2-Chlorotrityl chloride polystyrene

Moreover, during the course of our studies, N- I -(4,4-di-methyl-2,6-dioxocyclohex-1 -ylidene)ethyl]hydroxylamine, Dde-NHOH was also successfully coupled with 2-chlorotrityl chloride polystyrene in excellent efficiency.1 The novel compound Dde-NHOH was prepared, in 51% yield, by reacting 2-acetyldi-medone with hydroxylamine in MeOH THF at 5°C for 3h, followed by recrystallization from ice-cold hexane the major side-product, which increases in quantity over prolonged reaction time, was the predicted cyclized derivative 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1,2-benzisoxazole. 

An alternative to the above is esterification by reaction of the salt of the Fmoc-amino acid with the halomethylphenyl-support (see Section 3.17). It was established in the 1960s that this method of esterifying A-alkoxycarbonylamino acids, which does not involve electrophilic activation, is not accompanied by enan-tiomerization. Examples of supports with haloalkyl linkers are bromomethylphe-noxymethyl-polystyrene and 2-chlorotrityl chloride resin (see Section 5.23). 

The leading solid phases are the 2-chlorotrityl chloride resins. Professor K. Barlos (University of Patras, Greece) has made the single most important contribntion to the development of these resins. They consist of a polystyrene-base resin crosslinked with a small amonnt of divinylbenzene and functionalized with 2-chlorotritiyl chloride. 

To negate the need to use the harsh and potentially hazardous deprotection reagent hydrazine, a superior alternative, which is particularly compatible for use in Fmoc/rBu solid phase synthesis, is Af-Fmoc-hydroxylamine, which can be used to effect a nucleophilic displacement reaction of 2-chlorotrityl chloride resin (33) (Figure 9). The resultant N-Fmoc-aminooxy-2-chlorotrityl polystyrene resin can be used for the synthesis of peptide hydroxamates as described in Protocol 8. 

Hydroxamic acids are an important class of compounds targeted as potential therapeutic agents. A-Fmoc-aminooxy-2-chlorotrityl polystyrene resin 61 allowed the synthesis and subsequent cleavage under mild conditions of both peptidyl and small molecule hydroxamic acids (Fig. 14) [70]. An alternative hydroxylamine linkage 62 was prepared from trityl chloride resin and tV-hydroxyphthalimide followed by treatment with hydrazine at room temperature (Scheme 30) [71]. A series of hydroxamic acids were prepared by the addition of substituted succinic anhydrides to the resin followed by coupling with a variety of amines, and cleavage with HCOOH-THF(l 3). 

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