- Auxiliary-controlled diastereoselective synthesis of a syn C-6-epimer of the ADAM 10 inhibitor GI254023X
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ADAM10 is a cell surface-expressed metalloprotease involved in various cell adhesion and proteolytic processes, in which biological studies have linked an over-expression of ADAM10 to the development and progression of various types of diseases including cancer. GI254023X is a hydroxamate metalloprotease inhibitor known for ADAM10 activity inhibition, but for which structure-activity based biological information for assessing anti-tumour and anti-inflammatory activity is lacking. In this work, an Evans’ asymmetric boron aldol reaction was used to synthesise a syn C-6-epimer of GI254023X intended for biological evaluation against the natural inhibitor.
- Nair, Shankari,Zeevaart, Jan Rijn,Hunter, Roger
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Read Online
- Nitrogen-containing organobases as promoters in the cobalt(II)-Schiff base catalyzed oxidative carbonylation of amines
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The use of organic bases as promoters in the cobalt(II)-Schiff base complex catalyzed oxidative carbonylation of amines was investigated. The generality of the reaction was also studied by submitting different amines to the same procedure and by changing the reaction conditions. Very good yields in the corresponding ureas were achieved in toluene with a catalyst loading of 0.5 mol % and using TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) as promoter. Methyl carbamates were obtained in methanol.
- Saliu, Francesco,Putomatti, Benedetto,Rindone, Bruno
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- Racemic auxiliaries: Applications to asymmetric synthesis
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Racemic auxiliaries have been successfully used to achieve asymmetric synthesis. Racemic Evans aldol products were obtained from racemic acyl oxazolidinones with good diastereocontrol. The enantiomers of the racemic aldol products were resolved by a lipase-catalysed acylation reaction. Hydrolysis afforded enantiomerically enriched oxazolidinones and enantiomerically enriched β-hydroxy acids.
- Neri, Claudia,Williams, Jonathan M.J.
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- Synthesis of 2-oxazolidinones by salen-Co-complexes catalyzed oxidative carbonylation of β-amino alcohols
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2-Oxazolidinones are synthesized in high yield by oxidative carbonylation of β-amino alcohols using salen-Co(II)/NaI or salen-Co(III)-I as a catalyst and using CO as the carbonyl source. Studies of functional group compatibility using a series of substituted salen-Co(II) or salen-Co(III)-I complexes demonstrate a broad tolerance of functionality during the carbonylation reaction.
- Liu, Jian-Ming,Peng, Xin-Gao,Liu, Jian-Hua,Zheng, Shu-Zhan,Sun, Wei,Xia, Chun-Gu
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- Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 1: Synthetic Strategy and Preparation of a Common Precursor
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The synthetic strategy for producing multigram quantities of (+)-discodermolide (1) using a hybridized Novartis-Smith-Paterson synthetic route via common precursor 3 is described. In the first part of this five-part series, we present a multikilogram preparation of α-methyl aldehyde 10 from Roche ester, its syn-aldol reaction with Evans boron enolate, removal of the chiral auxiliary, and the preparation of Weinreb amide 3 (Smith common precursor). The common precursor was produced without any chromatography.
- Mickel, Stuart J.,Sedelmeier, Gottfried H.,Niederer, Daniel,Daeffler, Robert,Osmani, Adnan,Schreiner, Klaus,Seeger-Weibel, Manuela,Berod, Brigitte,Schaer, Karl,Gamboni, Remo,Chen, Stephen,Chen, Weichun,Jagoe, Christopher T.,Kinder Jr., Frederick R.,Loo, Mauricio,Prasad, Kapa,Repic, Oljan,Shieh, Wen-Chung,Wang, Run-Ming,Waykole, Liladhar,Xu, David D.,Xue, Song
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- Carbonylation with CO2 and phosphorus electrophiles: A convenient method for the synthesis of 2-oxazolidinones from 1,2-amino alcohols
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2-Oxazolidinones were prepared in good yields from 1,2-amino alcohols and CO2 in the presence of tetramethyl-phenylguanidine (PhTMG) as a base and a variety of phosphorus electrophiles under mild conditions. This procedure is advantageous over previous methodologies and relies on a novel carbonylation procedure that utilizes nontoxic CO2 and phosphorus electrophiles. Georg Thieme Verlag Stuttgart.
- Paz, Jairo,Pérez-Balado, Carlos,Iglesias, Beatriz,Mu?oz, Luis
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- Direct catalytic asymmetric α-amination of aldehydes
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The first direct catalytic asymmetric α-amination of aldehydes is described herein. α-Unbranched aldehydes react in this novel proline-catalyzed reaction with dialkyl azodicarboxylates to give α-amino aldehydes in excellent yields and enantioselectivities. Copyright
- List, Benjamin
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Read Online
- Stereochemical consequences of the use of chiral N-phosphoryl oxazolidinones in the attempted kinetic resolution of bromomagnesium alkoxides
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A number of chiral N-phosphoryl oxazolidinones have been prepared and evaluated as asymmetric phosphoryl transfer agents with the magnesium alkoxide of 1-phenyl ethanol. The reaction proceeded with little stereoselection, which was shown to be a consequence of the reaction mechanism that occurs with inversion of configuration at phosphorus consistent with in-line attack opposite the leaving group.
