Chem Soc Rev View Article Online REVIEW ARTICLE View Journal New advances in dual stereocontrol for Cite this: DOI: 10.1039/c3cs60068h asymmetric reactions Jorge Escorihuela,a M. Isabel Burgueteb and Santiago V. Luis*b Received 19th February 2013 Achieving dual stereocontrol in asymmetric reactions using a single enantiomer for the building of the DOI: 10.1039/c3cs60068h chiral catalyst or auxiliary is a very important goal in enantioselective synthesis as it eliminates the need for having available the two enantiomers of the auxiliary or catalyst designed. Recent strategies and www.rsc.org/csr advances towards this goal during the last four years will be discussed throughout this review. Introduction compounds, one enantiomer may exhibit favourable physio- logical activity, while the other may have no activity, inhibit Chirality represents an important phenomenon in chemical favourable physiological activity or, in some cases, exhibit sciences and in particular in the area of asymmetric synthesis, undesirable physiological properties. For example, the enantiomers in which the production and analysis of chiral molecules of chiral drugs such as omeprazole, ibuprofen and DOPA have been the subject of extensive and on-going research.1 A exhibit different pharmacological and pharmacokinetic activities wide variety of compounds exhibiting physiological activity, because their activity is based on the interaction with enzymes such as drugs, pesticides, and flavourings, are chiral. In those and receptors consisting of amino acids and other chiral biomolecules.2 In this regard, consideration of chirality is now an integral part of drug research and development and a Centro de Reconocimiento Molecular y Desarrollo Tecnolo´gico, the associated regulatory processes. Advances in chemical Departamento de Quı´mica, Universitat Polite´cnica de Vale`ncia, Camino de Vera s/n, 46022 Valencia, Spain technologies connected with the synthesis, separation, and Downloaded by Georgetown University Library on 21/04/2013 21:25:34. b Published on 16 April 2013 http://pubs.rsc.org | doi:10.1039/C3CS60068H Department of Inorganic and Organic Chemistry, Universitat Jaume I, analysis of pure enantiomers, together with administrative 12070 Castello´n, Spain. E-mail: [email protected] regulatory measures, have resulted in an increase in the number Jorge Escorihuela was born in M. Isabel Burguete graduated in 1979 in Castello´n, Spain. He Chemistry at the University of graduated in Chemistry in 2003 Zaragoza in Spain and after a at the Jaume I University of stay at the University of Castello´n (Spain) and received a Pittsburgh (USA) under the grant from the Spain Ministry of supervision of Dr J. Rebek, she Education to pursue his PhD completed her PhD at the under the supervision of University of Valencia in 1989 Santiago V. Luis and M. Isabel under the direction of Dr F. Burguete. He received his PhD in Gavin˜a working on regulated Green Chemistry in 2009. His crown ethers and convergent doctoral research was focused on diacids. In 1989 she took an Jorge Escorihuela developing new chiral catalysts M. Isabel Burguete academic appointment at the derived from amino acids and University Jaume I in Castello´n their application in asymmetric reactions. After completing his (Spain) where she is currently Professor of Organic Chemistry. Her PhD, he joined Prof. Angel Maquieira’s group at Universitat main field of research is the development of new tools, in particular Polite´cnica de Vale`ncia as a research scientist in 2010. His homogeneous and supported catalysis approaches, in green and research interest is centred on the design of biosensors in silicon- sustainable chemistry. based materials and DNA microarrays. This journal is c The Royal Society of Chemistry 2013 Chem. Soc. Rev. View Article Online Review Article Chem Soc Rev of newly registered chiral drugs containing only one of the attention has been paid to study the induction of both enantio- enantiomers. Therefore, the development of methods that can selectivities using a single chiral source by changing the reaction selectively produce each one of the enantiomers of a compound conditions. This chirality switching can be achieved in different with high enantiomeric excess is very important.3,4 ways, most often using different Lewis acids coordinated to Development of novel chiral ligands for an efficient asym- the chiral ligand, by modification of the solvent system or by metric transformation has become increasingly important in introducing structural features that modify the catalytic mecha- current asymmetric catalysis.5–7 Among the different types of nism or the structure of the catalytic site.12–15 chemical methods used to obtain optically active compounds, In many cases, experimental observations