2-chlorotrityl chloride resin

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). 

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,... 

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. 

Attachment of carboxylic acids to supports as trityl esters is achieved by treatment of the corresponding trityl chloride resin with the acid in the presence of an excess of a tertiary amine (Figure 3.5 see also Section 13.4.2). This esterification usually proceeds more quickly than the acylation of benzyl alcohol linkers. Less racemization is generally observed during the esterification of A-protected a-amino acids with trityl linkers than with benzyl alcohol linkers [47], If valuable acids are to be linked to insoluble supports, quantitative esterification can be accomplished by using excess 2-chlorotrityl chloride resin, followed by displacement of the remaining chloride with methanol [64]. 

Illustrative examples of cleavage reactions of /V-arylbenzylaminc derivatives are listed in Table 3.25. Aromatic amines can be immobilized as /V-bcnzylanilincs by reductive amination of resin-bound aldehydes or by nucleophilic substitution of resin-bound benzyl halides (Chapter 10). The attachment of the amino group of 5-aminoin-doles to 2-chlorotrityl chloride resin has been reported [486]. Anilines have also been linked to resin-bound dihydropyran as aminals [487]. 

Histidine and histamine derivatives, as well as other imidazoles, have been successfully immobilized by N-tritylation of the imidazole ring with trityl chloride resin [534] (Entry 2, Table 3.29 see also Section 15.8) or with 2-chlorotrityl chloride resin [535-537]. Histidine can also be linked to insoluble supports as the N-dinitrophenyl deriva-... 

Only a few examples have been reported of the etherification of alcohols with resin-bound diarylmethyl alcohols (Entry 5, Table 3.30 Entry 5, Table 3.31 [564]). Diarylmethyl ethers do not seem to offer advantages over the more readily accessible trityl ethers, which are widely used as linkers for both phenols and aliphatic alcohols. Attachment of alcohols to trityl linkers is usually effected by treating trityl chloride resin or 2-chlorotrityl chloride resin with the alcohol in the presence of a base (phenols pyridine/THF, 50 °C [565] or DIPEA/DCM [566] aliphatic alcohols pyridine, 20-70 °C, 3 h-5 d [567-572] or collidine, Bu4NI, DCM, 20 °C, 65 h [81]). Aliphatic or aromatic alcohols can be attached as ethers to the same type of light-sensitive linker as used for carboxylic acids (Section 3.1.3). 

As solid support use Rink-amide MBHA resin (0.6 mmol/g, 100-200 mesh, MultiSynTec, Bochum, Germany) to obtain C-terminal peptide amides and Wang-resin (1.2 mmol/g, 100-200 mesh, MultiSynTec) or 2-chlorotrityl chloride resin (1.5 mmol/g, 100-200 mesh, Novabiochem, Merck KGaA, Darmstadt, Germany) to produce C-terminal free acids. 

Chlorotrityl chloride resin was obtained from CBL (Patras). Fmoc-amino acids and their derivatives were purchased either from Advanced Chemtech, Nova-Biochem, SNPE or Bachem (Switzerland). Solvents, AcOH, TFA and TFE were of analytical grade, purchased either from Merck or Fluka and used without further purification. TLC was performed on a precoated silica gel 60 F254 (Merck) aluminium plates employing the following solvent systems chloro-form/methanol/acetic acid (90 12 2) and (85 10 5), toluene/methanol/acetic acid (70 30 15) and (90 10 10). All HPLC runs were performed on a Merck Hitachi... 

The preparation of protected peptides and their sequential condensation were done on the 2-chlorotrityl chloride resin (Fig. 1). 

Fig. l The use of the 2-chlorotrityl chloride resin for the preparation of protected peptides and proteins. Either amino acids (a) or fully protected peptide fragments (b) are condensed to the growing peptide chain on the resin. 

The fully protected peptides were synthesized either on a manual shaker or after optimization of coupling conditions [18] on an automatic peptide synthesizer (ACT 200) from Advanced Chemtech using the 2-chlorotrityl chloride resin and Fmoc/t-Butyl strategy [2]. The coupling with TBTU/DIEA [2] and the... 

