Parallel solid-phase syntheses of 1,3,4-thiadiazolium-2-aminides.

An efficient and advantageous solid-phase strategy has been developed to synthesize 1,3,4-thiadiazolium-2-aminides. The title compounds were prepared in parallel fashion according to the following compact route: (i) anchoring of aromatic aldehydes to the solid support; (ii) solution preparation of 1,4-disubstituted thiosemicarbazides from hydrazines plus isothiocyanates; (iii) trimethylsilyl chloride-promoted cyclization between the resin-bound aldehydes and 1,4-disubstituted thiosemicarbazides; and (iv) removal of the products from the solid support by acid treatment. The products (17 made in all) were cleaved with high initial purities (90-98%) and obtained in generally good isolated yields (53-94%, with one exception).

Backbone Amide Linker (BAL) Strategy for N(alpha)()-9-Fluorenylmethoxycarbonyl (Fmoc) Solid-Phase Synthesis of Unprotected Peptide p-Nitroanilides and Thioesters(1).

A 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 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 peptide p-nitroanilides and thioesters have been prepared in excellent yields and purities, with minimal racemization.