68978-89-2Relevant articles and documents
A multifaceted secondary structure mimic based on piperidine-piperidinones
Xin, Dongyue,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
, p. 3594 - 3598 (2014/04/17)
Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1-faf crystallized in a conformation that is estimated to be 0.91 kcal-mol-1 above the minimum energy solution state. Do we know, when designing a new peptidomimetic scaffold like the one shown, how it can resemble secondary structures? Design and modular synthesis of this elongated mimic is reported, and the structure is related to ideal and real structures at PPI interfaces.
Aza-β3-cyclopeptides: A new way of controlling nitrogen chirality
Mocquet, Clemence,Salauen, Arnaud,Claudon, Paul,Le Grel, Barbara,Potel, Michel,Guichard, Gilles,Jamart-Gregoire, Brigitte,Le Grel, Philippe
supporting information; experimental part, p. 14521 - 14525 (2010/02/28)
Sixteen and 24 membered aza-β3-peptidic macrocycles containing a α-hydrazinoacid or a β3-aminoacid were synthesized. The conformation of these pseudopeptides was determined by using NH chemical shift analysis, NH extinction, VT-NMR e
Structures of β-amino ester enolates: New strategies using the method of continuous variation
Liou, Lara R.,McNeil, Anne J.,Toombes, Gilman E. S.,Collum, David B.
supporting information; experimental part, p. 17334 - 17341 (2009/09/07)
The solution structures of four enolates derived from β-amino esters are investigated using 6Li NMR spectroscopy in conjunction with the method of continuous variation (method of Job). Ensembles of homo- and heteroaggregated enolates are generated by mixing enantiomers ofa single enolate (R/S mixtures), opposite antipodes of two different en olates (R/S mixtures), and the same antipodes of two different enolates (RIR mixtures). The numbers of observable aggregates and their dependence on the mole fraction of the two enolates confirm the hexamer assignments. Inherent symmetries observable in the 6Li NMR spectra show the stereochemistry of chelation about the hexagonal drum.
Lipase-involved strategy to the enantiomers of 4-benzyl-β-lactam as a key intermediate in the preparation of β-phenylalanine derivatives
Li, Xiang-Guo,Kanerva, Liisa T.
, p. 197 - 205 (2007/10/03)
A simple chemoenzymatic method for the preparation of the enantiomers of 4-benzyl-β-lactam (4-benzylazetidin-2-one) from allylbenzene has been described. The enantiomers of this key intermediate have been used to produce the corresponding enantiomers of β-phenylalanine and N-Boc-protected β-phenylalanine amide through the simple cleavage of the lactam ring by acid-catalyzed hydrolysis and by ammonolysis, respectively. Burkholderia cepacia lipase-catalyzed kinetic double resolution techniques were responsible for achieving enantiopurity in the products. This was performed through the acylation of N-hydroxymethylated β-lactam followed by the butanolysis of the obtained (S)-ester. Direct lipase-catalyzed cleavage of the β-lactam ring has also been studied.
PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED BETA AMINO ACID DERIVATIVES
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Page/Page column 27-28, (2008/06/13)
The present invention relates to a process for the efficient preparation of enantiomerically enriched beta amino acid derivatives wherein the amino group is unprotected. The product chiral beta amino acid derivatives are useful in the asymmetric synthesis of biologically active molecules. The process comprises an enantioselective hydrogenation of an amine-unprotected prochiral beta-amino acrylic acid or derivative thereof in the presence of a rhodium metal precursor complexed with a chiral mono- or bisphosphine ligand.
Highly efficient synthesis of β-amino acid derivatives via asymmetric hydrogenation of unprotected enamines
Hsiao, Yi,Rivera, Nelo R.,Rosner, Thorsten,Krska, Shane W.,Njolito, Eugenia,Wang, Fang,Sun, Yongkui,Armstrong III, Joseph D.,Grabowski, Edward J. J.,Tillyer, Richard D.,Spindler, Felix,Malan, Christophe
, p. 9918 - 9919 (2007/10/03)
A direct asymmetric hydrogenation of unprotected enamino esters and amides is described. Catalyzed by Rh complexes with Josiphos-type chiral ligands, this method gives β-amino esters and amides in high yield and high ee (93-97% ee). No acyl protection/deprotection is required. Copyright
(α-aminophosphino) peptide derivatives, method for making same and therapeutic applications thereof
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, (2008/06/13)
The invention concerns compounds derived from (α-aminophosphino) peptides, of general formula (I), in which R1and R2each represents a hydrogen atom or taken together form an imine with the adjacent nitrogen atom; R3represents an alkyl group, an alkenyl group, a phenyl group, a benzyl group, all these groups capable of being substituted or not, a hydrogen atom, a cycloalkyl group, a cycloalkylmethyl group or finally, a methyl group substituted by a heterocyclic, aromatic or saturated group; R4represents a phenyl group, a benzyl group, these groups capable of being substituted or not, a hydrogen atom, an alkyl group, analkenyl group or a cycloalkyl group; R5represents an alkyl group, an alkenyl group, a phenyl group, a benzyl group, all these groups capable of being substituted or not, a hydrogen atom, a cycloalkyl, cycloalkylmethyl group or finally a methyl group substituted by a heterocyclic, aromatic or saturated group; R6, R7and R8can in particular represent a hydrogen atom, an alkyl group, a phenyl group substituted or not . . . n is equal to 0 or 1, in the form of enantiomers, diastereoisomers or racemic mixtures, their salts, their method of preparation and their therapeutic applications.
