Metal‐Free,Regioselective Triazole Ligations that Deliver Locked cis Peptide Mimetics

Metal‐free triazole turns : 1,5‐Disubstituted peptidyl triazoles are obtained regioselectively from the 1,3‐dipolar cycloaddition of peptidyl phosphoranes and azides. Peptide turns are thus formed that contain a conformationally locked cis peptide bond. Being regioselective and free of heavy metals, this reaction may find broad application in chemical biology and medicinal chemistry.

     

Solid-phase synthesis of biaryl cyclic peptides by borylation and microwave-assisted intramolecular Suzuki-Miyaura reaction

Miyaura borylation and Suzuki-Miyaura cross-coupling have been combined to set up an efficient strategy for the solid-phase synthesis of biaryl cyclic peptides. The Miyaura borylation was the key step in obtaining the linear peptidyl resin precursor containing both the boronate and the halogenated derivative of an aromatic amino acid. The Suzuki-Miyaura macrocyclization was performed under microwave irradiation leading to biaryl cyclic peptides of different ring sizes.     

Phosphinofenchol or metastable phosphorane? Phosphorus derivatives of fenchol

Not the expected phosphinofenchol 1 but phosphorane 2 is obtained after reaction of 2-lithio(diphenylphosphino)benzene with (-)-fenchone. Surprisingly, ONIOM(B3LYP/6-31G*:UFF) computations of 1 and 2 as well as B3LYP analyses of smaller model systems point to a lower thermodynamic stability of phosphoranes relative to their isomeric alkoxyphosphines. An analogue inherent instability is computed for the methylphosphorane 10, which is also synthesized and characterized by X-ray analysis. Decreasing ring size in cyclic phosphoranes, that is, from five- to four-membered ring systems, destabilizes cyclic phosphoranes even more. This computational prediction is verified experimentally by reaction of lithiomethyl(diphenylphosphine) with (-)-fenchone and subsequent isolation of the corresponding phosphinofenchol. Protonation or alkylation of phosphoranide intermediates can account for the formation of metastable phosphoranes.     

2-Formyl-5-nitrothiophene as a reagent for phosphoranes

2-Formyl-5-nitrothiophene has high reactivity with respect to phosphoranes, with which it reacts quantitatively to give l-aryl-3-(5-nitro-2-thienyl)propenones. The reaction can be used for the qualitative detection of phosphoranes.     

Fmoc solid-phase synthesis of peptide thioesters using an intramolecularn,S-acyl shift

[reaction: see text] We describe the Fmoc solid-phase synthesis of peptide thioesters based on the alkylation of the safety-catch sulfonamide linker with a protected 2-mercaptoethanol derivative. The thioester is generated on the solid phase after the peptide chain assembly as a consequence of an intramolecular N,S-acyl shift. Depending on the stability of the spacer separating the sulfonamide linker from the resin toward TFA, treatment of the peptidyl resin with TFA led to a soluble or supported deprotected thioester.     

π-SCF-MO-Berechnungen an phosphoranen

The ground state properties of three phosphoranes are calculated by use of a semiempirical π-SCF-MO-method. The resulting relative thermōdynamic stabilities are correlated with the reactivities of those phosphoranes.     

Reaction of 2-trifluoromethyl-4H-3,1-benzoxazin-4-one derivatives with carboethoxymethylenetriphenylphosphorane

Treatment of a series of 2-trifluoromethyl-4H-3,1-benzoxazin-4-one derivatives 1 with carboethoxymethyl-enetriphenylphosphorane 2 yielded the phosphoranes 3 in boiling toluene solution. Thermolysis of these phosphoranes 3 gave esters 6.     

