The effect of nitro substitution on the photochemistry of benzyl benozhydroxamate: Photoinduced release of benzohydroxamic acid

The redox congener of the important signaling agent nitric oxide (NO), nitroxyl or nitrosyl hydride (HNO) has also been demonstrated to induce distinct physiological effects. The aim of this study was to determine if benzohydroxamic acid, which was selected as a stable model compound of HNO donors, could be released by the o-nitrobenzyl photolabile protecting group (PPG) in a wavelength-dependent manner. It was expected that selective irradiation of the o-nitrobenzyl chromophore would favor the release of benzohydroxamic acid over undesired products associated with N-O bond cleavage. Quantum yields for the release of benzohydroxamic acid protected by the o-nitrobenzyl PPG increased at longer wavelengths, with a concomitant decrease in the yield of minor products. Through the use of triplet photosensitizers, triplet quenchers, computational methods, and the position of the nitro substituent, insights into the nature of the mechanism were suggested.     

Wavelength-selective cleavage of o-nitrobenzyl and polyheteroaromatic benzyl protecting groups

Evaluation of the wavelength-selective cleavage of five photolabile protecting groups from two different families has been performed. Alanine, as a model bifunctional target molecule was masked at the amino terminal with o-nitrobenzyl group and at the carboxylic terminal with benzyl-type nitrogen and oxygen polyheteroaromatics, namely acridine, (thioxo)benzocoumarin and a coumarin built on the julolidine nucleus. The photosensitivity of the corresponding alanine conjugates was studied at selected wavelengths with HPLC/UV and ¹H NMR monitoring. The release of the fully deprotected molecule could be achieved by sequential irradiation in variable irradiation times, which were dependent on the heteroaromatic group used.     

Bis(4,5-dimethoxy-2-nitrophenyl)ethylene glycol: a new and efficient photolabile protecting group for aldehydes and ketones

Synthesis of a new photolabile protecting group, bis(4,5-dimethoxy-2-nitrophenyl)ethylene glycol (4) from 4,5-dimethoxy-2-nitrobenzyl alcohol in three steps in good yields is described. The acetals and ketals of 4 are stable against acidic and basic reaction conditions and are cleaved smoothly on irradiation at 350 and 400 nm with regeneration of carbonyl compounds in high yields and efficiency.     

Oxidation with a photolabile carbonyl protecting group

A novel oxidation approach utilizing a robust photolabile carbonyl protecting group reagent (1) as the oxidizing reagent has been developed. Different from existing methods, this approach oxidizes primary alcohols to the photosensitive acetals (e.g., 3), providing another unique approach to the protected aldehydes. Thus, for the first time, oxidation and protection are achieved in one reaction. Secondary alcohols are oxidized to the corresponding ketones. Moreover, the photolabile protecting group (PPG) also oxidizes ethers and esters. The oxidation is presumably via hydride abstraction by the tritylium ion generated from 1 under acidic conditions. However, the mechanisms for primary alcohols and secondary alcohols are slightly different.     

Synthesis and characterization of photolabile o-nitrobenzyl derivatives of urea

We present here the synthesis and characterization of four photolabile derivatives of urea in which alpha-substituted 2-nitrobenzyl groups are covalently attached to the urea nitrogen. These derivatives photolyze readily in aqueous solution to release free urea. The alpha-substituents of the 2-nitrobenzyl group strongly influence the rate of the photolysis reaction measured with transient absorption spectroscopy. Rates of photolysis at pH 7.5 and room temperature (approximately 22 degrees C) for N-(2-nitrobenzyl)urea, N-(alpha-methyl-2-nitrobenzyl)urea, N-(alpha-carboxymethyl-2-nitrobenzyl)urea, and N-(alpha-carboxy-2-nitrobenzyl)urea are, respectively, 1.7 x 10(4), 8.5 x 10(4), 4.0 x 10(4), and 1.1 x 10(5) s(-)(1). The quantum yields determined by measurement of free urea following irradiation by a single laser pulse at 308 nm were 0.81 for N-(2-nitrobenzyl)urea, 0.64 for N-(alpha-methyl-2-nitrobenzyl)urea, and 0.56 for N-(alpha-carboxy-2-nitrobenzyl)urea. The caged N-(alpha-carboxy-2-nitrobenzyl)urea is not a substrate of the enzyme urease, while the photolytically released urea is. Also, neither this caged urea nor its photolytic side products inhibit hydrolysis of free urea by urease. Thus, the alpha-carboxy-2-nitrobenzyl derivative of urea is suitable for mechanistic investigations of the enzyme urease.     

