Peptides allylated

If the Claisen rearrangement is carried out with peptide allylic esters, the transfer of an allylic side chain to the a-position of the C terminal amino acid results in a modification of the peptide chain. This concept is comparable to the alkylations of peptide enolates described by Seebach et al. [93]. If it is possible to carry out the rearrangement not only with amino acids but also with peptide esters, the question arises if it is possible to transfer the chiral information from the peptide chain to the new chiral center formed during the rearrangement process, prohahly via some peptide metal enolate complexes. 

A wide variety of a-tnfluoromethyl a-amino acids are readily available from the reaction of 5-fluoro-4-tnfluoromethyl-l,3 azoles with allylic alcohols [138, 139] a-Tnfluoromethyl-subsumted a-amino acids show anubactenal and antihy pertensive activity Some are highly specific enzyme inhibitors (suicide inhibitors) and may be important as bioregulators [140] Furthermore, they are interesting candidates for peptide modification... 

A benzyl carbonate was prepared in 83% yield from the sodium alkoxide of glycerol and benzyl chloroformate (20°, 24 h). It was also prepared by a lipase-catalyzed ester exchange with allyl benzyl carbonate. It is cleaved by hydrogenolysis (H2/Pd-C, EtOH, 20°, 2 h, 2 atm, 76% yield) and electrolytic reduction (—2.7 V, R4N X, DMF, 70% yield). A benzyl carbonate was used to protect the hydroxyl group in lactic acid during a peptide synthesis." ... 

Ethers with a tertiary, benzylic, or allylic group cleave by an S l or FI mechanism because these substrates can produce stable intermediate carbocations. These reactions are often fast and take place at moderate temperatures. fcrf-Butyl ethers, for example, react by an El mechanism on treatment with trifluoroacetic acid at 0 °C. We ll see in Section 26.7 that the reaction is often used in the laboratory synthesis of peptides. 

Hoveyda and coworkers [142] developed the Cu-catalyzed allylic substitutions of phosphonate derivatives with pyridinyl peptide structures as efficient ligands. The structure of the ligands was chosen through synthesis, and analysis of libraries. Optimized compounds were used as ligands for the... 

Allylic hydroxycrotyl-oligoethylene glyco-n-alkanoyl (HYCRON) linker 25 was applied to the synthesis of protected peptides and glycopep-tides [31]. HYCRON is stable to both acidic and basic conditions and is compatible with Boc- and Fmoc-based chemistry. The preparation of this novel linker is only two steps from commercially available materials. H YCRON linker can be cleaved under neutral conditions using Pd catalyst (Scheme 9). 

Seitz O, Kunz H. HYCRON, an allylic anchor for high-efficiency solid phase synthesis of protected peptides and glycopeptides. J Org Chem 1997 62 813-826. 

The idea of Hoveyda with co-workers to employ their peptide ligands (e.g., 295) as chiral inductors in allylic substitutions with dialkylzincs turned out to be very rewarding.399-401 As a result of meticulous screening of numerous optically active ligands, copper salts, and substrates under various conditions, they achieved excellent results for aliphatic alkenes. Particularly, allylic substitution products with tertiary 297 and quaternary 299 carbon centers were obtained regioselectively and with 78-96% ee (Scheme 151).401... 

Part of our original vision with BAL was to use allyl chemistry to introduce a third dimension of orthogonality and access cyclic peptides. However, we observed that with BAL-anchored glycyl... 

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. 

O Dangles, F Guibe, G Balavoine, S Lavielle. A Marquet. Selective cleavage of the allyl and allyloxycarbonyl groups through palladium-catalyzed hydrostannolysis with tributyltin hydride. Application of the selective protection-deprotection of amino acid derivatives and in peptide synthesis. J Org Chem 52, 4984, 1987. 

H Kunz, B Dombo. Solid phase synthesis of peptides and glycopeptides on polymeric supports with allylic anchor groups. Angew Chem Int Edn Engl 27, 711, 1988. 

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. 

Peptide 21, synthesized using the C-terminal enzymatic-cleavable choline ester (Scheme 11), was also synthesized using the C-terminal allyl ester protecting group (Scheme 12). The selective Pd(0)-catalyzed... 

C-terminal deprotection was performed using morpholine as an allyl trap, resulting in high yields. The most significant advantage of the allyl group in this peptide synthesis in comparison with the choline ester is that it overcomes the solubility problem encountered in the enzymatic deprotection approach. The deprotection of the allyl ester is performed in organic solvents, in which these lipidated peptide are readily soluble. ... 

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