- Jones, Simon,Selitsianos, Dimitrios
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- Synthesis of chiral oxazolidin-2-ones and imidazolidin-2-ones via DMAP- catalyzed isocyanation of amines with di-tert-butyl dicarbonate
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Oxazolidin-2-ones and imidazolidin-2-ones are prepared under mild reaction conditions by DMAP-catalyzed isocyanation of 1,2-aminoalcohols and 1,2-diamines with di-tert-butyl dicarbonate and subsequent cyclization.
- Knoelker, Hans-Joachim,Braxmeier, Tobias
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- Continuous Flow Synthesis of Carbonylated Heterocycles via Pd-Catalyzed Oxidative Carbonylation Using CO and O2 at Elevated Temperatures and Pressures
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A continuous-flow Pd-catalyzed oxidative carbonylation protocol utilizing CO and O2 gas for the synthesis of carbonylated heterocycles is described. The optimization of temperature, pressure, CO/O2 ratio, catalyst loading, and reaction time resulted in process intensified conditions for this transformation. The optimized continuous flow conditions (120 °C, 20 bar pressure, 24 min residence time) were used to prepare a number of benzoxazolone, 2-benzoxazolidinone, and other biologically and synthetically important five- and six-membered carbonylated heterocycles in good overall yield and purity (14 examples). The continuous-flow process enables the safe and scalable oxidative carbonylation using CO/O2 under elevated pressures and temperatures.
- Chen, Yuesu,Hone, Christopher A.,Gutmann, Bernhard,Kappe, C. Oliver
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Read Online
- Room Temperature Cu-Catalyzed N-Arylation of Oxazolidinones and Amides with (Hetero)Aryl Iodides
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N,N′-Bis(pyridin-2-ylmethyl)oxalamide (BPMO) was found to be an apposite promoter for the Cu-catalyzed N-arylation of oxazolidinones and primary and secondary amides with (hetero)aryl iodides at room temperature. Excellent chemoselectivity reached between
- Bhunia, Subhajit,De, Subhadip,Ma, Dawei
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supporting information
(2022/02/09)
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- Atomically Dispersed High-Density Al–N4 Sites in Porous Carbon for Efficient Photodriven CO2 Cycloaddition
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Highly active catalysts that can directly utilize renewable energy (e.g., solar energy) are desirable for CO2 value-added processes. Herein, aiming at improving the efficiency of photodriven CO2 cycloaddition reactions, a catalyst composed of porous carbon nanosheets enriched with a high loading of atomically dispersed Al atoms (≈14.4?wt%, corresponding to an atomic percent of ≈7.3%) coordinated with N (AlN4 motif, Al–N–C catalyst) via a versatile molecule-confined pyrolysis strategy is reported. The performance of the Al–N–C catalyst for catalytic CO2 cycloaddition under light irradiation (≈95% conversion, reaction rate = 3.52 mmol g?1 h?1) is significantly superior to that obtained under a thermal environment (≈57% conversion, reaction rate = 2.11 mmol g?1 h?1). Besides the efficient photothermal conversion induced by the carbon matrix, both experimental and theoretical analysis reveal that light irradiation favors the photogenerated electron transfer from the semiconductive Al–N–C catalyst to the epoxide reactant, facilitating the formation of a ring-opened intermediate through the rate-limiting step. This study not only provides an advanced Al–N–C catalyst for photodriven CO2 cycloaddition, but also furnishes new insight for the rational design of superior photocatalysts for diverse heterogeneous catalytic reactions in the future.
- Yang, Qihao,Peng, Huaitao,Zhang, Qiuju,Qian, Xu,Chen, Xu,Tang, Xuan,Dai, Sheng,Zhao, Jiajun,Jiang, Kun,Yang, Qiu,Sun, Jian,Zhang, Linjuan,Zhang, Nian,Gao, Honglin,Lu, Zhiyi,Chen, Liang
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- Towards the Sarpagine-Ajmaline-Macroline Family of Indole Alkaloids: Enantioselective Synthesis of an N-Demethyl Alstolactone Diastereomer
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the strategy involving the use of functionalized tetrahydro-6H-cycloocta[b]indol-6-one is reported as a key intermediate for synthesis of members of the sarpagine-ajmaline-macroline family of monoterpene indole alkaloids. The desired tricycle was synthesized through the following key steps: 1) Evans’ syn-selective aldolization; 2) Liebeskind–Srogl cross-coupling using the phenylthiol ester of 3-chloropropanoic acid as a surrogate of acrylic thioester for the synthesis of 2,3-disubstituted indoles; and 3) ring-closing metathesis (RCM) for the formation of the eight-membered ring. An N-allylation followed by intramolecular 1,4-addition was planned for synthesis of the vobasine class of natural products. However, attempted cyclizations under a diverse set of conditions involving anionic, radical, and organopalladium/organonickel species failed to produce the bridged ring system. On the other hand, esterification of the pendant primary alcohol function with acetoacetic acid, followed by intramolecular Michael addition, afforded the desired tetracycle with excellent diastereoselectivity. Subsequent functional group manipulation and transannular cyclization of the amino alcohol afforded the N(1)-demethyl-3,5-diepi-alstolactone. We believe that the same synthetic route would afford the alstolactone should the amino alcohol with appropriate stereochemistry be used as the starting material.
