Synthesis of reversible cyclic peptides

A novel approach for the synthesis of cyclic peptides that can exist in either linear or cyclized conformations is described. Synthesis of the peptides was achieved via a modified solid phase methodology. The reversible linear/cyclized (i.e., open/closed) states are controlled via the reduction/oxidation of a disulfide bond incorporated into the backbone of the peptide chain.     

Synthesis of ‘difficult’ peptide sequences: application of a depsipeptide technique to the Jung-Redemann 10- and 26-mers and the amyloid peptide Aβ(1-42)

Recently a 26-mer peptide 1 incorporating Ser and Thr was described as a ‘difficult’ sequence that could not be synthesized by standard methods. If the first Ser residue was used to incorporate a depsipeptide unit, the resulting hybrid was readily assembled. The 26-mer ester was then converted to the native peptide by an O→N acyl shift. The technique may be general for other systems containing appropriate Ser and Thr units and was demonstrated here for the case of the amyloid peptide Aβ(1-42).     

Segment Coupling to a Highly Hindered N-Terminal, Alamethicin-Related alpha-Aminoisobutyric Acid (Aib) Residue

A model [6+5] segment coupling process involving a C-terminal valine hexapeptide acid and a resin-attached pentapeptide amide, which N-terminated in a hindered Aib unit, was examined using a variety of HOAt-derived coupling reagents. Best results were observed with N-HAPyU in DCM solvent in which loss of configuration amounted to 5.8%.     

Emixustat的合成

以3-氨基-1-［3-(环己基甲氧基)苯基］丙-1-醇为原料,经氨基保护、氧化、手性还原、脱保护和成盐等5步反应合成了Emixustat,总收率30.7％,其结构经¹H NMR和MS（ESI）确证。     

Diastereoselective [2+2] photocycloaddition of polymer-supported cyclic chiral enone with ethylene

The phenylmenthyl derivative, previously shown to be very effective chiral auxiliaries in the diastereoselective [2+2] photocycloaddition of cyclic enones with the simplest olefin, ethylene, was attached to poly(ethylene glycol)-grafted Wang resin. We then investigated the diastereoselective [2+2] photocycloaddition on solid support in several solvents. As the result, we accomplished good selectivity in toluene as well as the recycle of the polymer-supported chiral auxiliary. This is the first example that bicyclo[4.2.0]octane derivative has been obtained photochemically on the solid support.     

3-(4-Hydroxymethylphenylsulfanyl)propanoic acid (HMPPA) as a new safety catch linker in solid phase peptide synthesis

A new safety catch linker, 3-(4-hydroxymethylphenylsulfanyl)propanoic acid (HMPPA), is described for use in solid phase peptide synthesis. The linker is readily synthesized from commercially available chemicals in a more cost efficient way compared to similar reported linkers. The HMPPA linker is easily attached to an amino derivatized solid support followed by on-resin oxidation of the thioether to sulfoxide, thereby making the linker very stable towards strong acid treatment. Final resin cleavage is performed by reductive acidolysis.     

Synthesis and properties of 3-arylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and related compounds: photo-induced autorecycling oxidation of some amines

Novel 3-phenyl- and 3-(4-nitrophenyl)cyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and the corresponding imino derivatives 5a,b and 6a,b were synthesized in modest to moderate yields by the abnormal and normal aza-Wittig reaction of 2-(1,3-diazaazulen-2-ylimino)triphenylphosphorane with aryl isocyanates and subsequent heterocyclization reaction with a second isocyanate. The related cationic compound, 1-methyl-3-phenylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-dionylium tetrafluoroborate 7a, was also prepared. The electrochemical reduction of these compounds exhibited more positive reduction potentials as compared with those of the related compounds of 3,10-disubstituted cyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1H,3H)-dione systems. In a search of the oxidizing ability, compounds 5a, 6a, and 7a were demonstrated to oxidize some amines to give the corresponding imines in more than 100% yield under aerobic and photo-irradiation conditions, while even benzylamine was not oxidized under aerobic and thermal conditions at 100 °C. The oxidation reactions by cation 7a are more efficient than that by 5a and 6a. Quenching of the fluorescence of 5a was observed, and thus, the oxidation reaction by 5a probably proceeds via electron-transfer from amine to the excited singlet state of 5a. In the case of cation 7a, the oxidation reaction is proposed to proceed via formation of an amine-adduct of 7a and subsequent photo-induced radical cleavage reaction.     

