Benzyl Alcohol Linkers

Acidolysis of benzylic C-O bonds becomes easier with increasing stability of the corresponding benzylic cation. The sensitivity of benzylic linkers towards acids can therefore be fine-tuned by varying the substitution pattern on the arene. Electron-donating substituents will increase the sensitivity towards acids, whereas electron-acceptors will diminish acid-sensitivity. This order of reactivity towards electrophiles 

Esters of the PAM linker are slightly more resistant towards acids than the corresponding 4-alkylbenzyl esters [5,25-27] (Table 3.1). The PAM linker is particularly well suited for solid-phase peptide synthesis using A-Boc amino acids because less than 0.02% cleavage of the peptide from the support occurs during the acidolytic deprotection steps [27], Esters of both the 4-alkylbenzyl alcohol and PAM linkers can also be cleaved by nucleophiles (see Sections 3.1.2 and 3.3.3). 

Name of linker/resin Structure Cleavage reagent Literature 

Dialkoxy- and trialkoxybenzyl esters are even more acid-labile than the Wang linker, and can, for example, be cleaved with dilute TFA, acetic acid, or hexafluoroiso-propanol without simultaneous acidolysis of Boc groups. These linkers thus enable the solid-phase synthesis of protected peptide fragments or other acid-sensitive products [33]. 

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Table 3.1 lists the most commonly used types of acid-sensitive benzyl alcohol linker. All these can be attached to various supports by the use of different types of spacer. Because resins bearing these linkers are commercially available, their preparation will not be discussed here. 

Table 3.1. Acid-labile benzyl alcohol linkers. See text for additional cleavage reagents.

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]. 

The main advantage of ferr-alkyl esters as linkers is their stability towards nucleophiles. For instance, no diketopiperazine formation is observed during the preparation of peptides containing carboxy-terminal proline, an otherwise common side reaction when using benzyl alcohol linkers (Section 15.22.1). 

Benzyl alcohol linkers, such as those described in Section 3.1.1.1, can also be cleaved by palladium-catalyzed hydrogenolysis. Carboxylic acids have, for example, been obtained by hydrogenolysis of insoluble benzyl esters with Pd(OAc)2/DMF/H2 [89,161]. Resin-bound benzylic carbamates [162,163] and amides [164] can also be released by treatment with Pd(OAc)2 in DMF in the presence of a hydrogen source, such as 1,4-cyclohexadiene or ammonium formate. These reactions are quite surprising, because they require the formation of metallic palladium within the gelated beads. 

The attachment of anilines to benzyl alcohol linkers as carbamates can be achieved either by reaction of aryl isocyanates with a resin-bound alcohol [498-500] or by treat-... 

Most acid-labile benzyl alcohol linkers suitable for the attachment of carboxylic acids to insoluble supports can also be used to attach aliphatic or aromatic alcohols as ethers. The attachment of alcohols as ethers is less easily accomplished than esterification, and might require the use of strong bases (Williamson ether synthesis [395,552,553]) or acids. These harsh reaction conditions limit the range of additional functional groups that may be present in the alcohol. Some suitable etherification strategies are outlined in Figure 3.31. Etherifications are treated in detail in Section 7.2. 

Figure 16.3 shows a representative example of the synthesis of peptides using the Boc strategy. Hydroxymethyl polystyrene can be used as the support or, if large peptides are to be prepared, polystyrene with the more acid-resistant PAM linker. Polyacrylamides [17] with a benzyl alcohol linker are also compatible with the Boc Strategy-... 

Fig. 12. (A) Zn poryphyrin molecule with benzyl alcohol linker. (B) Cyclic voltamo-...

The same method can be used for the construction of Asn- or Gin-containing head-to-tail cyclic peptides, using a benzhydrylamine instead of a benzyl alcohol linker, as shown by Tromelin et al. [19]. The synthesis of an 18-mer head-to-tail cyclic peptide designed to mimic a loop involved in the curaremimetic action of a snake toxin protein, cycto(Asn-Tyr-Lys-Lys-Val-Trp-Arg-Asp-His-Arg-Gly-Thr-Ile-Ile-Glu-Arg-Gly-Pro), was prepared. 

Photolabile linkers play an important role in solid-phase organic synthesis (SPOS) due to their stability under both acidic and basic conditions. The ONb photolabile linker was modified to improve cleavage rates and yields Fmoc-Tos-OFI was released in 87% yield after 23 h (Scheme 4) [24]. Specifically, the primary alcohol was changed to a secondary benzylic alcohol and the attachment to the resin was through an alkyl chain as opposed to an amide function. Linker 20 was used for the production of carboxylic acids or carbohydrates. A second example... 

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. 

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. 

Support-bound non-benzylic alcohols can also be used to immobilize carboxylic acids as esters (Table 3.3). The advantage of this type of linker is its stability towards electrophiles. Attachment of carboxylic acids is usually realized by acylation of the resin-bound alcohol with a reactive acid derivative. 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Benzyl carbamate protection (Cbz or Z group see Table 10.15) was initially chosen by Merrifield for solid-phase peptide synthesis [255], The strongly acidic conditions required for its solvolysis (30% HBr in AcOH, 25 °C, 5 h) demanded the use of an acid-resistant nitrobenzyl alcohol linker. Z-protection of the a-amino group in solid-phase peptide synthesis was, however, quickly abandoned and replaced by the more acid-labile Boc protection. Benzyl carbamates can be cleaved by strongly ionizing... 

Benzyl Alcohols, Esters Benzyl-type linkers... 

Benzyl-type linkers are the most common anchoring groups for various kinds of functionality. Esters, amides, amines, alcohols, and thiols, in particular, can be immobilized by this linker family. This was demonstrated by Merrifield [2] and Wang [19] and is the starting point of modern linker development. Benzylic linkers are typically cleaved by strong acids (for example trifluoroacetic acid, TFA), which cause protonation and subsequent elimination. A nucleophilic scavenger usually quenches the resonance-stabilized cation thus formed. 

The prototype of a functional group with an appropriate breakable bond is the Wang resin 3, which contains a 4-hydroxybenzyl alcohol linker moiety. The benzyl alcohol hydroxyl group can be functionalized using either electrophilic or nucleophilic substrates (Scheme 6.1.1) to give a benzylic linkage. It is very stable in many reactions, but can be cleaved by acids such as trifluoroacetic acid or HF. Acids, alcohols, esters, and amides can be obtained as products after cleavage. 

The two epoxide enantiomers (i-) and (-) 7.71 were selected as chemical starting points for library generation Their synthesis from shikimic acid with reasonable overall yields was already known (248, 249), and they had a carboxylic acid handle for SPS. The other key intermediates were the three benzylnitrone carboxylic acids 7.72a-c, which were prepared from the corresponding benzyl alcohols (250,251) (Fig. 7.40). The two epoxycyclohexenols were supported onto a PEG-based resin, loaded with a photolabile linker, to give resin-bound 7.73a,b (from now on only one enantiomer will be shown in the figures, but the synthetic pathway was continued with both... 

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