- A Next-Generation Air-Stable Palladium(I) Dimer Enables Olefin Migration and Selective C?C Coupling in Air
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We report a new air-stable PdI dimer, [Pd(μ-I)(PCy2tBu)]2, which triggers E-selective olefin migration to enamides and styrene derivatives in the presence of multiple functional groups and with complete tolerance of air. The same dimer also triggers extremely rapid C?C coupling (alkylation and arylation) at room temperature in a modular and triply selective fashion of aromatic C?Br, C?OTf/OFs, and C?Cl bonds in poly(pseudo)halogenated arenes, displaying superior activity over previous PdI dimer generations for substrates that bear substituents ortho to C?OTf.
- Kundu, Gourab,Rissanen, Kari,Schoenebeck, Franziska,Sperger, Theresa
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p. 21930 - 21934
(2020/10/02)
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- Macrocyclic MCL-1 inhibitors and methods of use
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The present disclosure provides for compounds of Formula (I) wherein A2, A3, A4, A6, A7, A8, A15, RA, R5, R9, R10A, R10B, R11, R12, R13, R14, R16, W, X, and Y have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents for the treatment of diseases and conditions, including cancer. Also provided are pharmaceutical compositions comprising compounds of Formula (I).
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Paragraph 0906
(2019/02/28)
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- 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid, its intermediate, preparation and application thereof
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The invention relates to 3-(trimethylsilyl) pyrrolidine-2-carboxylic acids, its intermediates , preparation and application thereof, the structural formula of the described 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid is (the structural formula of the described 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid is shown in the description). The preparation method uses chiral proline as raw material, and carries out C-H bond activation reaction with silanization reagent after protective group and adjuvant are introduced, then an intermediate is obtained after removing protective group; the intermediate can remove auxiliary groups under the acid action and the described 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid can be obtained. 3-(trimethylsilyl) pyrrolidine-2-carboxylic acids are used in asymmetric catalytic reactions. The reaction condition of the 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid is mild, with high chemical yield, which provides a new way for the synthesis of the silicon-containing structural analogue, and the prepared (2R, 3R)-3-(trimethylsilyl) pyrrolidine-2-carboxylic acid, (2S, 3S)-3-(trimethylsilyl) pyrrolidine-2-carboxylic acid can be used as chiral catalyst for asymmetric reaction, and has good application prospect.
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Paragraph 0065; 0066
(2018/10/19)
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- HUMAN PLASMA KALLIKREIN INHIBITORS
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Disclosed are compounds of formula I, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also provided are pharmaceutical compositions comprising at least one compound of the invention, and methods involving use of the compounds and compositions of the invention in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.
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Page/Page column 73
(2017/05/10)
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- BIPHENYL COMPOUNDS AND USES THEREOF
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The present invention relates to biphenyl compounds and uses thereof in medicine. Specifically, the present invention relates to a compound of Formula (I), or a stereoisomer, a geometric isomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer, an N-oxide, a hydrate, a solvate, a metabolite, a hydrolysate, a pharmaceutically acceptable salt or a prodrug thereof. The compound disclosed herein is used as a therapeutic agent particularly a GPR40 agonist for treating diabetes and metabolic disease in a patient.
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Paragraph 00191
(2015/05/19)
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- Synthesis of (-)-(S, S)-clemastine by invertive N → C aryl migration in a lithiated carbamate
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The first enantioselective synthesis of the antihistamine agent clemastine, as its (S,S)-stereoisomer, has been achieved by ether formation between a proline-derived chloroethylpyrrolidine and an enantiomerically enriched tertiary alcohol. The tertiary alcohol was formed from the carbamate derivative of α-methyl-p-chlorobenzyl alcohol by invertive aryl migration on lithiation. The (S,S)-stereochemistry of the product confirms the invertive nature of the rearrangement.
