Solid-phase synthesis via 5-oxazolidinones. Ring opening reactions with amines and reaction monitoring by single bead FT-IR microspectroscopy

Abstract

Until recently, large compound libraries produced by solid-phase synthesis have been restricted to those of linear peptides and oligonucleotides, but the need for development and synthesis of libraries of small organic molecules using this method is growing rapidly.1 We are interested in developing strategies and chemistries that would allow entry to combinatorial libraries of peptidomimetic structures on solid support. Our approach to the synthesis of peptide mimetics involves attachment of an essential amino acid residue via its side-chain functionality to the solid support. A similar strategy has been employed by Ellman in creating a peptidomimetic library using the hydroxyethylamino isostere of phenylalanine found in most HIV protease inhibitors anchored via the secondary alcohol.2 Anchoring the amino acid side chain to polymeric supports is now widely used to prepare head-to-tail cyclic peptides via solid-phase-mediated cyclization.3 Typically, Asp or Glu are attached via their ω-carboxyls to hydroxymethyl or aminomethyl resins, with the expectation that the corresponding peptides containing Asp/Glu or Asn/Gln, respectively, will be obtained after final cleavage from the resin. The most widely practiced strategy to obtain head-to-tail cyclic peptides uses the three-dimensional Fmoc/t-Bu/allyl orthogonal protection scheme. Kates et al. developed the use of R-allyl-protected aspartic acid for automated continuous flow synthesis of cyclic peptides containing Asp or Asn residues via side-chain anchoring to the resin followed by on-resin cyclization,4 which is applicable to Gluand Gln-containing sequences. Also, the Fmoc/allyl ester protection scheme was applied to anchor lysine via its -amino group.3e Additionally, side-chain attachment to Merrifield (chloromethylated polystyrene) resin has been applied to cysteine in its unprotected form; this has allowed both Nand C-terminal derivatization.5 In the latter case, C-terminal derivatization to amides and esters required carboxylic acid activation with BOP reagent.