NG-2,2,5,7,8-pentamethylchroman-6-sulphonyl-L-arginine: A new acid labile derivative for peptide synthesis

A new acid labile protecting group for the guanidino side chain functionality of arginine has been developed. N_G-(2,2,5,7,8-Pentamethyl-chroman-6-sulphonyl)-L-arginine, prepared from Nα-benzyloxycarbonyl-L-arginine and 2,2,5,7,8-pentamethylchroman-6-sulphonyl chloride, is cleaved rapidly in trifluoroacetic acid (TFA) or 50% TFA in dichloromethane at room temperature.     

The revised structure of an oxidation product from the reaction of an α-tocopherol model compound, 2,2,5,7,8-pentamethylchroman-6-ol,with potassium superoxide; 6 -hydroxy -2,2,6,7,8- pentamethylchroman- 5 (6H) -one1

The previously reported structure of an oxidation product obtained from the reaction of an (α-tocopherol model compound(1) with KO₂ is revised to 6-hydroxy-2,2,6,7,8-pentamethylchroman-5(6H)-one(3) on the basis of the X-ray crystallographic and ¹⁸O-labeling studies.     

High-pressure (2+2)cycloaddition of toluene-4-sulphonyl isocyanate to glycals

High-pressure (2+2)cycloaddition of toluene-4-sulphonyl isocyanate to glycals is examined. Reactions proceed regiospecifically to afford single products in case of all 3-substituted glycals. Upon heating or even after standing at room temperature adducts undergo retro-addition to give starting glycals. Various aspects of the cycloaddition are discussed, especially ret-ro-reaction and rearrangement of β-lactams to α,β-unsaturated amides.     

Application of an automated synthesis suite to parallel solution-phase peptide synthesis

An in-house developed automated synthesis suite was used to prepare a library of 72 tetrapeptide derivatives, the starting materials for pharmaceutically attractive pentapeptides, employing a convergent strategy. An initial set of 18 dipeptides were synthesized on a large-scale (100-1000 g) using automated synthesis workstations, and then 72 tetrapeptides were synthesized on a medium scale (5-10 g) using an automated system. Each di- or tetrapeptide was prepared in a single operating cycle using a modified methanesulfonic acid method, then a sub-library of 56 pentapeptides were synthesized in parallel, on a small-scale (100 mg-1 g) using a robotic workstation.     

The oxazole-triamide rearrangement. Application to peptide synthesis

The carboxyl group of a N-acylated amino acid may be protected by conversion to an oxazole derivative which, on photoxygenation, regenerates the carboxyl group in activated (triamide) form for peptide synthesis.     

Ionic-liquid-supported peptide synthesis demonstrated by the synthesis of Leu(5)-enkephalin

A new strategy for the synthesis of oligopeptides was developed using an ionic liquid as a soluble support. The efficiency of this ionic liquid-phase approach was demonstrated by the synthesis of a bioactive pentapeptide, Leu(5)-enkephalin, in good yield and reasonable purity. The structures and purities of the reaction intermediates in each step were verified easily by routine spectroscopic analysis, and no chromatographic procedures were needed during the synthesis.     

Solid-phase synthesis of peptide ribonucleic acids (PRNA)

The range of available peptide ribonucleic acid (PRNA) monomers was fully expanded for the use in solid-phase synthesis of PRNA oligomers, which were designed to reversibly control the recognition and complexation behavior of the complementary DNA/RNA by external factors. A couple of PRNA 12-mers with desired purine-pyrimidine mixed sequences were prepared indeed in high yields by the solid-phase synthesis.     

Solution synthesis of human peptide YY (hPYY)

Human peptide YY (hPYY) was synthesized in a conventional manner by assembling six peptide fragments followed by deprotection with 1 M trimethylsilyl trifluoromethanesulfonate (TMSOTf)-thioanisole in trifluoroacetic acid (TFA). After purification by gel-filtration on Sephadex G-25, followed by reversed-phase high-performance liquid chromatography, a highly purified sample of synthetic hPYY was obtained. When administered in dogs, synthetic hPYY was as active as synthetic porcine PYY in terms of the effects on systemic arterial blood pressure, and splanchnic blood flow.     

