- Ground-State Electron Transfer as an Initiation Mechanism for Biocatalytic C-C Bond Forming Reactions
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The development of non-natural reaction mechanisms is an attractive strategy for expanding the synthetic capabilities of substrate promiscuous enzymes. Here, we report an "ene"-reductase catalyzed asymmetric hydroalkylation of olefins using α-bromoketones as radical precursors. Radical initiation occurs via ground-state electron transfer from the flavin cofactor located within the enzyme active site, an underrepresented mechanism in flavin biocatalysis. Four rounds of site saturation mutagenesis were used to access a variant of the "ene"-reductase nicotinamide-dependent cyclohexanone reductase (NCR) from Zymomonas mobiles capable of catalyzing a cyclization to furnish β-chiral cyclopentanones with high levels of enantioselectivity. Additionally, wild-type NCR can catalyze intermolecular couplings with precise stereochemical control over the radical termination step. This report highlights the utility for ground-state electron transfers to enable non-natural biocatalytic C-C bond forming reactions.
- Fu, Haigen,Lam, Heather,Emmanuel, Megan A.,Kim, Ji Hye,Sandoval, Braddock A.,Hyster, Todd K.
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supporting information
p. 9622 - 9629
(2021/07/01)
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- Ring-closing metathesis approaches towards the total synthesis of rhizoxins
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Efforts are described towards the total synthesis of the bacterial macrolide rhizoxin F, which is a potent tubulin assembly and cancer cell growth inhibitor. A significant amount of work was expanded on the construction of the rhizoxin core macrocycle by ring-closing olefin metathesis (RCM) between C(9) and C(10), either directly or by using relay substrates, but in no case was ringclosure achieved. Macrocycle formation was possible by ring-closing alkyne metathesis (RCAM) at the C(9)/C(10) site. The requisite diyne was obtained from advanced intermediates that had been prepared as part of the synthesis of the RCM substrates. While the direct conversion of the triple bond formed in the ring-closing step into the C(9)-C(10) E double bond of the rhizoxin macrocycle proved to be elusive, the corresponding Z isomer was accessible with high selectivity by reductive decomplexation of the biscobalt hexacarbonyl complex of the triple bond with ethylpiperidinium hypophosphite. Radical-induced double bond isomerization, full elaboration of the C(15) side chain, and directed epoxidation of the C(11)-C(12) double bond completed the total synthesis of rhizoxin F.
- Altmann, Karl-Heinz,Liniger, Marc,Neuhaus, Christian M.
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supporting information
(2020/10/18)
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- Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study
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Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.
- Ma, Weifeng,Chen, Peng,Huo, Xiansen,Ma, Yufeng,Li, Yanhong,Diao, Pengcheng,Yang, Fang,Zheng, Shengquan,Hu, Mengjin,You, Wenwei,Zhao, Peiliang
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- Synthesis of various cyclopropyl methyl bromide and its derivatives from ketones and/or aldehydes and some β-dicarbonyl compounds in the presence of BrCN and Et3N
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The ultimate goal in this paper has been developed for the synthesis of structurally various bromomethyl cyclopropane via an α-bromoketone and/or aldehydes with ethyl cyanoacetate or malononitrile and cyanogen bromide (BrCN) in the presence of Et3N to give products in excellent yields within about 3?s. All structures were characterized by IR, 1H-NMR, 13C-NMR, and Mass spectroscopy techniques. The reaction mechanism was discussed.
- Gholizadeh, Saeed,Safa, Kazem D.,Noroozi Pesyan, Nader
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p. 1239 - 1253
(2019/04/27)
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- Silica gel catalyzed α-bromination of ketones using N-bromosuccinimide: An easy and rapid method
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An easy and rapid method for the α-bromination of ketones using N-bromosuccinimide (NBS) catalyzed by silica gel in methanol under reflux conditions was developed. The expected products were formed in excellent isolated yields within a short period of time (5-20 min). Major advantages of the present procedure include use of inexpensive and readily available catalyst, exclusion of pre- and post-chemical treatment of catalyst and use of methanol as solvent instead of ethers and chlorinated solvents.
