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Backbone Amide Linker (BAL) Strategy forNα-9-Fluorenylmethoxycarbonyl (Fmoc) Solid-Phase Synthesis ofUnprotected Peptide p-Nitroanilides and Thioesters1


novel and general backbone amide linker (BAL) strategy has been devised for preparation of C-terminal modified peptides containing hindered, unreactive, and/or sensitive moieties, in concert with N(alpha)()-9-fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis protocols. This strategy comprises (i) start of custom peptide synthesis by anchoring the penultimate residue, with its carboxyl group orthogonally protected, through the backbone nitrogen, (ii) continuation with standard protocols for peptide chain elongation in the C --> N direction, (iii) selective orthogonal removal of the carboxyl protecting group, (iv) solid-phase activation of the pendant carboxyl and coupling with the desired C-terminal residue, and (v) final cleavage/deprotection to release the free peptide product into solution. 

To illustrate this approach, several model  custom peptide synthesis and thioesters have been prepared in excellent yields and purities, with minimal racemization. Such compounds are very difficult to prepare by standard Fmoc chemistry, including the BAL strategy as originally envisaged.

The extent of aspartimide formation and subsequent conversion to the alpha-or beta-piperidide was characterized and quantitated by analytical reversed-phase high-performance liquid chromatography and fast atom bombardment mass spectrometry. Aspartimide formation occurred for X = Arg(Pmc), Asn(Trt), Asp(OtBu), Cys(Acm), Gly, Ser, Thr and Thr(tBu). No single approach was found that could inhibit this side reaction for all sequences. The most effective combinations, in general, for minimization of aspartimide formation were (i) tert-butyl side-chain protection of aspartate, piperidine for removal of the Fmoc group, and either 1-hydroxybenzotriazole or 2,4-dinitrophenol as an additive to the piperidine solution; or (ii) 1-adamantyl side-chain protection of aspartate and 1,8-diazabicyclo(5.4.0)undec-7-ene for removal of the Fmoc group.
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