Asymmetric synthesis of a chroman derivative (vitamin e precursor)

Chromanmethanol $\text{2}$, a chiral intermediate for the synthesis of α-tocopherol $\text{1}$, is prepared from α-hydroxy aldehyde $\text{5}$, which is obtained by an asymmetric synthesis in over 95% ee.     

Phosphinamide-directed benzylic lithiation. Application to the synthesis of peptide building blocks

N-benzyldiphenylphosphinamides are deprotonated at the NCalpha position diastereospecifically upon treatment with t-BuLi in diethyl ether at low temperature. The reaction of the anions with alkyl, acyl, and tin halides, aliphatic and aromatic aldehydes, and Michael acceptors allowed installation of a variety of functional groups into the benzylic arm in excellent yields. Cleavage of the P-N linkage affords 1,2-amino alcohols and alpha-, beta-, and gamma-amino acids.     

An improved procedure for N- to C-directed (Inverse) solid-phase peptide synthesis

A method for solid-phase peptide synthesis in the N- to C-direction that delivers good coupling yields and a low degree of epimerization is reported. The optimized method involves the coupling, without preactivation, of the resin-bound C-terminal amino acid with excess amounts of amino acid tri-tert-butoxysilyl (Sil) esters, using HATU as coupling reagent and 2,4,6-trimethylpyridine (TMP, collidine) as a base. For the amino acids investigated, the degree of epimerization was typically 5%, except for Ser(t-Bu) which was more easily epimerized (ca. 20%). Five tripeptides (AA(1)-AA(2)-AA(3)) with different properties were used as representative model peptides in the development of the synthetic method: Asp-Leu-Glu, Leu-Ala-Phe, Glu-Asp-Val, Asp-Ser-Ile, and Asp-D-Glu-Leu. The study used different combinations of HATU and TBTU as activating agents, N, N-diisopropylethylamine (DIEA) and TMP as bases, DMF and dichloromethane as solvents, and cupric chloride as an epimerization suppressant. The epimerization of AA(2) in the coupling of AA(3) was further reduced in the presence of cupric chloride. However, the use of this reagent also resulted in a decrease in loading onto the resin and significant cleavage between AA(1) and AA(2). Experiments indicated that the observed suppressing effect of cupric chloride on epimerization in the present system merely seemed to be a result of a base-induced cleavage of the oxazolone system, the key intermediate in the epimerization process. Consequently, the cleavages were most pronounced in slow couplings. An improved synthesis of fully characterized amino acid tri-tert-butoxysilyl (Sil) ester hydrochloride building blocks is presented. The amino acid Sil esters were found to be stable as hydrochlorides but not as free bases. Although only a few peptides have been used in this study, we believe that the facile procedure devised herein should provide an attractive alternative for the solid-phase synthesis of short (six residues or less) C-terminally modified peptides, e.g., in library format.     

High-pressure bulk synthesis of crystalline C(6)N(9)H(3).HCl: a novel c(3)n(4) graphitic derivative

