Linker fluorous

An important part of fluorous synthesis is related to the development of fluorous linkers for chromatography-free purifications. In discovery and medicinal chemistry labs, a major task is to synthesize small-scale but large numbers of compounds ... 

Zhang, W. 2009b. Fluorous linker-facilitated chemical synthesis. Chemical Reviews, 109 749-795. 

A tempting comparison is that between standard solid-phase chemistry and fluorous chemistry. Both of these techniques have several attributes in common, including the use of linkers, frequent use of scavengers, and utility in many similar applications. Even though the use of standard solid-phase chemistry has many advantages, some aspects of polymer-supported synthesis strategies have drawbacks. Eluorous chemistry has in many ways marketed itself as an alternative to solid-sup-port chemistry due to its superior performance in a number of respects. ... 

A traceless perfluoroalkylsulfonyl linker for the deoxygenation of phenols has been reported by Holmes. A more lightly fluorous variant has also been presented by Zhang, where microwave heating was applied to increase the speed of the reaction. The traceless tag was exemplified in syntheses of triaryl-substituted pyrimidines and hydantoins (Reaction Scheme 10). 

A somewhat different approach was used by Vincent in phase-switching reactions using pyridyl-labelled substrates and products. The pyridyl-containing tag is here thought of as a masked phase tag, which allows for phase switching with the help of a heavy fluorous copper(ll)-carboxylate complex. Comparison with a non-fluorous system indicated that a problem of release of the strongly coordinating pyridine linker was avoided in the fluorous approach. ... 

Each fluorous tag (also called protecting group or linker) has two attachment points. One is permanently bound to a perfluoroalkyl (Rf) chain and the other is temporarily attached to a reaction substrate so that it can be cleaved to release the product from the support at... 

A recent example of the parallel synthesis of different quinazoline-2,4-dione derivatives (46) demonstrates how to combine the advantages of fluorous synthesis with those of solid-phase chemistry without using expensive perfluorinated solvents [22] (Scheme 3.22). In the beginning, a fluorous benzyl alcohol (47) is adsorbed on fluorous reversed-phase silica gel (FRPSG). Then, in a sequence of splits and reactions, the linker group, which remains bound to the FRPSG by fluorophilic interactions, is converted into a library of differently substituted carboxamido-urethanes (48). These are cyclized and the liberated quinazoline-2,4-diones (46) are eluted from the support with the fluorophobic solvents water and CHjCN/... 

Fluorous synthesis has certain analogies to solid-phase synthesis the fluorous label and the fluorous phase fulfil functions similar to those of the linker and the solid phase in that both provide a means of removing the attached compound from the reaction mixture (one because of its high affinity to the fluorous phase, the other via a covalent link to the solid support).The similarity, however, also extends to the necessity of additional synthesis steps involved in the attachment to and cleavage from the linker. Otherwise, the fluo-... 

Metathesis cascades have underpinned the synthesis of diverse small molecule libraries.Metathesis is a superb pairing reaction for the build-couple-pair approach first, it can yield many dilferent ring systems and, second, alkenes (and alkynes) are compatible with the many reactions that may be used to connect building blocks. Metathesis has been used to prepare a library of natural product-like molecules (Scheme 1.7). Initially, unsaturated building blocks were attached iteratively to fluorous-tagged linker to yield metathesis precursors 20. Crucially, alternative attachment reactions were used such that the building blocks were connected through bonds that either did, or... 

Scheme 1.7 Synthesis of natural product-like molecules with unprecedented scaffold diversity. Initially, building blocks were added iteratively to a fluorous-tagged linker, with intermediates purified by fluorous-solid phase extraction. Metathesis cascades were used to reprogramme the scaffolds and to release final products from the fluorous-tagged linker. Reagents and conditions. (1) Grubbs first-generation catalyst, 21a 23% 21b 56% (2) fluorous-tagged Hoveyda-Grubbs second-generation eatalyst, 21c 33%.

The SPOR of two fluorous analogues of a tumor PET tracer, aminocyclobutane carboxylic acid (ACBC, 24 and 26) is described in Scheme 13.8." The FACBC ([ F]fluoro-aminocyclobutane carboxylic acid) preciusor was fully protected and attached to the resin by a perfluoroalkyl ether linker. FACBC 24 was obtained in two steps cleavage by a fluorination step, followed by deprotection under acidic conditions. The corresponding methylene-FACBC analogue (25) was obtained by the same strategy. Notably, no linker was... 

---