Comparative study of polyaromatic and polyheteroaromatic fluorescent photocleavable protecting groups

Fluorescent conjugates of N-benzyloxycarbonyl protected γ-aminobutyric acid were prepared by coupling to its C-terminus several polyheteroaromatic, based on the oxobenzopyran skeleton (trivially known as coumarin) and polyaromatic labels, such as naphthalene and pyrene. Photophysical properties were evaluated, as well as their behaviour towards photocleavage by irradiation in MeOH/HEPES buffer solution (80:20), in a photochemical reactor at different wavelengths (254, 300, 350 and 419 nm), followed by HPLC/UV monitoring.     

Palladium-catalyzed carbonylation of haloindoles: no need for protecting groups

[reaction: see text] For the first time, palladium-catalyzed carbonylations of unprotected bromoindoles have been performed successfully with different N- and O-nucleophiles. Various indole carboxylic acid derivatives are accessible in excellent yield. For example, aminocarbonylation of 4-, 5-, 6-, or 7-bromoindole with arylethylpiperazines provides a direct one-step synthesis for CNS active amphetamine derivatives.     

A new protecting group for the exocyclic amino groups of nucleosides

A new protecting group has been developed for the exocyclic amino groups of nucleosides that occur in DNA. 3-Phenyl-[{N-(2-trimethylsilyl-ethoxycarbonyl)-2-amino}]-propanoic acid used as the protective agent.     

Photolabile protecting groups in metal-organic frameworks: preventing interpenetration and masking functional groups

Photolabile groups can be incorporated into metal-organic frameworks (MOFs) and then quantitatively cleaved following MOF formation. Here, a 2-nitrobenzyl ether prevents lattice interpenetration (catenation) in a cubic MOF derived from zinc(II). Subsequent photolysis unmasks a hydroxyl group, and produces an open MOF that cannot be synthesized directly.     

S-pixyl analogues as photocleavable protecting groups for nucleosides

Several analogues of the 9-phenylthioxanthyl (S-pixyl) photocleavable protecting group have been synthesized, containing substituents on the 9-aryl ring and on the thioxanthyl backbone. Each analogue protected the 5'-hydroxy moiety of thymidine in good to excellent yield. The protected substrates were deprotected in 1:1 water:acetonitrile with irradiation at 300 nm, resulting in recovered thymidine in excellent yield, except for the nitro-substituted analogues which gave substantially lower yields. Substrates with 2,7-dibromo or 3-methoxy substitution on the thioxanthyl backbone were also deprotected efficiently with irradiation at 350 nm. Shorter irradiation times were observed in the less nucleophilic solvent mixture of 1:9 trifluoroethanol:acetonitrile, with no formation of secondary photooxidation products. Photodeprotection with high yields was also achieved in the absence of solvent, with no secondary photoproducts.     

Development of tyrosinase labile protecting groups for amines

[reaction: see text] The development of two novel protecting groups for amines is described. Thus, a range of amines have been converted to ureas, and the deprotection of these upon exposure to mushroom tyrosinase (E.C. 1.14.18.1) has been demonstrated.     

Epoxides as alkene protecting groups. A mild and efficient deoxygenation

Dimethyl diazomalonate smoothly deoxygenates epoxides to alkenes with rhodium(II) acetate catalysis.     

Fluorous dimethylthiocarbamate (DMTC) protecting groups for alcohols

N,N-Bis(perfluoroalkyl)thiocarbamoyl chlorides (^FDMTC-Cls) were synthesized as reagent for the protection of alcohols. Using the crystalline ^FDMTC-Cls, the ^FDMTC groups were introduced into the alcohol molecules in excellent yields in the presence of sodium hydride in THF at room temperature. The products were separated from the excess alcohols by solid-phase extraction with a fluorous reverse-phase silica gel column (Fluorous Solid Phase Extraction; FSPE). The ^FDMTC groups were readily removed by oxidation with m-chloroperbenzoic acid (m-CPBA) and subsequent hydrolysis with KHCO₃.     

Acid-labile protecting groups for the synthesis of lipidated peptides

Lipidated peptides and their neolipoprotein derivatives are efficient tools for the investigation of biological processes in molecular detail. These compounds are often acid- and base-labile, and their synthesis requires the use of a combination of blocking groups that can be removed under very mild conditions. In this article we demonstrate that the Boc urethane and different trityl-type protecting groups can be cleaved selectively under acidic conditions that are mild enough to be compatible with the demands of lipopeptide synthesis. Thus, the Boc group was cleaved with TMS triflate in the presence of lutidine, and the methyltrityl (Mtt) and the methoxytrityl (Mmt) group were removed with 1% TFA in dichloromethane in the presence of triethylsilane as cation scavenger. Removal of the phenylfluorenyl group was achieved with up to 3% TFA in dichloromethane in the presence of triethylsilane at 0 degrees C. These protecting-group techniques were successfully applied in the synthesis of differently lipidated H-Ras peptides.     