- Dagoneau, Dylan,Wang, Qian,Zhu, Jieping
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supporting information
p. 4866 - 4873
(2020/04/15)
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- One-pot synthesis of oxazolidinones and five-membered cyclic carbonates from epoxides and chlorosulfonyl isocyanate: Theoretical evidence for an asynchronous concerted pathway
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The one-pot reaction of chlorosulfonyl isocyanate (CSI) with epoxides having phenyl, benzyl and fused cyclic alkyl groups in different solvents under mild reaction conditions without additives and catalysts was studied. Oxazolidinones and five-membered cyclic carbonates were obtained in ratios close to 1:1 in the cyclization reactions. The best yields of these compounds were obtained in dichloromethane (DCM). Together with 16 known compounds, two novel oxazolidinone derivatives and two novel cyclic carbonates were synthesized with an efficient and straightforward method. Compared to the existing methods, the synthetic approach presented here provides the following distinct advantageous: being a one-pot reaction with metal-free reagent, having shorter reaction times, good yields and a very simple purification method. Moreover, using the density functional theory (DFT) method at the M06-2X/6-31+G(d,p) level of theory the mechanism of the cycloaddition reactions has been elucidated. The further investigation of the potential energy surfaces associated with two possible channels leading to oxazolidinones and five-membered cyclic carbonates disclosed that the cycloaddition reaction proceeds via an asynchronous concerted mechanism in gas phase and in DCM.
- Demir, Esra,Sari, Ozlem,?etinkaya, Yasin,Atmaca, Ufuk,Erdem, Safiye Sa?,?elik, Murat
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p. 1805 - 1819
(2020/11/07)
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- Novel chiral stationary phases based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin combining cinchona alkaloid moiety
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Novel chiral selectors based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin connecting quinine (QN) or quinidine (QD) moiety were synthesized and immobilized on silica gel. Their chromatographic performances were investigated by comparing to the 3,5-dimethyl phenylcarbamoylated β-cyclodextrin (β-CD) chiral stationary phase (CSP) and 9-O-(tert-butylcarbamoyl)-QN-based CSP (QN-AX). Fmoc-protected amino acids, chiral drug cloprostenol (which has been successfully employed in veterinary medicine), and neutral chiral analytes were evaluated on CSPs, and the results showed that the novel CSPs characterized as both enantioseparation capabilities of CD-based CSP and QN/QD-based CSPs have broader application range than β-CD-based CSP or QN/QD-based CSPs. It was found that QN/QD moieties play a dominant role in the overall enantioseparation process of Fmoc-amino acids accompanied by the synergistic effect of β-CD moiety, which lead to the different enantioseparation of β-CD-QN-based CSP and β-CD-QD-based CSP. Furthermore, new CSPs retain extraordinary enantioseparation of cyclodextrin-based CSP for some neutral analytes on normal phase and even exhibit better enantioseparation than the corresponding β-CD-based CSP for certain samples.
- Zhu, Lunan,Zhu, Junchen,Sun, Xiaotong,Wu, Yaling,Wang, Huiying,Cheng, Lingping,Shen, Jiawei,Ke, Yanxiong
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p. 1080 - 1090
(2020/05/25)
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- Synthesis of a diastereomer of the marine macrolide lytophilippine A
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The synthesis of a diastereomer of lytophilippine A required 22 longest linear steps using known building blocks. Cross-metathesis/asymmetric aldol addition and regioselective esterification/ring-closing metathesis served as efficient combi tools for scaffold construction. Detailed NMR investigations in different solvent (systems) provide evidence for a deep-seated configurational misassignment of the molecule named lytophilippine A.
- Klüppel, André,Gille, Annika,Karayel, Ceren Ester,Hiersemann, Martin
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supporting information
p. 2421 - 2425
(2019/03/29)
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- Concise and Additive-Free Click Reactions between Amines and CF3SO3CF3
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Trifluoromethyl trifluoromethanesulfonate has proved to be an excellent reservoir of difluorophosgene and a promising click ligation for amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under metal- and additive-free conditions. The reactions are rapid, efficient, selective, and versatile, and can be performed in benign solvents, giving products in excellent yields with minimal efforts for purification. The characteristics of the reactions meet the requirements of a click reaction. The use of trifluoromethyl trifluoromethanesulfonate as a click reagent is advantageous over other “CO” sources (e.g., TsOCF3, PhCO2CF3, CsOCF3, AgOCF3, and triphosgene) because this reagent is readily accessible; easy to scale up; and highly reactive, even under metal- and additive-free conditions. It is anticipated that CF3SO3CF3 will be increasingly as important as SO2F2 as a click agent in future drug design and development.
