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, including PNAs, 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) rapid, continuous syntheses in solution, (b) very rapid solid phase syntheses of longer peptides, and (c) peptides subject to base-catalyzed side reactions, such as peptide thio esters of possible use in new techniques for peptide ligation. Further studies on two new peptide-bond protecting groups, the Fm- and Dcpm 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 and the azanaphthotriazoles. Mechanistic studies on the operation of these new coupling reagents will point the way to greater coupling efficiency and speed.
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| Carpino, Louis A; Abdel-Maksoud, Adel Ali; Ionescu, Dumitru et al. (2007) 1,1-dioxonaphtho[1,2-b]thiophene-2-methyloxycarbonyl (alpha-Nsmoc) and 3,3-dioxonaphtho[2,1-b]thiophene-2-methyloxycarbonyl (beta-Nsmoc) amino-protecting groups. J Org Chem 72:1729-36 |
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