Visible-Light Mediated Tryptophan Modification in Oligopeptides Employing Acylsilanes

A method for the selective tryptophan modification and labelling of tryptophan-containing peptides is described. Photoirradiation of acylsilanes generates reactive siloxycarbenes which undergo H−N-insertion into the indole moiety of tryptophan to give stable silyl protected hemiaminals. This method is successfully applied to chemically modify various tryptophan containing oligopeptides. The method enables the selective introduction of alkynes to peptides that are eligible for further alkyne-azide click chemistry. In addition, the dansyl fluorophore can be conjugated to a peptide using this approach.     

Chemoenzymatic Late-Stage Modifications Enable Downstream Click-Mediated Fluorescent Tagging of Peptides

Aromatic prenyltransferases from cyanobactin biosynthetic pathways catalyse the chemoselective and regioselective intramolecular transfer of prenyl/geranyl groups from isoprene donors to an electron-rich position in these macrocyclic and linear peptides. These enzymes often demonstrate relaxed substrate specificity and are considered useful biocatalysts for structural diversification of peptides. Herein, we assess the isoprene donor specificity of the N1-tryptophan prenyltransferase AcyF from the anacyclamide A8P pathway using a library of 22 synthetic alkyl pyrophosphate analogues, of which many display reactive groups that are amenable to additional functionalization. We further used AcyF to introduce a reactive moiety into a tryptophan-containing cyclic peptide and subsequently used click chemistry to fluorescently label the enzymatically modified peptide. This chemoenzymatic strategy allows late-stage modification of peptides and is useful for many applications.     

Late-stage C−H Functionalization of Tryptophan-Containing Peptides with Thianthrenium Salts: Conjugation and Ligation

Bioorthogonal late-stage diversification of structurally complex peptides bears enormous potential for drug discovery and molecular imaging, among other applications. Herein, we report on a palladium-catalyzed C−H arylation of tryptophan-containing peptides with readily accessible and modular arylthianthrenium salts. Under exceedingly mild reaction conditions, the late-stage diversification of structurally complex peptides was accomplished. The tunability and ease of preparation of arylthianthrenium salts allowed the expedient stitching of tryptophan-containing peptides with drug, natural product, and peptidic scaffolds by forging sterically congested biaryl linkages. The robustness of the palladium catalysis regime was reflected by the full tolerance of a plethora of sensitive and coordinating functional groups. Hence, our manifold enabled efficient access to highly decorated, labelled, conjugated, and ligated linear and cyclic peptides.     

PHOTO-OXIDATION OF N'-FORMYLKYNURENINE AND TRYPTOPHAN PEPTIDES BY SUNLIGHT OR SIMULATED SUNLIGHT

Abstract— N'-Formylkynurenine, a photochemical breakdown product of tryptophan in proteins, was exposed to sunlight or simulated sunlight at neutral pH. N-Formylanthranilic acid and 4-hydroxyquinoline were identified in the reaction products. Neither has been previously described as a photo-oxidation product of tryptophan-containing compounds. They were not found after photo-oxidation of glycyltryptophan or tryptophylglycine, although the indole ring was broken in both compounds.     

Heck reaction of arenediazonium salts with N,N-diprotected allylamines. Synthesis of cinnamylamines and indoles

Novel palladium-catalyzed reactions of arenediazonium tetrafluoroborates with N,N-diprotected allylamines are presented. The reaction of arenediazonium tetrafluoroborates with N,N-(Boc)(2) allylamine allows for an easy approach to cinnamylamines whereas using 2-alkynyl-N-(allyl)trifluoroacetanilides and 2-iodo-N-(allyl)trifluoroacetanilide the reaction provides a useful tool for appending indole rings to aniline fragments.     

