- Synthesis of conformationally restricted analogs of kainic acid. Is the conformation of the C4-substituent of kainoid important to its neuroexcitatory activity?
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Conformationally restricted analogs of kainic acid, which have an azabicyclo[3.3.0]octane system, were synthesized through the intramolecular addition reaction of trimethylenemethane to the α,β-unsaturated ester. Every synthesized isomer showed very weak depolarizing activity. These results indicate that the plane of the isopropenyl group of kainic acid should be diagonal to the pyrrolidine ring to show potent activity.
- Hashimoto, Kimiko,Ohfune, Yasufumi,Shirahama, Haruhisa
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Read Online
- A stereodivergent approach to (-)-α-kainic acid and (+)-α-allokainic acid utilizing the complementarity of alkyne and allene cyclizations
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A formal synthesis of (+)-α-allokainic acid and a total synthesis of (-)-α-kainic acid were carried out using a short, efficient, and highly stereoselective approach. From an alkyne precursor, a nickel-catalyzed cyclization and a palladium-catalyzed rearrangement were utilized in the synthesis of (+)-α-allokainic acid. From an allene precursor, a nickel-catalyzed cyclization was utilized in the synthesis of (-)-α-kainic acid. The allene cyclization used in the latter sequence was the first example of a metal-catalyzed cyclization of this type.
- Chevliakov, Maxim V.,Montgomery, John
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Read Online
- Total syntheses of isodomoic acids G and H: An exercise in tetrasubstituted alkene synthesis
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A unified approach to the pyrrolidine triacid natural products isodomoic acids G and H has been developed. Total syntheses of both natural products were completed, and determination of the correct stereostructure of isodomoic acid G was established by com
- Ni, Yike,Kassab, Refaie M.,Chevliakov, Maxim V.,Montgomery, John
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Read Online
- Nickel and palladium catalysis in the stereoselective synthesis of functionalized pyrrolidines: Enantioselective formal synthesis of (+)-α- allokainic acid
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Neuroexcitatory natural products are accessible from 1 via the intermediate 2, which is obtained by Ni-catalyzed cyclization, transposition of the protecting group, and Pd-catalyzed reduction with allylic transposition. This stepwise formation of stereocenters allows a highly direct and stereoselective synthesis of the excitatory amino acid (+)-α- allokainic acid, which displays an all-trans arrangement of the substituents about the pyrrolidine ring. TBS = tert-butyldimethylsilyl.
- Chevliakov, Maxim V.,Montgomery, John
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Read Online
- Discovery of highly potent dual EP2and EP3agonists with subtype selectivity
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The cyclic carbamate derivatives, 2-{[2-((4S)-4-{(1E,3R)-8-fluoro-3-hydroxy-4,4-dimethyl-1-octenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid (5) and 2-{[2-((4S)-4-{(1E,3R)-3-[1-(4-fluorobutyl)cyclobutyl]-3-hydroxy-1-propenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid (7) were identified as the first potent dual EP2and EP3agonists with selectivity against the EP1and EP4subtypes. Compounds 5 and 7 demonstrated highly potent dual EP2and EP3agonist activity with EC50values of 10 nM or less. In addition, these compounds possess structural features distinct from natural prostaglandins, such as a cyclic carbamate moiety, a dimethyl or cyclobutyl group and a terminal fluorine atom.
- Kinoshita, Akihiro,Higashino, Masato,Aratani, Yoshiyuki,Kakuuchi, Akito,Matsuya, Hidekazu,Ohmoto, Kazuyuki
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Read Online
- Metal-Free Selective Modification of Secondary Amides: Application in Late-Stage Diversification of Peptides
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Here we solve a long-standing challenge of the site-selective modification of secondary amides and present a simple two-step, metal-free approach to selectively modify a particular secondary amide in molecules containing multiple primary and secondary amides. Density functional theory (DFT) provides insight into the activation of C-N bonds. This study encompasses distinct chemical advances for late-stage modification of peptides thus harnessing the amides for the incorporation of various functional groups into natural and synthetic molecules.
- Adebomi, Victor,Sriram, Mahesh,Streety, Xavier,Raj, Monika
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supporting information
p. 6189 - 6193
(2021/08/01)
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- HETERCYCLIC COMPOUNDS FOR THE TREATMENT OF DISEASE
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Described herein are heterocyclic compounds, compositions, and methods for their use for treatment of disease.
