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Organic Letters Apr 2013In the presence of a catalytic amount of L-proline (10 mol %), transamidations of carboxamides with amines were achieved under solvent-free conditions. The...
In the presence of a catalytic amount of L-proline (10 mol %), transamidations of carboxamides with amines were achieved under solvent-free conditions. The transamidation process is compatible with a wide range of amines.
Topics: Amides; Amines; Catalysis; Combinatorial Chemistry Techniques; Molecular Structure; Proline; Stereoisomerism
PubMed: 23473076
DOI: 10.1021/ol4002625 -
Molecules (Basel, Switzerland) Feb 2013Among the twenty natural proteinogenic amino acids, proline is unique as its secondary amine forms a tertiary amide when incorporated into biopolymers, thus preventing... (Review)
Review
Among the twenty natural proteinogenic amino acids, proline is unique as its secondary amine forms a tertiary amide when incorporated into biopolymers, thus preventing hydrogen bond formation. Despite the lack of hydrogen bonds and thanks to conformational restriction of flexibility linked to the pyrrolidine ring, proline is able to stabilize peptide secondary structures such as b-turns or polyproline helices. These unique conformational properties have aroused a great interest in the development of proline analogues. Among them, proline chimeras are tools combining the proline restriction of flexibility together with the information brought by natural amino acids side chains. This review will focus on the chemical syntheses of 3-substituted proline chimeras of potential use for peptide syntheses and as potential use as tools for SAR studies of biologically active peptides and the development of secondary structure mimetics. Their influence on peptide structure will be briefly described.
Topics: Peptides; Proline; Protein Structure, Secondary
PubMed: 23429346
DOI: 10.3390/molecules18022307 -
The Journal of Organic Chemistry Mar 2019Fluorinated proline derivatives have found diverse applications in areas ranging from medicinal chemistry over structural biochemistry to organocatalysis. Depending on...
Fluorinated proline derivatives have found diverse applications in areas ranging from medicinal chemistry over structural biochemistry to organocatalysis. Depending on the stereochemistry of monofluorination at the proline 3- or 4-position, different effects on the conformational properties of proline (ring pucker, cis/ trans isomerization) are introduced. With fluorination at both 3- and 4-positions, matching or mismatching effects can occur depending on the relative stereochemistry. Here we report, in full, the syntheses and conformational properties of three out of the four possible 3,4-difluoro-l-proline diastereoisomers. The yet unreported conformational properties are described for (3 S,4 S)- and (3 R,4 R)-difluoro-l-proline, which are shown to bias ring pucker and cis/ trans ratios on the same order of magnitude as their respective monofluorinated progenitors, although with significantly faster amide cis/ trans isomerization rates. The reported analogues thus expand the scope of available fluorinated proline analogues as tools to tailor proline's distinct conformational and dynamical properties, allowing for the interrogation of its role in, for instance, protein stability or folding.
Topics: Halogenation; Molecular Conformation; Proline; Stereoisomerism
PubMed: 30777755
DOI: 10.1021/acs.joc.8b02920 -
Biophysical Journal Aug 2003Proline isomerization is well known to cause additional slow phases during protein refolding. We address a new question: does the presence of prolines significantly... (Comparative Study)
Comparative Study
Proline isomerization is well known to cause additional slow phases during protein refolding. We address a new question: does the presence of prolines significantly affect the very fast kinetics that lead to the formation of folding intermediates? We examined both the very slow (10-100 min) and very fast (4 micro s-2.5 ms) folding kinetics of the two-domain enzyme yeast phosphoglycerate kinase by temperature-jump relaxation. Phosphoglycerate kinase contains a conserved cis-proline in position 204, in addition to several trans-prolines. Native cis-prolines have the largest effect on folding kinetics because the unfolded state favors trans isomerization, so we compared the kinetics of a P204H mutant with the wild-type as a proof of principle. The presence of Pro-204 causes an additional slow phase upon refolding from the cold denatured state, as reported in the literature. Contrary to this, the fast folding events are sped up in the presence of the cis-proline, probably by restriction of the conformational space accessible to the molecule. The wild-type and Pro204His mutant would be excellent models for off-lattice simulations probing the effects of conformational restriction on short timescales.
