Design and Synthesis of Nucleoproline Amino Acids for the Straightforward Preparation of Chiral and Conformationally Constrained Nucleopeptides

A straightforward synthesis of orthogonally protected nucleoproline (Nup) amino acids and their coupling to oligomers are described. A key step is the attachment of alkynylated nucleobases to Fmoc‐protected 4‐azidoproline (Fmoc‐Azp‐OH) by a Cu‐catalyzed 1,3‐dipolar cycloaddition (‘click reaction’). The developed protocol allows preparation of the nucleoprolines in scales of >30 g. Solid‐phase peptide synthesis proved to be straightforward with these Nup amino acids. The resulting oligonucleoproline peptides adopt defined helices, are very well H₂O soluble, and show comparable cell‐penetrating properties as recently reported α‐nucleoalanine peptides.     

A Novel 1‐Glycosyl‐1H‐triazole‐Based P,N Ligand for Rhodium‐Catalyzed Asymmetric Hydrosilylation of Ketones

A novel class of chiral glycosyl‐triazole‐based P,N ligands were synthesized by ‘click chemistry’ and were applied to the Rh‐catalyzed asymmetric hydrosilylation of a range of substituted acetophenones. Enantioselective hydrosilylation of acetophenone gave (S)‐1‐phenylethanol in moderate enantioselectivity (72% ee) and in good conversion (93%).     

One‐Step Synthesis of Dialkyl 2‐[(4‐Methylphenyl)sulfonyl]‐1H‐pyrrole‐3,4‐dicarboxylates by Reaction of Acetylenedicarboxylates with ‘Tosylmethyl Isocyanide’ (TsMIC) and Triphenylphosphine

The reactive 1 : 1 adducts in the reaction between Ph₃P and dialkyl acetylenedicarboxylates have been trapped with ‘tosylmethyl isocyanide’ (TsMIC ; 1 ) to yield dialkyl 2‐[(4‐methylphenyl)sulfonyl]‐1H‐pyrrole‐3,4‐dicarboxylates 3 (Scheme 1). The structures of the highly functionalized compounds 3 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this type of cyclization is proposed (Scheme 2).     

Synthesis of 1,4‐Diazabutadienes (=N,N′‐Ethane‐1,2‐diylidenebis[amines]) by Grinding

A simple and convenient method for the synthesis of 1,4‐diazabutadienes (=N,N′‐ethane‐1,2‐diylidenebis[amines]) by grinding glyoxal (=ethanedial) or an α‐diketone and anilines (=benzenamines) in the presence of TsOH in a mortar with a pestle is described. By this way, 1,4‐diazabutadienes were obtained in good to excellent yields.     

Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds

Herbal mixtures like ‘Spice’ with potentially bioactive ingredients were available in many European countries since 2004 and are still widely used as a substitute for cannabis, although merchandized as ‘herbal incense’. After gaining a high degree of popularity in 2008, big quantities of these drugs were sold. In December 2008, synthetic cannabinoids were identified in the mixtures which were not declared as ingredients: the C₈ homolog of the non‐classical cannabinoid CP‐47,497 (CP‐47,497‐C8) and a cannabimimetic aminoalkylindole called JWH‐018. In February 2009, a few weeks after the German legislation put these compounds and further pharmacologically active homologs of CP‐47,497 under control, another cannabinoid appeared in ‘incense’ products: the aminoalkylindole JWH‐073. In this paper, the results of monitoring of commercially available ‘incense’ products from June 2008 to September 2009 are presented. In this period of time, more than 140 samples of herbal mixtures were analyzed for bioactive ingredients and synthetic cannabimimetic substances in particular. The results show that the composition of many products changed repeatedly over time as a reaction to prohibition and prosecution of resellers. Therefore neither the reseller nor the consumer of these mixtures can predict the actual content of the ‘incense’ products. As long as there is no possibility of generic definitions in the controlled substances legislation, further designer cannabinoids will appear on the market as soon as the next legal step has been taken. This is affirmed by the recent identification of the aminoalkylindoles JWH‐250 and JWH‐398. As further cannabinoids can be expected to occur in the near future, a continuous monitoring of these herbal mixtures is required. The identification of the synthetic opioid O‐desmethyltramadol in a herbal mixture declared to contain ‘kratom’ proves that the concept of selling apparently natural products spiked with potentially dangerous synthetic chemicals/pharmaceuticals is a continuing trend on the market of ‘legal highs’. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of Trifluoromethylated Monoterpene Amino Alcohols