- Mohan Reddy, Bodireddy,Venkata Ramana Kumar, Velpula,Chinna Gangi Reddy, Nallagondu,Mahender Rao, Siripragada
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p. 179 - 182
(2014/02/14)
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- Bromination of enamines from tertiary amides using the petasis reagent: A convenient one-pot regioselective route to bromomethyl ketones
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An original one-pot synthesis of bromomethyl ketones is achived using the Petasis reagent (dimethyltitanocene) as a key for enamine generation. Several amides were used to test the limits of the procedure by changing either the alkyl chain R or the amino portion of the starting materials. The enamines generated in situ were allowed to react with bromine at low temperature followed by hydrolysis to yield bromomethyl ketones in excellent yields (85 to 95%). Mechanistic details and optimum conditions for the reaction are briefly discussed. The present approach offers several advantages such as regioselectivity in enamine formation, good yields, mild reaction conditions, and ease of experimentation.
- Kobeissi, Marwan,Cherry, Khalil,Jomaa, Wissam
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supporting information
p. 2955 - 2965
(2013/09/02)
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- Oxidative bromination of ketones using ammonium bromide and oxone
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A highly efficient, environmentally safe and economic method for selective α-monobromination of aralkyl, cyclic, acyclic, 1,3-diketones and β-keto esters and α,α-dibromination of 1,3-diketones and β-keto esters without catalyst is reported using ammonium bromide as a bromine source and oxone as an oxidant. The reaction proceeds at ambient temperature and yields range from moderate to excellent. Bromination of unsymmetrical ketones takes place at the less substituted α-position predominantly. Aromatisation of tetralones is also carried out with this reagent system.
- MacHarla, Arun Kumar,Chozhiyath Nappunni, Rohitha,Marri, Mahender Reddy,Peraka, Swamy,Nama, Narender
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supporting information; experimental part
p. 191 - 195
(2012/01/17)
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- Fast oxidation of secondary alcohols by the bromate-bromide system using cyclic microwave heating in acidic water
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We report an improved, gentle, cyclic microwave activation technique for the oxidation of secondary alcohols using nonhazardous hypobromous acid (BrOH) as the reagent in acidic water. Several aliphatic and aromatic secondary alcohols were successfully oxidized to the corresponding ketones using this technique in high yields and with only minor amounts of side products.
- P??kk?nen, Sanna,Pursiainen, Jouni,Lajunen, Marja
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scheme or table
p. 6695 - 6699
(2011/02/23)
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- N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists
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The present invention provides a method of treatment of a subject suffering from a disease, such as schizophrenia, for which the administration of an NK-3 antagonist is indicated which comprises administering to that subject a therapeutically effective amount of a compound of formula I: wherein, generally, Q is R1 is benzyl, phenyl, thiophene or imidazolyl optionally substituted with C1-4alkyl or halogen, such as methyl, fluorine or bromine; R2 is hydrogen or C1-4alkyl such as methyl; R3 is phenyl; R4 is hydrogen; R5 is hydrogen or C1-6alkylcarbonyl such as methylcarbonyl; X is —SO2— or —C(O)N(R2)SO2— where R2 is preferably hydrogen; Y is a bond, CH2 or Z1 where Z1 is —N(Rf)— in which Rf is C1-6alkylcarbonyl such as ethylcarbonyl; and R6 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or benzimidazolonyl optionally substituted with one or two groups chosen from C1-6alkyl and benzyl, such as methyl, ethyl and benzyl; or a pharmaceutically acceptable salt thereof.
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Page/Page column 27
(2010/11/30)
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- Process for preparing a substituted imidazopyridine compound
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The present invention provides a new process for large-scale preparation of substituted imidazopyridine compound of formula (1) wherein R1 is C1-C6 alkoxy or NH2 group, comprising the step of reacting a compound of formula (2) with a 3-halo-2-butanone compound in cyclohexanone.
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- Induction period in the BrO3 -, Ce(III), H2SO4, oxalic acid and ketone oscillating reaction
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Contrary to what has been thought, systems classified as bromine- hydrolysis-controlled (BHC) show an induction period. In studies on the effect of a family of ketones upon this type of oscillators, it was found that an induction period appears in an interval of concentrations of the ketone, or in an interval of the value of the enolization constant. Simulations of the processes involved and a corresponding explanation are shown in this paper.
- Berenstein, Igal,Agreda, Jesus,Barragan, Daniel
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p. 4601 - 4603
(2007/10/03)
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- Scavenger assisted combinatorial process for preparing libraries of tertiary amine compounds
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This invention relates to a novel solution phase process for the preparation of tertiary amine combinatorial libraries. These libraries have utility for drug discovery and are used to form wellplate components of novel assay kits.