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Paragraph 0023
(2018/12/13)
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- Synthesis and evaluation of a potent, well-balanced EP2/EP3 dual agonist
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A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2 = 1.1 nM, EP3 = 1.0 nM) with acceptable selectivity over the EP1 and EP4 subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.
- Kinoshita, Akihiro,Higashino, Masato,Yoshida, Koji,Aratani, Yoshiyuki,Kakuuchi, Akito,Hanada, Keisuke,Takeda, Hiroyuki,Naganawa, Atsushi,Matsuya, Hidekazu,Ohmoto, Kazuyuki
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p. 200 - 214
(2017/12/06)
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- NOVEL BENZODIOXANE-PIPERIDINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATIONS FOR TREATING NEUROPSYCHIATRIC DISORDERS
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The present invention concerns benzodioxane-piperidine with general formula I: wherein notably: R1 represents one or more identical or different substituent(s) on the benzene ring, each independently representing a hydrogen or halogen atom, or a C1-4 alkyl group, or a C1-4 alkoxy group or a C1-4 hydroxyalkyl group or a C1-4 alkylcarbonyl or an alkoxycarbonyl group or an OH group or an SO2R group with R alkyl, or a CN group, or a CF3 group, or an OCF 3 group; n=1, 2 or 3;m=0 or 1, andR2 represents one or more identical or different substituent(s) on the oxazolidinone or morpholinone ring, each independently representing: a hydrogen atom, a C1-4 alkyl group, or a C1-4 alkoxy group, or a C1-4 hydroxyalkyl group, or an alkylcarbonyl group, or an alkoxycarbonyl group, or an alkoxyphenyl group.
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Paragraph 1234; 1277-1280
(2015/12/05)
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- COMPOUNDS AND METHODS FOR TREATING BACTERIAL INFECTIONS
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Compounds of formula (I), pharmaceutically acceptable salts thereof, and uses of the compounds of formula (I) for treating bacterial infections are disclosed.
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Paragraph 0540; 0541
(2014/08/06)
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- (1R,4R) 7-OXO-2-AZABICYCLO[2.2.2]OCT-5-ENE AND DERIVATIVES THEREOF
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This invention provides novel (1R,4R) 7-oxo-2-azabicyclo[2.2.2]oct-5-ene and derivatives thereof, preferably in substantially enantiomerically enriched forms, intermediates thereto, and processes of their synthesis.
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Paragraph 0044
(2013/08/15)
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- Synthesis of tryptophans by Lewis acid promoted ring-opening of aziridine-2-carboxylates: Optimization of protecting group and Lewis acid
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The preparation of tryptophan derivatives through the Lewis acid promoted substitution of aziridine carboxylates with indole was found to be accompanied by a ring-expansion reaction to generate an oxazolidinone byproduct. The ratio of tryptophan to oxazol
- Tirotta, Ilaria,Fifer, Nathan L.,Eakins, Julia,Hutton, Craig A.
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p. 618 - 620
(2013/02/23)
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- A ferrocenyl-DHIPOH/Cu(OAc)2 complex for diastereo- and enantioselective catalysis of the 1,4-addition of glycine derivatives to alkylidene malonates
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A planar chiral ferrocene derivative Fc-DHIPOH served as an excellent N,O- chiral ligand for asymmetric copper catalyzed 1,4-addition of glycine derivatives to alkylidene malonates. The corresponding 1,4-adducts were obtained in high yields with excellent enantioselectivities up to 95% ee.
- Shi, Yu-Hua,Wang, Zheng,Hu, Bin,Wang, Ming,Fossey, John S.,Deng, Wei-Ping
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supporting information; experimental part
p. 6010 - 6013
(2012/01/04)
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- 2,6-Disubstituted and 2,2,6-trisubstituted piperidines from serine: Asymmetric synthesis and further elaboration
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(Figure presented) 4-Hydroxy-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl esters, which are readily prepared from serine and terminal acetylenes, undergo Claisen rearrangement to piperidine derivatives when heated with butyl vinyl ether in the presence of Hg(OAc)2 and Et3N. This route to optically pure piperidines having substituents α to nitrogen is general, and the rearrangement products are versatile intermediates for making a broad range of amines containing a substituted piperidine subunit.
- Acharya, Hukum P.,Clive, Derrick L. J.
