Alkanes traceless linkers

The first traceless linker was developed by Kamogawa and coworkers in 1983 [82]. Starting from a polymer-bound sulfonylhydrazine, sulfonylhydrazone resin 88 was formed by reaction with ketones or aldehydes. The cleavage step was conducted either by reduction with sodium borohydride or lithium aluminium hydride to yield alkanes 89 or by treatment with base to give the corresponding alkenes 90 in a Bamford-Stevens reaction (Scheme 16.20). This work was a pioneering approach in the field of traceless tinkers. 

Scheme 16.22 Traceless linker for alkanes according to Janda et al.

A tetrahydropyranyl linker is an acid-sensitive linker for alcohols. Nitrile oxides were generated in situ from tetrahydropyranyl-linked nitro alkanes and phenyl isocyanate under Mukaiyama conditions, and reactions with various alkynes gave resin-bound isoxazoles (Scheme 11.39). Cleavage with diluted trifluoroacetic acid gave isoxazoles as primary alcohols in a traceless manner. A library of 3-hydroxymethyl-4,5-disubstituted isoxazoles was prepared in a parallel and automated fashion by a 96-well plate synthesizer with an average yield of 60%. 

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