BACKBONE AMIDE LINKER (BAL) STRATEGY FOR SOLID-PHASE SYNTHESIS OF C-TERMINAL-MODIFIED AND CYCLIC-PEPTIDES

Peptide targets for synthesis are often desired with C-terminal end gr oups other than the more usual acid and amide functionalities. Relativ ely few routes exist for synthesis of C-terminal-modified peptides-inc luding cyclic peptides-by either solution or solid-phase methods, and known routes are often limited in terms of ease and generality. We des cribe here a novel Backbone Amide Linker (BAL) approach, whereby the g rowing peptide is anchored through a backbone nitrogen, thus allowing considerable flexibility in management of the termini. Initial efforts on BAL have adapted the chemistry of the tris(alkoxy)benzylamide syst em exploited previously with PAL anchors. Aldehyde precursors to PAL, e.g. 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid, were reductively c oupled to the alpha-amine of the prospective C-terminal amino acid, wh ich was blocked as a tert-butyl, allyl, or methyl ester, or to the app ropriately protected C-terminal-modified amino acid derivative. These reductive aminations were carried out either in solution or on the sol id phase, and occurred without racemization. The secondary amine inter mediates resulting from solution amination were converted to the 9-flu orenylmethoxycarbonyl (Fmoc)-protected preformed handle derivatives, w hich were then attached to poly(ethylene glycol)-polystyrene (PEG-PS) graft or copoly(styrene-l% divinylbenzene) (PS) supports and used to a ssemble peptides by standard Fmoc solid-phase chemistry. Alternatively , BAL anchors formed by on-resin reductive amination were applied dire ctly. Conditions were optimized to achieve near-quantitative acylation at the difficult step to introduce the penultimate residue, and a sid e reaction involving diketopiperazine formation under some circumstanc es was prevented by a modified protocol for N-alpha-protection of the second residue/introduction of the third residue. Examples are provide d for the syntheses in high yields and purities of representative pept ide acids, alcohols, N,N-dialkylamides, aldehydes, esters, and head-to -tail cyclic peptides. These methodologies avoid postsynthetic solutio n-phase transformations and are ripe for further extension.