- Fournier, Anne M.,Brown, Robert A.,Farnaby, William,Miyatake-Ondozabal, Hideki,Clayden, Jonathan
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supporting information; experimental part
p. 2222 - 2225
(2010/08/04)
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- Synthesis, characterisation and in vitro cytotoxicity studies of a series of chiral platinum(II) complexes based on the 2-aminomethylpyrrolidine ligand: X-ray crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N-dimethyl-2(R)-aminomethylpyrrolidine)
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A series of platinum(II) complexes were synthesised based on the enantiomerically pure amino acid proline. Novel synthetic pathways were developed, adapted from standard peptide chemistry, to produce the 2-aminomethylpyrrolidine (pyrr) ligand and its derivatives with differing arrangements of methyl substituents at the exocyclic amine sites. The crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N,N-dimethyl-2(R)-aminomethylpyrrolidine) is reported and the five-membered ligand ring has been shown to be in an envelope conformation. Cytotoxicity studies were carried out on the ovarian cancer A2780 tumour cell line and its cisplatin-resistant variant, A2780cisR. Remarkably good activity was seen for several of the drugs when compared to cisplatin despite the addition of substantial steric bulk to the amine groups, and there was a lack of cross-resistance with cisplatin seen for some compounds.
- Diakos, Connie I.,Zhang, Mei,Beale, Philip J.,Fenton, Ronald R.,Hambley, Trevor W.
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experimental part
p. 2807 - 2814
(2009/10/10)
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- Large nonlinear effect observed in the enantiomeric excess of proline in solution and that in the solid state
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(Chemical Equation Presented) A clue to the origin of chirality? A solution of proline with high enantiomeric excess (85-99% ee) was obtained from solid proline of only 10% ee through novel dissolution and crystallization processes (see scheme). This observation may be an explanation for the origin of chirality on Earth.
- Hayashi, Yujiro,Matsuzawa, Masayoshi,Yamaguchi, Junichiro,Yonehara, Sayaka,Matsumoto, Yasunobu,Shoji, Mitsuru,Hashizume, Daisuke,Koshino, Hiroyuki
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p. 4593 - 4597
(2007/10/03)
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- Role of secondary structure in the asymmetric acylation reaction catalyzed by peptides based on chiral Cα-tetrasubstituted α-amino acids
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In a recent series of papers, Miller and co-workers were able to show that His(π-Me)-based, terminally protected peptides are potent catalysts of the asymmetric acyl transfer reaction, useful for the kinetic resolution of alcohols. In a structure-supporting solvent, one of the most active compounds, an Aib-containing tetrapeptide, is folded in a doubly intramolecularly H-bonded β-hairpin motif incorporating a type-II′ β-turn conformation. In this work, we have expanded the study of the Miller tetrapeptide by examining a set of analogues and shorter sequences (dipeptide amides), characterized by chiral Cα-tetrasubstituted α-amino acids of diverging bulkiness and optical configuration. Peptide synthesis in solution, conformational analysis by FT-IR absorption and 1H NMR techniques, and screening of catalytic activity as well have been performed. Our results confirm the close relationship between the β-hairpin 3D-structure and the catalytic activity of the peptides. A tetrapeptide analogue slightly more selective than the Miller compound has been found. However, the terminally protected, industrially more appealing, dipeptide amides are poorly effective.
- Formaggio, Fernando,Barazza, Alessandra,Bertocco, Andrea,Toniolo, Claudio,Broxterman, Quirinus B.,Kaptein, Bernard,Brasola, Elena,Pengo, Paolo,Pasquato, Lucia,Scrimin, Paolo
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p. 3849 - 3856
(2007/10/03)
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- Enantioselective Enzymatic Cleavage of N-Benzyloxycarbonyl Groups
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A new enzymatic process for the enantioselective cleavage of N-benzyloxycarbonyl (Cbz) groups from protected amino acids and related compounds has been developed. The Cbz-deprotecting enzyme was isolated from cell extracts of Sphingomonas paucimobilis SC 16113 and purified to homogeneity. The purified protein has a molecular weight of 155,000 daltons and a subunit size of 44,000 daltons.