o-nitrobenzyl photolabile protecting groups with red-shifted absorption: syntheses and uncaging cross-sections for one- and two-photon excitation

We evaluated the o-nitrobenzyl platform for designing photolabile protecting groups with red-shifted absorption that could be photolyzed upon one- and two-photon excitation. Several synthetic pathways to build different conjugated o-nitrobenzyl backbones, as well as to vary the benzylic position, are reported. Relative to the reference 4,5-dimethoxy-2-nitrobenzyl group, several o-nitrobenzyl derivatives exhibit a large and red-shifted one-photon absorption within the near-UV range. Uncaging after one-photon excitation was studied by measuring UV-visible absorption and steady-state fluorescence emission on model caged ethers and esters. In the whole series investigated, the caged substrates were released cleanly upon photolysis. Quantum yields of uncaging after one-photon absorption lie within the 0.1-1 % range. We observed that these drop as the maximum wavelength absorption of the o-nitrobenzyl protecting group is increased. A new method based on fluorescence correlation spectroscopy (FCS) after two-photon excitation was used to measure the action uncaging cross section for two-photon excitation. The series of o-nitrobenzyl caged fluorescent coumarins investigated exhibit values within the 0.1-0.01 Goeppert-Mayer (GM) range. Such results are in line with the low quantum yields of uncaging associated with cross-sections of 1-50 GM for two-photon absorption. Although the cross-sections for one- and two-photon absorption of o-nitrobenzyl photolabile protecting groups can be readily improved, we emphasize the difficulty in enlarging the corresponding action uncaging cross-sections in view of the observed trend of their quantum yield of uncaging.     

Brominated hydroxyquinoline as a photolabile protecting group with sensitivity to multiphoton excitation

The synthesis and photochemistry of a new photolabile protecting group for carboxylic acids based on 8-bromo-7-hydroxyquinoline (BHQ) is described. BHQ possesses a greater single photon quantum efficiency than 4,5-dimethoxy-4-nitrobenzyl ester (DMNB) and 6-bromo-7-hydroxycoumarin-4-ylmethyl (Bhc), and it has sufficient sensitivity to multiphoton-induced photolysis for use in vivo. Its increased solubility and low fluorescence make it quite useful as a caging group for biological messengers. [structure: see text]     

Catalytic Lewis acid phosphorylation with pyrophosphates

We report a method for the Lewis acid catalyzed phosphorylation of alcohols with pyrophosphates. Ti(O^tBu)₄ was found to be the most effective catalyst in the phosphorylation of both primary and secondary alcohols with tetrabenzylpyrophosphate, providing conversions between 54% and >98% and isolated yields between 50% and 97%. Other pyrophosphates with orthogonal protecting groups were synthesized and screened to validate the generality of the approach. This study will describe how benzyl, methyl, ethyl, allyl, and o-nitrobenzyl pyrophosphates are all effective phosphorylating agents under Lewis acid catalysis.     