Chiral amino alcohols can be prepared by reaction of chiral epoxides with amines. Enantiopure (25, 3.R)-2,3-epoxy-3-phenylpropanol anchored to Merrifield resin has been used for ring-opening with secondary amines in the presence of lithium perchlorate to afford polymer-supported chiral amino alcohols 47 (Eq. 18) [56], By analogy, (2i ,35)-3-(cis-2,6-dimethylpiperidino)-3-phenyl-l,2-propanediol has been anchored to a 2-chlorotrityl chloride resin (48). Although this polymer had high catalytic activity in the enantioselective addition of diethylzinc to aldehydes, the selectivity of the corresponding monomeric catalyst was higher (97 % ee) in the same reaction. 

Racemization occurring during esterification of protected amino acids to hydroxymethyl polymers is a well-recognized problem.PP l This reaction is promoted by the use of DMAP as catalyst,P l and racemization is particularly pronounced in the case of cysteine.P By the use of optimized esterification methods racemization can be reduced, but not totally sup-pressed.P l When starting with halomethyl-functionalized resins, such as 2-chlorotrityl chloride resin,P l bromo-SASRIN resin,P l or 4-(bromomethyl)phenoxyacetamide res-in,P l racemization levels are significantly lowered. Alternatively, racemization is largely prevented by using the TDO esters without DMAP,f P°l or PyAOP in the presence of DIPEA at low temperature.P l... 

The use of hindered handles or functionalized solid supports would minimize piperazine-2,5-dione formation. Thus, the tertiary alcohol handle 4-(l, l -dimethyl-l -hydroxy-propyl)phenoxyacetic acid (DHPP, 1, Table and the 2-chlorotrityl chloride resin [Trt(2-Q)-C1 resin, are both very convenient for this purpose.t 1 An alternative proce-... 

Fig. 17.9 Solid-phase synthesis of a dapoxyl dye library (a) 2-chlorotrityl chloride resin, DIEA, THF (b) 10% piperidine, DMF (c) R2-C6H5-COOH, HATU, DIEA, CH2C12 (d) Ph3PCl2, TEA, CH2C12 (e) 1%TFA, CH2C12...

Commercially available 2-chlorotrityl chloride resin was treated with piperazine and washed with DMF (three times), MeOH (three times), THF (three times), and CH2CI2 (three times), and dried. 

We chose 2-chlorotrityl chloride resin for the attachment of acrylic acid, because in solution-phase chemistry the best results have been obtained by using aryl acrylates or (erf-butyl acrylates [21], In addition to DABCO (1,4-diazabicyclo [2.2.2]octane) - the most common tertiary cyclic amine for this type of reaction - we also used the more reactive 3-quinuclidinol (3-hydroxy-quinuclidine, 3-HQN) for the Baylis-Hillman reaction with aldehydes. We used 26 different aldehydes and obtained good to excellent purities, as determined by analytical HPLC. 

The three-component Baylis-Hillman reaction was also performed on 2-chlorotrityl chloride resin by treating polymer-bound acrylic acid with aldehydes and sulfonamides in dioxane at 70 °C for 16 h under DABCO catalysis (Fig. 6.4). Both scaffolds, 3-hydroxy-2-methylidene propionic acids as well as 2-methylidene-3-aminoarylsulfonyl-propionic acids, are precursors for the synthesis of MCSLs. 

It was assumed that the low enantioselectivity was probably due to a lack of bulky susbstituents on the primary hydroxy group of the chiral aminodiol. The cis 2,6-dimethylpiperidine-derived aminoalcohol 151 was anchored to 2-chlorotrityl chloride resin (Barlos resin) leading to polymerie ligand 152 (Scheme 71, Table 8). 

Two trityl-based supports are presently in common use for the production of peptide adds by Fmoc SPPS 2-chlorotrityl chloride resin 7 (12) and 4-(chloro(diphenyl)methyl)benzoyl resin 8 (13). 

These resins are extremely moisture sensitive, and so it is essential that all reagents and glassware should be dried thoroughly before use. 2-Chlorotrityl chloride resin can be stored desiccated at room temperature 4-(chloro-(diphenyl)methyl)benzoyl resins should be generated from the precursor trityl alcohol immediately before use as described in Protocol 5. The chemical characteristics of 7 and 8 are identical. 

Chlorotrityl chloride resin is normally supphed with a displaceable chlorine content of 1.0-1.6 mmol/g. For the purposes of peptide synthesis, this substitution can sometimes be too high and can be reduced by treating the resin with a sub-stoichiometric amount of amino acid derivative and then capping imreacted sites with MeOH. 

Protocol 3. Esterification of Fmoc-Cys(Trt)-OH onto 2-chlorotrityl chloride resin (49,53)... 

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. 

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