A Pro-Fluorescent Ubiquitin-Based Probe to Monitor Cysteine-Based E3 Ligase Activity.

Protein post-translational modification with ubiquitin (Ub) is a versatile signal regulating almost all aspects of cell biology, and an increasing range of diseases is associated with impaired Ub modification. In this light, the Ub system offers an attractive, yet underexplored route to the development of novel targeted treatments. A promising strategy for small molecule intervention is posed by the final components of the enzymatic ubiquitination cascade, E3 ligases, as they determine the specificity of the protein ubiquitination pathway.

Synthesis of N-Protected Amino Sulfenyl Methyl Formamides and Sulfonyl Methyl Formamides: A Simple Protocol.

Chiral amino acid-derived formamides represent one of the most versatile components in multicomponent reactions. Herein, we describe a facile synthesis of N-protected amino sulfenyl methyl formamides and sulfonyl methyl formamides the Mannich reaction of N-protected amino alkyl thiols followed by oxidation using 3-chloroperbenzoic acid (-CPBA). This protocol is applicable to a wide range of Fmoc- and Cbz-protected amino acids.

Tubulysin Synthesis Featuring Stereoselective Catalysis and Highly Convergent Multicomponent Assembly.

A concise and modular total synthesis of the highly potent N-desacetoxytubulysin H () has been accomplished in 18 steps in an overall yield of up to 30%. Our work highlights the complexity-augmenting and route-shortening power of diastereoselective multicomponent reaction (MCR) as well as the role of bulky ligands to perfectly control both the regioselective and diastereoselective synthesis of tubuphenylalanine in just two steps. The total synthesis not only provides an operationally simple and step economy but will also stimulate major advances in the development of new tubulysin analogues.

Cysteine Isocyanide in Multicomponent Reaction: Synthesis of Peptido-Mimetic 1,3-Azoles.

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.

Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics.

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.