- Widely Exploited, Yet Unreported: Regiocontrolled Synthesis and the Suzuki–Miyaura Reactions of Bromooxazole Building Blocks
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An approach to synthesis of 2-, 4-, and 5-bromooxazoles is described. The method was optimized, and its scope was extended to all three isomeric parents, as well as various alkyl- and aryl-substituted bromooxazoles. It was found that direct regiocontrolled lithiation followed by reaction with electrophilic bromine source was common for all substrates and led exclusively to the target substituted 2-, 4- and 5-bromooxazoles on multigram scale. The utility of the multipurpose building blocks obtained in this work was demonstrated in the Suzuki–Miyaura cross-coupling reaction under parallel synthesis conditions.
- Solomin, Vitalii V.,Radchenko, Dmytro S.,Slobodyanyuk, Evgeniy Y.,Geraschenko, Oleksandr V.,Vashchenko, Bohdan V.,Grygorenko, Oleksandr O.
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p. 2884 - 2898
(2019/03/07)
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- Three-Component [2+2+1] Gold(I)-Catalyzed Oxidative Generation of Fully Substituted 1,3-Oxazoles Involving Internal Alkynes
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Three-component [2+2+1] gold(I)-catalyzed reaction of internal alkynes (alkynyl esters or -ketones), nitriles, and 2-chloropyridine N-oxide led to a wide range of fully substituted 1,3-oxazoles (32 examples; up to 92% isolated yields). Nitrile R3/su
- Dubovtsev, Alexey Yu.,Dar'in, Dmitry V.,Kukushkin, Vadim Yu.
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supporting information
p. 2926 - 2935
(2019/04/26)
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- CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
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Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.
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-
Paragraph 1396
(2018/04/17)
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- POLYMYXIN ANALOGS USEFUL AS ANTIBIOTIC POTENTIATORS
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The disclosure provides compounds of the formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of either of the foregoing. The variables A, R1, and R2 are defined in the disclosure. The disclosure further includes pharmaceutical compositions comprising a compound of formula I together with at least one pharmaceutically acceptable carrier. The disclosure also includes a method of sensitizing bacteria to an antibacterial agent, comprising administering to a patient infected with the bacteria, simultaneously or sequentially, a therapeutically effective amount of the antibacterial agent and a compound of formula (I).
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-
Paragraph 0149
(2017/12/09)
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- Towards New Tricyclic Motifs: Intramolecular C–H Arylation as the Key Step in a Formal [3+3] Cyclocondensation Strategy
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Tricyclic scaffolds structurally related to the well-known benzodiazepine class of drugs show diverse biological activities strikingly different from those of their benzodiazepine counterparts. Interested by this scaffold-hopping perspective, we previousl
- Vrijdag, Johannes L.,De Ruysscher, Dries,De Borggraeve, Wim M.
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p. 1465 - 1474
(2017/04/01)
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- The synthesis of novel disorazoles
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Big little brother: The simplified disorazole analogue 1 exhibits its cytotoxic activity at low nanomolar concentrations and provides selectivities not observed for the parent natural product.
- Schaeckel, Romy,Hinkelmann, Bettina,Sasse, Florenz,Kaiesse, Markus
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supporting information; experimental part
p. 1619 - 1622
(2010/06/16)
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- PYRROLE ANTIFUNGAL AGENTS
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The invention provides compounds of formula (I), and pharmaceutically and agriculturally acceptable salts thereof; wherein: R1, R2, R3, R4, R5, R6, A1, L1 and n are as defined herein. These compounds and their pharmaceutically acceptable salts are useful in prevention or treatment of a fungal disease. Compounds of formula (I), and agriculturally acceptable salts thereof, may also be used as agricultural fungicides.
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Page/Page column 152
(2009/12/05)
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- Oxidative rearrangements of isobenzofurans: Studies toward the synthesis of the ajudazols
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(Chemical Equation Presented) We present a new facet of isobenzofuran chemistry which allows for its efficient manipulation to generate biologically relevant entities. This methodology has been successfully applied toward the synthesis of ajudazol A.
