- Continuous flow synthesis of α-halo ketones: Essential building blocks of antiretroviral agents
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The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ~4.5 h (87% yield).
- Pinho, Vagner D.,Gutmann, Bernhard,Miranda, Leandro S. M.,De Souza, Rodrigo O. M. A.,Kappe, C. Oliver
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- Homologation of α-amino acids to β-amino acids using Boc2O
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The use of Boc2O as a coupling agent in the homologation of N-urethane protected-α-amino acid to its β-homomers by the Arndt-Eistert method is described. The homologation gives good yields without racemization. The use of Boc2O as a
- Vasanthakumar, Ganga-Ramu,Patil, Basanagoud S.,Suresh Babu, Vommina V.
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- Studies towards the preparation of sparteine-like diamines for asymmetric synthesis
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A route for the preparation of sparteine-like diamines starting from naturally occurring amino acids has been explored. Starting from the amino acids (S)-proline and (S)-phenylalanine, two novel sparteine-like diamines 2 and 3 have been prepared. The synthetic route involves Dieckmann condensation followed by a double Mannich reaction to set up the tricyclic structure with control of the relative stereochemistry. During the Dieckmann and Mannich reactions it was found that racemisation occurred either via retro-Michael or retro-Mannich processes. Conditions for preventing racemisation in the Dieckmann reaction were uncovered but it was not possible to prevent racemisation during the double Mannich reaction. Thus, the two novel sparteine-like diamines 2 and 3 have been prepared in racemic form. The Royal Society of Chemistry 1999.
- Harrison, Justin R.,O'Brien, Peter,Porter, David W.,Smith, Neil M.
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- Iminium ion-enamine cascade cyclizations: Facile access to structurally diverse azacyclic compounds and natural products
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A one-pot, mild, two-component iminium ion-enamine cascade reaction to construct structurally diverse azacyclic frameworks from l-proline and l-pipecolic acid, and its application to indolizidine and quinolizidine alkaloids and azasteroids, is reported.
- Hanessian, Stephen,Chattopadhyay, Amit Kumar
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supporting information
p. 232 - 235
(2014/01/23)
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- Continuous flow synthesis of β-amino acids from α-amino acids via Arndt-Eistert homologation
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A fully continuous four step process for the preparation of β-amino acids from their corresponding α-amino acids utilizing the Arndt-Eistert homologation approach is described. the Partner Organisations 2014.
- Pinho, Vagner D.,Gutmann, Bernhard,Kappe, C. Oliver
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p. 37419 - 37422
(2014/12/09)
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- CuI-promoted one-pot synthesis of N-boc protected β-ketotriazole amino acids: Application in the synthesis of new class of dipeptidomimetics
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One-pot click chemistry of Nα-Boc-bromomethylketones, NaN3 and propiolic acid affords N-Boc protected 1,4- disubstituted 1,2,3-β-ketotriazole acids in good to excellent yield. The use of CuI as catalyst and DMSO as solvent leads the click react
- Vishwanathaa,Narendra,Sureshbabu, Vommina V.
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p. 308 - 314
(2012/07/17)
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- Kinetic deconjugation: A gateway to the synthesis of Xxx-Gly (E)-alkene dipeptide isosteres
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A new method for the preparation of Xxx-Gly (E)-alkene dipeptide isosteres (EADIs), using LDA deprotonation followed by 1 N HCl quench, was explored. The method, named kinetic deconjugation, enabled the synthesis of Tyr-Gly, Gly-Gly, Ser-Gly, Pro-Gly, and
- Proteau-Gagné, Arnaud,Nadon, Jean-Franois,Bernard, Sylvain,Guérin, Brigitte,Gendron, Louis,Dory, Yves L.
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supporting information; experimental part
p. 6603 - 6605
(2012/02/03)
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- Synthesis of 6- and 7-membered cyclic enaminones: Scope and mechanism
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Six- and seven-membered cyclic enaminones can be prepared using common, environmentally benign reagents. Amino acids are used as synthetic precursors allowing diversification and the incorporation of chirality. The key reaction in this multistep process involves deprotection of Boc-amino ynones and subsequent treatment with methanolic K2CO3 to induce cyclization. A β-amino elimination side reaction was identified in a few labile substrates that led to either loss of stereochemical purity or degradation. This process can be mitigated in specific cases using mild deprotection conditions. NMR and deuterium-labeling experiments provided valuable insight into the workings and limitations of this reaction. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond-making and bond-breaking, thus changing the mode of addition to a 6-endo-trig cyclization. This method can be used to construct an array of monocyclic and bicyclic scaffolds, many of which are found in well-known natural products (e.g., indolizidine, quinolizidine, and Stemona alkaloids).
- Niphakis, Micah J.,Turunen, Brandon J.,Georg, Gunda I.
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supporting information; experimental part
p. 6793 - 6805
(2010/12/20)
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- Total syntheses of arylindolizidine alkaloids (+)-ipalbidine and (+)-antofine
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This paper presents the first application of two recently developed reactions to natural product synthesis. The first method involves a 6-endo-trig cyclization to prepare a versatile chiral enaminone building block. The second is a direct C-H arylation reaction. As a showcase for the utility of these methods, (+)-antofine and (+)-ipalbidine were synthesized in only 8 steps and 24-26% overall yields.
- Niphakis, Micah J.,Georg, Gunda I.
