- Phosphorus-Based Organocatalysis for the Dehydrative Cyclization of N-(2-Hydroxyethyl)amides into 2-Oxazolines
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A metal-free, biomimetic catalytic protocol for the cyclization of N-(2-hydroxyethyl)amides to the corresponding 2-oxazolines (4,5-dihydrooxazoles), promoted by the 1,3,5,2,4,6-triazatriphosphorine (TAP)-derived organocatalyst tris(o-phenylenedioxy)cyclotriphosphazene (TAP-1) has been developed. This approach requires less precatalyst compared to the reported relevant systems, with respect to the phosphorus atom (the maximum turnover number (TON) ~30), and exhibits a broader substrate scope and higher functional-group tolerance, providing the functionalized 2-oxazolines with retention of the configuration at the C(4) stereogenic center of the 2-oxazolines. Widely accessible β-amino alcohols can be used in this approach, and the cyclization of N-(2-hydroxyethyl)amides provides the desired 2-oxazolines in up to 99% yield. The mechanism of the reaction was studied by monitoring the reaction using spectral and analytical methods, whereby an 18O-labeling experiment furnished valuable insights. The initial step involves a stoichiometric reaction between the substrate and TAP-1, which leads to the in situ generation of the catalyst, a catechol cyclic phosphate, as well as to a pyrocatechol phosphate and two possible active intermediates. The dehydrative cyclization was also successfully conducted on the gram scale.
- Soleymani Movahed, Farzaneh,Foo, Siong Wan,Mori, Shogo,Ogawa, Saeko,Saito, Susumu
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p. 243 - 257
(2021/12/17)
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- Synthesis of 2-oxazolines by in situ desilylation and cyclodehydration of β-hydroxyamides
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A powerful method for the synthesis of 2-oxazolines from silyl-protected β-hydroxyamides is reported. Using diethylaminosulfur trifluoride (DAST) or its tetrafluoroborate salt (XtalFluor-E), silyl-protected β-amidoalcohols can be in situ deprotected and d
- Brandst?tter, Marco,Roth, Fabian,Luedtke, Nathan W.
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- The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions
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A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor. The
- Gl?ckner, Steffen,Tran, Duc N.,Ingham, Richard J.,Fenner, Sabine,Wilson, Zoe E.,Battilocchio, Claudio,Ley, Steven V.
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p. 207 - 214
(2015/02/02)
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- Synthesis of 2-oxazolines and related N-containing heterocycles using [Et2NSF2]BF4 as a cyclodehydration agent
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The preparation of 2-oxazolines and related N-containing heterocycles from the corresponding hydroxyamides using XtalFluor-E ([Et2NSF 2s]BF4) as a cyclodehydration agent is described. A wide range of heterocycles are obtai
- Pouliot, Marie-France,Angers, Laetitia,Hamel, Jean-Denys,Paquin, Jean-Fran?ois
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supporting information; experimental part
p. 4121 - 4123
(2012/08/28)
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- ETHYNYLBENZENE DERIVATIVES
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Disclosed are compounds of formulae (I), (II), and (II)I: and pharmaceutically acceptable salts thereof, wherein the variables, R, R1, R2, R3, R101, L, D, Q, Y, X, and Z are defined herein. These compounds are useful for treating Gram-negative bacteria infections.
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- Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold
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Compounds inhibiting LpxC in the lipid A biosynthetic pathway are promising leads for novel antibiotics against multidrug-resistant Gram-negative pathogens. We report the syntheses and structural and biochemical characterizations of LpxC inhibitors based on a diphenyl-diacetylene (1,4-diphenyl-1,3-butadiyne) threonyl-hydroxamate scaffold. These studies provide a molecular interpretation for the differential antibiotic activities of compounds with a substituted distal phenyl ring as well as the absolute stereochemical requirement at the C2, but not C3, position of the threonyl group.
- Liang, Xiaofei,Lee, Chul-Jin,Chen, Xin,Chung, Hak Suk,Zeng, Daina,Raetz, Christian R.H.,Li, Yaoxian,Zhou, Pei,Toone, Eric J.
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p. 852 - 860
(2011/03/19)
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- Structure-activity relationship of new anti-tuberculosis agents derived from oxazoline and oxazole benzyl esters
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During the syntheses and studies of natural iron chelators (mycobactins), we serendipitously discovered that a simple, small molecule, oxazoline-containing intermediate 3 displayed surprising anti-tuberculosis activity (MIC of 7.7?μM, average). Herein we
- Moraski, Garrett C.,Chang, Mayland,Villegas-Estrada, Adriel,Franzblau, Scott G.,M?llmann, Ute,Miller, Marvin J.
