The proposed work involves the development of new amino-protecting groups and new coupling reagents for use in the synthesis of biologically active materials such as pharmaceuticals, polynucleotides, peptides, and small proteins. For ease of operation following the deblocking procedure, emphasis is placed on amino-protecting groups leading to (a) volatile (b) totally insoluble (e.g., polymeric) and/or (c) infinitely water-soluble or easily extracted by-products. Especially important are groups cleaved by mild organic bases or relatively non-basic nucleophiles under non- hydrolytic conditions or even under neutral conditions (solvent deblocking, etc.). A large new class of protecting groups subject to deblocking under conditions of Michael addition will be studied in detail in terms of applicability to the synthesis of long chain peptides or small proteins. Currently the preferred representative of this category is the benzothiophenesulfone-2-methyloxycarbonyl (Bsmoc) protecting group. Other protective functions designed for "backbone protection" will be examined as an aid to solving the problem of sequence-dependent breakdown in coupling efficiency. New types of coupling reagents based on acid fluorides and 1-hydroxy-7-azabenzotriazole have been found to be far more efficient than classical reagents both in terms of speed, generality, and epimerization control. These new, highly efficient coupling procedures will be applied to the fully automated synthesis of longer peptides and small proteins which have previously been shown to contain difficult sequences (HIV-1 protease (1-99), HIV-1-specific virus protein U, etc.).