Linker Photolabile

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... 

Peukert S, Giese B. The pivaloyglycol anchor group A new platform for a photolabile linker in solid-phase synthesis. J Org Chem 1998 63 ... 

Holmes CP, Jones DG. Reagents for combinatorial organic synthesis Development of a new o-nitrobenzyl photolabile linker for solid-phase synthesis. J Org Chem 1995 60 2318-2319. 

Scheme 5.5 Structure and properties of the photolabile linker 17 used for solid-phase synthesis of dodecasaccharide 28.

Schreiber and co-workers (436) prepared a library calculated to contain 2.18 million polycyclic compounds through the 1,3-dipolar cycloaddition of a number of nitrones with alkenes supported on TentaGel S NH2 resin (Scheme 1.83). (—)-Shikimic acid was converted into the polymer bound epoxycyclohexenol carboxylic acid 376 (or its enantiomer), coupled to the resin via a photolabile linker developed by Geysen and co-workers (437) to allow release of the products from the resin in the presence of live cells by ultraviolet (UV)-irradiation. A range of iodoaromatic nitrones (377) was then reacted with the ot,p-unsaturation of the polymer-bound amide in the presence of an organotin catalyst, using the tandem esterification/ dipolar cycloaddition methodology developed by Tamura et al. (84,85) Simultaneous cyclization by PyBrop-mediated condensation of the acid with the alcohol... 

This chemistry was repeated with a traceless photolabile linker.60 The desired biphenyl was formed, but the couplings gave side products, and all yields of the desired biphenyl were lower than 30%. 

An interesting application of the 3-methoxybenzoin-based photolabile linker has been described in which the dithiane, ( )-(3- 2-(l,3-dithian-2-yl)-l-[(9-fluorenylmethoxy-carbonyl)oxy]-2-phenylethyl)benzyl)oxy] acetic acid (126, Scheme 33), a transiently masked form of the caging moiety, is incorporated into a peptide chain generated by solid-phase synthesis. 248 ... 

Photosensitive linkers (see Section 3.1.3) enable the direct analysis of support-bound intermediates by MALDI-TOF MS [14,95,96]. Alternatively, compounds linked to insoluble supports by non-photolabile linkers can be analyzed directly by means of TOF-SIMS [97]. 

Photolabile linkers for amides are most often based on 2-nitrobenzyl derivatives (Table 3.10 for the preparation of these and similar linkers, see also [147,153,235]). The mechanism of photolysis is the same as for the related 2-nitrobenzyl alcohol linkers (Section 3.1.3). 

A class of photolabile linkers has been developed to circumvent the use of silyl ethers as linkers and allow for the use of temporary silyl protecting groups.34,35 Photolabile linkers, such as 2, often involve the use of o-nitrobenzyl ether groups. This functional group is stable to a variety of conditions however, cleavage from the polymer support is often slow and... 

The encoding tags are halophenoxy derivatives of aliphatic alcohols and are attached to either a photolabile linker as a carbonate or an oxidatively cleavable linker as an ether. The photolabile linker/tag complex is especially well suited to encode peptide libraries through attachment to approximately 1% of the amino groups of each amino acid synthon at eachstage of the synthesis. For structure determination, the tags are released by photolysis at 360 nM. 

Also in the field of combinatorial synthesis, photolabile linkers have now been evolved that are photolyzed at a high rate, although this is often quite solvent-dependent [285,288]. The a-methyl-2-nitro-5-methoxy-4-(3/-carboxypropyloxy)benzylamino structure has proved to be particularly... 

Brown BB, Wagner DS, Geysen HM, A single-bead decode strategy using electrospray ionization mass spectrometry and a new photolabile linker 3-amino-3 (2-nitrophenyl) propionic acid, Mol. Diversity, 1 4-12, 1995. 

Photolabile linkers use light to break the bond between the elaborated intermediate and the linker, thus releasing pure eompound from the SPS into solution without interference from potentially troublesome side products. This advantage has encour-... 

Four recent examples of universal linkers/supports, in which the first nucleoside is anchored onto the preformed linker-support construct, are shown in Fig. 2.14. The disulfide linker 2.33 has been used to prepare terminal 3 -phosphate ONs (94, 95) through cleavage with a solution of ammonia in dithiothreitol. The photolabile linker 2.34 (96) is used to prepare 3 -alkyl carboxylic acids. The allyl-based linker 2.35 (97) is used to prepare free 3 -OH ONs by cleavage with Pd(0) and treatment with an aqueous buffer at pH 10. The linker 2.36 (98) differs from those discussed so far in... 

Sofia et al. (41) reported a SP library of disaccharides L7 made by 1300 individuals and inspired by the disaccharide core of moenomycin A, a bacterial cell wall inhibitor (Fig. 4.8). Both the structure of the library and its main features are shown in Fig. 4.8. The four major disaccharide scaffolds (X, Y, and W variations) were either built on resin via glycosylation or attached onto the photolabile linker, and subsequently decorated by introduction of Ri, R2, and R3 radiofrequency encoding (42) was used to obtain a large number of discretes with an affordable number of reactions. The... 

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