Scope of the allylation reaction with [RuCp(PP)]+ catalysts: changing the nucleophile or allylic alcohol

The scope of the dehydrative allylation reaction using allyl alcohol as allyl donor with [RuCp(PP)]⁺ complexes as catalysts is explored. Aliphatic alcohols are successfully allylated with allyl alcohol or diallyl ether, obtaining high selectivity for the alkyl allyl ether. The reactivity of aliphatic alcohols is in the order of primary > secondary ? tertiary. The tertiary alcohol 1‐adamantanol reacts extremely slowly in the absence of strong acid, but when HOTs is added, reasonable yields of 1‐adamantyl allyl ether are obtained. The alkyl allyl ether is found to be the thermodynamically favored product over diallyl ether. Apart from alcohols, thiols and indole are also efficiently allylated, while aniline acts as a catalyst inhibitor. Allylation reactions with various substituted allylic alcohols give products with retention of the substitution pattern. It is proposed that a Ru(IV) σ‐allyl species plays a key role in the mechanism of these allylation reactions. Copyright © 2010 John Wiley & Sons, Ltd.     

Trifluoromethylation and Monofluoroalkenylation of Alkenes through Radical–Radical Cross-Coupling

The first visible-light-induced trifluoromethylation and monofluoroalkenylation of simple alkenes via a challenging radical–radical cross-coupling step was achieved. This method provided a mild, step-economical and redox-neutral route to privileged two different fluorinated difunctionalized allyl compounds. The utility of this method is illustrated by late-stage modification of medically important molecules.     

Trialkylsilyl triflimides as easily tunable organocatalysts for allylation and benzylation of silyl carbon nucleophiles with non-genotoxic reagents

Trialkylsilyl triflimides generated in situ are unique catalysts for the electrophilic benzylation or allylation of trialkylsilylenol ethers or allyl trialkylsilanes with non-genotoxic alkylating reagents such as benzyl and allyl acetates. In most cases the reactions are fast at room temperature and yields are high. The reaction works particularly well with electron-rich benzyl donors including derivatives of pyrrole, indole and furane.     

PHOTOSENSITIZED SPLITTING OF PYRIMIDINE DIMERS BY INDOLE DERIVATIVES AND BY TRYPTOPHAN-CONTAINING OLIGOPEPTIDES AND PROTEINS

Abstract— Indole derivatives including tryptophan can be used as photosensitizers of the splitting of pyrimidine dimers. The reaction can take place in frozen aqueous solutions as well as in fluid medium. Electron transfer from the indole ring to the dimer appears to be involved in the photosensitized reaction. Solvated electrons produced by flash photolysis in the presence of indoles or by pulse radiolysis are also able to split thymine dimers.
The splitting of pyrimidine dimers in DNA can be photosensitized by indole derivatives such as serotonin and by tryptophan-containing oligopeptides. Several methods including fluorescence and nuclear magnetic resonance have been used to show that the indole ring of these oligopeptides is able to stack with bases in nucleic acids. These stacked complexes are involved in the photosensitized reaction.
The splitting of pyrimidine dimers in DNA has also been photosensitized by the protein coded by gene 32 of phage T4 which binds strongly and cooperatively to single-stranded DNA. The mechanism of the splitting reaction as well as the possible use of this reaction to investigate the role of tryptophan residues in the binding of proteins to nucleic acids are discussed.     

Total synthesis of (±)-cycloclavine and (±)-5-epi-cycloclavine

Novel routes to the naturally occurring indole alkaloid cycloclavine and its unnatural C(5)-epimer are described. Key features include the rapid construction of the heterocyclic core segments by two Diels-Alder reactions. An indole annulation was accomplished by a late-stage intramolecular Diels-Alder furan cycloaddition, and a methylenecyclopropane dienophile was used for a stereoselective intramolecular [4 + 2] cycloaddition to give the cyclopropa[c]indoline building block present in cycloclavine.     

A cationic cyclisation route to prenylated indole alkaloids: synthesis of malbrancheamide B and brevianamide B, and progress towards stephacidin A

The synthesis of the prenylated indole alkaloids, malbrancheamide B and brevianamide B have been accomplished, starting with a prenylated proline derivative created using the Seebach ‘self-reproduction of chirality’ method, and using a cationic cascade sequence as the key step to form late-stage bridged diketopiperazine intermediates.     

