—, (4) —NH—CO—, (5) —CO—NH—, (6) —NH—CH2—, (7) —CH2—NH—, (8) —CH2—CO—, (9) —CO—CH2—, (10) —NH—S(O)l—, (11) —S(O)l—NH—, (12) —CH2—S(O)— or (13) —S(O)l—CH2— (l denotes 0, 1 or 2); and X represents a chain represented by (1) a single bond, (2) an optionally substituted C1-6 alkylene chain, (3) an optionally substituted C2-6 alkenylene chain, (4) an optionally substituted C2-6 alkynylene chain, (5) a formula —Q— (wherein Q represents oxygen atom, sulfur atom, CO or N(R2) (wherein R2 represents a C1-6 alkyl group or a C1-6 alkoxy group)), (6) —NH—CO—, (7) —CO—NH—, (8) —NH—CH2—, (9) —CH2—NH—, (10) —CH2—CO—, (11) —CO—CH2—, (12) —NH—S(O)m—, (13) —S(O)m—NH—, (14) —CH2—S(O)m—, (15) —S(O)m—CH2— (wherein m denotes 0, 1 or 2) or (16) —(CH2)n—O— (wherein n denotes an integer from 1 to 6).
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- Method for preparing chiral diphosphines
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The invention concerns a method for preparing a compound of formula (1) wherein: A represents naphthyl or phenyl optionally substituted; and Ar1, Ar2independently represent a saturated or aromatic carbocyclic group, optionally substituted.
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- Preparation of 1-aminoalkylphosphonic acids and 2-aminoalkylphosphonic acids by reductive amination of oxoalkylphosphonates
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By reacting dialkyl 1-oxo- or 2-oxoalkylphosphonates with benzhydrylamine followed by reduction with triacetoxyborohydride and acid hydrolysis gave corresponding aminoalkylphosphonic acids with satisfactory yields. The use of benzylamine, α-methylbenzylamine and tritylamine was unsuccessful in the case of dialkyl 1-oxoalkylphosphonates whereas conversion of 2-oxoalkylphosphonates was also achieved although with lower yields.
- Ryglowski, Artur,Kafarski, Pawel
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p. 10685 - 10692
(2007/10/03)
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- Metabolism of allylbenzene 2',3'-oxide and estragole 2'3'oxide in the isolated perfused rat liver
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The metabolism of allylbenzene 2',3'-oxide, estragole 2'3'oxide, allylbenzene and estragole was studied in the isolated perfused rat liver. Formation of dihydrodiol and glutathione conjugate metabolites was detected for both epoxides and the presence of d
- Luo,Guenthner
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p. 588 - 596
(2007/10/03)
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- Preparation of 1,4-Dienes from 2-(2-Hydroxyalkylseleno)benzothiazoles by the Reaction Involving Se -> O Azaaromatic Ring Rearrangement
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The reactions of 2-(2-oxoalkylseleno)benzothiazoles with allylic Grignard reagents in the presence of BF3*OEt2 gave the corresponding 2-benzothiazoles which, on treatment with Ph3P and NaH, afforded 1,4-dienes in good to excellent yields.
- Shibata, Koichi,Mitsunobu, Oyo
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p. 3163 - 3173
(2007/10/02)
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- Alkylation of Benzene with α-Diazoketones via Cycloheptatrienyl Intermediates
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Benzyl ketones can be synthesised efficiently from benzene and α-diazoketones with sequential catalysis by rhodium(II) trifluoroacetate and trifluoroacetic acid; the process involves cycloheptatrienyl intermediates.
- McKervey, M. Anthony,Russell, D. Noel,Twohig, M. Fiona
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p. 491 - 492
(2007/10/02)
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- MONOHALOMETHYLLITHIUM XCH2Li : STABILIZATION OF A POTENTIAL SYNTHETIC REAGENT
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The preparation of monohalomethyllithium XCH2Li is achieved by Bromine-lithium exchange from the corresponding Bromohalomethane in the presence of one equivalent of lithium bromide at -110 degC in THF-Ether-Pentane solutions.This reagent, on coupling with various carbonyl compounds leads to halohydrins, epoxides and α-halomethyl ketones with high yields.
- Tarhouni, R.,Kirschleger, B.,Rambaud, M.,Villieras, J.
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p. 835 - 838
(2007/10/02)
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- β-Substituted Organolithium Compounds from Chlorohydrins: Application to the Direct Synthesis of Bifunctionalized Organic Cpmpounds
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The reaction of different chlorohydrins with n-butyl-lithium at -78 deg C followed by metallation wiht lithium naphthalenide at the same temperature leads to very reactive organolithium compounds bearing an alkoxide function at the β-position with respect to metal.The reaction of these intermediates with several electriphiles leads to mono- as well as bi-functionalized organic compounds.Thus, treatment of these dianions with deuterium oxide, oxygen, carbon dioxide, benzyl bromide, dimethyl disulphide, and carbonyl compounds, gave 2-deuterioalcohols, 1,2-diols, β-hydroxy-acids, 2-benzyl alcohols, 2-hydroxy-thioethers, and 1,3-diols respectively.The preparation of β-substituted organolithium derivatives can be alternatively carried out starting from α-chloroketones by the same procedure.When the lithium atom is linked to a secondary carbon atom the dianions are very unstable and decompose, even at -100 deg C, by β-elimination yielding the corresponding olefins.
- Barluenga, Jose,Florez, Josefa,Yus, Miguel
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p. 3019 - 3026
(2007/10/02)
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