Trityl alcohol linkers

Esters of unsubstituted, polystyrene-bound trityl alcohol are too acid-sensitive to be useful for solid-phase synthesis [49]. Even treatment with alcohols or HOBt can lead to significant product release from the support. More stable towards solvolysis is 

The most valuable property of 2-chlorotrityl esters is their high stability towards nucleophiles and bases. 2-Chlorotrityl esters have been successfully used at elevated temperatures (e.g. 80 °C, 5 h, toluene [63]), although prolonged heating can lead to cleavage [63], 

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Neither the trialkoxybenzhydryl alcohol linker nor other types of benzhydryl alcohols [44,45,48] have found widespread use as linkers for carboxylic acids. These linkers do not seem to offer special advantages compared with benzyl alcohol or trityl linkers. 

Attachment of carboxylic acids to supports as trityl esters is achieved by treatment of the corresponding trityl chloride resin with the acid in the presence of an excess of a tertiary amine (Figure 3.5 see also Section 13.4.2). This esterification usually proceeds more quickly than the acylation of benzyl alcohol linkers. Less racemization is generally observed during the esterification of A-protected a-amino acids with trityl linkers than with benzyl alcohol linkers [47], If valuable acids are to be linked to insoluble supports, quantitative esterification can be accomplished by using excess 2-chlorotrityl chloride resin, followed by displacement of the remaining chloride with methanol [64]. 

Tertiary aliphatic alcohol linkers have only occasionally been used in solid-phase organic synthesis [73], This might be because of the vigorous conditions required for their acylation. Esterification of resin-bound linker 4 with /V-Fmoc-prolinc [72,74] could not be achieved with the symmetric anhydride in the presence of DMAP (20 h), but required the use of /V-Fmoc-prolyl chloride (10-40% pyridine in DCM, 25 °C, 10-20 h [72]). A further problem with these linkers is that they can undergo elimination, a side reaction that cannot occur with benzyl or trityl linkers. Hence, for most applications in which a nucleophile-resistant linker for carboxylic acids is needed, 2-chlorotri-tyl- or 4-acyltrityl esters will probably be a better choice than ferf-alkyl esters. 

Trityl-based resins are highly acid-labile. The steric hindrance of the linker prevents diketopiperazine formation and the resins are recommended for Pro and Gly C-terminal peptides. Extremely mild acidolysis conditions enable the cleavage of protected peptide segments from the resin. These resins are commercially available as their chloride or alcohol precursors. The trityl chloride resin is extremely moisture-sensitive, so reagents and glassware should be carefully dried before use to avoid hydrolysis into the alcohol form. It is necessary to activate the trityl alcohol precursor and it is highly recommended to reactivate the chloride just before use see Note 4). After activation, attachment of the first residue occurs by reaction with the Fmoc amino acid derivative in the presence of a base. This reaction does not involve an activated species, so it is free from epimerization. Special precautions should be taken for Cys and His residues that are particularly sensitive to epimerization during activation (Table 2). 

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). 

Trityl resins are particularly suitable for immobilization of nucleophilic substrates such as acids, alcohols, thiols, and amines. They are quite acid-sensitive and are cleavable even with acetic acid this is useful when acid-labile protecting groups are used. The stability of trityl resin can be tailored by use of substituted arene rings, as shown by chlorotrityl resin, which furnishes a more stable linker than the trityl resin itself. Steric hindrance also prohibits formation of diketopiperazines during the synthesis of peptides. Orthogonality toward allyl-based protective groups was demonstrated in the reverse solid-phase peptide synthesis of oligopeptides [30] (Scheme 6.1.4). 

A 9-phenylfluoren-9-yl-based linker can also be used for the attachment of alcohols. This Hnker shows improved acid stability compared with the trityl Hnker. The Hnker has been appHed to the synthesis of a peptide alcohol [71]. 

A recently reported Hnker for alcohols is based on the 2-(diphenylmefhylsilyl)e-thoxymefhyl protecting group (64, Fig. 6). like other add-labile linkers, such as the THP or trityl Hnkers, it is stable under basic conditions [73]. The Hnker is also suitable for the attachment of amino functions. 

A traditional linker for cleavage of alcohols is the trityl linker. 

Note that many of the hnker units described above are available in multiple forms, aUowing a range of substrates to be attached and cleaved. A discussion of all these related linker units is outside the scope of this chapter, but Kurosu has written a comprehensive review. By way of example, multiple versions of the Rink (Table 1.1, Entries 2 and 3) and trityl hnker units (Table 1.1, Entries 5 and 6) are commercially available and can be selected according to the desired substrate. However, beyond these general hnker units, there are also examples of substrate-specific hnker units. Eor example, the benzhydrylamine (BHA, Table 1.1, Entry 8) and Sieber (Table 1.1, Entry 9)" linkers find widespread use as acid labile carboxamide linker units, while the DHP (Table 1.1, Entry 10)" and sUyl linker units (e.g.. Table 1.1, Entry 11) can be used to attach alcohols to polymer supports. ... 

The use of acidic gaseous reagents, HCl and TFA, for cleavage of acids, alcohols, and amines attached to trityl linker functionalized supports has been reported (15). Jayawickreme et al. (16) used TFA for gradual cleavage of compounds from a solid support. The use of gaseous hydrogen fluoride (HF) has also been described for the release of compounds from the / -methyl-benzhydrylamine (MBHA) (17-20) and dialkoxybenzylamine (21-23) linkers. 

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