- Features of Auxiliaries That Enable Native Chemical Ligation beyond Glycine and Cleavage via Radical Fragmentation
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Native chemical ligation (NCL) is an invaluable tool in the total chemical synthesis of proteins. Ligation auxiliaries overcome the requirement for cysteine. However, the reported auxiliaries remained limited to glycine-containing ligation sites and the acidic conditions applied for cleavage of the typically applied N-benzyl-type linkages promote side reactions. With the aim to improve upon both ligation and cleavage, we systematically investigated alternative ligation scaffolds that challenge the N-benzyl dogma. The study revealed that auxiliary-mediated peptide couplings are fastest when the ligation proceeds via 5-membered rather than 6-membered rings. Substituents in α-position of the amine shall be avoided. We observed, perhaps surprisingly, that additional β-substituents accelerated the ligation conferred by the β-mercaptoethyl scaffold. We also describe a potentially general means to remove ligation auxiliaries by treatment with an aqueous solution of triscarboxyethylphosphine (TCEP) and morpholine at pH 8.5. NMR analysis of a 13C-labeled auxiliary showed that cleavage most likely proceeds through a radical-triggered oxidative fragmentation. High ligation rates provided by β-substituted 2-mercaptoethyl scaffolds, their facile introduction as well as the mildness of the cleavage reaction are attractive features for protein synthesis beyond cysteine and glycine ligation sites.
- Loibl, Simon F.,Dallmann, Andre,Hennig, Kathleen,Juds, Carmen,Seitz, Oliver
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p. 3623 - 3633
(2018/02/16)
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- Cysteine Isocyanide in Multicomponent Reaction: Synthesis of Peptido-Mimetic 1,3-Azoles
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An alternative approach toward the simple and robust synthesis of highly substituted peptidic thiazole derivatives using Ugi-multicomponent reaction (U-MCR) is described. Thus, we introduced the enantiopure (R)-2-methyl-2-isocyano-3-(tritylthio)propanoate as a novel class of isocyanide in MCR. This bifunctional isocyanide was found to undergo mild cyclodehydration to afford thiazole containing peptidomimetics in a short synthetic sequence. Several examples of bis-heterocyclic rings were also synthesized through the proper choice of the aldehyde component in the U-4CR. The method opens a wide range of applications toward the synthesis of nonribosomal natural products and other bioactive compounds.
- Vishwanatha, Thimmalapura M.,Kurpiewska, Katarzyna,Kalinowska-Tlu?cik, Justyna,D?mling, Alexander
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p. 9585 - 9594
(2017/09/23)
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- Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics
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A general strategy is introduced for the efficient synthetic access of disulfide linked artificial macrocycles via a Ugi four-component reaction (U4CR) followed by oxidative cyclization. The double-mercapto input is proposed for use in the Ugi reaction, thereby yielding all six topologically possible combinations. The protocol is convergent and short and enables the production of novel disulfide peptidomimetics in a highly general fashion.
- Vishwanatha, Thimmalapura M.,Bergamaschi, Enrico,D?mling, Alexander
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supporting information
p. 3195 - 3198
(2017/06/23)
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- Peptide Weinreb amide derivatives as thioester precursors for native chemical ligation
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Peptide Weinreb amide derivatives with an N-substituted mercaptoethyl group are designed as thioester precursors for native chemical ligation. We show that these amides undergo rapid ligation with a cysteinyl peptide under normal NCL conditions to form various Xaa-Cys peptide bonds, including the difficult Val-Cys junction. Facile synthesis of the Weinreb amide linkers allows easy access to this new type of peptide thioester precursor by standard Fmoc solid phase synthesis.
- Rao, Chang,Liu, Chuan-Fa
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p. 2491 - 2496
(2017/04/03)
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- Tandem thiol switch synthesis of peptide thioesters via N-S acyl shift on thiazolidine
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An efficient "thiol switch" approach for the synthesis of peptide thioesters via an acid-catalyzed N-S acyl shift and a thioester exchange reaction in tandem with concurrent removal of protecting groups is described. This method employs novel 2-(thiomethyl)thiazolidine (TMT)-anchored resins and is fully compatible with Fmoc chemistry.
- Sharma, Rohit K.,Tam, James P.
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supporting information; experimental part
p. 5176 - 5179
(2011/12/15)
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- Peptide ligation assisted by an auxiliary attached to amidyl nitrogen
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New thiol-containing auxiliaries were developed for peptide ligation. They were placed at the amidyl N-atom in the second amino acid residue of a peptide fragment. With the new auxiliaries, peptide ligation could be conducted at non-Cys and non-Gly sites. Compared to other recently developed auxiliaries, an important feature of the present design was that the new auxiliaries were generally applicable and readily removable.
- Li, Juan,Cui, Hong-Kui,Liu, Lei
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scheme or table
p. 1793 - 1796
(2010/06/13)
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