Pseudorotation barriers of biological oxyphosphoranes: a challenge for simulations of ribozyme catalysis

Pseudorotation reactions of biologically relevant oxyphosphoranes were studied by using density functional and continuum solvation methods. A series of 16 pseudorotation reactions involving acyclic and cyclic oxyphosphoranes in neutral and monoanionic (singly deprotonated) forms were studied, in addition to pseudorotation of PF5. The effect of solvent was treated by using three different solvation models for comparison. The barriers to pseudorotation ranged from 1.5 to 8.1 kcal mol(-1) and were influenced systematically by charge state, apicophilicity of ligands, intramolecular hydrogen bonding, cyclic structure and solvation. Barriers to pseudorotation for monoanionic phosphoranes occur with the anionic oxo ligand as the pivotal atom, and are generally lower than for neutral phosphoranes. The OCH3 groups were observed to be more apicophilic than OH groups, and hence pseudorotations that involve axial OCH3/equatorial OH exchange had higher reaction and activation free energy values. Solvent generally lowered barriers relative to the gas-phase reactions. These results, together with isotope 18O exchange experiments, support the assertion that dianionic phosphoranes are not sufficiently long-lived to undergo pseudorotation. Comparison of the density functional results with those from several semiempirical quantum models highlight a challenge for new-generation hybrid quantum mechanical/molecular mechanical potentials for non-enzymatic and enzymatic phosphoryl transfer reactions: the reliable modeling of pseudorotation processes.     

第五、六族元素的有机化合物在有机合成中应用的研究——ⅩⅥ.膦、胂叶立德的X光电子能谱研究

本文报导了利用X光电子能谱(XPS)对一些膦,胂叶立德化合物的P-C键和As-C键的研究。测定了膦化合物的P 2p和胂化合物的As 3d电子的结合能量(E_b)。按改进的Pauling电负性法计算了被测原子的有效电荷。根据与三苯基膦(三苯基胂)比较的结果,讨论了结合能位移(即化学位移)与结构的关系。我们认为所测原子的E_b升高,说明它带正电荷,应是叶立德结构。又从化学位移的相对变化率不同,似乎胂化合物叶立德贡献多,而膦化合物叶仑贡献多,这与二者的化学反应活性相符     

Self-consistent spectrophotometric basicity scale in acetonitrile covering the range between pyridine and DBU

A self-consistent spectrophotometric basicity scale in acetonitrile, including DBU, ten (arylimino)tris(1-pyrrolidinyl)phosphoranes, two (arylimino)tris(dimethylamino)phosphoranes, 2-phenyl-1,1,3, 3-tetramethylguanidine, 1-(2-tolyl)biguanide, benzylamine, two substituted benzimidazoles, pyridine, and ten substituted pyridines, has been created. The span of the scale is almost 12 pK(a) units. Altogether, 29 different bases were studied and 53 independent equilibrium constant measurements were carried out, each describing the relative basicity of two bases. The scale is anchored to the pK(a) value of pyridine of 12.33 that has been measured by Coetzee et al. Comparison of the basicity data of phenyliminophosphoranes and phenyltetramethylguanidines implies that the P=N bond in the (arylimino)tris(1-pyrrolidinyl)phosphoranes involves contribution from the ylidic (zwitterionic) structure analogous to that found in phosphorus ylides.     

Synthesis of 2-alkenyl-3-(alkoxycarbonyl)furans based on Feist-Benary cyclocondensation of (2,4-dioxobutylidene)phosphoranes with alpha-haloketones and alpha-chloracetaldehyde

3-Acyl-2-alkenylfurans were prepared by "Feist-Benary cyclocondensation" of (2,4-dioxobutylidene)phosphoranes with chloracetaldehyde and alpha-haloketones and subsequent Wittig reactions.     

