Trityl linker

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. 

For the Mannich reaction, a screw-capped fritted glass reaction vessel was charged with the resin (0.3 g, 0.75 mmol g ), Cu Cl (45 mg, 0.45 mmol), and benzaldehyde (0.16 mL, 1.57 mmol). After shaking for 0.5 h, phenyl-acetylene (0.173 niL, 1.57 mmol) was added to the mixture, and the reaction vessel was heated at 85 °C with shaking for 3 h. The resin was filtered hot and washed thoroughly with dioxane (once), DMF (three times), 20% aqueous AcOH (once), DMF (once), 7 m NH4OH (once), DMF (once), MeOH (three times), THF (three times), and CH2CI2 (three times). 

Cleavage of the desired product from the solid support was accomplished 

A secondary amine can be attached to the 2-chlorotrityl resin in the presence of 

Recently, a modified trityl linker for amines (36) (Fig. 4) has been introduced, and was used for the synthesis of polyamine derivatives [40]. 

---

With the following examples, we will investigate and discuss the following (a) Scale-up phenomena of different solid phase reactions and the corresponding on-bead analytics (b) the effect of loading (an equivalent to concentration in solution-phase chemistry) (c) comparison with the solution-phase alternative and (d) the synthesis and use of new trityl linkers. 

For these reasons, an alternative route and more acid labile linkers compared to p-carboxy trityl linker 24a initially used were sought, to avoid high concentrations of TFA for the final cleavage. The synthesis of the alkoxysubstitued linkers 24b (Meisenbach and Voelter 1997) and 24c, which can be synthesised directly on the solid support in five steps, offer the possibility of linkers with tailor-made stability. 

A van Vliet, RH Smulders, BH Rietman, GI Tesser. Protected peptide intermediates using a trityl linker on a solid support, in R Epton, ed. Innovations and Perspectives in Solid Phase Synthesis. Proceedings of the 2nd Symposium. Intercept, Andover,... 

Neither the trialkoxybenzhydryl alcohol linker nor other types of benzhydryl alcohols [44,45,48] have found widespread use as linkers for carboxylic acids. These linkers do not seem to offer special advantages compared with benzyl alcohol or trityl linkers. 

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]. 

Tertiary aliphatic alcohol linkers have only occasionally been used in solid-phase organic synthesis [73], This might be because of the vigorous conditions required for their acylation. Esterification of resin-bound linker 4 with /V-Fmoc-prolinc [72,74] could not be achieved with the symmetric anhydride in the presence of DMAP (20 h), but required the use of /V-Fmoc-prolyl chloride (10-40% pyridine in DCM, 25 °C, 10-20 h [72]). A further problem with these linkers is that they can undergo elimination, a side reaction that cannot occur with benzyl or trityl linkers. Hence, for most applications in which a nucleophile-resistant linker for carboxylic acids is needed, 2-chlorotri-tyl- or 4-acyltrityl esters will probably be a better choice than ferf-alkyl esters. 

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). 

Usually, it is different to make a clear distinction between linker and spacer. The linker is the minimum part of the resin required for the functional cleavage (for silyl linkers it is the silyl group, for trityl linkers it is the triphenylmethyl moiety, and for the triazene linker it is the 1-aryltriazenyl group, etc.). The spacer is, therefore, the part between the linker and the resin as depicted in Figure 6.1.1. 

So far undisclosed in the peer-reviewed literature are contributions by the company Graffinty (www.graffmity.de.) [31]. It has built up a technology platform in which combinatorial libraries are generated by solid-phase methodology using an acid-labile S-trityl linker. After cleavage the free thiols of the small molecules react... 

Fill the SPPS reactor (at least 2/3 of volume) with a 50/50 DCM/acetic anhydride solution (in case of trityl linker, see Note 7) and mix for 3 min. 

Photoacoustic spectra of resin samples have also been reported (16,17). The photoacoustic spectrum of TentaGel S beads coupled via a trityl linker with Fmoc-protected tryptophan is shown in Fig. 4. Compared with the photoacoustic spectrum of native aminoethyl TentaGel S beads, the appearance of diverse carbonyl bands is clearly seen the ester band of the linker at 1750 cm-1, the carbamate band of Fmoc protecting group at 1723 cm-1, and the amide I band at 1660 cm-1. 

Figure 4 Photoacoustic spectrum of native aminoethyl TentaGel S beads (lower curve) and of TentaGel S beads coupled via a trityl linker with Fmoc-protected tryptophan (upper curve). The carbonyl bands of the ester (at 1750 cm1), of the carbamate (at 1723 citT1), and of the amide (at 1660 cm-1) are clearly seen in the overlay plot. The spectra were obtained with 50 scans at 8 cm-1 resolution by means of a Bruker IFS 55 spectrophotometer equipped with a MTEC photoacoustic detector.

For combinatorial chemistry applications, high-quality FT-Raman spectra can be obtained directly from resin beads, i.e., no cleavage of the molecules from the polymeric support is necessary. This is shown in Fig. 5, where the spectra of TentaGel S beads coupled via a trityl linker with Fmoc-protected tryptophan and the native aminoethyl TentaGel S beads are overlaid. As expected, significant differences in the spectra occur in the spectral region between 1620 and 1500 cm-1 where aromatic rings show pronounced Raman activity. 

A trityl linker has also been used for the preparation of an estradiol suUamate library according to Scheme 18. The sulfamate 37, derived from estrone and prepared in solution, was attached to the trityl linker and was modified after cleavage of the trifluoroacetyl group to yield the desired target compounds of type 38 [41],... 

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

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 useful application of trityl linkers involves anchoring one function of a symmetrical diol [70-73] or diamine [74,75], enabling subsequent transformations to be conducted on the second functional group before acid-induced cleavage. Trityl resins can be used for anchoring phenols, such as 4-hydroxybenzaldehyde, in the presence of pyridine. The product was transformed via an oxime into isoxazolines, which were cleaved from the resin using TFA-CH2CI2 (1 99) [76]. 

Figure 7.3 K Ras4B C-terminal peptide was synthesized employing the trityl linker and after purification was reacted with a K-Ras thioester (K-Ras 1-174 MesNa) via EPL, yielding the semisynthetic K-Ras4B. Purity and identity of the purified protein were characterized by SDS-PAGE and MALDi-TOF. SDS-PAGE sodium dodecyl sulfate/polyacrylamide gel electrophoresis, MALDi-TOF matrix-assisted laser desorption ionization/time of flight.

---