- 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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- 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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- 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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- 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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- 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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- 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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