Linker cyclative cleavage

After removal of the protecting group (PG) from 134, the system was amenable to the oxidation/nucleophilic substitution process. Since this hnker represents a reversal of the original phenylhydrazide hnker, the traceless part stayed on the sohd support and the desired compound 135 was released. The utility of the linker was demonstrated in the synthesis of mono-ketopiperazines resulting from a cyclative cleavage. 

Scheme 2 Synthesis of hydantoins by cyclative cleavage of a carbamate linker.

Cyclative cleavage strategies (e.g., metathesis and heterocycle ring formation), traceless linkers (e.g., Si, Ge linkers or via chemical reactions such as desulfurization, decarboxylation and cycloreversion) and cleavage steps designed to liberate an increasing diversity of functional groups are illustrated in Section 2.4.4. 

An alternative cleavage method affording amines involved cyclative cleavage of the linker [152]. 

Pavia s linker unit exploits amide or urea bond formation with concomitant displacement of the solid support, which is by far the most common approach for achieving cyclative cleavage. The first example of such an approach was Marshall s preparation of cyclic dipeptides, as shown in Table 1.3, Entry 1. Besides this, such classical cyclization C—N bond forming reactions have been used to prepare ambitious synthetic targets using SPOS,... 

TMTt deprotection was performed in extremely careful conditions (1 min stirring at rt, five cycles, extensive washing) to avoid the cleavage of the DES linker oxidation with Dess-Martin reagent was performed successfully to give 3.123 (Fig. 3.44). 

Solid-phase parallel synthesis mimics the previously described solution phase strategy. This approach easily lends itself to both semi- and full automation. In contrast to the solution phase method, purification is easily achieved by simply washing the resin beads, and the reactions can be driven to completion by excess reagents, multiple cycles, and microwave techniques. The initial building block or scaffold is attached to the resin bead by a detachable linker. At the end of the synthesis, the final construct is released under the appropriate cleavage conditions for automated purification, usually by high-pressure liquid chromatography (HPLC). This allows bioanalysis of the final product in aqueous solution under standard assay conditions. 

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