Catechol boron halides: mild and selective reagents for cleavage of common protecting groups

Catechol boron halides (1,X=Cl, Br) cleave certain ether, ester and carbamate protecting groups under mild conditions. The scope and selectivity of these readily available reagents has been examined.     

Design and application of esterase-labile sulfonate protecting groups

Three esterase-labile, but chemically-stable sulfonate protecting groups have been designed and synthesized. One of these sulfonate esters allowed the cytoplasmic delivery and unmasking of a sulfonated dye in live cells.     

A new reagent for the cleavage of NPS-amino protecting groups in peptide synthesis.

The value of several reagents capable of removing quantitatively the α-amino protecting group of NPS-aminoacyl- or peptidyl-derivatives is assessed, by comparison with the reagents currently used, i.e. hydrogen chloride, RS^–-nucleophiles or alkyl thioamides, especially with regard to reaction specificity and end-product solubility. New reagents proposed, 3-nitro-4-mercapto-benzoic acid, and its methyl ester, appear to optimize the numerous, and often competing, requirements. These were probed, under conditions suitable for both conventional and solid-phase methods, on a series of model compounds, including diversely protected amino acids and short peptides, as well as for the actual synthesis of a triacontapeptide by the stepwise, solid-phase approach.     

3-butenyl esters as convenient protecting groups for carboxylic acids

Carboxylic acids were protected as their corresponding 3-butenyl esters. Deprotection was carried out via ozonolysis and β-elimination of the resultant 3-acyloxypropanal.     

A comparative study of quantitative structure-activity relationship methods based on gallic acid derivatives

By using hologram quantitative structure-activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) methods, the relationships between the structures of 49 gallic acid derivatives and their analgesic activity have been investigated to yield statistically reliable models with considerable predictive power. The best HQSAR model was generated using atoms, bond and connectivity as fragment distinction parameters and fragment size 5-7 from a hologram length of 307 with 3 components. High conventional r2 (r2 = 0.825) and cross-validation r2 (r2(cv) = 0.726) values were obtained. CoMFA analyses varying lattice size and location, grid spacing, probe charges and using, Tripos standard and Indicator force field were performed. The best model was developed with 4 components using sp3-hybridized carbon atom with +1.0 charge as probe, grid spacing (2 A), lattice offset (1.0, 3.0, -2.5). The CoMFA model showed a conventional correlation coefficient r2 of 0.889 and across-validation r2(cv) equals to 0.633. The robustness and predictive ability of the HQSAR and CoMFA models have been validated by means of an external test set. The results indicate that both models possess high statistical quality in the prediction of analgesic potency of novel gallic acid analogs.     

Mono- and dimethylbenzyls as new protecting groups for no-carrier-added nucleophilic aromatic radiofluorination

In this work, we tested the applicability of several methyl substituted benzyl groups as an alternative to the methyl group for the protection of the hydroxyl groups in the nucleophilic aromatic radiofluorination. As a model synthesis, the no-carrier-added (n.c.a.) preparation of 2-[¹⁸F]fluoro-3-hydroxy-6-methylpyridine from O-protected 3-hydroxy-6-methyl-2-nitropyridine was chosen. Conditions for acidolytic and hydrogenolytic cleavage of heteroaryl esters were studied. Among various protecting groups tested, 4-methylbenzyl and 2,4-dimethylbenzyl groups proved to be the best by resulting in about 70% yields of [¹⁸F]-labelled product after hydrolysis with 32% HCl at 120 °C for 10 min. Furthermore, 4-methylbenzyl ester cleaved readily under catalytic transfer hydrogenation condition using ammonium formate and 10% Pd/C in boiling methanol to give 2-[¹⁸F]fluoro-3-hydroxy-6-methylpyridine in radiochemical yield of 75% within a reaction time of 10 min. Conditions for the cleavage of both 4-methylbenzyl and 2,4-dimethylbenzyl esters are well suited for the implementation into an automated synthesis module.     

Polyene synthesis: A comparative study

As part of an effort to synthesize the polyene macrolide antibiotics, a comparison of several methods of polyene synthesis has been carried out with the finding that superior results were obtained using the Wollenberg vinyl ether method.