Fmoc/tBu chemistry

RESINS AND LINKERS FOR SYNTHESIS OF PEPTIDES USING FMOC/TBU CHEMISTRY... 

FIGURE 5.17 Resins and linkers for synthesis of peptides using Fmoc/tBu chemistry. The linkers are secured to supports by reaction with aminomethyl resins. A protected amino acid is anchored to the support as an ester by reaction with a hydroxyl or chloro group (italicized). The alkoxy and phenyl substituents render the benzyl esters sensitive to the cleavage reagents. 

FIGURE 5.18 Resins and linkers for synthesis of peptide amides using Fmoc/tBu chemistry. Chain assembly is effected after removal of the Fmoc group. Treatment with CF3C02H releases a peptide amide by cleavage at the NH-CH/CH2 bond. 

FIGURE 5.20 Resins for the synthesis of protected peptides using Fmoc/tBu chemistry. The first residue is esterified to the handle by reaction with the italicized functional group. The protected peptide is detached by cleavage of the ester bond with 1% CF3C02H for (A) and (B) and 10% CF3C02H for (C). 

During the first decade when solid-phase synthesis was executed using Fmoc/tBu chemistry, the first Fmoc-amino acid was anchored to the support by reaction of the symmetrical anhydride with the hydroxymethylphenyl group of the linker or support. Because this is an esterification reaction that does not occur readily, 4-dimethylaminopyridine was employed as catalyst. The basic catalyst caused up to 6% enantiomerization of the activated residue (see Section 4.19). Diminution of the amount of catalyst to one-tenth of an equivalent (Figure 5.21, A) reduced the isomerization substantially but did not suppress it completely. As a consequence, the products synthesized during that decade were usually contaminated with a small amount of the epimer. In addition, the basic catalyst was responsible for a second side reaction namely, the premature removal of Fmoc protector, which led to loading of some dimer of the first residue. Nothing could be done about the situation,... 

FIGURE 5.23 Synthesis of cyclic peptides by head-to-tail cyclization of resin-bound peptides using Boc/Bzl chemistry59 and Fmoc/tBu chemistry.60 The carboxy-terminal protectors are orthogonal to the other protectors. The nature of the linker determines the nature of the product. Both chemistries are compatible with the two types of linkers. All = allyl. 

Benzhydryl- (phenylbenzyl) and 4-methylbenzhydrylamine resins (see Section 5.18) are available for preparing primary amides, using Boc/Bzl chemistry. 4-Methylben-zhydrylamine, Rink amide, Sieber amide and dhnethoxytritylamine resins and the linkers PAL and XAL (see Section 5.20) are available for preparing primary amides, using Fmoc/tBu chemistry. Secondary amides can be synthesized by making use of AJ-alkyl-Sieber or ALalkyl-PAL linkers. 

The synthesis of the linear octapeptide was performed applying Fmoc/tBu chemistry and starting from 0.82 g (0.39 mmol-g-1, 0.32 mmol) of Fmoc-Ser(tBu)-HMPAA-resin (Millipore). Iturinic acid was coupled as the jV-Boc derivative. After deprotection and cleavage with TFA/H20 (95 5), the product was purified by preparative RP-HPLC yield 37 mg (74%). 

Head-to-Side-Chain and Side-Chain-to-Side-Chain Cyclized Peptides with Fmoc/tBu Chemistry General Procedure ... 

Among the electrophilic handles proposed for head-to-tail and side-chain-to-tail cyclization of peptides on solid support by intrachain aminolysis with concurrent detachment of the product from the resin in the protected form (see Section 6.8.3.1.3), generally the oxime resin (also called Kaiser resin)1364 365 and a thioester resin[363l are recommended (see Scheme 14). In addition to the classical head-to-tail cyclization,[3431 the oxime resin is used for side-chain cyclizations as well as for the synthesis of multicyclic peptides vide infra). Due to its dual functions, the oxime resin can be employed only with Boc/Bzl chemistry it is not compatible with Fmoc/tBu chemistry where the basic N -deprotection leads to free amino groups and thus to premature cyclization reactions. To avoid this premature cleavage of the... 

During attachment of a chiral amino acid ester to the resin, the base required in the reaction, particularly when used in excess, leads to facile racemizationJ369,4011 This occurs by C -proton abstraction and enolization of the amino acid ester (see Vol. E 22a, Section 1.2.1.2 and Section 7.4), which may also occur during chain assembly in the repetitive base treatments, especially with Fmoc/tBu chemistry and in case of razemization-prone amino acid residues. Thus careful control of the base is required or the use of dipeptide building blocks such as Fmoc-Asp-Gly-OFm,t369 as Ca-proton abstraction is not stabilized by enolization. 

Experimental procedures for synthesis of peptides on solid supports by the Fmoc/tBu chemistry are reported in Section 4.3.2.2.3, and for solution and solid-phase synthesis of glyco- and phosphopeptides or sulfated peptides in Sections 6.3, 6.5, and 6.6, respectively. 

Boc group has been used in the Fmoc/tBu chemistry on solid phase for semipermanent N -protection (Section 4.3.2.2).t °l... 

Qeavage of the A "-Dde and N"-l-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl groups is performed with 2% anhydrous hydrazine or hydrazine hydrate in DMF at room temperature (on resin, 3 x 2min). This leads to a l,5,6,7-tetrahydro-4//-indazol-4-one 25 as the byproduct (Scheme 10), which can be monitored by UV spectroscopy at 220 or 290 nm.O Since hydrazine will also remove Fmoc groups, the assembly of the peptide by Fmoc/tBu chemistry must be completed prior to the cleavage of the Dde or l-(4,4-dimethyl-2,6-diox-ocyclohexyhdene)-3-methylbutyl groups. 

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