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scheme or table
p. 5223 - 5233
(2010/09/05)
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- Fluorogenic peptide substrates for serine and threonine phosphatases
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Figure presented A new fluorescent assay for Ser/Thr protein phosphatases has been developed. Hydrolysis of a phosphoSer residue liberates the Ser hydroxyl group, which induces a cyclization reaction on the N-terminal carbamate and releases a fluorescent reporter. Sequence selectivity is observed using several peptide substrates against alkaline phosphatase (ALP), bacteriophage protein phosphatase (-PPase), and vaccinia H1 related phosphatase (VHR). These studies suggest that the assay could be a useful tool for profiling the substrate specificities of medicinally important phosphatases.
- Xue, Fengtian,Seto, Christopher T.
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supporting information; experimental part
p. 1936 - 1939
(2010/07/06)
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- Efficient regio- And stereoselective formation of azocan-2-ones via 8-endo cyclization of α-carbamoyl radicals
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The iodine-atom-transfer 8-endo cyclization of α-carbamoyl radicals was investigated experimentally and theoretically. With the aid of Mg(CIO 4)2 and a bis(oxazoline) ligand, N- ethoxycarbonylsubstituted N-(pent-4-enyl)-2-iodoalkanamides underwent 8-endo cyclization leading to the formation of only the corresponding 3,5-trans-substituted azocan-2-ones in excellent yields. Similarly, the BF 3·OEt2/H2O-promoted reactions of N-ethoxycarbonyl-N-(2-allylaryl)-2-iodoalkanamides afforded exclusively the benzazocanone products with a 3,5-cis configuration in high yields. The bidentate chelation of substrate radicals not only significantly improved the efficiency of cyclization but also resulted in the change of stereochemistry of azocanone products from 3,8-iransto 3,8-cis. Theoretical calculations at the UB3LYP/6-31G* level revealed that the cyclization of N-carbonyl- substituted α-carbamoyl radicals occurs via the E-conformational transition states without the presence of a Lewis acid. On the other hand, the cyclization proceeds via the Z-conformational transition states when the substrates form the bidentate chelation with a Lewis acid. In both cases, the 8-endo cyclization is always fundamentally preferred over the corresponding 7-exo cyclization. The complexed radicals having the more rigid conformations also allow the better stereochemical control in the iodine-atom-abstraction step. To further understand the reactivity of a-carbamoyl radicals, the competition between the 8-endo and 5-exo cyclization was also studied. The results demonstrated that the 8-endo cyclization is of comparable rate to the corresponding 5-exo cyclization for a-carbamoyl radicals with fixed Z-conformational transition states. As a comparison, the 8-endo mode is fundamentally preferred over the 5-exo mode in the cyclization of NH-amide substrates because the latter requires the Z-conformational transition states, whereas the former proceeds via the more stable E-conformational transition states.
- Fang, Xinqiang,Liu, Kun,Li, Chaozhong
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supporting information; experimental part
p. 2274 - 2283
(2010/05/01)
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- Latrunculin analogues with improved biological profiles by "diverted total synthesis": Preparation, evaluation, and computational analysis
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Deliberate digression from the blueprint of the total syntheses of latrunculin A (1) and latrunculin B (2) reported in the accompanying paper allowed for the preparation of a focused library of "latrunculin-like" compounds, in which all characteristic str
- Fuerstner, Alois,Kirk, Douglas,Fenster, Michael D. B.,Aissa, Christophe,De Souza, Dominic,Nevado, Cristina,Tuttle, Tell,Thiel, Walter,Mueller, Oliver
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p. 135 - 149
(2007/10/03)
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- Synthesis and biological activity of S-oxo-[(methylthio)-methyl]cysteinols
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A convenient route was developed to synthesize S-oxo-[(methylthio)-methyl]cysteinols on a large scale from cheap l-serine as the starting material. The structures of diastereoisomers were determined by NMR, CD spectra, and X-ray diffraction analysis. All four diastereoisomers were examined for their ability to inhibit certain bacteria from growing.
- Xi, Zhen,Cheng, Xiao-Feng,Chen, Wen-Bin,Cao, Li-Qiang
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p. 3337 - 3339
(2007/10/03)
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- Domino intramolecular enyne metathesis/cross metathesis approach to the xanthanolides. Enantioselective synthesis of (+)-8-epi-xanthatin
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The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24, which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.
- Kummer, David A.,Brenneman, Jehrod B.,Martin, Stephen F.
