Isocyanate and carbodiimide synthesis by nitrene-group-transfer from a nickel(II) imido complex

The imido complex (dtbpe)Ni(N(2,6-(CHMe2)2C6H3)) reacts with CO and CNCH2Ph with addition at the Ni-N bond to give (dtbpe)Ni(C,N:eta 2-C(O)N(2,6-(CHMe2)2C6H3)) and (dtbpe)Ni(C,N:eta 2-C(NCH2Ph)N(2,6-(CHMe2)2C6H3)); both complexes react further with CO to liberate the isocyanate and carbodiimide ligands with formation of (dtbpe)Ni(CO)2.     

Copper(II) mediated facile and ultra fast peptide synthesis in methanol

A novel, ultrafast, mild and scalable amide bond formation strategy in methanol using simple thioacids and amines is described. The mechanism suggests that the coupling reactions are initially mediated by CuSO(4)·5H(2)O and subsequently catalyzed by in situ generated copper sulfide. The pure peptides were isolated in satisfactory yields in less than 5 minutes.     

A racemization test in peptide synthesis using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM)

Racemization of the C-terminal amino acid (Ala) has been studied in various solvents during coupling between 4-methoxybenzyloxycarbonyl (Z(OMe))-Gly-L-Ala-OH and phenylalanine benzyl ester (H-Phe-OBzl) with 4-(4,6-dimethoxy-1,3,5-thiazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). The reaction occurred without substantial racemization in AcOEt, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), CH3CN, and 2-PrOH, while a slight racemization was observed in dimethyl sulfoxide (DMSO), EtOH, and MeOH. The extent of racemization may correlate with the polarity of the solvents.     

A new method for the detection of racemization during peptide synthesis: stereoselective hydrolysis of diastereomeric peptides by leucine aminopeptidase

A suitably protected dipeptide of configuration L -D , e.g. Z-L -Ala-D -Ala is coupled with an all L alanine peptide, e.g. L -Ala-L -Ala-ONb

1 Abbreviations according to the IUPAC-IUB rules, ‘Symbols for Amino-Acid Derivatives and Peptides, Recommendations (1971)’'. see e.g. J. biol. Chemistry 247, 977 (1972). In particular the following abbreviations have been used: Z = benzyloxycarbonyl-, -ONb = p-nitrobenzyloxy-, -ONSu = succinimido-oxy-. Additional abbreviations are LAP = leucine aminopeptidase, DCCI = N,N′-dicyclohexylcarbodiimide, DMF = dimethylformamide.

. The blocking groups are removed and the free peptide hydrolyzed by leucine amino peptidase (E.C. 3.4.1.1). This enzyme shows absolute L -specificity for the penultimate peptide bond from the amino end and therefore cleaves only the all L peptide formed through racemization. The amount of free alanine determined by amino acid analysis gives a multiple of the degree of racemization. The sensitivity of the test allows 0.1% of (L -Ala)₄ to be detected in the synthesis of L -Ala-D -Ala-L -Ala-L Ala. Coupling of Z-L -Ala-D -Ala and Z-L -Ala-D -Phe with di- and trialanine peptides has been studied using DCCI and DCCI + 1-hydroxybenzotriazole as coupling reagents. The degree of racemization was around 80% for the coupling by DCCI in DMF but was reduced to 0.2–0.4% in the presence of 2 equivalents of 1-hydroxybenzotriazole. Coupling using the succinimide esters Z-L -Ala-D -Ala-ONSu and Z-L -Ala-D -Phe-ONSu resulted in 0.8 to 10% racemization, depending on the solvent and base used.     

Copper(II) tetrafluoroborate as a novel and highly efficient catalyst for acetal formation

Commercially available copper(II) tetrafluoroborate hydrate has been found to be a highly efficient catalyst for dimethyl/diethyl acetal formation in high yields from aldehydes and ketones by reaction with trimethyl/triethyl orthoformate at room temperature and in short period. Acetalisation was carried out under solvent-free conditions with electrophilic aldehydes/ketones. For weakly electrophilic aldehydes/ketones (e.g., benzaldehyde, cinnamaldehyde and acetophenone) and for aldehydes having a substituent that can coordinate with the catalyst, the corresponding alcohol was used as solvent.     

