Linkers peptide thioester preparation

A more versatile route to synthesize peptide thioesters is by the preparation of a peptide thioacid via the solid-phase method and then reaction with a halo derivative to form the thioester. This route can be achieved via the preparation of thioester linkers that can be applied in stepwise solid-phase peptide synthesis. The general structure of the N-protected amino thioacid attached to the linker is shown in Scheme 14. t65-80 ... 

Camarero et al. [108] used the hydrazine safety-catch linker to prepare peptide thioesters. After assembling the peptide using standard Fmoc protocols, the fully protected peptide resin was activated by mild oxidation with N-bromosuc-cinimide (NB S) in the presence of pyridine, forming a reactive acyl diazene that was then deaved with an a-amino add S-alkyl thioester such as H-AA-SEt, where AA is Gly or Ala. After TFA deprotection, peptide thioesters were obtained in good yields. Although the oxidation step did produce racemization, and other sensitive amino acids such as Tyr(tBu) and Trp(Boc) were not affected, Met and Cys presented some problems. Met was completely oxidized, and a reductive cleavage was required. For Cys, the Cys(Trt) derivative should be avoided and use of Cys(Npys) or Cys(S-StBu) is recommended instead. 

Hojo H, Kwon Y, Kakuta Y, Tsuda S, Tanaka I, Hikichi K, Aimoto S (1993) Development of a linker with an enhanced stability for the preparation of peptide thioesters and its application to the synthesis of a stable-isotope-labeUed Hu-type DNA-binding protein. Bull Chem Soc Jpn 66 2700-2706... 

The investigation of minor groove-binding polyamides was greatly accelerated by the implementation of solid-phase synthesis [48]. Originally demonstrated on Boc-y9-Ala-PAM resin with Boc-protected monomers, it was also shown that Fmoc chemistry could be employed with suitably protected monomers and Fmoc-y9-Ala-Wang resin (Fig. 3.8) [49]. Recently, Pessi and coworkers used a sulfonamide-based safety-catch resin to prepare derivatives of hairpin polyamides [50]. Upon activation of the linker, resin-bound polyamides were readily cleaved with stoichiometric quantities of nucleophile to provide thioesters or peptide conjugates. 

Fmoc-protected amino acid fluorides 307 were found to be excellent reagents for the acylation of sulfonamide safety-catch linkers (SCLs) 306 suitable for the subsequent preparation of peptide C-terminal thioesters (Equation 57). This generally applicable approach enables high loadings on different types of resins using short reaction times with low levels of racemization <20020L1187>. 

C-terminal thioester peptides can be prepared in a straightforward manner by using Boc-SPPS [76, 77]. The thioester group is typically an integral component of the resin linker and stepwise chain elongation is conducted under in situ neutralization conditions developed by Kent et al. to ensure the efficiency of couplings... 

---