Phenacyl linker

Scheme 17.13 Intramolecular cydization of phenacyl linkers to form oxazinone 29 or diketopiperazines 30.

The development of light-sensitive protective groups began in the early 1960s [129-131] and led to the identification of several functionalities that could be selectively cleaved under UV irradiation (for a review, see [132]). Some of these protective groups, such as 2-nitrobenzyl esters, carbonates, or carbamates [131,133-135], benzoin [136-139], and other phenacyl esters [140] were also found to be useful as photocleavable linkers. 

Most photocleavable linkers for carboxylic acids used today are based on the photoisomerization of 2-nitrobenzyl esters and on the light-induced cleavage of phen-acyl esters (Figure 3.10). Several possible mechanisms have been proposed for the photolytic cleavage of benzoin esters. One of the most recent is the dissociation of the excited phenacyl ester into a carboxylate and a phenacyl cation ( photosolvolysis , Figure 3.10 [136]). 

Hydroxy linkers bearing an electron-withdrawing group such as an a-carbonyl (oxyacyl resins, phenacyl type-linkers or glycolic acid derivatives) are also suitable for the nucleophilic release of ester bound compounds. The glycolamidic ester linker 10 has been successfully used to synthesize peptides by the Fmoc/tBu strategy. It is compatible with the repetitive piperidine treatment but peptides can be cleaved with dilute NaOH solutions, ammonia or alkoxides [9], Esters bound to oxyacyl resins 8 have been reported to be cleavable by thiolysis, saponification, ammonia, hydrazine and potassium cyanide (complexed with dicyclohexyl-18-crown-6) [10, 11],... 

Figure 17.5 Bathochromic and hyperchromic shifts of n-Mt orTt-Mt absorbances of nitrobenzyl-derived photolabile linkers 13 (—) 14 ( ) 15 (- ), and phenacyl (—).

Wang [40] transferred the known photoreactivity of the phenacyl group, especially a-methyl substituted, to a PS resin in 1976 for peptide synthesis (Scheme 17.12). The resin 26 is easily available by Friedel-Crafts acylation of PS, and its photolytic cleavage of a tetrapeptide appeared to be superior to that of the o-nitro-benzyl linker under similar reaction conditions. The a-methylphenacyl linker gave... 

Recently, Belshaw [44] reported a safety-catch photolabile linker based on the phenacyl group that permits selective photorelease of oligonucleotides from a solid substrate. The safety-catch concept is based on masking the carbonyl group as a dimethyl ketal that renders the linker photoinert during oligonucleotide synthesis (Scheme 17.14). 

Scheme 17.14 Use of a safety-catch photolabile linker based on the phenacyl group for the selective photorelease of oligonucleotides.

Giese has reported [51, 52] that the triplet state of an excited phenacyl ketone can undergo intramolecular hydrogen atom abstraction from an attached peptide, resulting in photocyclization of the phenacyl group with peptides, and cyclization with peptide backbone. One of the attractions of the DMP linker is that their fast photoenolization will probably help to minimize unwanted hydrogen atom abstraction from an attached peptide. 

Scheme 16.9. Modification and photolytic cleavage of a phenacyl ester-based linker.

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