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experimental part
p. 1703 - 1716
(2010/06/19)
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- Modular phosphite-oxazoline/oxazine ligand library for asymmetrie Pd-catalyzed allylic substitution reactions: scope and limitations - origin of enantioselectivity
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A library of phosphite-oxazoline/oxazine ligands L1-L15a-h has been synthesized and screened in the Pd-catalyzed allylic substitution reactions of several substrate types. These series of ligands can be prepared efficiently from easily accessible hydroxyl amino acid derivatives. Their modular nature enables the substituents/configurations in the oxazoline/oxazine moiety, alkyl backbone chain and in the biaryl phosphite moiety to be easily and systematically varied. By carefully selecting the ligand components, therefore, high regio- and enantioselectivities (ee values up to 99%) and good activities have been achieved in a broad range of mono- and disubstituted linear hindered and unhindered liner and cyclic substrates. The NMR studies on the Pd-π-allyl intermediates provide a deeper understanding about the effect of the ligand parameters on the origin of enantioselectivity. It also indicates that the nucleophilic attack takes place predominantly at the allylic terminal carbon atom located trans to the phosphite moiety.
- Dieguez, Montserrat,Pamies, Oscar
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experimental part
p. 3653 - 3669
(2009/04/23)
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- Determination of the complete absolute configuration of petriellin A
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We report the full structural determination of the depsipeptide petriellin A. The absolute configuration of the amino acid residues, N-methyl isoleucine and N-methyl threonine, have been determined by a combination of HPLC and TLC comparison of synthetic Marfey's derivatives and Marfey's derivatives of the natural product hydrolysate. The configuration of the chiral centres in these two N-methylated residues was found to be the same as those of the common unmethylated l-amino acids. CSIRO 2006.
- Aurelio, Luigi,Brownlee, Robert T. C.,Dang, Jason,Hughes, Andrew B.,Polya, Gideon M.
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p. 407 - 414
(2008/02/04)
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- Functionalised 2,3-dimethyl-3-aminotetrahydrofuran-4-one and N-(3-oxo-hexahydrocyclopenta[b]furan-3a-yl)acylamide based scaffolds: Synthesis and cysteinyl proteinase inhibition
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A stereoselective synthesis of functionalised (2R,3R)-2,3-dimethyl-3- amidotetrahydrofuran-4-one, its (2S,3R)-epimer and (3aR,6aR)-N-(3-oxo- hexahydrocyclopenta[b]furan-3a-yl)acylamide cysteinyl proteinase inhibitors has been developed using Fmoc-protected scaffolds 6-8 in a solid-phase combinatorial strategy. Within these scaffolds, the introduction of an alkyl substituent α to the ketone affords chiral stability to an otherwise configurationally labile molecule. Preparation of scaffolds 6-8 required stereoselective syntheses of suitably protected α-diazomethylketone intermediates 9-11, derived from appropriately protected α-methylthreonines (2R,3R)-12, (2R,3S)-13 and a protected analogue of (1R,2R)-1-amino-2- hydroxycyclopentanecarboxylic acid 14. Application of standard methods for the preparation of amino acid α-diazomethylketones, through treatment of the mixed anhydride or pre-formed acyl fluorides of intermediates 12-14 with diazomethane, proved troublesome giving complex mixtures. However, the desired α-diazomethylketones were isolated and following a lithium chloride/acetic acid promoted insertion reaction provided scaffolds 6-8. Elaboration of 6-8 on the solid phase gave α,β-dimethyl monocyclic ketone based inhibitors 38a-f, 39a,b,d,e,f and bicyclic inhibitors 40a-e that exhibited low micromolar activity against a variety of cysteinyl proteinases.
- Watts, John,Benn, Alex,Flinn, Nick,Monk, Tracy,Ramjee, Manoj,Ray, Peter,Wang, Yikang,Quibell, Martin
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p. 2903 - 2925
(2007/10/03)
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- New Dihydroxy Bis(Oxazoline) Ligands for the Palladium-Catalyzed Asymmetric Allylic Alkylation: Experimental Investigations of the Origin of the Reversal of the Enantioselectivity
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The origin of the reversal of the enantioselectivity in the palladium-catalyzed allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate anion using chiral dihydroxy bis(oxazoline) "BO" ligands derived from (1S,2S)-(+)-2-amino-1-ph
- Ait-Haddou, Hassan,Hoarau, Olivier,Cramailere, Dimitri,Pezet, Frederic,Daran, Jean-Claude,Balavoine, Gilbert G. A.