Anodic formation of 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and 2(3-aryl-5-methyl-1H-[1,2,4]triazol-1-yl)-5-aryl-1,3,4-thiadiazoles

3,6-Disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles together with the unknown systems 2-(3-aryl-5-methyl-1H-[1,2,4]triazol-1-yl)-5-aryl-1,3,4-thiadiazoles were obtained by anodic oxidation, under aprotic conditions, of aryl aldehyde N-(5-aryl-1,3,4-thiadiazol-2-yl) hydrazones. Mechanistic proposals are given.     

Synthesis of substituted 4-(1H-indol-6-yl)-1H-indazoles as potential PDK1 inhibitors

The development of a preparative route to a series of novel 4-(1H-indol-6-yl)-1H-indazole compounds as potential PDK1 inhibitors is described. The synthetic strategy centres on the late-stage Suzuki cross-coupling of N-unprotected indazole and indole fragments. The use of a monoligated palladium catalyst system was found to be highly beneficial in the cross-coupling reaction. The indazole and indole fragments were constructed by diazotisation/cyclisation and S_NAr/reductive cyclisation sequences, respectively.     

Domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylalkylidene)malononitriles: synthesis of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans and a rare case of [1,5] sigmatropic shift of the nitro group

A variety of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans were easily synthesized in good yields under mild conditions by a domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylethylidene)- and 2-(1-phenylpropylidene)malononitriles. In the latter case, intermediate 7-amino-10-methyl-10-nitro-9-phenyl-6-(trifluoromethyl)-10,10a-dihydro-6H-benzo[c]chromene-8-carbonitriles were isolated as a result of a rare [1,5] sigmatropic shift of the nitro group.     

Reaction of Some Heterocyclic Formamidines with Trimethylsilylethynyllithium

The reaction of a 2-[(dimethylamino)methyleneamino]pteridine, two 2-[(dimethylamino)methyleneamino]pyrimidines, and a 2-[(dimethylamino)methyleneamino]pyrido[2,3-d]pyrimidine with trimethylsilylethynylithium in the presence of benzyl chloroformate leads to the corresponding 2-[bis(trimethylsilylethynyl)methylamino]-substituted heterocycles. A series of such substrates was prepared and some of the factors which permit this transformation were delineated. An X-ray crystal structure was determined of one of the products - 2-[bis(trimethylsilylethynyl)methylamino]-5,6,7,8-tetrahydro-3-(2,2-dimethylpropanoyloxymethyl)quinazolin-4-one.     

Synthese und Reaktionsverhalten von 3-(Bis(alkylthio)methylen)-3H-isobenzofuran-1-on-und 2-(Bis(alkylthio)methylen)-3(2H)-benzofuranon-Derivaten

Summary 3(Bis(alkylthio)methylene)-3H-isobenzofuran-1-ones2a–e and 2-(bis(alkylthio)methylene)-3(2H)-benzofuranone derivatives4a–c are obtained by reaction of phthalides1a–d or 3(2H)-benzofuranone (coumaranone3), respectively, with carbon disulfide under basic conditions followed by alkylation. The reaction behaviour of the new compounds2 and4 is investigated. 2-((2-Dimethylthio-1-oxo)ethyl)benzoic acid N,N-dimethylamide (7a) and 2-((2-dimethylthio-1-oxo)ethyl)-benzoic acid 2-methylpiperidide (7b) are surprisingly formed instead of the methylthio substitution products by treatment of2a with the corresponding amine in the presence of aluminum chloride.

Herrn Professor Dr. Dr. h. c.Waldemar Adam zum 60. Geburtstag gewidmet     

Preparation of peptide thioesters using Fmoc strategy through hydroxyl side chain anchoring

In the course of the chemical synthesis of human protein mitogaligin, we present here a simple method to prepare peptide thioesters using Fmoc chemistry. The hydroxyl side chain of serine was reacted with a trichloroacetimidate Wang resin to anchor it on solid phase. After peptide elongation and orthogonal unmasking of the C-terminus, the amino thioester was introduced under optimized conditions to avoid epimerization.     