- Song, Hai-Xia,Han, Zhou-Zhou,Zhang, Cheng-Pan
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supporting information
p. 10907 - 10912
(2019/08/02)
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- Access towards enantiopure α,α-difluoromethyl alcohols by means of sulfoxides as traceless chiral auxiliaries
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A new methodology to access enantiopure α,α-difluoromethyl alcohols is hereby being described. The strategy relies on the use of an enantiopure aryl α,α-difluoromethyl sulfoxide employed as chiral and removable auxiliary for the stereoselective difluoromethylation of carbonyl derivatives. The obtained α,α-difluoro-β-hydroxysulfoxides displayed unprecedented diastereomeric ratios.
- Batisse, Chloé,Panossian, Armen,Hanquet, Gilles,Leroux, Frédéric R.
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supporting information
p. 10423 - 10426
(2018/09/21)
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- Synthesis of new C3 symmetric amino acid- and aminoalcohol-containing chiral stationary phases and application to HPLC enantioseparations
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We recently reported a new C3-symmetric (R)-phenylglycinol N-1,3,5-benzenetricarboxylic acid-derived chiral high-performance liquid chromatography (HPLC) stationary phase (CSP 1) that demonstrated better results as compared to a previously described N-3,5-dintrobenzoyl (DNB) (R)-phenylglycinol-derived CSP. Over a decade ago, (S)-leucinol, (R)-phenylglycine, and (S)-leucine derivatives were used as the starting materials of 3,5-DNB-based Pirkle-type CSPs for chiral separation. In this study, three new C3-symmetric CSPs (CSP 2, 3, and 4) were prepared by combining the ideas and results mentioned above. Here we describe the synthetic procedures and applications of the new C3-symmetric CSPs (CSP 2–CSP 4).
- Yu, Jeongjae,Armstrong, Daniel W.,Ryoo, Jae Jeong
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- (Enantio)selective Hydrogen Autotransfer: Ruthenium-Catalyzed Synthesis of Oxazolidin-2-ones from Urea and Diols
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A novel strategy for the synthesis of oxazolidin-2-ones from vicinal diols and urea is described. In this heterocycle synthesis, two different C?O and C?N bonds are sequentially formed in a domino process consisting of nucleophilic substitution and alcohol amination. The use of readily available starting materials and the good atom economy render this process environmentally benign. While this transformation is already highly chemo- and regioselective, we also developed the first asymmetric version of this method using (R)-(+)-MeO-BIPHEP as the chiral ligand.
- Pe?a-López, Miguel,Neumann, Helfried,Beller, Matthias
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supporting information
p. 7826 - 7830
(2016/07/07)
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- Syntheses of (+)-30-epi-, (-)-6-epi-, (±)-6,30-epi-13,14-Didehydroxyisogarcinol and (±)-6,30-epi-Garcimultiflorone A Utilizing Highly Diastereoselective, Lewis Acid-Controlled Cyclizations
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The first syntheses of 13,14-didehydroxyisogarcinol (6) and garcimultiflorone A (5) stereoisomers are reported in six steps from a commercially available phloroglucinol. Lewis acid-controlled, diastereoselective cationic oxycyclizations enabled asymmetric syntheses of (-)-6-epi-6 and (+)-30-epi-6. A similar strategy enabled production of the meso-dervied isomers (±)-6,30-epi-6 and (±)-6,30-epi-5. Finally, a convenient strategy for gram scale synthesis was developed utilizing diastereomer separation at a later stage in the synthesis that minimized the number of necessary synthetic operations to access all possible stereoisomers.
- Boyce, Jonathan H.,Eschenbrenner-Lux, Vincent,Porco, John A.
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supporting information
p. 14789 - 14797
(2016/11/18)
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- Chemoselective room temperature E1cB N-N cleavage of oxazolidinone hydrazides from enantioselective aldehyde α-hydrazination: Synthesis of (+)-1,4-dideoxyallonojirimycin
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Room temperature E1cB N-N cleavage of oxazolidinone hydrazides via N-alkylation with diethyl bromomalonate and potassium or caesium carbonate as base in acetonitrile is presented. The new method has a much improved chemoselectivity, which is illustrated by a concise total synthesis of the piperidine iminosugar (+)-1,4-dideoxyallonojirimycin.
- Ferreira, Jasmin,Rees-Jones, Sophie C. M.,Ramaotsoa, Valerie,Msutu, Ath'enkosi,Hunter, Roger
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p. 1545 - 1549
(2016/02/09)
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- Enantioselective synthesis of putative lipiarmycin aglycon related to fidaxomicin/tiacumicin B
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An enantioselective synthesis of a putative lipiarmycin aglycon was accomplished and features: 1) Brown's enantioselective alkoxyallylboration and allylation of aldehydes, 2) chain elongation by iterative Horner-Wadsworth-Emmons olefination, 3) Evans' aldol reaction and 4) an enediene ring-closing metathesis. A neighboring-group-assisted chemoselective reductive desilylation was uncovered in this study and was instrumental to the realization of the present synthesis.