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p. 699 - 707
(2007/10/03)
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- Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
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The subject invention provides pharmaceutical compounds useful in the treatment of Type II diabetes. These compounds are advantageous because they are readily metabolized by the metabolic drug detoxification systems. Particularly, thiazolidinedione analogs that have been designed to include esters within the structure of the compounds are provided. This invention is also drawn to methods of treating disorders, such as diabetes, comprising the administration of therapeutically effective compositions comprising compounds that have been designed to be metabolized by serum or intracellular hydrolases and esterases. Pharmaceutical compositions of the ester-containing thiazolidinedione analogs are also taught.
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- Benzamide bioisosteres incorporating dihydroheteroazole substructures: EPC synthesis and SAR leading to a selective dopamine D4 receptor partial agonist (FAUC 179)
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Conformationally restricted benzamide bioisosteres were investigated when the chiral phenyldihydroimidazole derivative 4e (FAUC 179) showed strong and highly selective dopamine D4 receptor binding (Kihigh = 0.95 nM). Mitogenesis experiments indicated partial agonist properties (42%). EPC syntheses of the target compounds of type 4 were performed starting from α-amino acids.
- Einsiedel, Juergen,Huebner, Harald,Gmeiner, Peter
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p. 2533 - 2536
(2007/10/03)
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- Synthesis of functionalized oxazolines and oxazoles with DAST and Deoxo-Fluor.
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[formula: see text] A mild and highly efficient cyclization of beta-hydroxy amides to oxazolines is described using DAST and Deoxo-Fluor reagents. A one-pot protocol for the synthesis of oxazoles from beta-hydroxy amides is also presented.
- Phillips,Uto,Wipf,Reno,Williams
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p. 1165 - 1168
(2007/10/03)
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- Preparation and Use of Aziridino Alcohols as Promoters for the Enantioselective Addition of Dialkylzinc Reagents to N-(Diphenylphosphinoyl) Imines
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A set of chiral aziridino alcohols 2-5 has been synthesized starting from either readily available amino acids (L-serine, L-threonine, and allo-L-threonine) or simple olefins (using Sharpless asymmetric aminohydroxylation and dihydroxylation reactions). Chiral ligands 2-5 have been tested as promoters for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl) imines 1. The influence of the substituants on the aziridine ring and the alcohol moiety on the selectivity has been studied, and in the best case, an enantiomeric excess of up to 94% could be obtained. Acidic hydrolysis of the initially formed N-protected amines 6 led to the corresponding free amines 7 without racemization. Although a stoichiometric amount of the ligand was used, about 90% of it could be recovered during the workup and reused without significant loss of chiral induction. The utility of the aziridino alcohols 2-5 as catalysts for the same reaction has also been evaluated and enantiomeric excesses of up to 76% were achieved using 0.25 equiv of the chiral ligand. A possible transition state for the addition reaction is also proposed.
- Andersson, Pher G.,Guijarro, David,Tanner, David
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p. 7364 - 7375
(2007/10/03)
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- Synthese d'oxazolines insaturees isomeres a partir d'aminoalcools chiraux en vue du greffage sur silice
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Synthesis of unsaturated oxazoline isomers from chiral amino alcohols for bonding to silica.In order to study their enantioselective ability, four chiral unsaturated oxazoline isomers were synthesized from (1S,2S)-2-amino-1-phenylpropane-1,3-diol and (2S,3R)-2-amino-3-hydroxybutanoic acid (S-threonine).A terminal double bond was introduced on these structures in order to be able to graft them onto silica and access chiral stationary phases for chromatography. - Keywords: chiral unsaturated oxazoline; heterocyclization; selective reaction; grafted silica
- Leveque, Hubert,Malhiac, Catherine,Speybrouck, David,Combret, Yvette,Guerpin, Valerie,Combret, Jean-Claude
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p. 801 - 807
(2007/10/02)
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- A short, stereospecific synthesis of dihydrooxazoles from serine and threonine derivatives
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Cyclization of serine and threonine derivatives with Burgess reagent provides a one-step, streospecific access to 4,5-dihydrooxazoles. Noteworthy features of this new methodology include mild experimental conditions, and the absence of β-lactam, aziridine
- Wipf, Peter,Miller, Chris P.