Rapid access to 3-(N-substituted)-aminoquinolin-2(1H)-ones using palladium-catalyzed C-N bond coupling reaction

A series of 3-(N-substituted)-aminoquinolin-2(1H)-ones have been synthesized by the palladium-catalyzed C-N coupling reaction starting from 3-bromoquinolin-2-(1H)-ones. Various nucleophiles including amines, amides, sulfonamides, carbamates and ureas have been used successfully. In all the cases, the reactions take place rapidly in 1,4-dioxane and proceed in good to excellent yield using palladium acetate as a catalyst, Xantphos as a ligand and Cs₂CO₃ as a base.     

AlCl3-mediated tandem Friedel-Crafts reactions of vinylidenecyclopropanes with acyl chlorides: a facile synthetic method for the construction of 1-[2-(2,2-diarylvinyl)-1-phenyl-3H-inden-5-yl]ethanone derivatives

AlCl₃-mediated tandem Friedel-Crafts reaction of vinylidenecyclopropanes with acyl chlorides produced the corresponding 1-[2-(2,2-diarylvinyl)-1-phenyl-3H-inden-5-yl]ethanone derivatives in moderate to good yields under mild conditions within short reaction time.     

1-[4-(二甲氨基)苯亚甲基氨基]-4-苯基硫脲的另一个手性对映体晶体结构

对-二甲氨基苯甲醛和苯基氨基硫脲缩合反应生成1-[4-(二甲氨基)苯亚甲基氨基]-4-苯基硫脲(DMB), 产物能从溶液中析出单一手性对映体晶体. 用单晶X射线衍射技术测定了它的绝对构型, 晶体属正交晶系, P2₁2₁2₁空间群, a＝0.7870(2) nm, b＝1.1560(2) nm, c＝1.6668(3) nm, V＝1.5164(5) nm³, Z＝4, D_c＝1.307 g/cm³, F(000)＝632, μ＝0.213 mm^－1, 2557个可观测点[I＞2s(I)]精修的最终残差因子: R＝0.0409, wR＝0.1061, Flack参数为0.00(9), 能够确定绝对构型. 化合物的晶体结构和大宗粉末样品的固体圆二色谱表明化合物在结晶过程中发生单一对映体的手性堆积.     

An efficient electrochemical method for a unique synthesis of new derivatives of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one

The electrochemical oxidation of catechols (1a-c) has been studied in the presence of 6-methyl-1,2,4-triazine-3-thion-5-one 3 in aqueous sodium acetate, using cyclic voltammetry and controlled-potential coulometry. A plausible mechanism for the oxidation of catechols and their reaction with 3 is presented. All the catechol derivatives (1a-c) were converted into 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives (6a-c) through a Michael-type addition reaction of 3 to anodically generated o-quinones. The electrochemical syntheses of 6a-c were successfully performed in one pot in an undivided cell using an environmentally friendly method with high atomic economy.     

Structure and Photosynthetic Mimicking of Bis(2,6-bis(benzimidazol-2-yl)pyridine)manganese(II)

Introduction　　Manganeseionsplayanimportantroleinthelight in ducedoxidationofwatertomolecularoxygeninphotosys temII (PSII)ofgreenplants.1 3Inrecentyears ,man ganesecomplexesofpolypyridineligands ,suchasbipyri dine ,1,10 phenanthrolineand 2 ,2′:6′,2″ terpyridine ,havehadconsiderableattentionasthecomplexesformedareusefulmodelsformanganese containingbimolecu lars .4 6 Therefore ,synthesisandcharacterizationofman ganeseinitsvariousoxidationstates ,withvariousligandtypesandnuclearities ,hav…     

Controlling the outcome of overacylation of N-protected aminooxyacetic acid during the synthesis of an aminooxy-peptide for chemical ligation

An aminooxy-containing peptide, the nucleophile partner for oxime ligations, is usually grafted on a NH₂-peptide resin by activating a protected aminooxyacetic acid as an active ester. Here, we have shown that its subsequent coupling to NH₂-peptide resin competes with the overacylation of the -NH-O- nitrogen and that the overacylation level increases with the basicity of the reaction mixture. Moreover, we found that overacylation is prevented when the COOH of the Aoa-derivatives is engaged in an amide bond.     

A novel synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones

An improved synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones, a known subclass of 4-deazatoxoflavins, is reported. The approach involves treatment of 3-methyl-6-(1-methylhydrazinyl)uracil with representative phenyl and alkyl glyoxal monohydrates, which in turn are obtained by selenium dioxide oxidation of the corresponding phenyl and alkyl methyl ketones. The first entry into 4-monosubstituted isomers is also reported.