Cleavage trityl amine

A traditional linker for cleavage of amines is the trityl linker. 

After acid-free cleavage from the resin 120 with 1,1,1-trifluoroethanol in CH2CI2 and chromatographic purification, building blocks 162-165 are obtained in yields of 8-40%. Although the yields of the products 162 and 164 are enhanced compared to 163 and 165 (40% 8% and 17% 12%, respectively), a completely selective synthesis does not seem to be possible by this approach. An interesting feature here was the publication of an acid-free procedure for the cleavage of amines from trityl resins and a refinement of the Kaiser test. 

Me3SiI, CH2CI2, 25°, 15 min, 85-95% yield.Under these cleavage conditions i,3-dithiolanes, alkyl and trimethylsilyl enol ethers, and enol acetates are stable. 1,3-Dioxolanes give complex mixtures. Alcohols, epoxides, trityl, r-butyl, and benzyl ethers and esters are reactive. Most other ethers and esters, amines, amides, ketones, olefins, acetylenes, and halides are expected to be stable. 

The bulky triphenylmethyl group has been used to protect a variety of amines such as amino acids, penicillins, and cephalosporins. Esters of N-trityl a-amino acids are shielded from hydrolysis and require forcing conditions for cleavage. The a-proton s also shielded from deprotonation, which means that esters elsewhere in the molecule can be selectively deprotonated. 

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). 

Tritylamines can serve as both linkers and protective groups for aliphatic amines because, unlike benzhydrylamines, they do not usually undergo acylation when treated with activated acid derivatives. Tritylation of aliphatic amines is readily accomplished by adding excess amine to a support-bound trityl chloride. Illustrative cleavage reactions are listed in Table 3.21. 

The trityl linkers were introduced to permit anchoring of carboxylic acids and other nucleophiles to a solid support and to effect cleavage reactions under very mild acidic conditions [64-67]. Various trityl resins, such as Ib-le (Table 1), have been developed that differ in the substitution pattern of the aromatic ring substituents in order to modify the cleavage properties by their influence on the stability of the trityl cation. For carboxylic acids, amines, and phenols, the chlorotrityl resin Ic affords a more stable anchor [65-67] than does resin lb. Similarly, resin le, which contains both fluoro and carbonyl ring substituents, proved to be very stable toward nucleophiles and was fully compatible with piperidine / / -Fmoc (9-fluorenylmethoxycar-bonyl) deprotections used in a model peptide synthesis. Cleavage of acids from le could be effected using dilute TFA in dichloromethane [68]. 

A benzyl halide solid support If (Table 1) has been reported [77] that affords anchoring groups which are less labile than trityl anchors Ib-le but more labile than anchors to chloromethyl-PS (la). Resin If has been used to prepare amides and sulfonamides by reaction with an amine followed by acylation or sulfonylation, respectively, and cleavage using 95% TFA. When the same reaction sequence was conducted on an analogous resin Ig prepared from Tentagel AC (acid-cleavable linker), the products could be cleaved under milder conditions (5% TFA) because of the greater stability... 

A new linker and a derived solid support based on the chlorofluorenyl residue li have been reported [82,83] that are analogous to the trityl supports in that carboxylic acids, amines, and phenols can be anchored. The resulting linkages proved to be more stable than those to the 2-chlorotrityl resins but could be cleaved by treatment with TFA. In the case of a carboxylic acid (Scheme 3), cleavage was achieved using 20% TFA in CH2Cl2-MeOH (9 1). 

Deprotection. The use of CAN in the cleavage of TBS ethers, trityl ethers, and -Boc-amines has been reported. 

Reaction of trityl chloride with an amine in an aqueous-organic solvent (e.g.water-diisopropylalcohol) °or in a nonaqueous one in the presence of a suitable base yields the desired product. The trityl-nitrogen bond (like the benzyl-nitrogen bond) is susceptible to reductive cleavage and can be removed by catalytic hydrogenation... 

The use of acidic gaseous reagents, HCl and TFA, for cleavage of acids, alcohols, and amines attached to trityl linker functionalized supports has been reported (15). Jayawickreme et al. (16) used TFA for gradual cleavage of compounds from a solid support. The use of gaseous hydrogen fluoride (HF) has also been described for the release of compounds from the / -methyl-benzhydrylamine (MBHA) (17-20) and dialkoxybenzylamine (21-23) linkers. 

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