Sieber amide linker

Several linkers have been developed that rely on the formation of highly stabilized aromatic carbocations. The most frequently used are the eponymous Sieber amide linker 36 [3] and Barany s 3-XAL linker 6 [4]. Both are based on a 3-methoxyxanthine scaffold, which owing to the highly stabilized nature of the xan-thenium ion can provide primary amides on treatment with 1% TFA in DCM, making them excellent tools for the synthesis of protected peptide carboxamides. The Sieber amide resin has also been used to prepare secondary amides via reductive alkylation of the amino group, acylation of the resultant amine and cleavage with dilute TFA [88]. Brill et al. [67] have effected transamination of trifluoroacety-lated Sieber amide resin in good yield. This approach offers considerable potential for the immobilization of amines on this support. 

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. 

Fmoc-based solid-phase glycopeptide synthesis is compatible with the standard linkers (handles) widely used in peptide synthesis, such as Rink amide, Wang, SASRIN (mild acid cleavage), 2-chlorotrityl chloride (protected peptide acid), and Sieber (protected peptide amides). For combinatorial one-bead one-compound studies, both the safety-catch amide linker (SCAL, stable to both acid and base until sulfone reduction) [24] and the photocleavable linker 4-[4-(l-aminoethyl)-2-methoxy-5-nitrophenoxy] butyric acid [25 ] have been successfully applied. These linkers are suitable for displaying the frilly deprotected glycopeptides on bead while allowing their nondestructive recovery after bead assay. Concerning... 

In addition to the procedures listed in Table 3.38, further reactions have been used to generate halides upon cleavage. In Section 3.5.2, iodolactonization is presented as a method for the preparation of iodomethyl lactones from resin-bound pentenoic or hexenoic acid derivatives. Closely related to the iodolactonization is the iodine-mediated formation of 2-(iodomethyl)tetrahydrofurans from resin-bound isoxazoli-dines (Entry 9, Table 3.38 for the mechanism, see Figure 15.5). Nitriles can also be prepared by cleavage and simultaneous dehydration of amides RCONH2 from the Rink or Sieber linkers with TFA anhydride (Entry 10, Table 3.38). 

Few preparations of nitriles have been performed on insoluble supports (Table 13.19). Aromatic and heteroaromatic nitriles have been prepared on solid phase from the corresponding iodoarenes by metallation followed by reaction with tosyl cyanide (Entry 1, Table 13.19). Moreover, the reaction of chloromethyl polystyrene with NaCN has been used to prepare support-bound benzyl cyanide (Entry 2, Table 13.19). Cleavage with simultaneous formation of nitriles can be achieved by treating polystyrene-bound sulfonylhydrazones with KCN (Entry 3, Table 13.19) or by cleaving amides from a Rink or Sieber linker with TFA anhydride (Entry 10, Table 3.38 [262]). Support-bound benzaldehydes have been converted into 3-aryl-2-propenenitriles by means of a Horner-Emmons reaction with (Et0)2P(0)CH2CN [263]. 

Sieber P (1987) A new acid-labile anchor group for the solid-phase synthesis of C-terminal peptide amides by the Fmoc method. Tetrahedron Lett 28 2107-2110 Mende F, Seitz O (2011) 9-Fluorenylmethoxycarbonyl-based solid-phase synthesis of peptide a-thioesters. Angew Chem Int Ed 50 1232-1240 Giiillier F, Grain D, Bradley M (2000) Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem Rev 100 2091-2158... 

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