- Erb, William,Grassot, Jean-Marie,Linder, David,Neuville, Luc,Zhu, Jieping
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supporting information
p. 1929 - 1932
(2015/02/19)
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- MACROCYCLIC PICOLINAMIDE COMPOUNDS WITH FUNGICIDAL ACTIVITY
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The invention relates to compounds of macrocyclic picolinamides of Formula I suitable to control or prevent growth of fungi.
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Paragraph 0087
(2015/04/15)
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- Synthesis of salicylic acid-based 1,3,4-oxadiazole derivatives coupled with chiral oxazolidinones: Novel hybrid heterocycles as antitumor agents
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A series of novel salicylic acid-based 1,3,4-oxadiazoles derivatives coupled with chiral oxazolidinones were synthesized to screen for their in vitro antitumor activity against five human cancer cell lines. Some of these compounds showed good antitumor activities with IC50values ranging from 31.19-57.21 μM. Among the tested compounds 11, 15, 19,23,24, and 34 showed broad-spectrum antitumor activity against all the cell lines. In particular, compound 19 revealed remarkable antitumor activity with IC50 = 31.19-41.87 μM. A431 was the most sensitive cell line against all the compounds studied, followed by HeLa, MCF-7, A549 and HepG2. Structures of newly synthesized compounds were confirmed by IR,1 H NMR, 13C NMR and HRMS spectral data
- Murty,Penthala, Raju,Nath, Lekshmi R.,Anto, Ruby John
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p. 1133 - 1142
(2015/03/31)
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- THIOARYL DERIVATIVES AS GPR120 AGONISTS
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The present invention relates to thioaryl derivatives of Formula 1 as defined in the specification, a method for preparing the same, a pharmaceutical composition comprising the same and use thereof. The thioaryl derivatives of Formula 1 according to the present invention promote GLP-1 formation in the gastrointestinal tract and improve insulin resistance in macrophages, pancreas cells, etc. due to anti-inflammatory action, and can accordingly be effectively used for preventing or treating diabetes, complications of diabetes, inflammation, obesity, non-alcoholic fatty liver, steatohepatitis or osteoporosis.
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Paragraph 1017-1018
(2014/05/24)
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- Directed orthometalation and the asymmetric total synthesis of N -deoxymilitarinone A and torrubiellone B
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A diverted total synthesis (DTS) approach to the total synthesis of pyridone alkaloids N-deoxymilitarinone A (8) and torrubiellone B (10) has been developed. The common intermediate 14 was first assembled by a dual directed orthometalation process using a methoxymethyl group as directed metalation group. Other crucial steps include the assembly of polyenes under aldol condensation for DTS using general and concise strategy and diastereoselective synthesis of the syn-dimethyl array by an Evans aldol reaction.
- Ding, Feiqing,William, Ronny,Leow, Min Li,Chai, Hua,Fong, Jacqueline Zi Mei,Liu, Xue-Wei
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supporting information
p. 26 - 29
(2014/01/23)
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- Collective synthesis of 4-hydroxy-2-pyridone alkaloids and their antiproliferation activities
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A collective synthesis of 4-hydroxy-2-pyridone alkaloids - specifically, pretenellin B, prebassianin B, farinosone A, militarione D, pyridovericin, and torrubiellone C - has been achieved. Key steps include using a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki-Miyaura cross-coupling reaction, a divergent synthesis approach of target molecules by aldol condensation of pyridone intermediate with homologous aldehydes, and an iterative synthesis of homologous aldehydes with all-trans-polyene backbones. Interestingly, among the six tumor cell lines investigated, torrubiellone C was found to induce potent and apoptotic inhibitory activities on Jurkat T cells with IC50 values of 7.05 μM. Hence, this approach could potentially contribute to the synthesis of bioactive small-molecule libraries as well as drug discovery.
- Ding, Feiqing,Leow, Min Li,Ma, Jimei,William, Ronny,Liao, Hongze,Liu, Xue-Wei
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supporting information
p. 2548 - 2554
(2014/10/15)
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- Synthesis and biological evaluation of paleo-soraphens
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Synthesis can provide molecules such as paleo-soraphens A and B (see scheme) that are genetically encoded but not obtained from the natural source. Although it is unclear whether this is part of an evolutionary process or the consequence of the chemical synthesis, the biological evaluation of these genetically encoded natural products can shed light on how natural products are structurally optimized with respect to their biological profile. Copyright
- Lu, Hai-Hua,Raja, Aruna,Franke, Raimo,Landsberg, Dirk,Sasse, Florenz,Kalesse, Markus
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supporting information
p. 13549 - 13552
(2014/01/06)
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- Synthesis of cyanoacetyl oxazolidinones
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Carefully controlled displacement of chiral chloroacetyl imides with cyanide afforded previously unreported cyanoacetimides in good overall yield. Knoevenagel condensation of the cyanoacetimides to furnish acrylonitriles was also demonstrated. Georg Thiem
- Weeber, Kaitlyn M.,Schwarz, Jacob B.