A novel carbon nitride compound, structurally related to the proposed graphitic phase of C(3)N(4), has been synthesized in a bulk well-crystallized form. The new material, with stoichiometry C(6)N(9)H(4)Cl, was prepared through a solid-state reaction of 2,4,6-triamino-1,3,5-triazine with 2,4,6-trichloro-1,3,5-triazine at 1.0-1.5 GPa and 500-550 degrees C and also through a self-reaction of 2-amino-4,6-dichloro-1,3,5-triazine at similar conditions. X-ray and electron diffraction measurements on the yellowish compound indicate a hexagonal space group (P6(3)/m) with cell parameters of a = 8.4379(10) A and c = 6.4296(2) A. This new compound possesses a two-dimensional C(6)N(9)H(3) framework that is structurally related to the hypothetical P6m2 graphitic phase of C(3)N(4), but with an ordered arrangement of C(3)N(3) voids. The large voids in the graphene sheets are occupied by chloride ions with an equivalent number of nitrogen atoms on the framework protonated for charge balance. The composition of the sample was determined by bulk chemical analysis and confirmed by electron energy loss (EELS) spectroscopy. The chemical and structural model is consistent with bulk density measurements and with the infrared and (13)C NMR spectra. This work represents the first bulk synthesis of a well-characterized and highly crystalline material containing a continuous network of alternating carbon and nitrogen atoms.     

Solution-phase synthesis of alpha-rat atrial natriuretic peptide (alpha-rANP)

alpha-Rat atrial natriuretic peptide (alpha-rANP) was synthesized by assembling five peptide fragments in solution, followed by HF-dimethylselenide-m-cresol deprotection and subsequent air-oxidation. Synthetic alpha-rANP exhibited more potent diuretic and natriuretic activity in rats than synthetic alpha-hANP.     

Solution-phase synthesis of alpha-human atrial natriuretic peptide (alpha-hANP)

Alpha-human atrial natriuretic peptide (alpha-hANP) was synthesized by assembling six peptide fragments in solution followed by deprotection with HF and subsequent air-oxidation. The trimethylbenzyl group was employed as an S-protecting group of cysteine. The HF-dimethylselenide-m-cresol system was employed as a final deprotecting reagent and, at the same time, as a reducing reagent of Met(O). Synthetic alpha-hANP elicited potent diuretic and natriuretic activity in rats.     

Thermal synthesis of the optical pure pentapeptide derivative Z-(L)-Ala-(L)-Phe-Gly-(L)-Phe-Gly-OMe

The pentapeptide Z-(L)-Ala-(L)-Phe-Gly-(L)-Phe-Gly-OMe was obtained by reacting the activated dipeptide derivative Z-(L)-Ala-(L)-Phe-OPcp with the amino peptide derivative TFA·H-Gly-(L)-Phe-Gly-OMe at 100–105°C under reduced pressure (10^?2-10-^?3 Torr) without using solvents. The product obtained by bulk condensation showed no racemization, whereas the product obtained by a matrix mediated condensation contained 5,5 % diastereomer Z-(L)-Ala-(D)-Phe-Gly-(L)-Phe-Gly-OMe. Separation of diastereomers was achieved by HPLC on a silicagel column.     

Enantioselective approach to indolizidine and quinolizidine scaffolds. Application to the synthesis of peptide mimics

An enantioselective approach to substituted indolizidine and quinolizidine frameworks has been developed. Key steps of the synthesis are the enantioselective, palladium-catalyzed N-allylation of an imide, the nucleophilic allylation of an acyliminium ion and a ring closing metathesis. This general strategy has been applied to the synthesis of indolizidine peptide mimics, starting from a chiral imide derived from l-aspartic acid. It was observed that the preexisting stereogenic center of this substrate has a moderate influence on the stereoselectivity of the electrophilic allylation, which is mainly determined by the sense of chirality of the catalyst.     

Calix(6)arene carboxylate derivative for solvent extraction separation of iron(III)

Hexaacetatocalix(6)arene was used for the solvent extraction of iron(III). About 7.5x10(-2) M extractant was used at pH 7.0 for the quantitative extraction of iron(III). The metal from the organic phase was stripped with 1.0 M hydrochloric acid and determined spectrophotometrically as its thiocyanate complex at 480 nm. Iron(III) was separated from large excesses of alkali and alkaline earths in the ratio 1:20. The transition and main group elements were tolerated in the ratio 1:10. The method was extended for the analysis of iron from its mineral, alloy and pharmaceutical preparation. The method is reproducible with SD+/-1.10%.