Chlorotrityl linker

In addition to the ionic liquid-mediated procedure in solution (see Scheme 6.112), Leadbeater and coworkers also presented a solid-phase protocol for a one-pot Mannich reaction employing the above mentioned chlorotrityl linker [67]. In this approach, p-chlorobenzaldehyde and phenylacetylene were condensed with readily prepared immobilized piperazines (Scheme 7.56). 

Experimental Procedure 13.7 (ionera procedure lor the attachment of f moc amino acids to a 2-chlorotrityl linker [225]... 

During neutralization of dipeptides linked to alcohol resins as esters, diketopipera-zines can be formed by intramolecular nucleophilic cleavage (Section 15.22.1). Dike-topiperazine formation during peptide synthesis can be avoided by acylating the first support-bound amino acid with a preformed N-protected dipeptide, or by using the 2-chlorotrityl linker, which cannot be readily cleaved by nucleophiles. 

The A-Fmoc-amino-oxy-2-chlorotrityl linker 1.9 (65) is derived from the commercially available, extremely popular 2-chlorotrityl chloride PS resin and has been used to prepare functionalized hydroxamic acids or peptidyl hydroxamic acids. The final compounds can be removed from the resin using 5% TFA-DCM. 

Fmoc-D-cycloserine (4-aminoisoxazolidine-3-one) and its enantiomer were immobilized on SASRIN resin or 2-chlorotrityl linker resins using Mitsunobu-type reaction or direct tritylation, respectively. The loading of the resulting resins (0.59-0.69 mmol g) was determined by spectrophotometry of the in rr/ -generated piperidine-dibenzofulvene... 

In addition to the linkers mentioned above, the chlorotrityl linker commonly applied for the binding of carboxylic acids can also be used for the attachment of secondary amines [37]. An example is the binding of piperazine as the amine component in a Mannich reaction on a solid support (Scheme 16). Reaction of an aldehyde with the resin-bound amine, followed by addition of acetyhde, led to solid-phase-bound intermediates of type 33, from which the final compounds 34 were obtained by acid-mediated cleavage. 

The 2-chlorotrityl linker has recently been used for the synthesis of libraries of peptidomimetics of type 35 [38, 39]. The actual synthesis is outlined in Scheme 17. 

With increasing use of Fmoc SPS, a number of base-mediated side reactions have been identified and reported that require careful awareness [61]. Some of these are described elsewhere in this volume (Chapters 2 and 4). The principal base-mediated side reactions are diketopiperazine formatioii caused by cyclization, particularly during A -deprotection of the residue adjacent to C-terminal resin-linked proline [62], and aspartimide formation, particularly at Asp-X residues [63,64]. The former can now be prevented by use of the substantially sterically hindered 2-chlorotrityl linker [65]. The latter side reaction is more difficult to control and appears to be largely sequence dependent. Asp-Gly, -Ser, -Thr, -Asn, and -Gin pairs are most at risk of potential imide formation, although several other Asp-X combinations have also been observed to cyclize [66,67]. For one sensitive peptide sequence, use of piperazine for A -deprotection eliminated this side reaction [68]. However, for another peptide, this base was ineffective (J Wade, unpublished). Reduction of the basicity of the piperidine solution by addition of... 

In a more recent study, microwave irradiation was used in the accelerated solid-phase synthesis of aryl triflates [67] (Scheme 16.45). Reducing the reaction times from 3-8 h under conventional heating conditions to only 6 min under the action of microwaves has made this procedure more amenable to high-throughput synthesis. The use of the commercially available chlorotrityl linker as a solid support... 

Similarly, a 20-membered ring was formed and released from a 2-chlorotrityl linker (Scheme 4). 

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