Biopolymer Synthesis on Solid Supports

The concept of solid phase synthesis began as a new approach to the preparation of peptides, but has been extended to the synthesis of polynucleotides, polysaccharides, polyamides and a variety of other classes of compounds. The solid support simplifies and accelerates the synthetic process, aids the separation of reagents and by-products, and reduces problems of insolubility of intermediates. The synthesis may involve a stepwise addition of monomer units or the condensation of preformed oligomer fragments. Large numbers of peptides and several small proteins have been synthesized by the solid phase method. To facilitate the synthesis we have developed a new, more acid-stable attachment of the peptide to the polystyrene support, in which the chain is anchored through a hydroxymethylphenylacetamidOmethyl group. Alternatively, the peptide chain can be anchored through a more labile alkoxybenzyl ester linkage, if the very acid-sensitive Bpoc group is used for Na_protection. The ideal design for a multi-step synthesis will depend on a combination of protecting groups that are removable by completely independent reaction mechanisms. Such a system is called orthogonal. A new amino protecting group, the dithiasuccinoyl (Dts) group, has been designed for that purpose. It is removed by reduction, but is stable to acids and photolysis and can be used in conjunction with these two orthogonal modes of deprotection. The synthesis of biopolymers on solid supports was illustrated by studies of the role of arginine in the neurotoxin, apamin, and of the substrate specificity of a histone deacetylase and by a recent synthesis of crystalline glucagon