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p. 11437 - 11449
(2007/10/03)
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- Versatile approach for the synthesis of novel seven-membered iminocyclitols via ring-closing metathesis dihydroxylation reaction
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Seven-membered iminocyclitols with diverse diastereomers were prepared starting with D- and L-serines and employing ring-closing olefin metathesis and dihydroxylation reaction sequence. The iminocyclitols were assayed for glycosidase inhibition and compound 20 was found to be a competitive inhibitor for β-glucosidase with Ki 26.3μM.
- Lin, Chang-Ching,Pan, Yi-Shin,Patkar, Laxmikant N.,Lin, Hsiu-Mei,Tzou, Der-Lii M.,Subramanian, Thangaiah,Lin, Chun-Cheng
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p. 3259 - 3267
(2007/10/03)
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- First total synthesis and stereochemical definition of isodomoic acid G
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(Matrix Presented) The first total synthesis and stereochemical definition of isodomoic acid G has been achieved. The key nickel-catalyzed coupling of an alkynyl enone with an alkenylzirconium allows formation of the pyrrolidine ring and most of the stere
- Ni, Yike,Amarasinghe, Kande K. D.,Ksebati, Bashar,Montgomery, John
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p. 3771 - 3773
(2007/10/03)
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- Sulfonamide inhibitors of aspartyl protease
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The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.
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- Rearrangements and racemisation during the synthesis of L-serine derived oxazolidin-2-ones
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The propensity for N-Boc-4-hydroxymethyl-oxazolidin-2-ones to undergo rapid O-O and N-O carbonyl transfer makes these L-serine derived chiral auxiliaries unsuitable for attachment to polymers.
- Bew, Sean P,Bull, Steven D,Davies, Stephen G,Savory, Edward D,Watkin, David J
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p. 9387 - 9401
(2007/10/03)
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- Process for the preparation of matrix metalloproteinase inhibitors
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The instant invention provides a process for the synthesis of matrix metalloproteinase inhibitors.
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- Synthesis of oxazolidinyl azacycles via ring-closing olefin metathesis: A practical entry to the synthesis of deoxy-azasugars and hydroxypyrrolizidines
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Starting with D- and L-serines, an expedient method for the preparation of oxazolidinyl piperidines, azepenes and azacyclooctenes was illustrated as a route to various deoxy-azasugars and hydroxypyrrolizidines. The ring-closing olefin metathesis of oxazolidinyl di-olefins was used as a key-step to construct the azacycles. Consecutive epoxidation, hydrolysis and transannulation of oxazolidinyl azacyclooctene led to hydroxypyrrolizidines.
- Subramanian, Thangaiah,Lin, Chang-Ching,Lin, Chun-Cheng
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p. 4079 - 4082
(2007/10/03)
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- Influence of lewis acids on the regioselectivity of N-Boc-aziridine-2-carboxylate microwave-assisted rearrangement
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The microwave assisted rearrangement of N-Boc-chiral aziridine-2-imides and esters to oxazolidin-2-ones in the presence of different Lewis acids is presented. The regioselectivity of the reaction strongly depends upon the Lewis acid selected and the react
- Cardillo,Gentilucci,Gianotti,Tolomelli
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p. 1309 - 1311
(2007/10/03)
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- IOOC route to substituted chiral pyrrolidines. Potential glycosidase inhibitors
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Branched-chain five-membered ring aza-sugar analogues, synthesized from amino acids by an intramolecular oxime-olefin cycloaddition reaction, the IOOC route, were found to be selective glycosidase inhibitors. The derivative 2,4(S)-di(hydroxymethyl)-3(S)-aminopyrrolidine, obtained from D-serine, was about 1 order of potency more active than its enantiomer obtained from L- serine.
- Falb, Eliezer,Bechor, Yosi,Nudelman, Abraham,Hassner, Alfred,Albeck, Amnon,Gottlieb, Hugo E.
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p. 498 - 506
(2007/10/03)
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- Investigations of a nucleophilic alaninol synthon derived from serine
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A nucleophilic synthon, (S)-(+)-4-(2-oxazolidonyl)-methyltriphenylphosphinyl iodide 6, available from L-serine in five steps (overall yield of 52%), reacts with aldehydes to produce alkenes in good to excellent yields (74-89%) and, in some cases, provides
- Sibi, Mukund P.,Rutherford, Drew,Renhowe, Paul A.,Li, Biqin
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p. 7509 - 7516
(2007/10/03)
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- Method for preparation of optically active diarylalanines
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A method for preparing a diarylalanine compound is provided. The method includes reacting a diarylaminopropanediol with a reducing agent to form a diarylaminopropanol compound and/or contacting a serine ester derivative with an aryl metal reagent to form diarylaminopropanediol. A diarylmethyloxazolidinone compound is also provided.
