Linker oxidatively labile

Stieber F, Grether U, Waldmann H. An oxidation-labile traceless linker for solid-phase synthesis. Angew Chem, Int Ed 1999 38 1073-1077. 

The iodination of cross-linked polystyrene has been achieved using iodine under strongly acidic reaction conditions [55] or in the presence of thallium(III) acetate [61], but this reaction does not proceed as smoothly as the bromination. More electron-rich arenes, such as thiophenes [45,62-64], furans [46], purines [65], indoles [66], or phenols [67,68] are readily halogenated, even in the presence of oxidant-labile linkers (Figure 6.2). Polystyrene-bound thiophenes have also been iodinated by lithiation with LDA followed by treatment with iodine [64],... 

Cross-linked polystyrene can be directly nitrated with fuming nitric acid at low temperatures (-25 °C to 0°C) [189,203,374] polymers with up to one nitro group per arene result [203]. Partial nitration can be achieved with milder nitrating agents, such as acetyl nitrate [203]. Because direct nitrations are not compatible with most linkers (which are often acid- or oxidant-labile), nitro compounds are generally not prepared on supports but in solution, and are then linked to the support. 

Semi995 Semenov, A.N. and Gordeev, K.Y., A Novel Oxidation-Labile Linker For Solid-Phase Peptide Synthesis, Int. J. Pept. Protein Res., 45 (1995) 303-304. 

Semenov AN, Gordeev KY (1995) A novel oxidation-labile linker for solid-phase peptide synthesis. Int J Pept Protein Res 45 303—304... 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

The Marshall Unker [23] has been widely used to synthesize compounds that can be cleaved by primary and secondary amines to afford the corresponding amides. Marshall linker was used in the synthesis of three or more diversity-site hbraries because it allowed the addition of one more diversity element at the cleavage step. While the original reported linker [23] involved the oxidation of the Unker before cleavage, the efficient release of the resin-bound compounds using nucleophiles from the unoxidized linker has been reported [16, 24]. Similarly to the acid-labile linkers, the kinetics of the cleavage reaction and time required for this reaction directly affect the synthesis efficiency, purity and yield of the final products. A cleavage study was carried out on seven resin-bound thiophenol esters (34—40) on Marshall Unker with 3 amines (41-43) (Scheme 12.11 and Tab. 12.4). 

Polystyrene-derived phenylboronic acids have been used for the attachment of diols (carbohydrates) as boronic esters [667]. Cleavage was effected by treatment with acetone/water or THF/water. This high lability towards water and alcohols severely limits the range of reactions that can be performed without premature cleavage of this linker. Arylboronic acids esterified with resin-bound diols can be oxidatively cleaved to yield phenols (Entry 8, Table 3.36). Alcohols have also been prepared by nucleophilic allylation of aldehydes with polystyrene-bound, enantiomerically enriched allyl-silanes [668], as well as by Pummerer reaction followed by reduction of resin-bound sulfoxides [669]. 

Methoxyphenyl ethers can be cleaved by mild oxidants (Entry 10, Table 7.8). Because many acid-labile linkers are also readily oxidized, care must be taken when applying this deprotection strategy. Benzyl ethers have been removed from Tentagel-or PEGA-bound carbohydrates by catalytic hydrogenation using palladium nanoparticles [112],... 

The diethanolamine linker 1.13 (70), obtained from aminomethyl PS resin and ethylene oxide, has been used to support boronic acids which, after SP transformations, were released with THF/H2O/ACOH 18/1/1 in 1 h at rt or, when acid-labile boronic acids were involved, with THF/H2O 9/1 in 2 h at rt. 

The linker is immobilized through the thiol group to form the 4-hydroxybenzene-thiomethyl-PS/DVB. In order to release the product from the resin the sulfide is oxidized with H202 to a base-labile sult one. 

The most commonly employed, oxidatively removable linker is related to the p-methoxybenzyl group (PMB) [64]. Resin-bound PMB can be cleaved by the action of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). The acid lability of PMB can be successfully reduced by attaching an acylamino moiety in tbe para position of the benzene ring. The PMB-derived linker may be attached to hydroxyl groups other tban tbe anomeric position to facilitate product purification and analysis (Scheme 20.20). 

An enzyme-labile so-called safety catch linker 452 was used successfully in various palladium-catalyzed cross-coupling reactions [592]. The linker 452, which releases a hydroxy or an amino functionality on enzymatic cleavage of its phenylacetamide moiety and subsequent rapid lactam formation, was attached to a soluble POE 6000 (polyethylene oxide) polymer and its free phenylacetic acid moiety was transformed to an m-iodobenzyl ester. The thus immobilized m-iodobenzyl alcohol was Heck-coupled with tert-butyl acrylate, and the coupling product 453 was cleaved off the solid support with penicillin G acylase under very mild conditions (pH 7, 37°C) (Scheme 8.84). 

Fig. 20.2 Six representative hybrid NORMs eontaining furoxan, nitrate, and NONOate warheads. Eaeh molecule incorporates at least two eomponent parts a bioactive carrier and a warhead. All examples shown have labile linkers that are bioactivated to release bioaetive molecules ineluding the warhead. In most eases the warhead requires further bioactivation to release NO bioaetivity. The figure illustrates the uniform dependence on reactions with biological thiols and products that will contribute to varied levels of cellular oxidative stress...

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