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- The chemistry of pseudomonic acid. 15. Synthesis and antibacterial activity of a series of 5-alkyl, 5-alkenyl, and 5-heterosubstituted oxazoles
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The synthesis of a range of 5-alkyl, 5-alkenyl, and 5-heterosubstituted 2- (1-normon-2-yl) oxazoles is described. The antibacterial activity was determined as the minimum inhibitory concentration against a range of Gram- positive and Gram-negative organisms using a standard Agar dilution procedure. Compounds possessing an acid functionality directly on, or close to, the ring were found to be of greatly decreased potency, while increasing lipophilicity with greater chain length led to increased potency of these derivatives.
- Brown, Pamela,Davies, David T.,O'Hanlon, Peter J.,Wilson, Jennifer M.
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p. 446 - 457
(2007/10/03)
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- SELECTIVE MONOBROMINATION OF KETONES BY BIS(DIMETHYLACETAMIDE)HYDROGEN TRIBROMIDE
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A unified procedure for the α-monobromination of ketones by bis(dimethylacetamide)hydrogen tribromide in methanol is proposed.Methyl aryl ketones with donating and moderately accepting substituents in the ring readily enter into the reaction. 1-Bromo ketones are mostly formed during the bromination of methyl alkyl ketones.
- Rodygin, M. Yu.,Mikhailov, V. A.,Savelova, V. A.
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p. 881 - 887
(2007/10/02)
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- Terpenes and Terpene Derivatives, XXIX Synthesis and Olfactive Properties of (-)- and rac-Silphiperfol-5-en-3-ol and of Some Tris-nor Derivatives
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The new sesquiterpene alcohols silphiperfol-5-en-3-ol and the corresponding 7-epi compound (+)-1b, important constituents of the essential oil of Artemisia laciniata have been synthesized in 13 steps by starting from (R)-(+)-pulegone (6) in an overall yield of 8percent.The key reaction is the copper-catalyzed 1,4-Grignard addition of the iodo acetal 34 to the enone (+)-4 in the presence of TMSCl and TMEDA to give the silyl ether 38.Hydrolysis with spontaneous aldol cyclization and dehydration leads to the silphiperfolenones (+)-2a,b which are separable by flash chromatgraphy.The reduction with L-selectrideR gives the alcohols (-)-1a and (+)-1b which are identical in all physical properties with the isolated natural compound.With LiAlH4 the diastereoisomers 42a,b are formed.Olfactive evaluation of the isomers (-)-1a and (+)-1b has shown that the odor of the naturally occuring mixture of 1a,b with the descriptors woody, ambergris, slightly camphoraceous is correctly assigned. (-)-1a represents the more woody and camphoraceous, (+)-1b the more animal facette of ambergris.The odor of rac-1a,b, of the diasteroisomers 42a,b and of the ketones (+)-2a,b is also described as well as that of the tris-nor-silphiperfolene derivatives 29-31. Key Words: Artemisia laciniata / Sesquiterpene alcohols, tricyclic / Structure-odor correlation / (R)-(+)-Pulegone / 1,4-Grignard reaction
- Weyerstahl, Peter,Brendel, Joachim
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p. 669 - 678
(2007/10/02)
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- REGIODEFINED SYNTHESIS OF α-BROMO, α-PHENYLTHIO, AND α-PHENYLSELENO KETONES BY MEANS OF SPECIFIC SUBSTITUTION OF THE TRIMETHYLSILYL GROUP IN α-TRIMETHYLSILYL KETONES
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Regiodefined α-monobromo ketones are readily obtained by the interaction of bromine with an equivalent of α-trimethylsilyl ketones, in an excellent yield.Analogoes selective substitution of the trimethylsilyl group on phenylthio and phenylseleno groups can be attained by the reaction of phenylsulfenyl chloride or phenylselenenyl bromide with α-trimethylsilyl ketones in the presence of zinc bromide in dichloromethane.
- Matsuda, Isamu,Sato, Susumu
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- Effet d'engrenage. VIII. Extension a des derives fonctionnels de l'alanine
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The gear effect has been discovered and studied for the first time on molecules where the interacting groups were alkyl substituents.In order to be closer to biochemical models, this effect has now been studied where one interacting group is asymmetric and functional.For this purpose eighteen new compounds derived from alanine have been prepared and studied by nmr and dynamic nmr.The gear effect is operating, and it appears to be a suitable means to modulate the interaction of two active functions.
- Blaive, Bruno,Roussel, Christian,Metzger, Jacques,Sandstroem, Jan
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p. 2212 - 2220
(2007/10/02)
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