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experimental part
p. 1993 - 1996
(2012/09/07)
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- The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1
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The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-ψ[COCH2]- Ser(Bz)-Xaa-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived β-keto imides were stereoselectively converted to α-substituted γ-keto imides. In addition, three corresponding tripeptides, composed of amide bonds, were synthesized for comparison of binding affinities. The six investigated compounds were all defined as high affinity ligands (Ki-values 14C]Gly-Sar uptake in Caco-2 cells. Consequently, the ketomethylene replacement for the natural amide bond and α-side chain modifications appears to offer a promising strategy to modify tripeptidic structures while maintaining a high affinity for hPEPT1.
- Thorn, Karina,Nielsen, Carsten Uhd,Jakobsen, Palle,Steffansen, Bente,Zercher, Charles K.,Begtrup, Mikael
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scheme or table
p. 4597 - 4601
(2011/09/12)
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- PHENYL ACETAMIDE DERIVATIVE
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[Problems] To provide a compound which is useful as a GK activator. [Means for Solving Problems] The present inventors have conducted extensive studies on a phenylacetamide derivative, and as a result, have confirmed that a phenylacetamide derivative having sulfonyl group and cycloalkyl group on the phenyl group and having heteroaryl group on the nitrogen atom in the amide has an excellent GK activation action, thereby completing the present invention. The compound of the present invention is useful as an agent for treating diabetes, in particular, type II diabetes, since it has an excellent GK activation action.
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Page/Page column 21
(2010/10/19)
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- Carbon dioxide as a carbonylating agent in the synthesis of 2-oxazolidinones, 2-oxazinones, and cyclic ureas: Scope and limitations
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Carbon dioxide can be used as a convenient carbonylating agent in the synthesis of 2-oxazolidinones, 2-oxazinones, and cyclic ureas. The transient carbamate anion generated by treating a primary or secondary amine group in basic media can be activated with phosphorylating agents such as Diphenylphosphoryl azide (DPPA) and Diphenyl chlorophosphate (DPPCl) but also with other types of electrophiles such as SOCl2, TsCl, or AcCl. The intramolecular trapping of the activated carbamate by a hydroxyl group leads to the formation of 2-oxazolidinones or 2-oxazinones in good to excellent yields. This methodology was successfully applied to the synthesis of cyclic ureas up to 7-membered rings from the corresponding diamines.
- Paz, Jairo,Perez-Balado, Carlos,Iglesias, Beatriz,Munoz, Luis
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supporting information; experimental part
p. 3037 - 3046
(2010/07/15)
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- Total synthesis of (-)-exiguolide
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The first total synthesis of the naturally occurring enantiomer of exiguolide ((-)-1) has been completed. This very convergent synthesis features the following as main steps: (I) a Trost's ruthenium-catalyzed ene-yne cross-coupling reaction (this complex transformation allows the challenging control of the C5-C28 double bond geometry along with the stereoselective construction of the tetrahydropyran ring A) and (II) a very efficient one-pot, two-step stereoselective conjugated allyllc alcohol substitution that allowed the control of the C15 stereogenic center.
- Cook, Cyril,Guinchara, Xavier,Liron, Frederic,Roulland, Emmanuel
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supporting information; experimental part
p. 744 - 747
(2011/03/17)
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- Design, synthesis, and biological activity of isophthalic acid derivatives targeted to the C1 domain of protein kinase C
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Protein kinase C (PKC) is a widely studied molecular target for the treatment of cancer and other diseases. We have approached the issue of modifying PKC function by targeting the C1 domain in the regulatory region of the enzyme. Using the X-ray crystal structure of the PKC δ C1b domain, we have discovered conveniently synthesizable derivatives of dialkyl 5-(hydroxymethyl)isophthalate that can act as potential C1 domain ligands. Structure-activity studies confirmed that the important functional groups predicted by modeling were indispensable for binding to the C1 domain and that the modifications of these groups diminished binding. The most promising compounds were able to displace radiolabeled phorbol ester ([3H]PDBu) from PKC α and δ at Ki values in the range of 200-900 nM. Furthermore, the active isophthalate derivatives could modify PKC activation in living cells either by inducing PKC-dependent ERK phosphorylation or by inhibiting phorbol-induced ERK phosphorylation. In conclusion, we report here, for the first time, that derivatives of isophthalic acid represent an attractive novel group of C1 domain ligands that can be used as research tools or further modified for potential drug development.
