TFA-mediated cleavage

This section describes the procedures used for cleavage of peptides from add-sensitive linkages. The protocols for the release of peptides from base-sensitive linkages are given in Chapter 6. 

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Entry 9 in Table 3.13 is an example of a safety-catch linker, which requires activation by TFA-mediated cleavage of a tert-butyl ether. The unactivated 2-(tm-butoxyj-phenyl esters are cleaved by amines 700 times more slowly than the corresponding 2-hydroxyphenyl esters [289]. A similar linker has been described [290], in which a benzyl ether is used instead of a ferf-butyl ether. Activation of this linker by debenzy-lation was achieved by treatment with HF or HBr/TFA [290]. 

Examples of the preparation of oxazines and thiazines on insoluble supports are listed in Table 15.34. 3,l-Benzoxazin-4-ones can be prepared by intramolecular O-acy-lation of /V-aminocarbonyl anthranilic acids (Entry 1, Table 15.34). The resulting ben-zoxazinones are sufficiently stable towards acids to enable TFA-mediated cleavage from a Wang linker [410]. 1,3-Oxazines have also been obtained by acidolytic cleavage of functionalized 3-amino-l-propanols from Wang resin (Entry 4, Table 3.30). 

Scheme 18.1 TFA-mediated cleavage of pseudoprolines to render the corresponding dipeptide.

The sample is now readily for further chemical transformations, or for TFA-mediated cleavage. 

Originally, Multipin peptide synthesis was performed using a Boc protocol (39) however, due to more streamlined handling (required for efficient multiple synthesis), Fmoc/tBu synthetic protocols are now used. The TFA-mediated cleavage method used with Fmoc/tBu synthesis is far more easily adapted for large numbers than the HF required with Boc synthesis. 

This was followed by the attachment of a suitable urea-bearing carboxylic acid to generate the handle for the synthesis of the heterocyclic moiety (Scheme 8.5). The dihydropyrimidine core was then assembled using a standard microwave-assisted Biginelli reaction at 140°C for 40 min using DMF/HCl (4 1), followed by a TFA-mediated cleavage of the target molecule from the resin. 

In an effort to prepare chiral 1,2-diamines, Coldham et al. started with the asymmetric deprotonation of A)-Boc-imidazolidine (25) using i ec-BuLi/(—)-sparteine. The deprotonation occurred exclusively at C-5 and trapping with methyldiphenylchlorosilane gave the 5-methyldiphenylsilylated imidazolidine (26) in high optical purity (ee 88%) (eq 16). Ethanolysis with malonic acid as catalyst led to the selective formation of the acyclic N-Boc-diamine, and TFA-mediated cleavage... 

Besides HF and TFA, the two extremes of acid treatment generally employed in the final deprotection step, alternative acids have been proposed, such as MsOH and TfOH, particularly in the context of arginine protection (Table 2). These acids, however, are known to generate serious side reactions such as aspartimide formationt and an N O shift at serine or threonine residues.Moreover, independent of the type of arylsulfonyl group employed, cations originating from the acid-mediated cleavage lead to alkylation and arylsulfonylation of reactive side chains, as present in tryptophan and tyrosine residues. Additionally, sulfation of hydroxy groups is even observed, as well as... 

Cleavage of the 5-(acetamidomethyl) group is achieved with metal ions such as mercury(II) in aqueous acetic acid or silver(I) in TFA.b In the latter case, the trifluoromethane-sulfonate salt was found to be superior to the trifluoroacetate, and silver tetrafluoroborate is an efficient alternative. While sensitive residues such as Met, Trp, and Tyr are largely unaffected by cleavage with silver(I) salts, mercury(II)-mediated cleavage has been reported to give side reactions at Trp residues, P which can be suppressed by operating in the... 

In this way, the desired metallated phthalocyanines remained on the solid support, while the unwanted by-products such as the symmetrically substituted B4-type moieties were formed in solution and could easily be discarded. After an acid-mediated cleavage from the resin using a TFA/TIPS/DCM mixture at ambient temperature, the e-amine of the lysine moiety of the metallated phthalocyanine was used for the attachment of suitable oligonucleotides connected with aryl aldehydes or acids (Scheme 8.9). Interestingly, both the reductive amination and the amidation reaction could be dramatically sped up using microwave irradiation, carrying out the reactions at 70-75°C for a mere 30 min. The reductive amination protocol was found to provide a far superior yield, owing to the competitive ester formation and hydrolysis observed in the microwave-assisted amidation protocol. 

A recent example of the application of solid phase Suzuki reactions to the synthesis of pharmaceutically important biaryl compounds was shown by Nielsen et aL [115]. A range of aryl-substituted pyrroloisoquinolines were synthesized from biarylalanine precursors in high purity (Scheme 39). This involved a Suzuki coupling of sohd-supported iodophenylalanine derivatives containing a masked aldehyde to various boronic acids, followed by hberation of the aldehyde, TFA-mediated intramolecular Pictet-Spengler reaction, and cleavage. 

Scheme 3) [30]. The pY + 3 diversity alcohols (Ri)-OI I (Fig. 15) were attached to the template through a Mitsunobu coupling to provide ether derivatives of 16. Palladium-mediated Alloc deprotection followed by amide formation using the phosphate-ester-containing diversity acids (R2)-C02H provided the fully coupled resin-bound products of 17. Cleavage from the resin with 95% TFA/H20, which also afforded benzyl phosphate deprotection, followed by reversed-phase (RP) semipreparative... 

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