Topics: Enzyme Activation; Enzyme Stability; Mutagenesis, Site-Directed; Mutation; Phosphoglycerate Kinase; Proline; Protein Conformation; Protein Denaturation; Protein Folding; Recombinant Proteins; Structure-Activity Relationship; Temperature; Yeasts
PubMed: 12885665
DOI: 10.1016/S0006-3495(03)74557-3 -
Carbohydrate Research Mar 2019Six different types of O-benzyl protected proline derivatives have been synthesized from D-glycals and 2C-formyl-glycals. One of the di-O-benzyl protected proline...
Synthesis of di- and trihydroxy proline derivatives from D-glycals: Application in the synthesis of polysubstituted pyrrolizidines and bioactive 1C-aryl/alkyl pyrrolidines.
Six different types of O-benzyl protected proline derivatives have been synthesized from D-glycals and 2C-formyl-glycals. One of the di-O-benzyl protected proline derivatives has been utilized for the synthesis of polysubstituted pyrrolizidines via [3 + 2] cycloaddition in a stereoselective manner. Further, we also report on the stereoselective synthesis of biologically active 1C-aryl/alkyl pyrrolidines i.e. 4-epi-radicamine B, 4-epi-radicamine A, 1C-butyl and 1C-methyl pyrrolidines through double reductive amination of a variety of D-glucal derived diketones with p-methoxybenzylamine.
Topics: Deoxyglucose; Molecular Structure; Proline; Pyrroles
PubMed: 30825721
DOI: 10.1016/j.carres.2019.02.004 -
The Journal of Organic Chemistry Jun 2006In peptides and proteins, the peptide bond between an amino acid and proline exists as an equilibrium mixture of the cis-imide and trans-imide due to the low energy...
In peptides and proteins, the peptide bond between an amino acid and proline exists as an equilibrium mixture of the cis-imide and trans-imide due to the low energy barrier in their interconversion. This feature greatly influences the structure and function of the proline-containing peptides and proteins. Therefore, restricting the amide bond with an (E)- or (Z)-alkene should provide a promising method for elucidating the structure-activity relationships of the peptide and the proteins. In this report, the regio- and stereoselective synthesis of cis-alanylproline (Ala-Pro) type (Z)-alkene dipeptide mimetic is described. The key steps of this synthesis are to introduce a C3 unit onto a gamma-phosphoryloxy-alpha,beta-unsaturated-delta-lactam with an organocopper-mediated anti-S(N)2' reaction and subsequently construct a five-membered proline-like cyclic structure with an intramolecular Suzuki coupling reaction. Hydrolysis of the amide bond in the resulting bicyclic lactam yields the desired cis-Ala-Pro type (Z)-alkene dipeptide isostere. The presented synthetic methodology should be applicable to the general syntheses of other cis-aminoacylproline type (Z)-alkene dipeptide mimetics.
Topics: Alkenes; Combinatorial Chemistry Techniques; Dipeptides; Molecular Conformation; Proline; Stereoisomerism
PubMed: 16776529
DOI: 10.1021/jo0606002 -
Biochemistry Aug 1998The slow fluorescence unfolding phase of bovine pancreatic ribonuclease A is studied by stopped-flow kinetics and site-directed mutagenesis of tyrosines to phenylalanine... (Comparative Study)
Comparative Study
The slow fluorescence unfolding phase of bovine pancreatic ribonuclease A is studied by stopped-flow kinetics and site-directed mutagenesis of tyrosines to phenylalanine and prolines to alanine. It is shown conclusively that this phase arises from two specific sources: Tyr92 reporting on the cis-trans isomerization of Pro93 and Tyr115 reporting on the cis-trans isomerization of Pro114. Previous studies have conjectured that the slow unfolding phase arises from only one source (Tyr92-Pro93 cis-trans isomerization) based primarily on studies of the homologous protein guinea pig ribonuclease A [Schmid, F. X., Grafl, R., Wrba, A., and Beintema, J. J. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 872-876]; it is proposed here that Lys113 in the latter protein interferes with the isomerization of the Lys113-Pro114 peptide group. The site-directed mutations studied here enable the individual isomerizations of Pro93 and Pro114 to be monitored, providing an optical technique by which these well-defined molecular folding events can be studied, under both folding and unfolding conditions, and compared to molecular simulations. The time constants for Pro93 and Pro114 isomerization agree closely with those of our box model of proline isomerization under unfolding conditions, which had been derived from exhaustive statistical modeling of double-jump refolding data [Juminaga, D., Wedemeyer, W. J., Garduño-Júarez, R., McDonald, M. A., and Scheraga, H. A. (1997) Biochemistry 36, 10131-10145].