For the first time, monoterpene trifluoromethylated β-hydroxy-benzyl-O-oximes were synthesized in 81–95% yields by nucleophilic addition of the Ruppert–Prakash reagent (TMSCF₃) to the corresponding β-keto-benzyl-O-oximes based on (+)-nopinone, (−)-verbanone and (+)-camphoroquinone. Trifluoromethylation has been determined to entirely proceed chemo- and stereoselective at the C=O rather than C=N bond. Trifluoromethylated benzyl-O-oximes were reduced to the corresponding α-trifluoromethyl-β-amino alcohols in 82–88% yields. The structure and configuration of the compounds obtained have been established.     

5-Amino-3-methyl-Isoxazole-4-carboxylic Acid as a Novel Unnatural Amino Acid in the Solid Phase Synthesis of α/β-Mixed Peptides

The hybrid peptides consisting of α and β-amino acids show great promise as peptidomimetics that can be used as therapeutic agents. Therefore, the development of new unnatural amino acids and the methods of their incorporation into the peptide chain is an important task. Here, we described our investigation of the possibility of 5-amino-3-methyl-isoxazole-4-carboxylic acid (AMIA) application in the solid phase peptide synthesis. This new unnatural β-amino acid, presenting various biological activities, was successfully coupled to a resin-bound peptide using different reaction conditions, including classical and ultrasonic agitated solid-phase synthesis. All the synthesized compounds were characterized by tandem mass spectrometry. The obtained results present the possibility of the application of this β-amino acid in the synthesis of a new class of bioactive peptides.     

Na2S还原法合成氨基二苯醚类化合物

用Na2S还原硝基二苯醚类化合物，成功地合成了一系列氨基二苯醚类化合物，产率在70％以上，产物结构经IR，1H NMR和MS表征。     

Synthesis of Two Natural Furan‐Cyclized Diarylheptanoids via 2‐Furaldehyde

Two natural diarylheptanoids, 2‐benzyl‐5‐(2‐phenylethyl)furan ( 1 ) and 2‐methoxy‐4‐{[5‐(2‐phenylethyl)furan‐2‐yl]methyl}phenol ( 2 ), were synthesized starting from 2‐furaldehyde. A Wittig reaction of 2‐furaldehyde with benzyltriphenylphosphonium bromide followed by reduction of the alkene C?C bond with Mg gave 2‐(2‐phenylethyl)furan ( 5 ). Lithiation of 5 with BuLi at ?78° followed by alkylation with benzyl bromide gave natural product 1 . In another approach, Friedel? Crafts acylation of compound 5 with benzoyl chloride followed by deoxygenation of the C?O group afforded 1 . The natural product 2 was also synthesized by acylation of 5 with 4‐acetoxy‐3‐methoxybenzoyl chloride ( 16 ) followed by deoxygenation and deacetylation.     

Reversal of the Stereochemical Course of 1‐Methyl‐1H‐indole Addition to Cinnamaldehyde with cis‐5‐Benzyl‐(2‐fluoromethyl)‐2,3‐dimethylimidazolidin‐4‐ones as Catalysts – a Puzzling ‘Fluorine Effect’

Replacement of the cis‐Me group by CH₂F in the imidazolidinone organocatalyst specified in the title (so‐called McMillan generation‐I catalyst) leads to reversal of the product configuration in the title reaction. The topicity reversal in the nucleophilic addition step must arise either from cis‐addition with respect to the benzylic substituent of an (E)‐iminium ion intermediate or from trans‐addition to the corresponding (Z)‐iminium ion. Mechanistic investigations have not provided evidence for either one of these two possibilities, so far.     

