Peptide bond isosteres: ester or (E)-alkene in the backbone of the collagen triple helix

[structure: see text] Collagen is the most abundant protein in animals. Interstrand N-H...O=C hydrogen bonds between backbone amide groups form a ladder in the middle of the collagen triple helix. Isosteric replacement of the hydrogen-bond-donating amide with an ester or (E)-alkene markedly decreases the conformational stability of the triple helix. Thus, this recurring hydrogen bond is critical to the structural integrity of collagen. In this context, an ester isostere confers more stability than does an (E)-alkene.     

Stereoselective synthesis of (Z)-alkene-containing proline dipeptide mimetics

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.     

Convergent approach to (E)-alkene and cyclopropane peptide isosteres

Trisubstituted (E)-alkene isosteres (TEADIs) and novel cyclopropane amide bond isosteres (CPDIs) were synthesized by aldimine addition and three-component aldimine addition-cyclopropanation methodologies, respectively. These new peptide mimetics can serve as beta-turn promoters.     

Serine-cis-proline and serine-trans-proline isosteres: stereoselective synthesis of (Z)- and (E)-alkene mimics by Still-Wittig and Ireland-Claisen rearrangements

Two new amide isosteres of Ser-cis-Pro and Ser-trans-Pro dipeptides were designed and stereoselectively synthesized to be incorporated into potential inhibitors of the phosphorylation-dependent peptidylprolyl isomerase Pin1, an essential regulator of the cell cycle. The cis mimic, the (Z)-alkene isomer, was formed through the use of a Still-Wittig [2,3]-sigmatropic rearrangement, while the trans mimic, the (E)-alkene, was synthesized through the use of an Ireland-Claisen [3,3]-sigmatropic rearrangement. Starting from N-Boc-Ser(OBn)-N(OMe)Me, both mimics were synthesized in Boc-protected form suitable for peptide synthesis with an overall yield of 20% in 10 steps for the cis mimic and 13% in eight steps for the trans mimic.     

Novel rearrangement of chloromethylvinylsilanes into allylsilanes. Stereoselective synthesis of metallated allylsilanes from 1-alkynes

Regio and stereoselective hydralumination of 1-(chloromethyldimethylsilyl)-1-alkyne with diisobutylaluminium hydride (DIBAH) affords (Z)-1-(chloromethyldimethylsilyl)-1-(diisobutylalumino)-1-alkene. Treatment of the aluminium-substituted vinylsilane with 3 equivalents of methyllithium affords (E)-1-(trimethylsilyl)-2-lithio-2-alkene as a sole product. Reaction of aluminium-substituted vinylsilane with trimethylaluminium in refluxing heptane produces a mixture of (E)-1-trimethyl-silyl-2-alumino-2-alkene and 2-trimethylsilyl-1-alkene. Reaction of 1-(chloromethyldimethylsilyl)-1-alkyne with triisobutylaluminium gives 2-(isobutyldimethylsilyl)-1-alkene exclusively. Reactions of the lithiated allylsilane with several electrophiles give the corresponding carbometallated products, allylsilanes bearing alkyl, allyl, vinyl, or alkoxycarbonyl groups. Protodesilylation of 3-(trimethylsilylmethyl)-1,3-decadiene gives 3-methylene-1-decene selectively. Reaction of trialkylaluminium with trimethylsilylethyne gives bistrimethylsilylated diene by successive addition of silylethyne to the aluminium reagent; in contrast, chloromethyldimethylsilylethyne gives the mono-adduct regio and stereoselectively.     

Synthesis of (Z)-alkene-containing cis-proline dipeptide mimetics using samarium(II) diiodide (SmI2)-mediated reductive alkylation reaction

The amide bond between an amino acid and proline can take the trans- or cis-conformation. The conformation influences both the structure and function of peptides and proteins. Therefore, constrained mimetic, which corresponds to Pro-dipeptides whose amide bond is replaced with an (E)- or (Z)-alkene, is a useful bioprobe for elucidating the structure-function relationship of peptides and proteins. Herein, we report the synthesis of cis-(Z)-alkene-containing Pro-dipeptide mimetics via a samarium(II) diiodide (SmI₂)-mediated reductive alkylation reaction.     

Synthesis of orthogonally protected disulfide bridge mimetics

Concise routes to four orthogonally protected, enantiopure disulfide bridge mimetics are reported. These four dicarba analogues possess an alkyne, an (E)-alkene, a (Z)-alkene, and an alkane as substitutes for the disulfide bridge. Selective deprotection of one of these mimetics is also illustrated.     