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supporting information; experimental part
p. 6019 - 6022
(2010/12/19)
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- 5-(2-Pyrrolidinyl)oxazolidinones and 2-(2-pyrrolidinyl)benzodioxanes: Synthesis of all the stereoisomers and α4β2 nicotinic affinity
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The four stereoisomers of 2-oxazolidinone 5-substituted with 1-methyl-2-pyrrolidinyl (1), of 1,4-benzodioxane 2-substituted with the same residue (2) and of the nor-methyl analogue of this latter (2a) were synthesized as candidate nicotinoids. Of the 12 c
- Pallavicini, Marco,Bolchi, Cristiano,Binda, Matteo,Cilia, Antonio,Clementi, Francesco,Ferrara, Rossana,Fumagalli, Laura,Gotti, Cecilia,Moretti, Milena,Pedretti, Alessandro,Vistoli, Giulio,Valoti, Ermanno
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scheme or table
p. 854 - 859
(2009/08/15)
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- COMPOUNDS HAVING PROLYL OLIGOPEPTIDASE INHIBITORY ACTIVITY
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The invention provides a compound of formula (I), wherein in the formula X, R1, R2 and R3 are as defined in claim 1, or a pharmaceutically acceptable salt or ester thereof, useful as a prolyl oligopeptidase inhibitor. The compounds of formula (I) can be used for the treatment of diseases or conditions where prolyl oligopeptidase inhibitors are indicated to be effective, for example for the treatment of neurodegenerative diseases, such as Alzheimer's disease and senile dementia
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- CONDENSED HETEROCYCLIC COMPOUNDS AS CALCITONIN AGONISTS
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The present invention relates to novel fused heterocyclic ring system compounds and methods for their use in the treatment and prevention of diseases or conditions which are related to irregular calcification.
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Page/Page column 139
(2010/02/07)
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- 4-Phenylbutanoyl-2(S)-acylpyrrolidines and 4-phenylbutanoyl-L-prolyl-2(S)-acylpyrrolidines as prolyl oligopeptidase inhibitors
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New 4-phenylbutanoyl-2(S)-acylpyrrolidines and 4-phenylbutanoyl-L-prolyl-2(S)-acylpyrrolidines were synthesized. Their inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. In the series of 4-phenylbutanoyl-2(S)-acylpyrrolidines, the cyclopentanecarbonyl and benzoyl derivatives were the best inhibitors having IC50 values of 30 and 23 nM, respectively. This series of compounds shows that the P1 pyrrolidine ring, which is common in most POP inhibitors, can be replaced by either a cyclopentyl ring or a phenyl ring, causing only a slight decrease in the inhibitory activity. In the series of 4-phenylbutanoyl-L-prolyl-2(S)-acylpyrrolidines the cyclopentanecarbonyl and benzoyl derivatives were not as active as in the series of 4-phenylbutanoyl-2(S)-acylpyrrolidines. The hydroxyacetyl derivative did however show high inhibitory activity. This compound is structurally similar to JTP-4819, which is one of the most potent prolyl oligopeptidase inhibitors. The acyl group in the two series of new compounds seems to bind to different sites of the enzyme, since the second series of new compounds did not show the same cyclopentanecarbonyl or benzoyl specificity as the first series.
- Wallen, Erik A.A.,Christiaans, Johannes A.M.,Saario, Susanna M.,Forsberg, Markus M.,Venaelaeinen, Jarkko I.,Paso, Hanna M.,Maennistoe, Pekka T.,Gynther, Jukka
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p. 2199 - 2206
(2007/10/03)
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- Oligomers of β2- and of β3-homoproline: What are the secondary structures of β-peptides lacking H-bonds?
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To study the role of H-bonds in stabilizing β-peptidic secondary structures, we have synthesized β-oligopeptides (up to the octadecamer 12) consisting of β2- and β3-homoproline, i.e., β-peptides lacking amide protons. The enantiomer purity of the building block β2-homoproline (nipecotic acid, 4) was determined by HPLC analysis of the N-(2,4- dinitrophenyl) derivative 5 on a Chiralcel-OD column (cf. Fig. 2). The CD spectra of the all-(S)-β2- and all-(S)-β3-HPro-containing, β-peptides display novel and intensive CD patterns which may be indicative of a secondary structure (cf. Fig. 3). It is noteworthy that a distinct CD pattern was observed with the β3-HPro derivatives containing as few as three residues (7a). The crystal structure of a N-deprotected β3-HPro-tripeptide 7c is presented (cf. Figs. 4 and 5), and a model for the structure of β- peptides consisting of β3-HPro is discussed (cf. Figs. 6 and 7).
- Abele, Stefan,Voegtli, Kurt,Seebach, Dieter
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p. 1539 - 1558
(2007/10/03)
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- The synthesis of a novel benzodiazocine via an intramolecular Staudinger/aza-Wittig cyclization
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The novel pyrrolobenzodiazocine (1) has been prepared by an intramolecular Staudinger/aza Wittig protocol from the precursor azido aldehyde (2) in a remarkable 93% yield. Aldehyde (2) was prepared by coupling protected homoprolinol with 2-azidobenzoic aci
- O'Neil, Ian A.,Murray, Clare L.,Potter, Andrew J.,Kalindjian, S. Barret
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p. 3609 - 3610
(2007/10/03)
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- SYNTHESIS OF DIAZOKETONES DERIVED FROM α-AMINO ACIDS; PROBLEM OF SIDE REACTIONS
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Optimum conditions of synthesis of eight diazoketones derived from optically active N-(t-butyloxycarbonyl)- and N-benzyloxycarbonylamino acids have been described.The problem of formation of by-products during Arndt-Eistert synthesis of β-homoamino acids at the stage of reaction of mixed anhydride with a weak nucleophile-diazomethane - has been discussed.
- Plucinska, Krystyna,Liberek, Bogdan
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p. 3509 - 3518
(2007/10/02)
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