A simple modification of our recently published protection scheme for carboxylic acids as amides resulted in a new protecting group with significantly improved properties. It requires shorter reaction times for deprotection and allows us to replace Cu(OTf)(2) by CuCl(2), indicating at the same time the importance of the nature of the anion of the Cu(2+) source. Since the new scheme fulfills all criteria required for an ideal protection group it should find widespread application in synthetic organic chemistry.

Free choice: Carboxamides of bispicolylamine are alternative protecting groups for carboxylic acids (see scheme). As a consequence of their straightforward applicability, their high chemical stability towards a broad range of conditions, and their selective cleavage under mild conditions to give either carboxylic acids or their methyl esters, this new protection method should find widespread application in the realm of organic synthesis.

Three structurally related relay protecting groups for carboxylic acids that are based on chelating amines have been developed. These protecting groups can easily be introduced by coupling the carboxylic acid and the corresponding amine in the presence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). In addition to being stable to a whole array of reaction conditions, these protecting groups are also stable under acidic and basic conditions, allowing them to be used in combination with the ester protection of carboxylic acids. The cleavage of these protecting groups is activated by the chelation of metal ions, involving an unusual coordination of the amide nitrogen. Despite their similarity, cleavage of these protecting groups is possible in both a stepwise and an orthogonal fashion by applying different metal salts.

We describe a general and versatile approach for the conversion of carboxylic acid amides into their corresponding esters despite the fact that the former are thermodynamically more stable. The transformations are mediated by the coordination of CuI by a chelating entity. The resulting weakening of the amide bond allows for nucleophilic attack by alcoholic hydroxyl functions. The principle is demonstrated for a wide variety of transformations, leading to different kinds of esters and lactones.

Inositol pyrophosphates constitute a family of hyperphosphorylated signaling molecules involved in the regulation of glucose uptake and insulin sensitivity. While our understanding of the biological roles of inositol heptaphosphates (PP-InsP 5 ) has greatly improved, the functions of the inositol octaphosphates ((PP) 2 -InsP 4 ) have remained unclear. Here we present the synthesis of two enantiomeric cell-permeant and photocaged (PP) 2 -InsP 4 derivatives and apply them to study the functions in living β-cells. Photorelease of the naturally occurring isomer 1,5-(PP) 2 -InsP 4 led to an immediate and concentration-dependent reduction of intracellular calcium oscillations, while other caged inositol pyrophosphates (3,5-(PP) 2 -InsP 4 , 5-PP-InsP 5 , 1-PP-InsP 5 , 3-PP-InsP 5 ) showed no immediate effect. Furthermore, uncaging of 1,5-(PP) 2 -InsP 4 but not 3,5-(PP) 2 -InsP 4 induced translocation of the C2AB domain of granuphilin from the plasma membrane to the cytosol. Granuphilin is involved in membrane docking of secretory vesicles. This suggests that 1,5-(PP) 2 -InsP 4 impacts β-cell activity by regulating granule localization and/or priming and calcium signaling in concert.