Tris(pentafluorophenyl)borane: a mild and efficient catalyst for the chemoselective tritylation of alcohols

An efficient acid-catalyzed protection of alcohols as trityl ethers is described using triphenylmethanol in the presence of tris(pentafluorophenyl)borane (3 mol %) in dichloromethane at room temperature. The chemoselectivity of this protocol is demonstrated by studying the tritylation of a primary alcohol in the presence of a secondary alcohol and also the mildness of this catalyst was studied with substrates containing acid labile protecting groups.     

An Efficient and Environmentally Friendly Method for Directly Converting Trityl and Benzyl Ethers to the Corresponding Acetates

Acid sensitive benzyl and trityl ethers are frequently used as protecting groups to mask alcohols. They are also needed to be transformed into more stable ester groups toward acids in multistep synthesis. A mild and efficient one‐pot protocol for the selective transformation of benzyl and trityl ethers into their corresponding acetates was successfully developed. Several distinct advantages to this procedure include direct transformation, minimal generation of waste, a non‐aqueous workup and the recovery and recycling of the benzyl acetate and trityl alcohol by‐products, which were readily recovered in greater than 90% yields.     

Efficient loading of primary alcohols onto a solid phase using a trityl bromide linker

The Letter describes an improved, rapid and mild strategy for the loading of primary alcohols onto a polystyrene trityl resin via a highly reactive trityl bromide linker. This protocol facilitates an efficient resin loading even of acid-sensitive or heat-labile alcohols, which otherwise require expensive or non-commercial resin types. Secondary alcohols were only attached in moderate to low yields, while attempts to load a tertiary alcohol expectedly failed. Importantly, selective attachment of diols via a primary alcohol group in the presence of more hindered alcohol groups proved possible. The effects of activation time and reagent excess as well as alcohol structure were investigated. This improved method provides a convenient access to O-linked resin-bound N-Fmoc-protected amino alcohols that may be employed in SPS of peptides with C-terminal alcohol functionalities. In the case of a sensitive alcohol containing an activated aziridine functionality, the use of the trityl bromide linker proved superior to a recently described silver triflate-assisted trityl chloride resin-based procedure.     

Azobenzene-tethered bis(trityl alcohol) as a photoswitchable cooperative Acid catalyst for morita-baylis-hillman reactions

Incorporation of an azobenzene core into tethered bis(trityl alcohol) allows the photoswitchable arrangement of the two trityl alcohol units through photoisomerization of azobenzene. The differently arranged trityl alcohol units change their cooperative function to reflect the positional relationships, and thus, the activity as a cooperative acid can be controlled by light stimuli.     

三苯甲基醚直接转化成丙酮化合物的反应

介绍了一种新的高效的由三苯甲基醚直接生成丙酮化合物的方法, 也就是使三氟乙酸条件下脱三苯甲基的反应和生成丙酮化合物的反应在一个反应瓶中同时进行, 使脱三苯甲基作用后生成的醇继续反应得到高产率的丙酮化合物. 这种方法对于分子中同时含有对酸敏感的其他官能团的三苯甲基醚分子的脱保护非常有用.     

Purification of crude DNA oligonucleotides by solid-phase extraction and reversed-phase high-performance liquid chromatography

Purification of target oligodeoxyribonucleotides from failure sequence by-products of synthesis is often required for polymerase chain reaction primers, DNA sequencing and other oligonucleotide applications. We have developed purification protocols based on a reversed-phase mechanism ("trityl on" purification) using a 96-well Oasis HLB extraction plate. The Oasis HLB sorbent combines excellent pH stability with a high loading capacity allowing for single-step purification of 0.2 microM scale synthesis. After sample loading and washing, the oligonucleotide trityl group is cleaved on the plate with 2% trifluoroacetic acid. Target DNA is eluted with acetonitrile-0.36 mM triethylamine acetate, pH 11.3 (10:90, v/v). Typical yield of purified product is 60-95%. Final purity, measured by capillary gel electrophoresis, was found to be 90% or greater. Alternatively, highly pure oligonucleotides can be obtained by a RP-HPLC "trityl off" method using an XTerra C18 column. The use of volatile triethylamine acetate buffer as an ion-pair for RP-HPLC eliminates the need for further desalting.     

