Although peptide chemistry has made great progress, the frequent occurrence of aspartimide formation during peptide synthesis remains a formidable challenge. Aspartimide formation leads to low yields in addition to costly purification or even inaccessible peptide sequences. Here, we report an alternative approach to address this longstanding challenge of peptide synthesis by utilizing cyanosulfurylides to mask carboxylic acids by a stable CC bond. These functional groups-formally zwitterionic species-are exceptionally stable to all common manipulations and impart improved solubility during synthesis. Deprotection is readily and rapidly achieved under aqueous conditions with electrophilic halogenating agents via a highly selective CC bond cleavage reaction. This protecting group is employed for the synthesis of a range of peptides and proteins including teduglutide, ubiquitin, and the low-density lipoprotein class A. This protecting group strategy has the potential to overcome one of the most difficult aspects of modern peptide chemistry.
a-Ketoacid-hydroxylamine (KAHA) ligation allows the coupling of unprotected peptide segments through the chemoselective formation of an amide bond. Currently,t he most widely used variant employs a5 -membered cyclic hydroxylamine that forms ah omoserine ester as the primary ligation product. In order to directly form amide-linked threonine residues at the ligation site,w ep repared an ew 4membered cyclic hydroxylamine building block. This monomer was applied to the synthesis of wild-type ubiquitinconjugating enzyme UbcH5a (146 residues) and Titin protein domain TI I27 (89 residues). Both the resulting UbcH5a and the variant with two homoserine residues showed identical activity to ar ecombinant variant in aubiquitination assay.
A short stereoselective synthesis of the Elisabethin A skeleton 4 is described, which opens a formal access to the diterpenes Elisapterosin B and Colombiasin A as well. Key reactions were an intermolecular endo-selective Diels-Alder reaction to generate the decalin part of the molecule, a chemo- and diastereoselective allylation of an aldehyde with allylzinc, a palladium ene annulation of the cyclopentane ring, and a novel sulfonium ylide induced fragmentation of a polycyclic ketone. Additional insights have been gained for the crucial epimerization at C-2.
The
α-ketoacid-hydroxylamine (KAHA) ligation allows
the coupling
of unprotected peptide segments. Currently, the most applied hydroxylamine
is the 5-membered cyclic hydroxylamine (S)-5-oxaproline,
which forms a homoserine ester as the primary ligation product. In
order to access native aspartic acid residues at the ligation site,
we synthesized a 4,4-difluoro version of this monomer. Upon KAHA ligation,
the resulting difluoro alcohol hydrolyzes to an aspartic acid residue
with little or no formation of aspartamide. We applied this monomer
for the synthesis of the hormone peptides glucagon and an insulin
variant, and as well for segment ligation of the peptides UbcH5a and
SUMO3.
Die Ligation von α‐Ketosäure‐Hydroxylamin (KAHA) erlaubt die chemoselektive Verknüpfung von ungeschützten Peptidsegmenten unter Bildung einer Amidbindung. Die zurzeit meistgenutzte Variante basiert auf einem fünfgliedrigen cyclischen Hydroxylamin, welches einen Homoserinester als Hauptligationsprodukt bildet. Ein neues viergliedriges cyclisches Hydroxylamin wurde synthetisiert, um die natürliche Aminosäure Threonin an der Ligationsstelle bildet. Dieses Monomer wurde für die Synthese der Proteine UbcH5a (146 Aminosäuren) und TI I27 (89 Aminosäuren) eingesetzt. Sowohl das so synthetisierte UbcH5a als auch die Variante, die unter Verwendung des fünfgliedrigen zyklischen Hydroxylamins synthetisiert wurde, zeigten identische Aktivitäten gegenüber der rekombinanten Variante in einem Ubiquitinierungs‐Assay.
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