Traceless-anchor

The traceless anchors based on silicon just described are limited by the need to synthesize a preformed handle consisting of the first building block and the silicon linker. Moreover, traceless release from conventional aryldialkylsilanes is complicated by their low hydrolytic stability and loss of silicon from the resin in the cleavage process. The silyl chloride resin 8h can be used to anchor aryl rings by reaction with aryllithium reagents. The anchor is stable to concentrated TFA and bases, but treatment with TBAF cleaves the final products [353]. 

Cleavage of all the linkers described above provide a functional group (carboxylic acid, amide, amine, etc) at the anchoring position. Silyl-based handles 71,72, and 73 as well as germanium-based handle 74 insert a C-H bond at the anchoring position and are referred to as traceless (Fig. 15) [82-... 

Solid-phase strategies associated with the construction of organic molecules and their functionalization are often limited by the nature of the anchoring group or the linker. Traceless linkers allow chemical transformations on the polymer bound molecules, which can be cleavage to the formation of a C-H bond on the seceding molecule and which enables the preparation of pure hydrocarbons (Table 3.13) [134, 190]. 

One prominent class of monofunctional anchor that provides access to molecules having no attachment memory for solid-phase synthesis is called traceless or clean break linkers.7,16-18 Although this definition could be used for the classification of linkers, one would advantageously... 

Stannaries have become prominent in multifunctional anchoring groups. A polymer-bound tin hydride 41 has been used to hydrostannylate alkynes under the action of palladium-catalysis to give polymer-bound alkenylstannanes 42. These alkenyl stannanes have been employed in intermolecular [45] and intramolecular Stille reactions [46]. Alkenylstannanes can also undergo protonation to give alkenes 44 in a traceless fashion. This linker is therefore multifunctional (Scheme 6.1.12). 

The most prominent anchors for traceless linkage of arenes are based on silyl linkers. Generation of a diverse benzodiazepine library [40] has clearly shown the advantages of this type of detachment because no additional functionality, which might bias the library, was preserved in the final molecules (Scheme 6.1.33). 

An anchor for traceless linking might also have a safety-catch function or be suitable for multifunctional cleavage. Linker systems enable the introduction of certain atoms or molecule fragments and will play an important role in the development of diverse organic substance libraries. It is important to point out that the final diversity is achieved on cleavage, and not in an additional solution phase re-... 

A traceless linker for anchoring secondary amines has been developed [123,124] and is referred to as the REM linker 21 (regenerated after cleavage, functionalized by Michael addition). Tertiary amines can be prepared on this support by conversion to a resin-bound quaternary ammonium salt followed by cleavage by base-induced Hofmann elimination [125]. The analogous vinyl sulfone resin 2m can also be used to anchor secondary amines and is stable to a greater range of reactants [126,127]. 

A photolabile thiol support 6d has been reported that can be used for anchoring reactive halides such as benzylic bromides [268,269]. After synthetic steps, photolysis at 350 nm in MeCN releases products with a hydrogen atom at the former point of attachment to the linker (which is defined as a traceless linker). 

The solid-phase synthesis of 1,4-benzodiazepines has been conducted using a traceless silicon anchor 8g that was prepared via a preformed handle. Cleavage from the resin was effected with HF [352] because the anchoring group was inert to concentrated aqueous TFA due to the highly electron-deficient character of the benzodiazepine ring. 

The synthesis of the GPI-anchored PrP by NCL constitutes the first synthesis of a GPI-AP containing more than 100 amino acids. It serves as a proof of principle for the use of NCL in the synthesis of large GPI-APs but it also points out the new challenges in the field such as incorporation of GPI with native lipids and more complex core structures into the GPI-APs and ultimately the development of traceless chemical methods for ligation of GPIs and proteins that will not incorporate an additional cysteine at the protein s C-terminus. 

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