Synthesis and conformation of dipeptide taste ligands containing homo-β-amino acid residues
Isernia,Bucci,De Napoli,Di Lello,Iacovino,Montesarchio,Piccialli,Rossi,Saviano,Benedetti
, p. 577 - 587 (2007/10/03)
The synthesis and conformational properties of a series of dipeptide taste ligands, differing from the commercial sweetener aspartame by the presence of a methylene group between the Cα and the C′ carbon atoms (as in homo-β-residues) in either the L-Asp or the L-Phe residues, are described. Homo-β-residues such as homo-β-aspartic acid, homo-β-phenylglycine and homo-β-phenylalanine, obtained by homologation of the corresponding proteinogenic α-amino acids, have been used in the solution peptide synthesis of the following aspartame analogues in protected and unprotected forms: NH2-homo-β-(L or D)-Asp-L-Phe-OMe, NH2-L-Asp-homo-β-L-Phg-OMe and NH2-L-Asp-homo-β-L-Phe-OMe. Lengthening of the peptide skeleton at the L-Asp site results in a drastic loss of sweetness with the production of tasteless compounds; on the other hand, lengthening of the skeleton at the C-terminal L-Phe site partially mantains the sweet taste in both NH2-L-Asp-hamo-β-L-Phe-OMe and NH2-L-Asp-homo-β-L-Phg-OMe. The solution conformation of the synthesized dipeptide taste ligands was investigated by NMR and circular dichroism techniques. The analysis of NMR data combined with restrained molecular dynamics calculations shows that all peptides are fairly flexible and they do not assume a preferred conformation in DMSO and methanol. The peptides containing homo-β-L-Phe and homo-β-L-Phg do adopt a discrete number of conformation among which mainly extended and 'L-shaped' conformation are represented The circular dichroism spectra are consistent with the NMR results, indicating a significant flexibility for these compounds. Copyright
Synthesis and biological evaluation of a cyclo-β-tetrapeptide as a somatostatin analogue
Gademann, Karl,Ernst, Martin,Hoyer, Daniel,Seebach, Dieter
, p. 1223 - 1226 (2007/10/03)
Short β-peptides can mimic natural peptide hormones, as has been shown with a cyclo-β-tetrapeptide (1) that displays micromolar affinity to human somatostatin receptors. β-Peptides are thus a promising new class of peptidomimetics with potential high bioa
On the Preparation of β-Amino Acids from α-Amino Acids Using the Arndt-Eistert Reaction: Scope, Limitations and Stereoselectivity. Application to Carbohydrate Peptidation. Stereoselective α-Alkylations of Some β-Amino Acids
Podlech, Joachim,Seebach, Dieter
, p. 1217 - 1228 (2007/10/02)
The Arndt-Eistert homologation of α-amino acids was studied to determine the stereoselectivity in this reaction by chromatographic up-to-date analytical methods.While carbamate-protected phenylglycine was transformed to the corresponding β-amino acid methyl ester with a stereoselectivity of only 9:1, all other tested amino acid derivatives (Ala, Phe, Ser, Orn, tert-Leu and perhydro-azepine-2-carboxylic acid, suitably protected) were homologated with full retention of configuration (products 9-17).The intermediate diazo ketones 1-8 were purified and characterized by their NMR spectra.When nucleophiles derived from partially protected sugars were present during decomposition of the diazo ketones (derived from amino acids or dipeptides), a strong dependence of the yield (products 21-24) on the degree of steric hindrance of the nucleophilic OH group was observed.Two of the β-amino acids obtained from the homologation reaction were transformed to α-substituted (25-27, 31, 32) and α,α-disubstituted β-amino acid derivatives (28, 29) with excellent selctivities (in most cases, a single diastereoisomer was obtained). - Key Words: β-Amino acids, α-branched/Glycopeptides