Biologically relevant phosphoranes: synthesis and structural characterization of glucofuranose-derived phosphoranes with penta- and hexacoordination at phosphorus

Carbohydrate-based phosphoranes were synthesized by reacting the appropriate diphenol with phosphorus trichloride followed by the addition of chloralose to form 1 and by the addition of isopropylidene-D-glucofuranose to form 2 and 3. Phosphorane 4 was obtained by reacting 1,2-O-isopropylidene-alpha-D-glucofuranosyl-3,5,6-phosphite (13) with a diphenol. For the synthesis of 5-9, the appropriate phosphite was reacted with isopropylidene-glucofuranose. X-ray analyses of 1-9 were carried out successfully. Hexacoordinated structures resulted via oxygen donor action at phosphorus in the cases of phosphoranes 1-3 and via sulfur donor action for phosphoranes 4-6. Trigonal bipyramidal structures formed for 7-9 with the carbohydrate components occupying axial-equatorial sites. The eight-membered ring of the diphenol moiety with weak or no donor groups in 7-9 occupied diequatorial sites of the trigonal bipyramid. Solution NMR data are in agreement with the assigned solid-state structures. Isomerism between penta- and hexacoordination is present in solution for 7. The isomerism observed for 7 and our previous study showing a rapid exchange process that reorients the carbohydrate component of the trigonal bipyramidal phosphorane suggest that these biophosphoranes may serve as models for active sites of phosphoryl-transfer enzymes. At an active site, this type of pseudorotational behavior provides a mechanism that could bring another active site residue into play and account for a means by which some phosphoryl-transfer enzymes express promiscuous behavior.     

Comparison of the applicability of 2-hydroxyethylsulfonylmethyl- and chloromethyl-polystyrenes in the solid-phase synthesis of protected peptides

In order to compare the applicability of resins in the preparation of protected peptides two solid-phase syntheses of a protected ACTH-(5–10)-hexapeptide have been performed, one using 2-hydroxyethylsulfonylmethyl-polystyrene and the other with Merrifield's chloromethylated polystyrene. To obtain a good comparison, equivalent methods were used as far as possible. Optimal conditions for deprotection of amino groups and for the liberation of the end-product were determined. Chromatographic examination of the crude fission products of the peptidyl resins presented important clues towards the nature of the underlying fission mechanism. Using an automated peptide synthesizer the pure end-product was obtained from both resins in approximately the same yield (ca. 70%). It appeared that the isolation of the product from the suffone resin is less laborious, since the critical alkali-treatment, necessary for the liberation of the product, proceeds faster and, if properly carried out, avoids transesterification.     

Formation of the cage-like phosphoranes with the P-C and P-N bonds in the reactions of 2-(2-benzylidenamino)phenoxy-4-tert-butylbenzo-1,3,2-dioxaphosphol with ethyl mesoxalate and ethyl trifluoropyruvate

The reaction of 2-(2-benzylidenamino)phenoxy-4-tert-butylbenzo-1,3,2-dioxaphosphol with ethyl mesoxalate and ethyl trifluoropyruvate resulted in the formation of tricyclic phosphoranes with the P-C and P-N bonds. The adduct emerged from the initial reaction of the P^III derivative with the activated ketone (1: 1), further underwent the transformation via the intramolecular reaction involving the benzylideniminoaryl substituent, which resulted in the formation of the cage-like phosphoranes.     

Synthesis of novel pyridocoumarins and benzo-fused 6-azacoumarins

Benzo[7,8]-fused 6-azacoumarins are prepared from 4-quinolinol by treatment with PPh₃ and DMAD, or from 3-formyl-4-quinolinol by Wittig reaction with carbalkoxyalkylidene(triphenyl)phosphoranes. Angular pyridocoumarins are prepared from 8- or 6-quinolinols with PPh₃ and DMAD, or from the reactions of 5,6- or 7,8-quinolinediones with carbalkoxymethylene(triphenyl)phosphoranes.     

Solid-phase synthesis of biaryl cyclic peptides containing a histidine-tyrosine linkage

A solid-phase strategy for the synthesis of biaryl cyclic peptides containing a side-chain to side-chain His-Tyr linkage was developed. The key step was the macrocyclization of a linear peptidyl resin incorporating a 5-bromohistidine and a 3-boronotyrosine via the formation of the biaryl bond by means of a microwave-assisted Suzuki-Miyaura reaction. This method allowed direct access to biaryl cyclic peptides containing a 3- or 5-amino acid ring and bearing the histidine residue at the N- or the C-terminus, being especially conducive for analogues in which this amino acid is located at the C-terminus. This study also served to establish a strategy for the synthesis of biaryl cyclic peptides derived from the two hemispheres of the natural biaryl bicyclic peptides aciculitins.     

