The proposed work involves the development of new ammo-protecting groups and new coupling reagents for use in the synthesis of biologically active materials such as Pharmaceuticals, polynucleotides, including PNA's, peptides, and small proteins. For ease of operation following the deblocking procedure, emphasis is placed on amino-protecting groups leading to (a) volatile, (b) infinitely water-soluble, or (c) easily-extracted by-products. Especially important are groups cleaved by mild organic bases or relatively non-basic nucleophiles under non-hydrolytic conditions. A large new class of protecting groups subject to deblocking under conditions of Michael addition typified by the Bsmoc function, will be studied in detail in terms of applicability to the synthesis of long-chain peptides or small proteins. The Bsmoc group will be examined for its application to (a) superfast solid phase syntheses of longer peptides, and (b) peptides subject to base-catalyzed side reactions and (c) "difficult" peptides subject to aggregation effects. Further studies on two new peptide-bond protecting groups, the Dcpm- and Dcpp functions, will probe applicability to problems of peptide insolubility and aggregation. Further optimization of new coupling systems based on 7-aza-1-hydroxybenzotriazole will be carried out, especially in the cases of HOAt-N-oxide, the corresponding pyrazines, phosphorus- based OAt esters, HODhat derivatives and immonium-style systems. Mechanistic studies on the operation of these new coupling reagents will point the way to greater coupling efficiency and speed. Comparison of solid phase syntheses for longer peptides will be carried out by automated techniques on an ABI 433A synthesizer and a CEM microwave synthesizer. Microwave irradiation is expected to allow for the most efficient syntheses, especially with Bsmoc and HOAt-based chemistry.