Blocked Phosphates as Photolatent Catalysts for Dynamic Photopolymer Networks

While latent catalysts are a well-established strategy for initiating and controlling the rate of polymerization reactions, their use in dynamic polymer networks is still in its infancy. The ideal latent catalyst should be thermally stable and release a highly active species in response to an external trigger. Here, we have synthesized a temperature resistant (>200 °C) organic phosphate with a photolabile o-nitrobenzyl protecting group that can be cleaved by UV light. Introduced in a visible light curable thiol-click photopolymer, the sequence-dependent λ-orthogonality of the curing and cleavage enables an efficient network formation at 451 nm, without premature release of the catalyst. Once cured, irradiation at 372 nm spatiotemporally activates the phosphate, which catalyzes transesterifications at elevated temperature. The formed catalyst has no effect on the thermal stability of the polymeric network and allows the activation of bond exchange reactions in selected domains of printed 3D objects.     

A new method for the cleavage of nitrobenzyl amides and ethers

A mild and efficient o- and p-nitrobenzyl cleavage protocol was developed. o- and p-nitrobenzyl groups were easily removed from a variety of substrates using 20% aqueous NaOH in methanol at 75 °C, presumably via oxidation at the benzylic position by oxygen dissolved in the solution. These easily introducible and removable nitrobenzyl groups can serve as valuable protecting groups for the synthesis of multifunctional, complex molecules.     

Regio- and stereoselective synthesis of Z-vinylic tellurides from propargylic alcohols: a route to chiral Z-enynes

tert-Butyldimethylsilyl ethers of propargylic alcohols are hydrotellurated regioselectively to give 1,2-Z-vinylic tellurides. Enantiomerically pure propargylic alcohols give enantiomerically pure vinylic tellurides, which are coupled with alkynes under Pd catalysis to give enantiomerically pure allylic enynols.     

Synthesis of photolabile 2-(2-nitrophenyl)propyloxycarbonyl protected amino acids

The 2-(2-nitrophenyl)propyloxycarbonyl (NPPOC) group has been introduced as a photolabile amino protecting group for amino acids to be used as building blocks in photolithographic solid-phase peptide synthesis. NPPOC-protected amino acids were found to be cleaved in the presence of UV light about twice as fast as the corresponding o-nitroveratryloxycarbonyl (NVOC)-protected amino acids.     

Light-directed radial combinatorial chemistry: orthogonal safety-catch protecting groups for the synthesis of small molecule microarrays

We describe the development of photolabile protecting groups based on the 3,4,5-trimethoxyphenacyl group (TMP). Orthogonal safety-catches were created by introducing an acid-activatible dimethyl ketal (AA-TMP) and an oxidatively activatible 1,3-dithiane (OA-TMP) into the photolabile TMP group. We demonstrate the application of these protecting groups in light-directed synthesis of small molecule microarrays with diversity elements radially attached to a hydroxyproline scaffold.     

Lead structures for applications in photodynamic therapy. Part 2: Synthetic studies for photo-triggered release systems of bioconjugate porphyrin photosensitizers

Photodynamic therapy (PDT) selectivity and specificity can be improved by binding the photosensitizers to target receptors. One approach is to cross-link porphyrins to a biological target receptor via the photocleavable o-nitrobenzyl linker, where a controlled released of the porphyrin can be monitored upon irradiation. The synthetic pathways involved esterification of a porphyrin-carboxylic acid and a unit containing the o-nitrobenzyl alcohol moiety and the bioconjugate. Reactions of a model porphyrin and o-nitrobenzyl alcohol using the carbonyl activating carbodiimide reagent DCC gave a stable N-acyl urea porphyrin, whereas use of EDAC (1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride) gave the desired compounds. Further studies were carried out on the attachment of carbohydrates (i.e., potentially receptor binding ligands) through such a linker to porphyrins. Preliminary irradiation experiments of such a compound show that upon UV irradiation (350 nm) for 80 min, approximately 50% of the porphyrin was cleaved to release the carboxylic acid porphyrin photosensitizer indicating the utility of such systems as photosensitizers delivery systems.     

A facile method for the rapid and selective deprotection of methoxymethyl (MOM) ethers

We describe a rapid and efficient method for selective deprotection of methoxymethyl (MOM) ethers using ZnBr₂ and n-PrSH, which completely removed MOM from diverse MOM ethers of primary, secondary, and tertiary alcohols or phenol derivatives. The deprotection takes less than ten minutes with both high yield and selectivity in the presence of other protecting groups. In addition, the rapid deprotection of MOM ethers of tertiary hydroxyls in high yield with no epimerization allows MOM to be a suitable protecting group for tertiary alcohols.     