Synthesis of ethyl 3-(hydroxyphenoxy)benzyl butylphosphonates as potential antigen 85C inhibitors

All three isomers of ethyl 3-(hydroxyphenoxy)benzyl butylphosphonates as potential antigen 85C inhibitors were synthesized from 3-bromobenzoic acid using Ullman diaryl ether synthesis combined with benzyl- and trityl protection strategy for the phenol hydroxyl groups.     

Enzymatic Synthesis of [3-14C]Cinnamic Acid

Convenient and efficient route of the synthesis of [3-¹⁴C] cinnamic acid is reported. [1-¹⁴C]Benzoic acid, prepared by carbonation of Grignard reagent with [¹⁴C]carbon dioxide, was reduced to [1-¹⁴C]benzyl alcohol. In the enzymatic step this alcohol was selectively oxidised to [1-¹⁴C]benzaldehyde using enzyme YADH (Ec. 1.1.1.1) and immediately condensed with malonic acid. This combined chemical and enzymatic approach allows to obtain [3-¹⁴C]cinnamic acid with radiochemical yield higher than 50% in respect to the starting alcohol.     

A catalytic method for chemoselective detritylation of 5′-tritylated nucleosides under mild and heterogeneous conditions using silica sulfuric acid as a recyclable catalyst

A rapid, mild and highly efficient procedure for the chemoselective deprotection of triphenylmethyl (trityl, Tr), p-anisyldiphenylmethyl (monomethoxytrityl, MMT) and di-(p-anisyl)phenylmethyl (dimethoxytrityl, DMT) groups from nucleoside trityl ethers has been established. The deprotection was achieved at room temperature, using a catalytic amount of silica sulfuric acid (SSA) in acetonitrile. The trityl nucleosides were deprotected in 2-17 min without any depurination. These conditions are compatible with other acid sensitive hydroxyl protecting groups such as p-methoxybenzyl (PMB), isopropylidene, cyclohexylidene, di-(p-anisyl)methylidene, triisopropylsilyl (TIPS) and t-butyldimethylsilyl (TBDMS).     

Reactivity of molecular oxygen with ethoxycarbonyl derivatives of tetrathiatriarylmethyl radicals

Tetrathiatriarylmethyl (TAM) radicals are commonly used as oximetry probes for electron paramagnetic resonance imaging applications. In this study, the electronic properties and the thermodynamic preferences for O2 addition to various TAM-type triarylmethyl (trityl) radicals were theoretically investigated. The radicals' stability in the presence of O2 and biological milieu was also experimentally assessed using EPR spectroscopy. Results show that H substitution on the aromatic ring affects the trityl radical's stability (tricarboxylate salt 1-CO2Na > triester 1-CO2Et > diester 2-CO2Et > monoester 3-CO2Et) and may lead to substitution reactions in cellular systems. We propose that this degradation process involves an arylperoxyl radical that can further decompose to alcohol or quinone products. This study demonstrates how computational chemistry can be used as a tool to rationalize radical stability in the redox environment of biological systems and aid in the future design of more biostable trityl radicals.     

An Efficient Procedure for Esterification of Aryloxyacetic Acid and Arylthioacetic Acid Catalyzed by Silica Sulfuric Acid

Aryloxyacetate and arylthioacetate are wildly used in herbicides, plant regulator and insecticides. Recently, Wille et al. have reported that methyl aryloxyacetate is an efficient agent to prevent and treat allergic contact dermatitis.[1] The most popular synthesis is by heating sodium phenoxide (mercaptide) with ethyl chloroacetate in DMF,[2] or by the esterification of acid with alcohol using concentrated H2SO4 as catalyst.[3] In this paper, synthesis of aryloxyacetate and aryl thioacetate from aryloxyacetic acid and arylthioacetic acid respectively in ether catalyzed by silica sulfuric acid in 83%～94% yields is described. The catalyst is reused for 3 times without significant loss of activity (Entry 4). Compared with common procedures, the present procedure possesses the advantages of the operational simplicity, short reaction time,less-corrosion, high yield and reusable catalyst.     

