Exploring the binding of peptidic West Nile virus NS2B-NS3 protease inhibitors by NMR.

West Nile virus (WNV) NS2B-NS3 protease is an important drug target since it is an essential protein for the replication of the virus. In order to determine the minimum pharmacophore for protease inhibition, a series of dipeptide aldehydes were synthesized. The 50% inhibitory concentration (IC(50)) measurements revealed that a simple acetyl-KR-aldehyde was only threefold less active than 4-phenyl-phenylacetyl-KKR-aldehyde (1) (Stoermer et al., 2008) that was used as the reference compound. The ligand efficiency of 0.40 kcal/mol/HA (HA=heavy atom) for acetyl-KR-aldehyde is much improved compared to the reference compound 1 (0.23 kcal/mol/HA). The binding of the inhibitors was examined using (1)H-(15)N-HSQC experiments and differential chemical shifts were used to map the ligand binding sites. The biophysical studies show that the conformational mobility of WNV protease has a major impact on the design of novel inhibitors, since the protein conformation changes profoundly depending on the structure of the bound ligand.

Total synthesis of echinopines A and B: exploiting a bioinspired late-stage intramolecular cyclopropanation.

Total synthesis of echinopine A and B have been accomplished, based on a strategy that involved two transition-metal-mediated ene-yne cycloisomerizations. A modified Pd-catalyzed enyne cycloisomerization/intramolecular Diels-Alder cascade rendered a more streamlined synthesis of tricyclic ketone 15, and a Ru-catalyzed ene-yne cycloisomerization/cyclopropanation resembled the late-stage [5/7] → [3/5/5/7] ring-forming sequence in the proposed biosynthetic pathway.

One-pot procedure for the synthesis of unsymmetrical diarylalkynes.

Unsymmetrical diarylalkynes are accessible by a one-pot procedure from two different aryl halides and (trimethylsilyl)acetylene. The three-component coupling is initialized by a Pd/Cu-catalyzed Sonogashira coupling of an aryl halide with (trimethylsilyl)acetylene. After subsequent desilylation of the formed aryl(trimethylsilyl)acetylene with aqueous potassium hydroxide, a second Sonogashira coupling with an aryl iodide that does not require any additional Pd/Cu-catalyst gives access to an unsymmetrical diarylalkyne.

The catalytic hydroamination of alkynes.

Catalytic additions of ammonia or primary and secondary amines to non-activated alkenes and alkynes are called hydroaminations. These reactions of fundamental simplicity represent the most atom efficient processes for the formation of amines, enamines and imines, which are important bulk and fine chemicals or building blocks in organic synthesis. Consequently, the development of corresponding hydroamination reactions has received much attention and great progress has been achieved in the case of catalytic hydroaminations of alkynes over the past four years. To illustrate this progress, this tutorial review will mostly focus on recent developments in the field of intermolecular hydroamination of alkynes that appeared in the literature between the end of 2002 and October 31, 2006.