Solid Phase Peptide Synthesis by Four Component Condensation: Peptide Formation on an Isocyano Polymer Support

The feasibility of peptide synthesis by four component condensation (4CC) [1] has been demonstrated [2]. In particular the advantages of peptide synthesis by 4CC, namely coupling without carboxyl activation, the possibility of reaction in highly polar media, and the effectively unimolecular nature of the coupling step in such coupling of peptide fragments are being recognized [3]. The unique feature of 4CC, i.e., the participation of four components in the reaction, provides a potentially versatile apparatus for combination with the so-called solid phase techniques [4]. In principle a number of strategies of solid phase peptide synthesis by four component condensation (SPPS-4CC) can be envisaged. Here we report some of our preliminary results on a novel strategy which is ideally suited for coupling of peptide segments on an isocyano polymer support. In addition the principle described here can be employed as an anchoring technique to initiate solid phase peptide synthesis by the stepwise (Merrifield-type) procedure [4]. According to this strategy, as outlined in Scheme I, a C-protected amino acid or peptide (H2N-PN, amine-component) and an N-protected amino acid or peptide (Pc-COOH, acid component) are coupled in the presence of an aldehyde and a polymer-bound isonitrile to produce the peptide product attached to the polymer through an auxiliary substituent on the N-terminal of the amine component. Removal of the peptide from the polymer involves the cleavage of this auxiliary substituent, leaving the co-product attached to the polymer. Non-destructive cleavage of the auxiliary substituent is, however, of prominent importance in the successful application of the method, and depends on the structure of the aldehyde. For the present study an aldehyde with an acidolytically cleavable 4CC product, namely l-methyl-3-formylindole [5], was used. (Work on the use of other cleavable aldehydes [2, 3, 6] is in progress.) For the polymer support, and with the use of polar solvents such as alcohols in mind, we examined a number of acrylamide containing resins carrying about 1-3 mmol/g isocyano groups and having various chemical structures, cross-linking, and topography. H-Leu-OEt and Boc-Gly-Ala-OH were also chosen as model amine and acid components according to Scheme I.