Oxidation of 2-methoxy-6-(1-methylethyl)naphthalene with oxygen

Abstract  

Aerobic oxidation of 2-methoxy-6-(1-methylethyl)naphthalene to hydroperoxide, alcohol, and ketone, is reported. These compounds, particularly 2-acetyl-6-methoxynaphthalene, are important intermediates in naproxen synthesis. N-Hydroxyphthalimide is shown here to be an efficient catalyst for oxidation to the hydroperoxide, 2-methoxy-6-(1-hydroperoxy-1-methylethyl)naphthalene, with a yield of 87%. However, the ketone and alcohol were obtained with lower yields, with a maximum yield of 13% for the ketone and 27% for the alcohol, using N-hydroxyphthalimide and Cu(II) acetylacetonate as a catalyst. The synthesis of the products 2-acetyl-6-methoxynaphthalene and 2-methoxy-6-(1-hydroxy-1-methylethyl)naphthalene via an initial oxidation step to the hydroperoxide followed by a hydroperoxide decomposition step is shown to be more efficient; the ketone and alcohol were obtained from 2-methoxy-6-(1-methylethyl)naphthalene with yields of 40 and 56%, respectively.     

Synthesis and high performance liquid chromatography/electrospray mass spectrometry single-bead decoding of split-pool structural libraries of polyamines supported on polystyrene and polystyrene/ethylene glycol resins

Natural polyamines are ubiquitous biomolecules present in all living cells. These cationic compounds play essential roles in both cell growth and differentiation and are known to interact in complex ways with polyanionic biomolecules. Consequently, there is significant interest in expanding nature's polyamine diversity using combinatorial synthesis and screening strategies. This article describes an efficient split-pool solid-phase synthetic strategy toward the generation of encoded libraries of polyamines via the exhaustive borane-promoted reduction of trityl-linked, resin-bound polyamides. Model structural libraries of tetra- and pentaamines were designed from a set of geometrically diverse amino acid building blocks. To encode the libraries, a partial termination synthesis approach was employed at the polyamide stage, allowing each library to be analyzed from single beads by HPLC/ESMS under two sets of conditions featuring both pH extremes. Determination of the sequence of polyamine residues was simply achieved by the mass differences observed between the full oligomers and the terminated ones. Both polystyrene- and TentaGel-supported libraries, including a library of 4913 pentaamines, were prepared and successfully decoded. For the TentaGel-supported libraries, suitable for on-bead aqueous screening of biomolecules, a novel trityl-derivatized resin was prepared in which the trityl group is anchored to the poly(ethylene glycol) chains via a methylene group. The resulting resin is much more resistant than other commercially available polystyrene-poly(ethylene glycol) trityl resins to the harsh borane reduction conditions required. Two workup conditions for the cleavage of the resultant borane-amine adducts were evaluated on the TentaGel bound polyamide 14. Although the two methods showed a comparable efficiency when using the polystyrene support, with 14 it was found that the piperidine-exchange method afforded polyamines of higher purity than the iodine-based oxidative method previously developed in our laboratory.     

Tethered libraries: solid-phase synthesis of substituted urea-linked bicyclic guanidines

The general concept of tethered combinatorial libraries of compounds in which two pharmacophores are found is described. In particular, an improved method for the solid-phase synthesis of bicyclic guanidines from reduced N-acylated dipeptides, and its use in the synthesis of urea-linked bicyclic guanidines, is described. The exhaustive reduction of glutamine-containing resin-bound N-acylated dipeptides, using borane-THF, generated compounds containing three secondary amines and one primary amine. Following selective trityl protection of the primary amine, treatment of the three secondary amines with thiocarbonyldiimidazole (CSIm2) and mercuric acetate (Hg(OAc)2) generated the resin-bound bicyclic guanidines. Following trityl deprotection, an Fmoc-amino acid was coupled. Upon removal of the Fmoc protecting group, the resulting primary amine was treated with hexyl isocyanate to generate the urea-linked bicyclic guanidines. The desired products were cleaved from the resin using hydrogen fluoride. The selection of building blocks and characterization of controls for the synthesis of a combinatorial library is discussed.     

