Kj. Jensen et al., BACKBONE AMIDE LINKER (BAL) STRATEGY FOR SOLID-PHASE SYNTHESIS OF C-TERMINAL-MODIFIED AND CYCLIC-PEPTIDES, Journal of the American Chemical Society, 120(22), 1998, pp. 5441-5452
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.