Styrene/(Styrene Derivative) and Styrene/(1-Alkene) Copolymerization using Ph2Zn-Additive Initiator Systems

Diphenylzinc-metallocene-MAO initiator systems have proven to be effective initiator systems for styrene and for substituted styrenes as well as for their styrene/(styrene-derivative) copolymerization. Titanocene produced almost pure syndiotactic polymers while zirconocenes gave atactic polystyrene together with a low content, less than 20%, of syndiotactic polystyrene. Systems including a zirconocene, particularly ethenyl(bisindenyl)zirconium dichloride were effective initiators of 1-alkene polymerization and of styrene/1-alkene copolymerization. Conversion to polymer increases with the molecular size of 1-alkene. Styrene derivative and styrene/(styrene derivative) polymerization was greatly influenced by the inductive effect of substituent and by steric hindrance due to the monomer.     

A palladium-catalyzed three-component cross-coupling of conjugated dienes or terminal alkenes with vinyl triflates and boronic acids

A three-component coupling of vinyl triflates and boronic acids to alkenes catalyzed by palladium is reported. Using 1,3-dienes, selective 1,2-alkene difunction-alization is observed, whereas the use of terminal alkenes results in 1,1-alkene difunctionalization. The reaction outcome is attributed to the formation of stabilized, cationic Pd-π-allyl intermediates to regulate β-hydride elimination.     

Stereoselective synthesis of (Z)-2-fluoro-1-alkenyl(phenyl)iodonium tetrafluoroborates

[reaction: see text] (Z)-2-Fluoro-1-alkenyl(phenyl)iodonium salts were stereoselectively prepared by the reaction of alkynyl(phenyl)iodonium salts with aqueous HF in good yields. The method is applicable to the synthesis of fluoroalkenyliodonium salts having functional groups such as ketone, ester, and chloride. (Z)-2-Fluoro-1-alkene, (Z)-2-fluoro-2-alkenoate, and (Z)-beta-fluoroenyne could be stereoselectively prepared from the fluoroalkenyliodonium salt.     

Stereoselective Synthesis of (Z)-1,2-Diarylthio-1-alkene via the Reaction of Diaryl Disulfides with Terminal Alkynes Catalyzed by Cesium Hydroxide

In the presence of a catalytic amount of cesium hydroxide under a nitrogen atmosphere, terminal alkynes reacted with diaryl disulfides at room temperature in dimethylformamide to give almost exclusively (Z)-1,2-diarylthio-1-alkene in good yields, but under an air atmosphere, the reaction gave a mixture of alkynyl sulfide and (Z)-1,2-diarylthio-1-alkene.     

Electrochemical polymerization of dicarboxylic acids—IV. Polymerization of sebacic acid

The electrolysis of sebacic acid was investigated in methanol, methanol:pyridine (1:1) and methanol:acetonitrile (1:1). The various products were analyzed. In methanol, the major product was the oligomeric carboxylic acid fraction (55%) and the yield of oligomeric hydrocarbons and polymer was lower. With the other two solvents, the polymer was the major product. Four types of hydrocarbons were formed: n-alkane, 1-alkene, x-alkene (the position of the double bond is not known) and cycloalkane. The polymers obtained in all the solvents had the character of cross-linked and branched polyethylene, having ester and methoxy groups. These polymers did not suffer degradation during basic hydrolysis. In comparison with adipic acid, sebacic acid had more tendency to yield polymer and carboxylic acids than hydrocarbons.     

Identification of isomeric structures of phenyl and trimethylsilyl substituted 1-alkenes by gas chromatography

Summary Gas chromatographic retention indices had been measured on two different stationary phases for phenyl and trimethylsilyl substituted 1-alkenes formed during the pyrolysis of a styrene-trimethylvinyl silane copolymer. Retention index differences due to the alteration of trimethylsilyl to phenyl substituent groups at different positions in the molecules of the 1-alkene skeleton were determined. Based on these values the isomeric structure of the pyrolysis products has been identified by determining the position of the trimethylsilyl and phenyl groups in these substituted 1-alkenes. The results correspond to the mechanism of the copolymer's thermal degradation.     

