Bernhard Westermann

Traceless tosylhydrazone-based triazole formation: a metal-free alternative to strain-promoted azide-alkyne cycloaddition.

The unprecedented impact of the Cu-mediated Huisgen cycloaddition reaction is demonstrated by its manifold applications in the life sciences and material sciences. 2] The requirement of a metal catalyst, however, has limited the utilization of this cycloaddition reaction in areas such as photophysical chemistry and chemical biology. Consequently, several metal-free processes have been developed to serve as orthogonal ligation methods. At present the foremost method is the strain-promoted azide–alkyne cycloaddition (SPAAC) as is reflected by the fast growing number of cyclooctyne derivatives developed by the groups of Bertozzi, Boons, Rutjes, and van Delft (Table 1). In addition to SPAAC, SPANC, and SPANOC, several other metal-free click methods relying on cycloaddition reactions with alkenes have received considerable attention. Disadvantages of these strategies are: 1) the formation of equimolar quantities of the 1,4 and 1,5 regioisomers; and 2) the requirement of functional handles on both substrates, for example, an activated double or triple bond and the appropriate complementary counterpart. To reduce the synthetic efforts, one of the functionalities should be readily available, that is, inherent to a large variety of starting materials, so that it can be used without further manipulation in a click-type reaction. In 1986 Sakai et al. described such a reaction for the elegant formation of triazoles and thiadiazoles. The Sakai approach relies on the condensation of a primary amine and an a,a-dichlorotosylhydrazone (1) to form regioselectively a 1,4-substituted triazole (3) under ambient reaction conditions (Scheme 1). As a result of the highly chemoselective character of this reaction, protecting group strategies, in principal, seem to be unnecessary. Surprisingly, this elegant and mild protocol for the formation of stable 1,2,3-triazoles has found only infrequent applications. Despite the evident potential of this reaction, it has not been fully exploited; that is, neither the mechanism nor the scope and limitations have been explored. Here we report our findings concerning the Sakai triazole formation reaction and demonstrate the suitability of this methodology as a strategy for metal-free triazole conjugation and an alternative to the traditional azide–alkyne cycloaddition. For the identification of the scope and limitations of the Sakai reaction, two a,a-dichlorotosylhydrazones (1a and 1b) were prepared and reacted with a variety of primary amines (2a–j). The reactions were performed either in a solvent mixture of acetonitrile and ethanol (1:1 v/v%) or in methanol, in the presence of six equivalents of N,Ndiisopropylethylamine (DiPEA). These simple reaction conTable 1: Cyclooctyne-based probes for metal-free triazole formation.

Highly Stereoselective Synthesis of Natural‐Product‐Like Hybrids by an Organocatalytic/Multicomponent Reaction Sequence

In an endeavor to provide an efficient route to natural product hybrids, described herein is an efficient, highly stereoselective, one-pot process comprising an organocatalytic conjugate addition of 1,3-dicarbonyls to α,β-unsaturated aldehydes followed by an intramolecular isocyanide-based multicomponent reaction. This approach enables the rapid assembly of complex natural product hybrids including up to four different molecular fragments, such as hydroquinolinone, chromene, piperidine, peptide, lipid, and glycoside moieties. The strategy combines the stereocontrol of organocatalysis with the diversity-generating character of multicomponent reactions, thus leading to structurally unique peptidomimetics integrating heterocyclic, lipidic, and sugar moieties.

Cation-π and π-π stacking interactions allow selective inhibition of butyrylcholinesterase by modified quinine and cinchonidine alkaloids.

Scaffold varied quaternized quinine and cinchonidine alkaloid derivatives were evaluated for their selective butyrylcholinesterase (BChE) inhibitory potential. K(i) values were between 0.4-260.5μM (non-competitive inhibition) while corresponding K(i)values to acetylcholinesterase (AChE) ranged from 7.0-400μM exhibiting a 250-fold selectivity for BChE. Docking arrangements (GOLD, PLANT) revealed that the extended aromatic moieties and the quaternized nitrogen of the inhibitors were responsible for specific π-π stacking and π-cation interactions with the choline binding site and the peripheral anionic site of BChEs active site.

CuAAC-mediated diversification of aminoglycoside-arginine conjugate mimics by non-reducing di- and trisaccharides

Di- and triguanidinylation of trehalose, sucrose, and melizitose has been achieved via a Huisgen-cycloaddition approach. They can serve as aminoglycoside-arginine conjugate mimics, which has been demonstrated by their biological profiles in assays against Bacillus subtilis. For comparative studies, tetraguanidinylated neamine and kanamycin derivatives have also been synthesized and evaluated.

Spin-labelled diketopiperazines and peptide–peptoid chimera by Ugi-multi-component-reactions

For the first time, spin-labelled coumpounds have been obtained by isonitrile-based multi component reactions (IMCRs). The typical IMCR Ugi-protocols offer a simple experimental setup allowing structural variety by which labelled diketopiperazines (DKPs) and peptide-peptoid chimera have been synthesized. The reaction keeps the paramagnetic spin label intact and offers a simple and versatile route to a large variety of new and chemically diverse spin labels.

Diversity Driven Decoration and Ligation of Fullerene by Ugi and Passerini Multicomponent Reactions

Aiming at providing an efficient and versatile method for the diversity-oriented decoration and ligation of fullerenes, we report the first C60 derivatization strategy based on isocyanide-multicomponent reactions (I-MCRs). The approach comprises the use of Passerini and Ugi reactions for assembling pseudo-peptidic scaffolds (i.e., N-alkylated and depsipeptides, peptoids) on carboxylic acid-functionalized fullerenes. The method showed wide substrate scope for the oxo and isocyanide components, albeit the Ugi reaction proved efficient only for aromatic amines. The approach was successfully employed for the ligation of oligopeptides and polyethyleneglycol chains (PEG) to C60 , as well as for the construction of bis-antennary as well as PEG-tethered dimeric fullerenes. The quantum yields for the formation of 1 O2 was remarkable for the selected compounds analyzed.