- Patel, Ramesh N.,Nanduri, Venkata,Brzozowski, David,McNamee, Clyde,Banerjee, Amit
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p. 830 - 834
(2007/10/03)
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- Simple and efficient preparation of (R)- and (S)-enantiomers of α-carbon deuterium-labelled α-amino acids
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A procedure for the synthesis of (R)- and (S)-enantiomers of α-carbon deuterium-labelled α-amino acids, exemplified for (R)- and (S)-[2-2H1]-Leu is described. Starting from the respective (S)- or (R)-enantiomer or from the racemic mixture of an α-amino acid the selective proton exchange at the α-carbon is carried out by racemization via a Schiff base in monodeuterated acetic acid as solvent which serves as deuterium source. After N-protection the racemic mixture is liquid chromatographically separated into the individual (R)- and (S)-enantiomers on preparative scale employing a chiral anion exchanger based on carbamoylated quinine as chiral selector. After deprotection the enantiomerically pure products can be obtained in good yields.
- Mitulovi, Goran,Laemmerhofer, Michael,Maier,Lindner, Wolfgang
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p. 449 - 461
(2007/10/03)
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- Enantiospecific syntheses of (R)- and (S)-proline and some derivatives from D-glucono-1,5-lactone
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Carbohydrate-based enantiospecific syntheses of (R)-proline 1 and (S)-proline 2 from the previously reported D-erythro-hexonate ester 9 are described. Azide-substitution reactions on appropriately activated intermediates derived from ester 9, followed by reductive cyclization (H2/Pd-C), gave the substituted pyrrolidines 14 and 22, which were converted into their corresponding N-Cbz derivatives 16 and 24 in conventional manner. Mild acidic hydrolysis of these, followed by oxidation (sodium metaperiodate), gave the protected prolinals 3 and 4, which on further oxidation (sodium chlorite), followed by catalytic hydrogenolysis, gave the prolines 1 and 2. The N-Cbz-prolinol derivatives 5 and 6 are also reported.
- Mazzini, Claudio,Sambri, Letitia,Regeling, Henk,Zwanenburg, Binne,Chittenden, Gordon J. F.
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p. 3351 - 3356
(2007/10/03)
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- Synthesis, antitumor activity, and nephrotoxicity of the optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato) platinum(II)
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The optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)platinum(II) (DWA2114, 1), which has potent antitumor activity against various tumors, were synthesized. They were examined for antitumor activity against Colon 26 carcinoma in a sc-iv system, and changes in urinary protein and sugar levels in drug-treated mice were used as an index of nephrotoxicity. In their effect on tumors, (+)-(S)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato) platinum(II) (6b) was more potent than the enantiomer 6a in that the effective dose of 6b was smaller than that of 6a; but, both drugs exhibited potent antitumor activity. On the other hand, a distinct difference between 6a and 6b was shown in their nephrotoxicity. Isomer 6b induced a great increase in urinary protein and sugar levels in mice, whereas 6a caused no increase in these levels.
- Morikawa,Honda,Endoh -i.,Matsumoto,Akamatsu -i.,Mitsui,Koizumi
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p. 837 - 842
(2007/10/02)
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- Alkyl 1-Chloroalkyl Carbonates: Reagents for the Synthesis of Carbamates and Protection of Amino Groups
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The synthesis of 1-chloroalkyl carbonates and their reaction with various type of amines are described.This reaction is useful for the synthesis of carbamate pesticides and for the protection of various amino groups, including amino acids.
- Barcelo, Gerard,Senet, Jean-Pierre,Sennyey, Gerard,Bensoam, Jean,Loffet, Albert
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p. 627 - 632
(2007/10/02)
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- 3-ACYL- AND 3-ALKOXYCARBONYL-2-OXAZOLONES AND THEIR HOMOPOLYMERS AS AMINO-PROTECTING REAGENTS
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3-Acyl and 3-alkoxycarbonyl-2-oxazolones as well as their homopolymers serve as practically usefull N-protecting reagents of amines including α-amino acids.
- Kunieda, Takehisa,Higuchi, Tsunehiko,Abe, Yoshihiro,Hirobe, Masaaki
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p. 3065 - 3066
(2007/10/02)
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