- Hobson, Stephen J.,Parkin, Andrew,Marquez, Rodolfo
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supporting information; experimental part
p. 2813 - 2816
(2009/05/27)
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- Large-scale preparation of 2-methyloxazole-4-carboxaldehyde
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The large-scale preparation of 2-methyloxazole-4-carboxaldehyde presents a significant challenge due to the physical characteristics of the molecule. A method for the preparation of 10-kg batches of 2-methyloxazole-4-carboxaldehyde is described. The key reaction is the reduction of the corresponding N-methoxy-N-methyl amide using lithium aluminium hydride, followed by workup and isolation by crystallization.
- Benoit, Georges-Emmanuel,Carey, John S.,Chapman, Alan M.,Chima, Ranjit,Hussain, Nigel,Popkin, Matthew E.,Roux, Guillaume,Tavassoli, Bahareh,Vaxelaire, Carine,Webb, Michael R.,Whatrup, David
-
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- Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol- 4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications
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Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5 field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the reinstatement of cocaine self-administration caused by the presentation of environmental cues previously associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of gaining a better understanding of the structural features relevant to its antagonist potency and with the ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine. These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists that are 490 and 230 times, respectively, better than that of MTEP.
- Iso, Yasuyoshi,Grajkowska, Ewa,Wroblewski, Jarda T.,Davis, Jared,Goeders, Nicholas E.,Johnson, Kenneth M.,Sanker, Subramaniam,Roth, Bryan L.,Tueckmantel, Werner,Kozikowski, Alan P.
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p. 1080 - 1100
(2007/10/03)
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- Synthesis of 4-arylethynyl-2-methyloxazole derivatives as mGluR5 antagonists for use in the treatment of drug abuse
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In structure-activity relationship studies directed toward the use of mGluR5 antagonists in the treatment of drug abuse, we sought a convenient means for gaining access to the oxazole analogues of MTEP. Toward this end, the aldehyde group in 2-methyloxazo
- Iso, Yasuyoshi,Kozikowski, Alan P.
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p. 243 - 246
(2007/10/03)
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- Enantioselective total synthesis of the antitumor macrolide rhizoxin D
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The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from γ-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner-Emmons olefination at the C(2)-C(3) olefin.
- Lafontaine, Jennifer A.,Provencal, David P.,Gardelli, Cristina,Leahy, James W.
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p. 4215 - 4234
(2007/10/03)
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- Utilization of alternate substrates by the first three modules of the epothilone synthetase assembly line
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The epothilones, a family of macrolactone natural products produced by the myxobacterial species Sorangium cellulosum, are of current clinical interest as antitumor agents. Inspection of the structure of the epothilones suggests a hybrid polyketide/nonribosomal peptide biosynthetic origin, and the recent sequencing of the epothilone biosynthetic gene cluster has validated this proposal. Here we have examined unnatural substrates with the first two enzymes of the biosynthetic pathway, EpoA and EpoB, to investigate the enzymatic construction of alternate heterocyclic structures and the subsequent elongation of these products by the third enzyme of the pathway, EpoC. The epothilone biosynthetic machinery can utilize serine to install an oxazole in place of a thiazole in the epothilone structure and will tolerate functionalized donor groups from the EpoA-ACP domain to produce epothilone fragments modified at the C21 position. These studies with the early enzymes of the epothilone biosynthesis cluster suggest that combinatorial biosynthesis may be a viable means for producing a variety of epothilone analogues that incorporate diversity into the heterocycle starter unit. Copyright
- Schneider, Tanya L.,Walsh, Christopher T.,O'Connor, Sarah E.
