HYCRAM

The allylic HYCRAM derivative was subsequently modified by insertion of a standard amino acid between the aminomethyl resin and the hydroxy butenoic acid moiety. Using this allylic anchor, the resin-linked, glycosylated HIV peptide T-derivative 164 was synthesized by application of Fmoc amino protection and sidechain protection with lert-butyl groups. The lac-tosamine peptide T (165) could be released from the resin by application of the palladium(0)-catalyzed allyl-transfer reaction to V-methyl aniline as the allyl acceptor. 

New allylic anchors as the HYCRAM (19) (hydroxycrotonylamide) [50] and HY-CRON (21) (hydroxycrotyl-oligoefhylene glycol-n-alkanoyl) [51] linker have been developed, which exhibit excellent properties for the solid-phase synthesis of protected peptides and glycopeptides. A more flexible spacer was inserted in the HY-CRON (21) linker between the anchor and the polymeric support in order to facilitate an efficient access to the Pd(0) complex during the detachment reaction. 

Peptide cleavage from the allyl-linker resin is achieved with morpholine in large excess in the presence of tetrakis(triphenylphosphine)palladium (10mol% based on the allylic substitution of the resin). (3-HYCRAM resin is a modification of HYCRAM containing a P-alanine residue as a spacer between the crotonoyl unit and the resin. It has been used for the solid-phase synthesis of glycopeptides by the Boc and Fmoc strategies.b 1 Difficulties may be... 

Observations - Compatible with Fmoc/tBu and Boc/Bnz SPPS strategy. - More stable against amines than Hycram linker (4-bromocrotoic acid). - Stable against bases (pyridine, NaOMe) and acids (TFA). ... 

W Kosch, J Maerz, KVD Bruch, H Kunz. Solid phase synthesis of glyco-peptide antigens on HYCRAM resin utilizing the allylic anchor principle. Proceedings of Innovation and Perspectives in Solid Phase Synthesis. Third International Symposium, Oxford, 1993, pp 267-272. 

Hycram resin, hydroxycrotonoylamidomethyl resin, an allyl-based handle resin connection for SPPS of peptides and, especially, for glycopeptides, which is stable to base and mild acid. The cleavage of the final product from the resin occurs under neutral conditions by treatment with (Ph3P)4Pd/THF/morpholine, and does not affect Boc, Fmoc, or glycosidic bonds [H. Kunz, B. Dombo, Angew. Chem. Int. Ed. 1988, 27, 711]. 

The success of allyl-based protection for carboxylic acids led to the development of aUyl-based linkers for the attachment of peptides and glycopeptides to a soM support during their synthesis. Kunz developed the first allyl-based linker, hydroxycrotonamide (HYCRAM), in 1988. Displacement of the allylic bromide in the precursor by a car-boxylate nucleophile permits the attachment of the C-terminal residue to the soM support (Scheme 6). Peptide synthesis using this linker was performed with Boc as the N-terminal blocking group, and the final peptide or glycopeptide was cleaved from the allylic Unker... 

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