Conformational properties of cyclic pentaalkoxy phosphoranes: Apical–equatorial attachment and nonchair conformation of the phosphorus-containing six-membered ring

A series of phosphoranes with pentacovalent phosphorus contained in a 1,3,2-dioxaphosphorinane ring have been studied by ¹H NMR. One compound was investigated by low-temperature ¹³C NMR and another by X-ray crystallography. Although the ¹H NMR parameters observed are time-averaged, the coupling constants can be accounted for if the phosphoranes have the six-membered ring attached apical–equatorial to phosphorus and occupy in solution rapidly isomerizing boat or slightly twisted boat conformations similar to that found in the X-ray study.     

Synthesis and X-Ray Analysis of New Spirophosphoranes

Abstract

2- and 3-hydroxyalkyliminophosphoranes and their valencetautomeric pentacoordinated phosphoranes are deprotonated by KH to give anionic pentacoordinated phosphoranes. Upon methylation the latter are converted into N-methyl derivatives. The geometries of these compounds are determined by X-ray analysis and n.m.r. spectroscopy.     

Thermodynamics of interactions of vancomycin and synthetic surrogates of bacterial cell wall

Glycopeptide antibiotics, including vancomycin, form complexes via a set of five hydrogen bonds with the acyl-l-Lys-d-Ala-d-Ala portion of the peptidyl stems of the bacterial cell wall peptidoglycan. This complexation deprives the organism from the ability to cross-link peptidyl stems of the peptidoglycan, leading to bacterial cell death. Four synthetic fragments as surrogates of the components of the bacterial cell wall have been prepared in our lab in multistep syntheses. These synthetic samples were used in investigations of the thermodynamics properties (DeltaG degrees , DeltaH degrees , and TDeltaS degrees ) for the complexation with vancomycin by isothermal titration calorimetry (ITC). Complexation with the glycopeptide analogues is largely enthalpy-driven (formation of five hydrogen bonds), and in the analogues with a single peptidyl stem, the complexation is 1:1. The complexation is more complicated with an approximately 2 kDa cell wall surrogate (compound 4), which possesses two peptidyl stems. The data were suggestive of interactions between the two vancomycin molecules, with an entropic penalty attributable to restriction of molecular movements within the complex due to restriction of motion of the highly mobile acyl-d-Ala-d-Ala moiety of the peptidyl stems. These data were reconciled with the recently determined NMR solution structure for the peptidoglycan fragment 4 and its implications for the larger cell wall.     

Novel results obtained by freezing berry pseudorotation of phosphoranes (10‐P‐5)

By freezing Berry pseudorotation of spirophosphoranes with recourse to the rigidity of the Martin bidentate ligand, we successfully prepared configurationally stable enantiomeric pairs of optically active phosphoranes, and could isolate “anti‐apicophilic” C‐apical O‐equatorial (O‐cis) phosphoranes. The effect of σ*_{P O} orbital of the O‐cis phosphorane was investigated both experimentally and theoretically. O‐cis phosphoranes were revealed to be much more electrophilic at the phosphorus atom than O‐trans isomers by experimental studies. The acidity of the α‐proton of an O‐cis benzylphosphorane was found to be higher than that of the corresponding O‐trans isomer. By the reaction of the α‐carbanion of an O‐cis benzylphosphorane with PhCHO, we succeeded in the first isolation and full structural characterization of a 12‐P‐6 phosphate bearing an oxaphosphetane ring, the intermediate in the Wittig type reaction using a 10‐P‐5 phosphorane. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:390–396, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10072