A Novel ‘Domino‐Click Approach’ to Unsymmetrical Bis‐1H‐1,2,3‐triazoles

Aryl azides 1 were treated with allenylmagnesium bromide ( 2 ) to generate 1,5‐disubstituted butynyl‐1H‐1,2,3‐triazoles 3 in a domino fashion, which upon Cu^I‐catalyzed 1,3‐dipolar cycloaddition with aryl azides 4 afforded novel bis‐1H‐1,2,3‐triazoles 5 in quantitative yields (Scheme 1 and Table).     

Synthesis of 1,2,3‐Triazole Analogues of Lincomycin

In search for new antibiotics we replaced the amide moiety of lincomycin 1 by a 1,2,3‐triazole ring. The 1,2,3‐triazoles 10a – 10k were obtained as single regioisomers by ‘click reaction’ of azide 5 with the alkyne 9k , derived from propyl hygric acid, and the alkyl, aryl, or cycloalkyl alkynes ribosomes 9a – 9j . The new analogues proved inactive towards wild‐type and A2058G mutant.     

Facile One‐Pot Synthesis of Monosubstituted 1‐Aryl‐1H‐1,2,3‐triazoles from Arylboronic Acids and Prop‐2‐ynoic Acid (=Propiolic Acid) or Calcium Acetylide (=Calcium Carbide) as Acetylene Source

The synthesis of monosubstituted 1‐aryl‐1H‐1,2,3‐triazoles was achieved in a one‐pot reaction from arylboronic acids and prop‐2‐ynoic acid or calcium acetylide (=calcium carbide), respectively, as a source of acetylene, with yields ranging from moderate to excellent (Scheme 1, Table 2). The reaction conditions were successfully applied to arylboronic acids, including analogs with various functionalities. Unexpectedly, the 1,2,3‐triazole moiety promoted a regioselective hydrodebromination (Scheme 2).     

化学和电化学方法合成苯/胺封端苯胺四聚体

利用改进了MacDiarmid氧化偶联方法合成了苯／胺封端的苯胺四聚体，通过对循环伏安曲线的分析，给出二聚体经由电化学氧化－化学偶联成为四聚体的机理，利用基质辅助激光解吸质谱和红外光谱对产物进行了表征。     

Identification and structural characterization of the synthetic cannabinoid 3‐(1‐adamantoyl)‐1‐pentylindole as an additive in ‘herbal incense’

Since the end of 2010, more than 20 synthetic cannabimimetics have been identified in ‘Spice’ products, demonstrating the enormous dynamic in this field. In an effort to cope with the problem, many countries have already undertaken legal measures by putting some of these compounds under control. Nevertheless, once a number of compounds were scheduled, they were soon replaced by other synthetic cannabinoids. In this article, we report the identification of a new – and due to its substitution pattern rather uncommon – cannabimimetic found in several ‘herbal incense’ products. The GC–EI mass spectrum first led to misidentification as the alpha‐methyl‐derivative of JWH‐250. However, since both substances show different retention indices, thin‐layer chromatography was used to isolate the unknown compound. After application of nuclear magnetic resonance spectroscopy, high‐resolution MS and GC–MS/MS techniques, the compound was identified as 3‐(1‐adamantoyl)‐1‐pentylindole, a derivative of JWH‐018 carrying an adamantoyl moiety instead of a naphthoyl group. This finding supports that the listing of synthetic cannabinoids as prohibited substances triggers the appearance of compounds with uncommon substituents. Moreover, it emphasizes the necessity of being aware of the risk of misidentification when using techniques sometimes providing only limited structural information like GC–MS. Copyright © 2012 John Wiley & Sons, Ltd.     

