Photocleavable linker

The proper choice of a suitable linker is a therefore a key consideration in the design of a solid-phase chemical route. Linkers have to be developed in order to be stable in the presence of reagents and to permit orthogonal cleavage under mild conditions. Often, cleavage conditions dictate the requirements for work-up and purification steps of the released compound. Different cleavage strategies have been developed such as photocleavable, safety catch and traceless linkers as mentioned in Section 3.2.2 [20]. 

The synthetic approach used in this work is shown in Scheme 9. Two known solution pathways were used to convert shikimic acid to an epoxide intermediate. In fact, both the (-)35 and the (+)36 enantiomers were formed. After minor synthetic transformations, these epoxides were linked to Ten-tagel S aminomethyl resin with an o-nitrophenyl-derived photocleavable linker 7437 via amide bond formation to give intermediate 75. The first point of variation was added via various iodo-benzyl nitrone carboxylic acids 76 via 1,3-dipolar addition/esterification reactions. Highly constrained resin-bound tetracyclic hydrooxazoles 77 were thereby produced. 

Avidin technology can also be applied to the isolation of proteins and other materials from cells. Because the irreversibility of the binding of biotin may be a problem, photocleavable biotin derivatives have been developed. In the following structure, the biotin derivative has been joined to a protein (as in the first equation in this box) and is ready for separation, perhaps on a column containing immobilized avidin or streptavidin. After separation the biotin together with the linker and photocleavable group are cut off by a short irradiation with ultra-... 

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]). 

The photocleavable linker allows detachment of the cyclic peptide from the resin to assess biological activity in solution. 

Glatthar, R. Giese, B. A new photocleavable linker in solid-phase chemistry for ether cleavage. Org. Lett. 2000, 2, 2315-2317. 

Screening the encoded library produced interesting structures to build an SAR and to design focused libraries of binders for the artificial receptor, but some limitations of these linkers for applications different from peptide chemistry are clearly evident. The carbonate bond connecting the electrophone tag and the photocleavable linker (Figure 9.8) is sensitive to many organic reaction conditions, and the carboxylate requires an amino- or hydroxy function to be linked to the resin after each synthetic step to be encoded. 

Partial release has been attempted even using single release linkers, taking advantage of predictable reaction kinetics for the cleavage reaction for example, the release of compounds from photocleavable linkers [56] was... 

The suitability of this technique for acid-labile (142) and photocleavable linkers (143) has been demonstrated. Other cleavage conditions that do not produce residues (e.g., cleavage with gaseous ammonia) could also be used in theory. TOF-secondary ion mass spectrometry (TOF-SIMS) (144) has also been validated to monitor SP peptide synthesis (145) and could in future increase the versatility of MS monitoring of SP reactions. 

Rodebaugh R, Fraser-Reid B, Geysen HM. A new o-nitrobenzyl photocleavable linker for solid phase synthesis. Tetrahedron Lett. 1997 38 7653-7656. 

PAL resin, fluorenylmethyloxycarbonyl (Fmoc) and butyloxycarbonyl (Boc) amino acids with standard side chain protection and Boc-Tyr(tBu)-OH were from Advanced ChemTech (Louisville, KY, USA). FmocLys(Dde ) was from BioChem (San Diego, CA, USA). Beta-endorphin and anti-P-endorphin (3-E7) were from Boehringer Mannheim. The photocleavable biotinylated linker was prepared according to the literature procedure (4). 

In a related approach, Fraser-Reid and co-workers used Chiron s polystyrene-grafted crowns with Rich s photocleavable o-nitrobenzyl linker [140] and NPG donors in the synthesis of trisaccharide 277 (O Scheme 42) [141]. After attachment of the first aminoglucosyl moiety to... 

More recently, Yanagawa and coworkers has further improved the mRNA display method by incorporation of a photocleavable 2-nitrobenzyl linker between genotype (mRNA) and phenotype (protein) to facilitate isolation of the mRNA for amplification or analysis.295 They demonstrated the utility of the photocleavable linker by also isolating FKBPla from an mRNA library using biotinylated FK506. 

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