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- Enhanced enantiocontrol in catalytic metal carbene transformations with dirhodium(II) tetrakis, Rh2(4S-MEOX)4
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The synthesis, spectral characteristics, and X-ray structures for dirhodium(II) tetrakis, Rh2(4S-MEOX)4, and the related dirhodium(II) tetrakis, Rh2(4S-THREOX)4, are reported.Comparison is made between these 2-oxooxazolidin-ligated dirhodium(II) catalysts for metal carbene transformations and those with comparable 2-oxopyrrolidine ligands, especially dirhodium(II) tetrakis, Rh2(5S-MEPY)4.Structure-selectivity comparisons reveal that Rh2(4S-MEOX)4 provides higher enantiocontrol and, in some cases, higher diastereocontrol than Rh2(5S-MEPY)4 in intramolecular carbon-hydrogen insertion reactions of sterically demanding diazoacetates and diazoacetamides and is the catalyst of choice for highly enantioselective diazodecomposition of adamantyl diazoacetates and N-(tert)butyldiazoacetamides.The structurally analogous Rh2(4S-THREOX)4 is nearly identical with Rh2(4S-MEOX)4 in its overall effect on selectivity.The net advantage of Rh2(4S-MEOX)4 lies in its wider openness for metal carbene transformations.
- Doyle, Michael P.,Dyatkin, Alexey B.,Protopopova, Marina N.,Yang, Chien I.,Miertschin, Charla S.,et al.
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p. 163 - 170
(2007/10/02)
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- Synthesis of N-BOC-D-Diphenylalanine from L-Serine Methyl Ester Hydrochloride
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A convenient six step synthesis of N-BOC-D-diphenylalanine from L-serine methyl ester hydrochloride is described.The preparation of a novel chiral auxiliary, an oxazolidinone derived from D-diphenylalaninol, is also described.
- Sibi, Mukund P.,Deshpande, Prasad K.,Loggia, Anthony J. La,Christensen, James W.
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p. 8961 - 8964
(2007/10/02)
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- A New Electrophilic Alaninol Synthon. A General Route to Oxazolidinones of D or (R)-2-Amino Alcohols from L-Serine
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A new electrophilic alaninol synthon, (S)-4-(4'-tolylsulfonyloxymethyl)oxazolidin-2-one, derived from serine, undergoes nucleophilic displacements with Gilman cuprates and/or Grignard/CuX reagents in high yields to provide (R)-4-substituted oxazolidinones.
- Sibi, Mukund, P.,Rutherford, Drew,Sharma, Rajiv
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p. 1675 - 1678
(2007/10/02)
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- Utilization of L-serine in an oxime olefin cycloaddition route to a functionalized asymmetric pyrrolidine, a selective α-glucosidase inhibitor
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A new route for asymmetric aza-sugar analogs starting with L-serine and utilizing an intramolecular oxime olefin cycloaddition has been successfully developed. A member of this family of branched chain sugar amino di(hydroxymethyl) pyrrolidines (1 and 2) exhibits selective inhibition of α-glucosidase, while no inhibition of β-glucosidase was detected.
- Hassner, Alfred,Falb, Eliezer,Nudelman, Abraham,Albeck, Amnon,Gottlieb, Hugo E.
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p. 2397 - 2400
(2007/10/02)
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- A convenient synthesis of chiral oxazolidin-2-ones and thiazolidin-2-ones and an improved preparation of triphosgene
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Oxazolidin-2-ones and thiazolidin-2-ones are conveniently prepared by condensation of L-serine, L-threonine and L-cysteine, respectively with triphosgene. The corresponding methyl esters may be subsequently obtained by quenching the reaction mixture with methanol, without prior need for the isolation of the free acids. An improved procedure for preparation of triphosgene using an internal cooling system is described.
- Falb,Nudelman,Hassner
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p. 2839 - 2844
(2007/10/02)
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- A NEW NUCLEOPHILIC ALANINOL SYNTHON FROM SERINE
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A new nucleophilic alaninol synthon derived from serine is reported.The utility of this reagent in the stereoselective synthesis of β,γ-unsaturated amino alcohols is described.
- Sibi, Mukund P.,Renhowe, Paul A.
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p. 7407 - 7410
(2007/10/02)
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