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p. 11272 - 11273
(2007/10/03)
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- Discovery of further pyrrolidine trans-lactams as inhibitors of human neutrophil elastase (HNE) with potential as development candidates and the crystal structure of HNE complexed with an inhibitor (GW475151)
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Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of
- Macdonald, Simon J. F.,Dowle, Michael D.,Harrison, Lee A.,Clarke, Geoffrey D. E.,Inglis, Graham G. A.,Johnson, Martin R.,Shah, Pritom,Smith, Robin A.,Amour, Augustin,Fleetwood, Gill,Humphreys, Davina C.,Molloy, Christopher R.,Dixon, Mary,Godward, Rosalind E.,Wonacott, Alan J.,Singh, Onkar M. P.,Hodgson, Simon T.,Hardy, George W.
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p. 3878 - 3890
(2007/10/03)
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- An efficient, practical approach to the synthesis of 2,4-disubstituted thiazoles and oxazoles: Application to the synthesis of GW475151
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GlaxoWellcome Research and Development, Chemical Development Division, Medicines Research Centre,. A new method for the synthesis of 2,4-disubstituted oxazoles and thiazoles and 2,4,5-trisubstituted oxazoles from readily available starting materials is described. The methodology has been applied on multigram scale and involves transfer of oxidation state through a molecular framework. In particular the oxazole-containing amino acid fragment of the 5,5-transfused lactam GW475151, 1, has been prepared in excellent yield and purity.
- Hermitage, Stephen A.,Cardwell, Kevin S.,Chapman, Tim,Cooke, Jason W. B.,Newton, Rebecca
-
-
- Studies of mild dehydrogenations in heterocyclic systems
-
The use of bromotrichloromethane-DBU is described for the selective oxidative conversion of several dihydro-heterocyclic systems to the corresponding heteroaromatics. Oxidative dehydrogenations to afford 4-hydroxy-2-pyridinones are examined under a variety of conditions. Studies of phenylselenenylation and peracid oxidation provide the novel spirocyclic oxirane 10.
- Williams, David R.,Lowder, Patrick D.,Gu, Yu-Gui,Brooks, Dawn A.
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p. 331 - 334
(2007/10/03)
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- Oxidation of oxazolines and thiazolines to oxazoles and thiazoles. Application of the Kharasch-Sosnovsky reaction
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Using a modification of the Kharasch-Sosnovsky reaction, the oxidation of oxazolines and thiazolines bearing a variety of 2-alkyl substituents (chiral and achiral) were smoothly oxidized to their corresponding oxazoles and thiazoles, respectively. The key feature involved in the successful implementation of this important oxidation was the use of a mixture of Cu(I) and Cu(II) salts to enhance the oxidation of the intermediate captodative radical, 24. The main limitation of this method was shown when the oxidation failed with oxazolines/thiazolines lacking the carboalkoxy group at C-4.
- Meyers,Tavares, Francis X.
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p. 8207 - 8215
(2007/10/03)
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- The Oxidation of 2-Oxazolines to 1,3-Oxazoles
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Oxazolines are readily oxidized to 1,3-oxazoles using NBS/peroxide or light or, more efficiently, by the Kharasch-Sosnovsky Reaction.
- Meyers, A. I.,Tavares, Francis
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p. 2481 - 2484
(2007/10/02)
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- Dimethyl Aminomalonate: A Useful C-3 Unit in a Mild, Direct Synthesis of Oxazole-4-carboxylates
-
N-Acyl derivatives of the title compound undergo oxidative cyclization upon treatment with N-chlorosuccinimide in DMF to form dimethyl 4,5-dihydro-5-(phenylthio)oxazole-4,4-dicarboxylates 4 which then are decarbomethoxylated with concomitant loss of thiop
- Shapiro, Rafael
-
p. 5759 - 5764
(2007/10/02)
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- ANOMALOUS METALATION BEHAVIOR IN 1,3-OXAZOLES. ALKYLATION OF 2-METHYL-4-CARBOXYOXAZOLES VIA THE CORNFORTH INTERMEDIATE
-
Metalation of the methyl group in the title compound is accomplished through the open chain Cornforth precursor.This technique is necessary due to the preferred metalation of the 5-H proton in oxazoles.
- Meyers, A. I.,Lawson, John P.
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p. 3163 - 3166
(2007/10/02)
-