- Af Genn?s, Gustav Boije,Talman, Virpi,Aitio, Olli,Ekokoski, Elina,Finel, Moshe,Tuominen, Raimo K.,Yli-Kauhaluoma, Jari
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supporting information; experimental part
p. 3969 - 3981
(2010/01/16)
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- New asymmetric synthesis of protein farnesyltransferase inhibitors via palladium-catalyzed cross-coupling reactions of 2-iodo-imidazoles
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Palladium catalyzed cross-coupling reactions of 2-iodoimidazole have been studied to synthesize imidazole-containing protein farnesyltransferase inhibitors. The Suzuki coupling reaction proved to be very efficient to introduce functionalized alkyl chains at the 2-position of the imidazole ring and a new synthesis of the required alkenylboronates was realised by a reaction of cross metathesis. Asymmetric synthesis of allyl succinic derivatives allowed us to synthesize chiral protein farnesyltransferase inhibitors through Suzuki coupling and to determine the influence of the stereochemistry of our inhibitors on the enzymatic activity.
- Kerherve, Jennifer,Botuha, Candice,Dubois, Joelle
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supporting information; experimental part
p. 2214 - 2222
(2009/09/04)
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- PROCESS FOR THE PREPARATION OF PERHYDROISOINDOLE DERIVATIVE
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The present invention relates to a novel, efficient and industrially advantageous process for preparing perhydroisoindole derivative, particularly (S)-mitiglinide of formula (I): and pharmaceutically acceptable salts thereof. Further, it relates to novel amide intermediates of formula (VI), including salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof useful in the process of present invention. Formula (VI): wherein R is selected from straight chain or branched C1-6 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl. The present invention also relates to amorphous form of mitiglinide calcium, its preparation and process for its conversion to crystalline mitiglinide calcium.
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Page/Page column 24-25
(2009/05/28)
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- Synthesis of α-keto-imides via oxidation of ynamides
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(Chemical Equation Presented) A de novo preparation of α-keto-imides via ynamide oxidation is described. With a number of alkyne oxidation conditions screened, a highly efficient RuO2-NaIO4 mediated oxidation and a DMDO oxidation have been identified to tolerate a wide range of ynamide types. In addition to accessing a wide variety of α-keto-imides, the RuO2-NaIO4 protocol provides a novel entry to the vicinal tricarbonyl motif via oxidation of push-pull ynamides, and imido acylsilanes from silyl-substituted ynamides. Chemoselective oxidation of ynamides containing olefins can be achieved by using DMDO, while the RuO 2-NaIO4 protocol is not effective. These studies provide further support for the synthetic utility of ynamides.
- Al-Rashid, Ziyad F.,Johnson, Whitney L.,Hsung, Richard P.,Wei, Yonggang,Yao, Pei-Yuan,Liu, Renhei,Zhao, Kang
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supporting information; experimental part
p. 8780 - 8784
(2009/04/11)
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- Synthetic studies on a marine natural product, palmerolide A: Synthesis of C1-C9 and C15-C21 fragments
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An efficient cross metathesis and Pd-catalyzed allylic rearrangement have been successfully used to construct the northern hemisphere of a cytotoxic marine natural product, palmerolide A. Georg Thieme Verlag Stuttgart.
- Kaliappan, Krishna P.,Gowrisankar, Parthasarathy
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p. 1537 - 1540
(2008/02/05)
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- The first asymmetric total syntheses and determination of absolute configurations of xestodecalactones B and C
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The first efficient asymmetric total syntheses of xestodecalactones B and C have been accomplished in 10 steps with an overall yield of 22 and 20.2%, respectively. The key steps involve the utility of Evans oxazolidinone-mediated syn-aldol condensations to establish the C-9 configuration and the macrolide ring formation by intramolecular acylation. The absolute configurations of xestodecalactones B and C have been determined via these syntheses.
- Liang, Qiren,Zhang, Jiyong,Quan, Weiguo,Sun, Yongquan,She, Xuegong,Pan, Xinfu
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p. 2694 - 2697
(2007/10/03)
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- Complex aldol reactions for the construction of dense polyol stereoarrays: Synthesis of the C33-C36 region of aflastatin A
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(Chemical Equation Presented) Facial selectivity in the addition of boron enolates of α-oxygenated ketones to anti-disposed α,β-bisalkoxy aldehydes is controlled by the aldehyde vicinal diol protecting group. Protection of the diol as an acetonide results in the exclusive formation of the anti-syn-anti stereoarray found in the C33-C36 region of aflastatin A.
- Evans, David A.,Glorius, Frank,Burch, Jason D.
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p. 3331 - 3333
(2007/10/03)
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- Chemically modified mutant serine hydrolases show improved catalytic activity and chiral selectivity
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This invention provides novel chemically modified mutant serine hydrolases that catalyze a transamidation and/or a transpeptidation and/or a transesterification reaction. The modified serine hydrolases have one or more amino acid residues in a subsite replaced with a cysteine, wherein the cysteine is modified by replacing the thiol hydrogen in the cysteine with a substituent group providing a thiol side chain comprising a moiety selected from the group consisting of a polar aromatic substituent, an alkyl amino group with a positive charge, and a glycoside. In particularly preferred embodiments, the substitutents include an oxazolidinone, a C1 to C15 alkyl amino group with a positive charge, or a glycoside.