Cesium hydroxide-catalyzed hydrothiolation of alkynyl selenides to highly stereo- and regioselectively synthesize(Z)- -organoseleno-2-arylthio-1-alkenes

In the presence of catalytic amount of cesium hydroxide the hydrothiolation of alkynyl selenides occurred at room temperature in DMF under nitrogen atmosphere to give exclusive(Z)-1-organoseleno-2-arylthio-1-alkene in excellent yields.It could provide a new and expedient way for the preparation of(Z)-1-arylseleno-2-arylthio-1-alkene.     

Synthesis of the C12-C24 fragment of peloruside A by silyl-tethered diastereomer-discriminating RCM

The C12-C24 fragment of peloruside A has been synthesized using, as a key step, a silyl-tethered ring closing metathesis reaction to form the C16-C17 (Z)-alkene. The metathesis reaction discriminates between diastereoisomers of the starting material. A diphenylsilyl bis-ether provides simultaneous protection for the C15 and C24 hydroxyl groups, and is expected to lead to high 1,5-anti selectivity in subsequent aldol reactions of the methyl ketone, allowing for a convergent stereoselective synthesis of peloruside A.     

Contribution of intramolecular C=O...H-N hydrogen bonding to the solvent-induced reentrant phase separation of poly(N-isopropylacrylamide)

Changes in the local environment around amide groups of poly(N-isopropylacrylamide) (PNiPA) during a solvent-induced reentrant phase separation have been investigated by infrared spectroscopy combined with quantum chemical calculations. The addition of methanol or tetrahydrofuran as a cosolvent to an aqueous solution of PNiPA causes spectral changes in the amide I regions. By preparing a dimer model compound for PNiPA, we can establish the assignment of the amide I bands for the polymer in solutions. Hydrogen-deuterium exchange experiments of the amide protons of PNiPA and its dimer models have revealed that the amide groups of PNiPA form an intramolecular C=O...H-N hydrogen bond even in a good solvent. The result has suggested that the change in the amide I envelope of PNiPA observed during the solvent-induced phase transition reflects the modification of the intramolecular C=O...H-N hydrogen bond of PNiPA as well as the variation in solvation state of the amide groups. On the basis of the assignment, we have discussed contributions of the intramolecular C=O...H-N hydrogen bond to the phase behavior of PNiPA.     

Synthesis of silica-based sulfonic cation-exchangers by the reaction of the addition of hydrosulfite ions to immobilized alkenes and their use in chromatography

A simple two-stage procedure was developed for synthesizing sulfonic cation exchangers on the basis of silica gel. It consists in the attachment of ω-alkene ethoxysilanes to the silica surface followed by their sulfonation under very mild conditions. The synthesized adsorbents have a uniform surface and a high density of attached ion-exchange groups (up to 0.27 mmol/g). The high rate and efficiency of the adsorption of cations enable the successful application of the synthesized materials in the adsorption preconcentration and chromatographic separation processes.     

氢氧化铯催化二硫醚、二碲醚与端炔反应研究

氢氧化铯催化下, 以商业THF作溶剂, 在氮气氛中二芳基二硫醚与端炔室温反应, 立体选择地生成(Z)-1,2-二芳硫基烯. 在空气氛中反应, 得到(Z)-1,2-二芳硫基烯与炔硫醚的混合物. 二芳基二碲醚与端炔反应, 不论在氮气氛中或空气氛中, 都只产生炔碲醚. 但是在氮气氛中炔碲醚的收率仅为空气氛中反应的50%, 对上述反应机理进行了讨论.     

Synthetic studies on (−)-FR182877: construction of the ABCD ring system via the intramolecular cycloadditions (2)

Construction of the ABCD ring system of (−)-FR182877 via the intramolecular Diels-Alder (IMDA) reaction and the highly diastereoselective intramolecular hetero-Diels-Alder (IMHDA) reaction is described. The IMHDA reactions of the substrates incorporating the oxabutadiene with the E- or Z-alkene were examined, revealing that the sole product was obtained from both substrates and the E-alkene geometry was found to be crucial to obtaining the desired product.     

Electrostatic versus steric effects in peptidomimicry: synthesis and secondary structure analysis of gramicidin S analogues with (E)-alkene peptide isosteres

A concise synthetic strategy was used for the first preparation of GS analogues with trisubstituted (E)-alkene peptide bond replacements. Solution and solid state conformational analysis demonstrated that the bistrifluoromethylated analogue was a superior mimic of the natural product, whereas the incorporation of methyl groups into the alkene peptide isostere led to a far greater perturbation of the secondary structure features of GS. The difference between CF3- and CH3-substitution can be explained by the superior electrostatic carbonyl group mimicry of the former function.