2-chlorotrityl

Fig. 7 Kinetics of microwave-assisted loading of 2-chlorotrityl chloride resin with Fmoc-isoleucine at 110 °C. For comparison, the dashed line indicates the level of loading after 1 h at room temperature...

Investigation of the microwave-assisted attachment of Fmoc-protected amino acids onto 2-chlorotrityl chloride resin indicated higher loadings and increased rates compared to standard room temperature procedures [146]. In this comparative study standard procedures yielded 0.37 mmol/g loading after 1 hour, whereas at 110 °C using microwave dielectric heating, a similar result (0.38 mmol/g) was obtained after only 15 min (Fig. 7). 

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). 

Mellor SL, McGuire C, Chan WC. lV-Fmoc-aminooxy-2-chlorotrityl polystyrene resin A facile solid-phase methodology for the synthesis of hydroxamic acids. Tetrahedron Lett 1997 38 3311-3314. 

Y-FMOC-AMINOOXY-2-CHLOROTRITYL POLYSTYRENE RESIN FOR HIGH THROUGHPUT SYNTHESIS OF HYDROXAMIC ACIDS... 

N-Fmoc-aminooxy-2-chlorotrityl polystyrene (212 mg, 0.95 mmol g 1,0.2 mmol) was placed in a reaction column (1.0 cm diameter alternatively, an appropriate reaction vessel can be used, e.g., Quest 210 synthesizer 5-mL reaction vessel) and preswollen in DCM DMF (1 1, 3mL) for 24 h (note 4). The resin was then washed with DMF (10min, 2.5 mL min-1) and Fmoc-depro-tected by treatment with 20% v/v piperidine in DMF (10 min, 2.5mL min-1). The resin was then washed with DMF (lOmin, 2.5 mL min ), after which excess DMF was removed. 

V-Fmoc-aminooxy-2-chlorotrityl polystyrene (100 mg, 1.00 mmol g 1, 0.1 mmol) was treated as outlined above and Fmoc-depro-... 

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. 

V-(9-Fluorcnylmethoxycarbonyl)aminooxy-2-chlorotrityl polystyrene was then N-deprotected within minutes by treatment with 20% v/v piperidine in DMF to afford the key intermediate aminooxy-2-chlorotrityl polystyrene. With this in hand, N-acylation was then carried out and, where appropriate, followed by a series of chemical transformations to yield resin-bound... 

In conclusion, we anticipate that A-Fmoc-aminooxy-2-chlorotrityl polystyrene will prove an indispensable reagent for the solid-phase synthesis of hydroxamic acids by multiple and combinatorial approaches. Not only is its production both efficient and cost effective, but release of the assembled hydroxamic acid derivative is readily accomplished using mild acidolytic reagents. 

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). 

CHLOROTRITYL CHLORIDE RESIN FOR SYNTHESIS USING FMOC/TBU CHEMISTRY... 

FIGURE 5.22 (A) Reaction of an Fmoc-amino acid with 2-chlorotrityl chloride resin.56 The ester bond formed is cleavable by the mild acid, which does not affect tert-butyl-based protectors. (B) Generation of a protected peptide containing cystine by detachment of a chain, deprotection of cysteine residues, and oxidation of the sulfhydryls by the reagent containing iodine. The cations produced are trapped by CF3CH2OH. 

K Barlos, O Chatzi, D Gatos, G Stavropoulus. 2-Chlorotrityl chloride resin. Studies on anchoring of Fmoc-amino acids and peptide cleavage. Int J Pept Prot Res 37,513,... 

K Barlos, D Gatos, S Kutsogianni, G Papaphotiou, C Poulus, T Tsegenidis. Solid phase synthesis of partially protected and free peptides containing disulphide bonds by simultaneous cysteine oxidation-release from 2-chlorotrityl resin. Int J Pept Prot Res 38, 562, 1991. 

Y Fujiwara, K Akaji, Y Kiso. Racemization-free synthesis of C-terminal cysteine-peptide using 2-chlorotrityl resin. Chem Pharm Bull (Jpn) 42, 724, 1994. 

Scheme 16 Synthesis of Sulfated Peptides with Tyrosine 0-Sulfate Synthons on 2-Chlorotrityl Resin as Proposed by Kitagawa1 581...

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. 

Mellor, S. L. McGuire, C. Chan, W. C. M-Fmoc-Aminooxy-2-Chlorotrityl Polystyrene Resin A Facile Solid-Phase Methodology for the Synthesis of Hydroxamic Acids, Tetrahedron Lett. 1997, 38, 3311. 

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