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- Chemical fixation of carbon dioxide co-catalyzed by a combination of Schiff bases or phenols and organic bases
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Binaphthyldiamino, ethyldiamino and cyclohexyldiamino Schiff bases can catalyze the reaction of epoxides with carbon dioxide in the presence of catalytic amounts of various organic bases to give the corresponding cyclic carbonates in high yields. The simplest binaphthyldiamino Schiff base, derived from the reaction of binaphthyldiamine with salicylaldehyde, gave the highest yield of cyclic carbonate. This catalytic system can be further simplified by use of a phenol instead of the Schiff base to give the corresponding cyclic carbonates in high yields as well. Mechanistic insights were obtained based on a deuterium labeling experiment, The reaction of aziridines with CO2 and epoxide with CS2 were also examined under the same reaction conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Shen, Yu-Mei,Duan, Wei-Liang,Shi, Min
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p. 3080 - 3089
(2007/10/03)
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- Carboxylation and Mitsunobu reaction of amines to give carbamates: Retention vs inversion of configuration is substituent-dependent
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(Equation Presented) A mild method for the synthesis of carbamates from amino alcohols involves sequential carboxylation with carbon dioxide, followed by a Mitsunobu reaction. Unexpectedly, the stereochemical course of the Mitsunobu reaction is dependent on whether the carbamic acid intermediate is N-substituted with hydrogen (retention) or carbon (inversion).
- Dinsmore, Christopher J.,Mercer, Swati P.
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p. 2885 - 2888
(2007/10/03)
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- SELECTED CGRP ANTAGONISTS, METHOD FOR PRODUCTION AND USE THEREOF AS MEDICAMENT
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The invention relates to CGRP antagonists of general formula (I), in which A, U, V, W, X and R1 to R 3 are as defined in claim 1, the tautomers, diastereomers, enantiomers, hydrates, mixtures, salts, hydrates of the salts, in particular the physiologically-acceptable salts thereof with inorganic or organic acids, medicaments containing said compounds and the use and methods for production thereof.
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Page/Page column 123-124
(2008/06/13)
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- First total synthesis of the antitumor compound (-)-kazusamycin A and absolute structure determination
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(Equation Presented) The first total synthesis of kazusamycin A, a potent antitumor compound from an actinomycete, has been achieved, and its absolute structure was determined. Paterson's stereoselective aldol reaction was successfully applied to construct the contiguous chiral centers by using an originally designed optically active 2-acyl-1,3-propanediol derivative.
- Arai, Noriyoshi,Chikaraishi, Noriko,Omura, Satoshi,Kuwajima, Isao
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p. 2845 - 2848
(2007/10/03)
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- Method for synthesizing epothilones and epothilone analogs
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A method for making epothilones and epothilone analogs is described, as are novel compounds made by the method. One embodiment of the method was used to synthesize epothilone B by a convergent approach that entailed Wittig coupling of an ylide derived from phosphonium bromide with an aldehyde. The former was prepared from propargyl alcohol by a nine-step pathway which installed both trisubstituted double bonds with clean Z configuration. Macrolactonization of a resulting seco acid provided the following intermediate diene epothilone analog. Selective saturation of the 9,10-olefin and subsequent epoxidation provided epothilone B.
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- SUBSTITUTED PHENYLSULFONAMIDE INHIBITORS OF BETA AMYLOID PRODUCTION
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Compounds of Formula I, wherein R1-R8 are defined herein are provided, together with pharmaceutically acceptable salts, hydrates, metabolites, and/or prodrugs thereof. Uses of these compounds for inhibiting beta amyloid production and for the prevention and treatment of Alzheimer’s Disease and Down’s syndrome are described.
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- New Routes to Chiral Evans Auxiliaries by Enzymatic Desymmetrisation and Resolution Strategies
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This paper describes how enantiomerically enriched Evans auxiliaries can be successfully prepared by either an enzymatic desymmetrisation strategy or an asymmetric synthesis using racemic auxiliaries and an enzymatic resolution. Desymmetrisation of N-Boc-protected serinol has been achieved in good yield and high enantiomeric excess using porcine pancreas lipase. This has been exploited in different ways to prepare enantiomerically enriched (4R)- and (4S)-substituted 2-oxazolidinones. In another approach to asymmetric synthesis, starting from a racemic Evans auxiliary, by means of a diastereoselective aldol reaction coupled with a lipase-catalysed resolution, we achieved the preparation of enantiomerically enriched β-hydroxy acids and enantiomerically enriched 2-oxazolidinones.
- Neri, Claudia,Williams, Jonathan M. J.
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p. 835 - 848
(2007/10/03)
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- Method for synthesizing epothilones and epothilone analogs
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A method for making epothilones and epothilone analogs is described, as are novel compounds made by the method. One embodiment of the method was used to synthesize epothilone B by a convergent approach that entailed Wittig coupling of an ylide derived from phosphonium bromide with an aldehyde. The former was prepared from propargyl alcohol by a nine-step pathway which installed both trisubstituted double bonds with clean Z configuration. Macrolactonization of a resulting seco acid provided the following intermediate diene epothilone analog. Selective saturation of the 9,10-olefin and subsequent epoxidation provided epothilone B.
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