Rapid one-pot iterative diselenide–selenoester ligation using a novel coumarin-based photolabile protecting group

The development of an iterative one-pot peptide ligation strategy is described that capitalises on the rapid and efficient nature of the diselenide–selenoester ligation reaction, together with photodeselenisation chemistry. This ligation strategy hinged on the development of a novel photolabile protecting group for the side chain of selenocysteine, namely the 7-diethylamino-3-methyl coumarin (DEAMC) moiety. Deprotection of this DEAMC group can be effected in a mild, reagent-free manner using visible light (λ = 450 nm) without deleterious deselenisation of selenocysteine residues, thus enabling a subsequent ligation reaction without purification. The use of this DEAMC-protected selenocysteine in iterative DSL chemistry is highlighted through the efficient one-pot syntheses of 60- and 80-residue fragments of mucin-1 as well as apolipoprotein CIII in just 2–4 hours.

A method for the rapid one-pot iterative assembly of proteins via diselenide–selenoester ligation (DSL) chemistry is described that capitalises on a novel coumarin-based photolabile protecting group for selenocysteine.     

Intramolecular sensitization of photocleavage of the photolabile 2-(2-nitrophenyl)propoxycarbonyl (NPPOC) protecting group: photoproducts and photokinetics of the release of nucleosides

Novel photolabile protecting groups based on the 2-(2-nitrophenyl)propoxycarbonyl (NPPOC) group with a covalently linked thioxanthone as an intramolecular triplet sensitizer exhibit significantly enhanced light sensitivity under continuous illumination. Herein we present a detailed study of the photokinetics and photoproducts of nucleosides caged with these new protecting groups. Relative to the parent NPPOC group, the light sensitivity of the new photolabile protecting groups is enhanced by up to a factor of 21 at 366 nm and is still quite high at 405 nm, the wavelength at which the sensitivity of the parent compound is practically zero. A new pathway for deprotection of the NPPOC group proceeding through a nitroso benzylalcohol intermediate has been discovered to complement the main mechanism, which involves beta elimination. Under standard conditions of lithographic DNA-chip synthesis, some of the new compounds, while maintaining the same chip quality, react ten times faster than the unmodified NPPOC-protected nucleosides.     

Synthesis of an o-Nitrobenzyl Attached A1 Adenosine Receptor Antagonist,a Prodrug Approach

Abstract

The o-nitrobenzyl group, possessing distinct advantage of being photolabile under mild conditions, was successfully connected to 8-(5,6-epoxynorbornan-2-yl)-1,3-dipropylxanthine (5), a high specific A₁ adenosine receptor antagonist. The resulting compound 4 would have potential use as a prodrug.     

Photo-triggered generation of a free thiol group on DNA: application to DNA conjugation

DNA oligomers possessing a 2-nitrobenzyl (NB) protected thiol group have been prepared. The photo-remove of the NB to generate a free thiol group in DNA has been analyzed by using reverse-phase HPLC and denaturing gel electrophoresis. The photo-triggered generation of the thiol function in DNA was applicable in the light-initiated ligation of thiol-modified DNA oligomers and Au–DNA conjugation.     

Regioselective synthesis of phthalans via Cu(OTf)2-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohols

An efficient, regioselective Cu(OTf)₂-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohol, which provides a concise access to functionalized phthalan in high yields has been developed. A wide range of substrates possessing terminal, internal, and heteroaromatic alkynes can be efficiently transformed into the targeted phthalans. Substrates with primary, secondary, and tertiary benzyl alcohols also proceed well to produce the corresponding phthalans in good yields. Irrespective of the nature of the substrates, the cyclization follows highly selective 5-exo-dig regiochemistry when regioselectivity is an issue.