Topics: Alanine; Animals; Cattle; Guinea Pigs; Isoenzymes; Models, Molecular; Mutagenesis, Site-Directed; Proline; Protein Conformation; Protein Folding; Ribonuclease, Pancreatic; Sequence Homology, Amino Acid; Tyrosine
PubMed: 9708999
DOI: 10.1021/bi981028e -
Pharmacology, Biochemistry, and Behavior May 1978Two- and five-day old chicks were injected intraventricularly with D-proline and structurally related compounds. D-proline produced convulsions and lethality, but was...
Two- and five-day old chicks were injected intraventricularly with D-proline and structurally related compounds. D-proline produced convulsions and lethality, but was non-amnestic, whereas the naturally-occurring isomer, L-proline, was non-convulsant and non-toxic but amnestic. D-proline convulsions were accompanied by decreased high frequency in the EEG and increased slow wave activity. High amplitude spiking was not observed. The lethality of D-proline was saline-dependent. Control experiments ruled out possible toxic factors such as hypertonicity, pH pyrogens, injection volume, or needle misplacement. The results demonstrate that saline and distilled water are not equivalent injection vehicles. A sodium-free vehicle may lead to artifacts but is advantageous in experiments in which amino acid transport must be minimized.
Topics: Animals; Chickens; Convulsants; Drug Interactions; Electroencephalography; Male; Proline; Sodium Chloride; Stereoisomerism
PubMed: 674269
DOI: 10.1016/0091-3057(78)90399-4 -
Acta Crystallographica. Section C,... Oct 2000In the title compound, C(16)H(17)NO(4), the benzyloxycarbonyl group is anti to the pyrrolic N atom. The molecules are joined into head-to-head dimers by hydrogen bonds...
In the title compound, C(16)H(17)NO(4), the benzyloxycarbonyl group is anti to the pyrrolic N atom. The molecules are joined into head-to-head dimers by hydrogen bonds involving the carboxylic acid groups. There is orientational disorder of these groups over two positions with approximately equal occupancy. A weaker hydrogen bond between the pyrrolic N atom and the carbonyl O atom of the benzyloxycarbonyl group joins the dimers into chains running parallel to the [110] direction.
Topics: Crystallography, X-Ray; Hydrogen Bonding; Models, Molecular; Molecular Conformation; Proline; Pyrroles
PubMed: 11025319
DOI: 10.1107/s010827010000980x -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2012As part of our ongoing studies to provide an experimental basis for the improved understanding of organocatalytic reaction mechanisms we present a study on the influence...
As part of our ongoing studies to provide an experimental basis for the improved understanding of organocatalytic reaction mechanisms we present a study on the influence of amine bases on enamine intermediate stabilization in proline catalysis. The (partial) deprotonation of the proline acid function is displayed by characteristic shifts of certain proton resonances and is also manifested by an increase of the amount of enamine intermediate upon reaching a critical pK(aH). Strong bases, such as 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), allow for outstanding enamine stabilization in various solvents and, hence, permit the detection of enamine species that have been inaccessible until now (illustrated by the observation of minor amounts of Z enamines). The in situ NMR detection of a prolinate-DBUH(+) ion pair supports the well-documented reversal of enantioselectivity of proline-catalyzed aminations in the presence of amine bases by disabling the bifunctional activity and switching to a "simple" stereocontrol effect (as known from the Jørgensen/Hayashi-type diarylprolinol ethers). In addition, the possibility of attractive ionic interactions between both the iminium ion and prolinate enamines available in the presence of strong amine bases suggests promotion of the Mannich pathway in aldol reactions to mainly form condensation products.
Topics: Alkalies; Amines; Carboxylic Acids; Catalysis; Kinetics; Magnetic Resonance Spectroscopy; Molecular Structure; Proline; Stereoisomerism
PubMed: 22328539
DOI: 10.1002/chem.201102660