Proline-catalysed Mannich reactions of acetaldehyde

Small organic molecules recently emerged as a third class of broadly useful asymmetric catalysts that direct reactions to yield predominantly one chiral product, complementing enzymes and metal complexes. For instance, the amino acid proline and its derivatives are useful for the catalytic activation of carbonyl compounds via nucleophilic enamine intermediates. Several important carbon-carbon bond-forming reactions, including the Mannich reaction, have been developed using this approach, all of which are useful for making chiral, biologically relevant compounds. Remarkably, despite attempts, the simplest of all nucleophiles, acetaldehyde, could not be used in this way. Here we show that acetaldehyde is a powerful nucleophile in asymmetric, proline-catalysed Mannich reactions with N-tert-butoxycarbonyl (N-Boc)-imines, yielding beta-amino aldehydes with extremely high enantioselectivities-desirable products as drug intermediates and in the synthesis of other biologically active molecules. Although acetaldehyde has been used as a nucleophile in reactions with biological catalysts such as aldolases and thiamine-dependent enzymes, and has also been employed indirectly, its use as an inexpensive and versatile two-carbon nucleophile in asymmetric, small-molecule catalysis will find many practical applications.     

Asymmetric spiroacetalization catalysed by confined Brønsted acids

Acetals are molecular substructures that contain two oxygen-carbon single bonds at the same carbon atom, and are used in cells to construct carbohydrates and numerous other molecules. A distinctive subgroup are spiroacetals, acetals joining two rings, which occur in a broad range of biologically active compounds, including small insect pheromones and more complex macrocycles. Despite numerous methods for the catalytic asymmetric formation of other commonly occurring stereocentres, there are few approaches that exclusively target the chiral acetal centre and none for spiroacetals. Here we report the design and synthesis of confined Br?nsted acids based on a C(2)-symmetric imidodiphosphoric acid motif, enabling a catalytic enantioselective spiroacetalization reaction. These rationally constructed Br?nsted acids possess an extremely sterically demanding chiral microenvironment, with a single catalytically relevant and geometrically constrained bifunctional active site. Our catalyst design is expected to be of broad utility in catalytic asymmetric reactions involving small and structurally or functionally unbiased substrates.     

Phagocyte-derived catecholamines enhance acute inflammatory injury

It is becoming increasingly clear that the autonomic nervous system and the immune system demonstrate cross-talk during inflammation by means of sympathetic and parasympathetic pathways. We investigated whether phagocytes are capable of de novo production of catecholamines, suggesting an autocrine/paracrine self-regulatory mechanism by catecholamines during inflammation, as has been described for lymphocytes. Here we show that exposure of phagocytes to lipopolysaccharide led to a release of catecholamines and an induction of catecholamine-generating and degrading enzymes, indicating the presence of the complete intracellular machinery for the generation, release and inactivation of catecholamines. To assess the importance of these findings in vivo, we chose two models of acute lung injury. Blockade of alpha2-adrenoreceptors or catecholamine-generating enzymes greatly suppressed lung inflammation, whereas the opposite was the case either for an alpha2-adrenoreceptor agonist or for inhibition of catecholamine-degrading enzymes. We were able to exclude T cells or sympathetic nerve endings as sources of the injury-modulating catecholamines. Our studies identify phagocytes as a new source of catecholamines, which enhance the inflammatory response.