of this dual stereo- asymmetric catalysis is very attractive because it easily produces control are still an unknown phenomenon and the sense of the desired enantiomer from a minimal amount of chiral enantioselectivity cannot be rationalized. On the other hand, the source.8 From a practical point of view, this methodology is design of effective catalytic asymmetric methods to induce a often limited by the need for being able to obtain both switch in the enantioselectivity of a reaction still remains a enantiomeric products in pure form through the corresponding significant challenge.16 catalytic asymmetric transformations. This condition was tradition- ally fulfilled through the preparation of the two enantiomers of Dual stereocontrol using changes in catalyst substituents the chiral catalyst. However, many natural chiral sources are available in only one absolute configuration. The other enantiomer, The development of efficient synthetic chiral catalysts, includ- which is naturally rare, requires resolution or complicated ing chiral metal complex catalysts and chiral organocatalysts, is synthetic procedures. Therefore, it would be desirable to have at the center of research in asymmetric catalysis. In the first in hand available synthetic methodologies to obtain both case, one of the key parameters influencing the efficiency and enantiomers of a product using reagents from a single chiral asymmetric inductions observed is the structure of the chiral source, allowing a dual stereocontrol in the reaction under ligand. The chiral ligand modifies the reactivity and selectivity study through manipulation of the reaction conditions or the of the metal center in such a way that one of two possible non-chiral components of the catalyst.9 enantiomeric products is formed preferentially. A crucial current objective is the design and synthesis of new chiral catalysts, which Dual stereocontrol enable challenging and/or previously unknown asymmetric Since the report by Mosher and co-workers in 1972 on the transformations to occur highly efficiently and, if possible, in asymmetric reduction of unsymmetrical ketones with stoichio- a predictable way. Until recently, strategies for controlling enantio- metric chiral alkoxyaluminium hydrides,10,11 several metal- selectivity in metal-catalysed asymmetric reactions have depended based methodologies for enantiodivergent catalysis, in which largely on the design and application of chiral ligands that would the ligand, the central metal and the reaction conditions can be provide optimum steric or electronic interactions between the 17–22 tuned for this purpose, have been studied. Recently much catalyst and the substrate at the transition state. In 2008, Zhang and co-workers reported a reversal of enantio- Downloaded by Georgetown University Library on 21/04/2013 21:25:34. selectivity for the palladium-catalysed asymmetric allylic sub- Published on 16 April 2013 http://pubs.rsc.org | doi:10.1039/C3CS60068H Santiago V. Luis carried out his stitution with metallocene-based planar chiral diphosphine studies in Chemistry at the ligands just by modification of the substituents adjacent to the 23 University of Zaragoza in Spain diphenylphosphine group on the Cp rings. They found that and completed his PhD at the ligands with ester moieties adjacent to the diphenylphosphine University of Valencia in Spain group gave excellent enantioselectivity (99% ee, S-configuration) in 1983 working on mechanistic in this reaction. When a ligand with hydroxyl groups was used, studies with Dr F. Gavin˜a. After a high catalytic activity and moderate enantioselectivity were postdoctoral work at the Univer- obtained. However, in this case, the major isomer was shown sity of Pittsburgh (USA) under the to have the opposite R-configuration (Scheme 1). supervision of Dr J. Rebek, in the A dramatic switch of enantioselectivity was found by Hou, area of supramolecular chemistry, Wu and co-workers in the asymmetric Heck reaction controlled by 24 he obtained an academic appoint- benzylic substituents of P,N-ligands. These authors observed that the corresponding palladium complexes showed high catalytic Santiago V. Luis ment at the University Jaume I in Castello´n (Spain) where he is currently Professor of Organic Chemistry and Head of the research group in supramolecular and sustainable chemistry. His main areas of research involve supramolecular and biomimetic chemistry, in particular involving pseudopeptidic structures, and developing new tools from a sustainable and green chemistry perspective, with a special emphasis on catalysis and flow chemistry. For the last decade he has been coordinating the Spanish MSc and PhD Interuniversity Scheme 1 Reversal of enantioselectivity in the asymmetric allylic amination of Programs