Polyelectrolyte-mediated non-micellar synthesis of monodispersed ‘aggregates’ of gold nanoparticles using a microwave approach

‘Aggregates’ of monodispersed gold nanoparticles were synthesized for the first time in large quantities. Those particles were made in presence or in absence of gold seed in a polyelectrolyte solution using microwave heating for about 30–60 s. The average diameters of the particles calculated from TEM and SEM analysis were 22 ± 2 nm. Our analysis found that the polyelectrolyte acted as a reducing as well as a stabilizing agent. It controlled the growth of particles by aligning them on the polymeric chain and the nanoparticles were subsequently self-assembled to form an ‘aggregate’ structure. The synthetic procedure is very fast and the particles are stable for at least 6 months under ambient conditions.     

Synthesis of Z‐Protected Aib‐ and Phe(2Me)‐Containing Pentapeptides and Their Crystal Structures

A series of pentapeptide derivatives containing α,α‐disubstituted α‐amino acids have been prepared by a combination of the ‘azirine/oxazolone method’ and segment condensations. X‐Ray crystal‐structure determinations of the molecular structures confirmed the presence of helical conformations stabilized by β‐turns of type III or III′. Pentapeptides containing (R)‐Phe(2Me) form a right‐handed helix, whereas those containing (S)‐Phe(2Me) adopt a left‐handed helical structure.     

‘Click Synthesis’ of 1H‐1,2,3‐Triazolyl‐Based Oxiconazole (=(1Z)‐1‐(2,4‐Dichlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone O‐[(2,4‐Dichlorophenyl)methyl]oxime) Analogs

The ‘click synthesis’ of some oxiconazole analogs 5a – 5v having 1H‐1,2,3‐triazolyl residues by Huisgen cycloaddition was achieved in four steps (Scheme 1). Oximation of phenacyl chloride ( 1 ) followed by azidation of 2‐chloro‐1‐phenylethanone oxime ( 2 ) provided azido ketoxime 3 . The CuI‐catalyzed Huisgen cycloaddition of 3 with terminal alkynes gave the 4‐substituted (at the triazole) 2‐(1H‐1,2,3‐triazol‐1‐yl)‐1‐phenylethanone oximes 4a – 4i . The O‐alkylation of 4a – 4i with various alkyl halides resulted in the formation of the target molecules 5a – 5v in good yields.     

Recent Advances in Rapid Synthesis of Non-proteinogenic Amino Acids from Proteinogenic Amino Acids Derivatives via Direct Photo-Mediated C–H Functionalization

Non-proteinogenic amino acids have attracted tremendous interest for their essential applications in the realm of biology and chemistry. Recently, rising C–H functionalization has been considered an alternative powerful method for the direct synthesis of non-proteinogenic amino acids. Meanwhile, photochemistry has become popular for its predominant advantages of mild conditions and conservation of energy. Therefore, C–H functionalization and photochemistry have been merged to synthesize diverse non-proteinogenic amino acids in a mild and environmentally friendly way. In this review, the recent developments in the photo-mediated C–H functionalization of proteinogenic amino acids derivatives for the rapid synthesis of versatile non-proteinogenic amino acids are presented. Moreover, postulated mechanisms are also described wherever needed.     

The ‘t‐Amino Effect’ of ortho‐Nitroso Amines. Synthesis of 2,6‐Diaminoadenine Derivatives from 6‐(Dialkylamino)‐5‐nitrosopyrimidines

The ‘t‐amino effect’ of amino‐nitroso compounds was documented by preparing the (dialkylamino)‐nitroso pyrimidines 4 – 18 , and cyclising them under thermal conditions in high yields to the purine derivatives 19 – 32 . The reactivity of the amino‐nitroso‐pyrimidines, particularly of 17 derived from diethyl iminodiacetate, and of 19 , derived from 1‐phenylimidazolidine, correlates with the stability of the intermediate azomethine ylide. Thermolysis of the amino‐nitroso‐pyrimidines 34 – 37 , possessing dialkylamino substituents at C(4) and C(6), proceeded by protiodenitrosation, leading to 38 – 41 .