Phenols linkers for

Alcohols and phenols can be attached to support-bound alcohol linkers as carbonates [467,665,666], although few examples of this have been reported. For the preparation of carbonates, the support-bound alcohol needs to be converted into a reactive carbonic acid derivative by reaction with phosgene or a synthetic equivalent thereof, e.g. disuccinimidyl carbonate [665], carbonyl diimidazole [157], or 4-nitrophenyl chloro-formate [467] (see Section 14.7). The best results are usually obtained with support-bound chloroformates. The resulting intermediate is then treated with an alcohol and a base (DIPEA, DMAP, or DBU), which furnishes the unsymmetrical carbonate. Carbonates are generally more resistant towards nucleophilic cleavage than esters, but are less stable than carbamates. Aryl carbonates are easily cleaved by nucleophiles and are therefore of limited utility as linkers for phenols. 

Few examples have been described of nucleophilic cleavage of carbonate- or carbamate-linked alcohols from insoluble supports. A serine-based linker for phenols releases the phenol upon fluoride-induced intramolecular nucleophilic cleavage of an aryl carbamate (Entry 2, Table 3.36). A linker for oligonucleotides has been described, in which the carbohydrate is bound as a carbonate to resin-bound 2-(2-nitrophen-yl)ethanol, and which is cleaved by base-induced 3-elimination (Entry 3, Table 3.36). Trichloroethyl carbonates, which are susceptible to cleavage by reducing agents such as zinc or phosphines, have been successfully used to link aliphatic alcohols to silica gel (Entry 4, Table 3.36). These carbonates can also be cleaved by acidolysis (Table 3.22). 

Support-bound phenols, oximes, and related compounds yield, upon acylation, esters that are highly susceptible to nucleophilic cleavage. These esters are often used as insoluble acylating agents for the preparation of amides or esters, but only occasionally as linkers for carboxylic acids [113]. These linkers are considered in Sections 3.3.3 and 3.5.1. 

Only a few examples have been reported of the etherification of alcohols with resin-bound diarylmethyl alcohols (Entry 5, Table 3.30 Entry 5, Table 3.31 [564]). Diarylmethyl ethers do not seem to offer advantages over the more readily accessible trityl ethers, which are widely used as linkers for both phenols and aliphatic alcohols. Attachment of alcohols to trityl linkers is usually effected by treating trityl chloride resin or 2-chlorotrityl chloride resin with the alcohol in the presence of a base (phenols pyridine/THF, 50 °C [565] or DIPEA/DCM [566] aliphatic alcohols pyridine, 20-70 °C, 3 h-5 d [567-572] or collidine, Bu4NI, DCM, 20 °C, 65 h [81]). Aliphatic or aromatic alcohols can be attached as ethers to the same type of light-sensitive linker as used for carboxylic acids (Section 3.1.3). 

A traceless perfluoroalkylsulfonyl linker for the deoxygenation of phenols has been reported by Holmes. A more lightly fluorous variant has also been presented by Zhang, where microwave heating was applied to increase the speed of the reaction. The traceless tag was exemplified in syntheses of triaryl-substituted pyrimidines and hydantoins (Reaction Scheme 10). 

Two new silyl linkers (61 and 62, Fig. 5) have been synthesized starting from Merrifield resin, 3-methyl-l,3-butanediol, and diphenyldichlorosilane or dimefhyl-dichlorosilane [64]. Linker 61 was used for the attachment of primary and secondary alcohols as well as for phenols, whereas tinker 62 was designed for the binding of tertiary alcohols. 

Resuspend DNA in 17 fil of water and repeat digestion in 5au3AI buffer with 4 U 5au3AI at 37°C for 1 hr. This step ensures that all ends are compatible for subsequent linker ligation. Phenol/chloroform extract and reprecipitate DNA. 

Amino Rosins. Melamine (l,3,5-triazine-2,4,6-triamine) [108-78-1] is reacted with formaldehyde [50-00-0] and alcohols to make melamine-formaldehyde (MF) resins, the most widely used cross-linkers for baked coatings. The ethers groups are activated toward nucleophilic substitution by the neighboring N. Hydroxyl, carboxylic acid, urethane, and phenols with an unsubstituted ortho position react (see Amino Resins). 

Phenolic resins were among the first synthetic resins explored by the coating industry, initially used to modify properties of oil-based varnishes as a replacement for some natural hard resins. They are essentially solvent-soluble phenol-formaldehyde condensates with reactive methyllol groups. They are widely used as cross-linkers for thermosetting baking finishes, yielding films with excellent solvent and corrosion resistance properties coupled with favorable mechanical properties. 

A second strategy is to attach a linker (also referred to as a handle or anchor) to the resin followed by assembly of the molecule. A linker is bifunctional spacer that serves to link the initial synthetic unit to the support in two discrete steps (Fig. 3). To attach a linker to a chloromethyl-PS resin, a phenol functionality such as handle 4 is used to form an ether bond (Fig. 4). To attach the same handle to an amino-functionalized support, acetoxy function 5 or a longer methylene spacer of the corresponding phenol is applied to form an amide bond. Both of these resins perform similarly and only differ in their initial starting resin [4], An alternative approach is to prepare a preformed handle in which the first building block is prederivatized to the linker and this moiety is attached to the resin. For peptide synthesis, this practice is common for the preparation of C-terminal peptide acids in order to reduce the amount of racemization of the a-carbon at the anchoring position [5],... 

Dihydropyran (DHP) linker 45 is a common handle that couples an alcohol to a solid support with subsequent release upon mild TFA conditions (Fig. 12) [54]. An alternative approach is to prepare an active carbonate linker. TV,TV -Disuccinimidyl carbonate (DSC), a valuable reagent for converting hydroxymethyl-based supports to their corresponding carbonates, was reacted with 4-hydroxymethylpolystyrene 46 and 4-nitrobenzamido (Nbb) 47 resins to anchor alcohols and phenols (Scheme 17) [55]. The final products were released from the solid support by HF and photolysis, respectively. 

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