A new entry to the isogeissoschizoid skeleton

[reaction: see text] The tetracyclic isogeissoschizoid skeleton has been prepared by a novel route that involves the ozonolysis and double reductive amination of a cyclopentene, a nickel-catalyzed cyclization, and a late-stage Fischer indole synthesis.     

An Apparent Umpolung Reactivity of Indole through [Au]-Catalysed Cyclisation and Lewis-Acid-Mediated Allylation

The sequential functionalization of indole C2 and C3 in an umpolung fashion was executed with a predesigned substrate and choice of reagents. The developed method comprises gold-catalysed alkynol cycloisomerisation/intramolecular addition of C2 of indole and subsequent BF₃ ⋅ OEt₂-mediated regioselective C3 allylation, resulting in the synthesis of the functionalized indoloisoquinolinone scaffold. The reaction involves 5-endo-alkynol cycloisomerisation and the dearomative addition of indole C2 to the intermediate oxocarbenium cation, which results in two equilibrating fused and spiropentacyclic intermediates, which upon treatment with allyl silane in the presence of BF₃ ⋅ OEt₂, undergo selective indole C3 allylation. Other nucleophiles, such as hydride, azide and indole, were also found to be compatible with this process.     

Fast and highly regioselective allylation of indole and pyrrole compounds by allyl alcohols using Ru-sulfonate catalysts

New Ru-sulfonate catalysts have been synthesized and shown to very rapidly allylate indole and pyrrole compounds using allyl alcohols as substrates. The observed regioselectivity is exceptionally high (up to 100% of the branched isomer). Density functional theory calculations explain these results.     

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.     

Simple glycosylation reaction of allyl glycosides

A simple glycosylation strategy employing only allyl glycosides is described. In a one-pot fashion, an allyl glycoside is first isomerized to the reactive 1-prop-en-yl glycoside intermediate, which subsequently undergoes glycosylation with a glycosyl acceptor, promoted by NIS at room temperature.     

Indoles

It has been found that arylhydrazones of carbonyl compounds smoothly undergo rearrangement into the corresponding indoles under the action of strong alkylating agents such as benzyl chloride, allyl bromide, and dimethyl sulfate in boiling methanol. The use of arylhydrazines substituted at the α-nitrogen atom leads to the formation of N-subsituted indoles; However, where a hydrazine of the type of ArNHNH₂ is used, a mixture of the corresponding indole and of the indole substituted on the nitrogen atom by the radical of the alkylating compound is formed.     

Gold-catalyzed heteroannulation and allyl migration: synthesis of highly functionalized indole derivatives

Highly substituted indole derivatives have been prepared in good to excellent yields by a novel gold-catalyzed cyclization accompanied by [3,3]-migration of the allyl strategy. We have been able to introduce an allyl group at the C1 position of pyrano[3,2-e]indol-6(7H)-one and pyrrolo[3,2-f]quinolin-7(6H)-one moieties that provide a scope for further transformation.     

Halocyclization of 3-allylthio-5H-[1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indole

The synthesis of 3-allylthio-5H-[1,2,4]triazino[5,6-b]indole has been carried out by the reaction of 3-mercapto-5H-[1,2,4]triazino[5,6-b]indole with allyl bromide in the NaOH–H₂O–DMSO system and in a one-pot synthesis from isatin-β-thiosemicarbazide. Halocyclization of allylthio-5H-[1,2,4]-triazino[5,6-b]indole synthesized the 3-halomethyl-3,10-dihydro-2H-[1,3]thiazolo[3',2':2,3][1,2,4]-triazino[5,6-b]indolium halides.     

Total synthesis of (+)-scholarisine A

An effective total synthesis and assignment of the absolute configuration of the architecturally challenging compound (+)-scholarisine A has been achieved via a 20-step sequence. Highlights include a reductive cyclization involving a nitrile and an epoxide, a modified Fischer indole protocol, a late-stage oxidative lactonization, and an intramolecular cyclization leading to the indolenine ring system of (+)-scholarisine A.