Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols

The chirality, or ‘handedness’, of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug candidate for biological evaluation. Despite many advances in asymmetric synthesis, developing general and practical strategies for obtaining all possible stereoisomers of an organic compound that has multiple contiguous stereocentres remains a challenge3. Here, we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastereo- and enantioselectivity. Specifically, we synthesized these amino-alcohol products using sequential, copper-hydride-catalysed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of the amino-alcohol products, which contain up to three contiguous stereocentres. We leveraged catalyst control and stereospecificity simultaneously to attain exceptional control of the product stereochemistry. Beyond the immediate utility of this protocol, our strategy could inspire the development of methods that provide complete sets of stereoisomers for other valuable synthetic targets.National Institutes of Health (U.S.) (Grant GM-58160

Metal-templated chiral Brønsted base organocatalysis

Inert octahedral chiral-at-metal complexes are an emerging class of asymmetric catalysts that exploit the globular, rigid nature and stereochemical options of octahedral compounds. While the central transition metal serves as a structural anchorpoint and provides metal centrochirality, catalysis is mediated through the organic ligand sphere, thereby merging the branches of transition metal catalysis and organocatalysis. Here we report the development of inert octahedral 3-aminopyrazolato iridium(III) complexes as novel chiral Brønsted base catalysts and demonstrate their merit with applications to highly effective asymmetric sulfa-Michael and aza-Henry reactions, permitting catalyst loadings down to 0.02 and 0.25 mol, respectively. The observed high stereocontrol can be rationalized by a bifunctional mode of action in which the iridium catalyst, after the initial proton transfer, controls a ternary complex through defined hydrogen bonding interactions. This work reveals the potential of octahedral metal complexes as chiral scaffolds for the design of high-performance asymmetric catalysts. © 2014 Macmillan Publishers Limited