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p. 907 - 910
(2007/10/02)
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- Stereoselective Alkylierung an C(α) von Serin, Gycerinsaeure, Thereonin und Weinsaeure ueber heterocyclische Enolate mit exocyclischer Doppelbindung
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The chiral, non-racemic title acids are converted to methyl dioxalene- (cf. 13), oxazoline- (4) and oxazolidine-carboxylates (cf. 9).Deprotonation by Li(i-Pr)2N at dry-ice temperature gives solutions of the litium enolates A-D with exocyclic enolate double bonds.These are stable enough with respect to β-elimination (Scheme 1) to be alkylated with or without cosolvents such as HMPA or DMPU.The products are formed in good to excellent yields and, with the exception of the tartrate derived acetonide (see Schemem 2), with diastereoselectivities above 90percent.While the tartrate- and threonine-derived enolates (A and B, resp.) are chiral due to the second stereogenic center of the precursors, the serine- and glyceric-acid-derived enolates are non-racemic due to a tert butyl-substituted (pivalaldehyde-derived) acetal center (C and D, resp.).The products of alkylation can be hydrolyzed to give α-branched tartaric acid (Scheme 2), allothreonine (Scheme 3), serine (Scheme 4), and glycerine-acid derivatives (Scheme 5) with quaternary stereogenic centers.The configurations of the products are determined by NOE-NMR measurements and by chemical correlation.These show taht the dioxolane-derived enolates A and D are alkylated preferentially from that face of the ring which is alredy substituted ('syn'-attack).The 'syn'-attack is postulated to arise from strong folding of the heterocyclic ring due to elelctronic repulsion between the enolate ?-system and non-bonding elelctron pairs on the heteroatoms (see Scheme 6).
- Seebach, Dieter,Aebi, Johannes D.,Gander-Coquoz, Marlyse,Naef, Reto
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p. 1194 - 1216
(2007/10/02)
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- α-ALKYLATION OF THREONINE
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The (S,S)- and the (S,R)-oxazolines 4, both readily available from L-threonine, are deprotonated with lithium diisopropylamide (LDA, -> 5) and alkylated diastereoselectively (>95 percent ds) to yield the 4,4-disubstituted oxazolines 7.The product of methy
- Seebach, Dieter,Aebi, Johannes, D.
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p. 3311 - 3314
(2007/10/02)
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- Access to (S)-2-Methyloxetane and the Precursor (S)-1,3-Butanediol of Hight Enantiomeric Purity
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(S)-2-Methyloxetane (1) and its precursor (S)-1,3-butanediol (2) were prepared in low to moderate chemical yield with less than 0.5percent racemization from (S)-ethyl lactate (4) and from (2S,3S)-allothreonine (14b).For the first time the enantiomeric purities of both the starting material and the product (1) were carefully determined by high-precision capillary gas chromatography on optically active resolving stationary phases.The validity of the quadrant rule, correlating the relative configuration of alkyloxiranes with the order of elution from manganese(II) bis (3) by complexation gas chromatography, is also confirmed for 2-methyloxetane (1).
- Hintzer, Klaus,Koppenhoefer, Bernhard,Schurig, Volker
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p. 3850 - 3854
(2007/10/02)
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- Von der basenkatalysierten Ringoeffnung von 2H-Azirinen zu einer α-Alkylierungsmethode von primaeren Aminen
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It is shown than fluorene-9'-spiro-2-(3-phenyl-2H-azirine) (1) on treatment with various alcohols in the presence of the corresponding alkoxide ions yields N-(9'-fluorenyl)benzimidates 2a-d (Scheme 1). 2,2,3-Triphenyl-2H-aziridine (3) reacts with methanol in a similar manner (Scheme 2).Benzimidates 2a (Scheme 3), 8 (Scheme 4) and 10 (Scheme 5) can easily be deprotonated by butyllithium (BuLi) or lithium diisopropylamide (LDA) in tetrahydrofuran (THF) to 1-methoxy-2-aza-allylanions, that can be alkylated, at C(3), exclusively, by various electrophiles (e.g.R-X (X = I, Br), RCHO or methyl acrylate (see also Scheme 6)).As the acidic hydrolyses (1 N HCl) of benzimidates 9 and 11 leads to the corresponding α-alkylated free amines 15 and 18 (Scheme 7 and 8), benzoyl derivatives 16 and 19 are obtained from the hydrolysis under basic conditions.On the other hand it is observed that a catalyzed Chapman rearrangement of 9 and 11 results in the formation of N-benzoyl-N-methyl derivatives 17 and 20 (Scheme 7 and 8).The described reactions offer a simple method for the α-alkylation of actived primary amines.
- Schulthess, Adrian Heinz,Hansen, Hans-Juergen
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p. 1322 - 1336
(2007/10/02)
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