Studies on amino acids and peptides-III. 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide,LR, as a new racemization free coupling reagent in peptide synthesis

The easily accessible 2,4-bis (4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide, $\text{LR}$, has been reacted with salts of N-protected amino acids $\text{1}$ (Z-Gly-OH, Boc-Gly-OH, Boc-S-Ser(Bzl)-OH, Boc-S-Tyr(Bzl)-OH, Z-S-Arg(Z₂)-OH, and Z-S-Pro-OH), at room temperature in CH₂Cl₂ to give the intermediates $\text{2}$, mixed anhydrides. When $\text{2}$ is treated with two moles of a base and one mole of the salt of an amino acid ester $\text{3}$ (TosOH·H-Gly-OBzl, HCl·H-Gly-OBzl, HCl·H-Gly-OEt, and HCl·H-S-Phe-OtBu) at 0°C, the expected peptide $\text{4}$ is isolated in high yields. LR is also found to be a useful reagent in a fragment coupling between Z-Gly-S-Ala-OH and TosOH·H-S-Leu-OBzl). This tripeptide was tested by means of HPLC (deprotection and amino acid analysis according to Izumiya was not necessary), and no epimerization (<0.7 %) was observed.     

Cobalt(II) chloride catalysed coupling of thiols and anhydrides: A new and efficient synthesis of thiol esters

Cobalt(II) chloride in acetonitrile catalyses the coupling of anhydrides or acid chlorides with thiols to yield thiol esters in excellent yields.     

Copper(II) bromide as efficient catalyst for silyl- to bisarylmethyl ethers interconversion (transprotection)

Primary and secondary silylated alcohols are easily converted to bis(methoxyphenyl)methyl (BMPM) ethers in good yields using CuBr₂ as catalyst in acetonitrile at room temperature. Various other protecting groups are compatible with this mild and convenient process.     

Improved procedure for the synthesis of thiazolium-type peptide coupling reagents: BMTB as a new efficient reagent

An efficient scalable synthesis of 2-halothiazolium-type peptide coupling reagents has been developed. The key step is the formation of the 2-bromothiazole scaffold through cyclization of α-thiocyanato ketones with hydrogen bromide. Using this method, the new coupling reagent 2-bromo-N-methylthiazolium bromide (BMTB) was synthesized. BMTB was tested in a difficult model coupling reaction of two sterically hindered N-methylated amino acids and showed higher activity than the well-established peptide coupling reagent HATU.     

A novel method for the synthesis of tetrahydrobenzo[a]-xanthen-11-one derivatives using cerium(III) chloride as a highly efficient catalyst

Cerium(III) chloride is found to be an highly efficient catalyst for the addition of aldehydes, β-naphthol and cyclic 1,3-dicarbonyl compounds/Meldrum's acid via a multicomponent reaction. The easy availability of starting materials, novel and eco-friendly procedure makes this strategy more useful for the preparation of tetrahydrobenzo[a]-xanthen-11-one, and benzo[f]chromen-3-one derivatives.     

Copper(II) bromide as an efficient catalyst for acetal to bisarylmethyl ether interconversion

Transprotection of acetals to bis(methoxyphenyl)methyl (BMPM) ethers can be efficiently achieved in the presence of copper dibromide as catalyst in acetonitrile at room temperature. Acetals are conveniently and selectively converted to the corresponding mono-protected diol with bis(methoxyphenyl)methyl isopropyl ether (BMPMOiPr) as the reagent. This new practical reagent allows the BMPM transfer to 1,3-dioxolanes or 1,3-dioxanes under copper catalysis. The reaction conditions are also very mild and tolerant to various functional groups, including other protecting groups.     

Bis(diphosphaferrocene) palladium(II) dimer complexes as efficient catalysts in the synthesis of arylboronic esters

Bis(diphosphaferrocenes)PdCl₂ dimers efficiently catalyse cross-coupling reactions between aryl iodides and pinacol borane in dioxane at 80 °C to afford the corresponding aryl boronic esters derivatives in excellent yields.     

Poly(1,4-butyl-bis-vinylpyridinium) borohydride as a new stable and efficient reducing agent in organic synthesis

The unstable sodium borohydride is stabilized on modified poly(4-vinylpyridinium), and it is used as an efficient and regenerable polymer-supported borohydride reagent for the reduction of a variety of carbonyl compounds, such as aldehydes, ketones, α,β-unsaturated carbonyl compounds, α-diketones and acyloins, in good to excellent yields.     

Nickel(II) chloride as an efficient and useful catalyst for chemoselective thioacetalization of aldehydes

A wide variety of acyclic and cyclic dithioacetals can be prepared chemoselectively from the corresponding aldehydes by employing a catalytic amount of nickel(II) chloride in dry CH₂Cl₂-MeOH (5:1) at room temperature in good yields. Some of the major advantages of this procedure are high chemoselectivity, ease of operation, high yields and also compatibility with other protecting groups.