The proposed work involves the development of new amino-protecting groups 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 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 new class of protecting group 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. Initial targets will be the corticotropin-release factor (CRF 1-41) and HIV-1 protease (1-99). Base- and nucleophile-sensitive amino-protecting groups show advantages in that the deblocking step liberates the amino group in the free form so that it is directly available to enter a subsequent coupling step, as for example during solid phase syntheses. New coupling agents specifically designed for use with base-sensitive protecting groups, such as protected amino acid fluorides, will be evaluated as rapid-acting coupling agents capable of allowing for fully automated, feedback-controlled syntheses of higher peptides. Base- sensitive protecting groups of different sensitivities will be evaluated for peptide bond protection thus allowing for new methods of executing segment condensation based on (a) enhanced solubility of individual segments and (b) racemization-free coupling via peptide-bond protection of the C-terminal carboxylic acid-bearing segment. For non-alpha protection (side chains) groups specifically designed to avoid the need for scavengers upon release of assembled peptides from resin supports will be investigated.
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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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