Pepti
de targets for synthesis are often
desired withC-terminal end groups other than the more usualacid and ami
de functionalities. Relati
vely few routes exist forsynthesis of C-terminal-modified pepti
des-includingcyclic pepti
des-by either solution or solid-phase methods, and knownroutes are often limited in terms ofease and generality. We
describe here a no
vel
Backbone
Ami
de Linker (BAL) approach, whereby thegrowingpepti
de is anchored through a backbone nitrogen, thus allowingconsi
derable flexibility in management of thetermini. Initial efforts on BAL ha
ve adapted the chemistry of thetris(alkoxy)benzylami
de system exploitedpre
viously with PAL anchors. Al
dehy
de precursors to PAL, e.g.5-(4-formyl-3,5-dimethoxyphenoxy)
valericacid, were reducti
vely coupled to the
![](/images/gifchars/alpha.gif)
-amine of the prospecti
veC-terminal amino acid, which was blockedas a
tert-butyl, allyl, or methyl ester, or to theappropriately protected C-terminal-modified amino acid
deri
vati
ve.These reducti
ve aminations were carried out either in solution oron the solid phase, and occurred withoutracemization. The secondary amine intermediates resulting fromsolution amination were con
verted to the9-fluorenylmethoxycarbonyl (Fmoc)-protected preformed handle
deri
vati
ves, which were then attached to poly(ethylene glycol)-polystyrene (PEG-PS) graft orcopoly(styrene-1% di
vinylbenzene) (PS) supports andusedto assemble pepti
des by standard Fmoc solid-phase chemistry.Alternati
vely, BAL anchors formed by on-resin reducti
ve amination were applied directly. Conditions wereoptimized to achie
ve
near-quantitati
ve acylationat the difficult step to introduce the penultimate residue, and a si
dereaction in
vol
ving diketopiperazine formationun
der some circumstances was pre
vented by a modified protocol forN
![](/images/gifchars/alpha.gif)
-protection of the second residue/introduction of the third residue. Examples are pro
vi
ded for thesyntheses in high yields and purities ofrepresentati
ve pepti
de acids, alcohols,
N,N-dialkylami
des,al
dehy
des, esters, and head-to-tail cyclic pepti
des.These methodologies a
void postsynthetic solution-phasetransformations and are ripe for further extension.