166169-08-0Relevant articles and documents
Features of Auxiliaries That Enable Native Chemical Ligation beyond Glycine and Cleavage via Radical Fragmentation
Loibl, Simon F.,Dallmann, Andre,Hennig, Kathleen,Juds, Carmen,Seitz, Oliver
, p. 3623 - 3633 (2018/02/16)
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.
Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics
Vishwanatha, Thimmalapura M.,Bergamaschi, Enrico,D?mling, Alexander
supporting information, p. 3195 - 3198 (2017/06/23)
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.
Tandem thiol switch synthesis of peptide thioesters via N-S acyl shift on thiazolidine
Sharma, Rohit K.,Tam, James P.
supporting information; experimental part, p. 5176 - 5179 (2011/12/15)
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.