An efficient synthesis of a potent PPARpan agonist

An efficient synthesis of 2-{4-[({4-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)thio]phenoxy}-2-methylpropanoic acid (1), a potent PPARpan agonist, is described. The seven-step synthesis, which afforded 1 in 30% overall yield, includes a highly regioselective carbon-sulfur bond formation via coupling of a bishydroxymethylthiazole (3) with 4-hydroxythiophenol, displacement of the remaining alcohol through a three-step telescoped sequence involving an efficient cleavage of an aryl mesylate, and an efficient and practical method of introducing an isobutyric acid fragment.     

Immobilization of Eversa® Transform via CLEA Technology Converts It in a Suitable Biocatalyst for Biolubricant Production Using Waste Cooking Oil

The performance of the previously optimized magnetic cross-linked enzyme aggregate of Eversa (Eversa-mCLEA) in the enzymatic synthesis of biolubricants by transesterification of waste cooking oil (WCO) with different alcohols has been evaluated. Eversa-mCLEA showed good activities using these alcohols, reaching a transesterification activity with isoamyl alcohol around 10-fold higher than with methanol. Yields of isoamyl fatty acid ester synthesis were similar using WCO or refined oil, confirming that this biocatalyst could be utilized to transform this residue into a valuable product. The effects of WCO/isoamyl alcohol molar ratio and enzyme load on the synthesis of biolubricant were also investigated. A maximum yield of around 90 wt.% was reached after 72 h of reaction using an enzyme load of 12 esterification units/g oil and a WCO/alcohol molar ratio of 1:6 in a solvent-free system. At the same conditions, the liquid Eversa yielded a maximum ester yield of only 34%. This study demonstrated the great changes in the enzyme properties that can be derived from a proper immobilization system. Moreover, it also shows the potential of WCO as a feedstock for the production of isoamyl fatty acid esters, which are potential candidates as biolubricants.     

Mass spectrometry in structural and stereochemical problems—CLVIII electron impact promoted fragmentation of triphenylmethyl ethers

The triphenylmethyl (trityl) moiety is frequently used for the protection of alcohols but the mass spectra of such trityl ethers have hitherto escaped scrutiny. It has now been found that triphenylmethyl derivatives of primary alcohols yield abundant molecular ions which permit the determination of the isotopic purity of the parent alcohol. Upon electron impact the triphenyl-methyl entity directs the fragmentation of trityl ethers as demonstrated by a detailed study of n-pentyl trityl ether and its deuterated analogs. Ions formed by migration of phenyl groups were observed in the mass spectra of the trityl ethers investigated as well as in the spectrum of triphenyl-methane itself.     

Characterization of organic substrates bound to cross-linked polystyrenes by 13C NMR spectroscopy

The ¹³C NMR spectra of a wide variety of organic substrates bound to 2% cross-linked polystyrenes may be obtained routinely, provided the resins can be sufficiently swollen. The ¹³C chemical shifts of polymer-bound trityl alcohol, polymer-bound monotrityl ethers of the symmertrical diols HO (CH₂)_nOH (n=2, 4, 6, 7, 9 and 10), and some related intermediates in the solid phase synthesis of insect pheromones are presented. ¹³C shift additivity correlations, differing little from those in free trityl ethers, are drawn.     

Solvent free oxidation of primary alcohols and diols using thymine iron(III) catalyst

In this study, we developed an efficient and selective iron-based catalyst system for the synthesis of ketones from secondary alcohols and carboxylic acids from primary alcohol. In situ generated iron catalyst of thymine-1-acetate (THA) and FeCl(3) under solvent-free condition exhibits high activity. As an example, 1-octanol and 2-octanol were oxidized to 1-octanoic acid and 2-octanone with 89% and 98% yields respectively.     

An improved and general synthesis of monomers for incorporating trityl linker groups into polystyrene synthesis supports

A straightforward synthesis of trityl alcohols in which one of the aryl rings is substituted with a vinyl group is presented. The synthesis of the alcohols involves the direct addition of the Grignard reagent prepared from 4-bromostyrene to substituted benzophenones. These compounds are used to incorporate trityl linker groups into polystyrene-based organic synthesis supports. Both non-cross-linked and cross-linked (JandaJel™) polystyrene have been prepared using these monomers.