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Chem Soc Rev Chem Soc Rev View Article Online TUTORIAL REVIEW View Journal | View Issue Recent advances in enzymatic and chemical Cite this: Chem. Soc. Rev., 2013, deracemisation of racemic compounds 42, 9268 Michał Rachwalski,*ab Niek Vermuea and Floris P. J. T. Rutjes*a Deracemisation of racemic compounds is still the most important strategy to produce optically pure compounds despite many recent advances in asymmetric synthesis. Especially deracemisation approaches that give rise to single enantiomers are preferred, which can be achieved either by invoking Received 30th May 2013 organocatalysts, metal complexes or enzymes – leading to dynamic kinetic resolution – or by applying DOI: 10.1039/c3cs60175g other deracemisation techniques based on stereoinversion or enantioconvergence. In this tutorial review, we will provide an overview of new, recently developed approaches that lead to the important www.rsc.org/csr goal of creating organic compounds of single chirality. Creative Commons Attribution 3.0 Unported Licence. Key learning points This tutorial review will: (1) Explain the importance of deracemisation (2) Introduce various strategies for deracemisation (3) Provide clear explanations of the mechanisms of deracemisation (4) Provide an overview of recent developments and state-of-the-art practical application of newly developed techniques (5) Offer a broader view on the general importance of chirality in (synthetic organic) chemistry This article is licensed under a 1 Introduction two enantiomers – commonly known as resolution – has been the most prominent way to separate two enantiomers in The synthesis of enantiomerically pure compounds remains a numerous applications. This resolution is often performed Open Access Article. Published on 24 September 2013. Downloaded 9/27/2021 11:56:55 PM. challenge in modern organic chemistry due to the importance of through addition of an enantiopure (auxiliary) reagent leading chirality in biological processes. The majority of biomolecules to the preferred formation of one diastereoisomer over the existing in living organisms are chiral and consist of only one of other, which on the basis of different physical properties can the two possible enantiomeric forms. As a result, molecular then be separated. Removal of the auxiliary compound produces the interactions of a racemic substrate with these biomolecules will desired enantiopure product. Another commonly used technique is always be different for one enantiomer than the other. This plays treatment of a racemate with an enzyme, which recognizes one a particularly important role in the pharmaceutical industry, but enantiomer and converts it into a different product, while the other also in other industrial sectors such as the food, and flavour and enantiomer remains untouched. At this point, the two enantiomeric fragrance industries. As a result, it is crucial for those industries forms have different physical properties and can be readily to produce many of their products (e.g. drugs, food additives, separated. These kinetic resolutions can be carried out in small vitamins) as single enantiomers. scale laboratory experiments, but also in large scale industrial The first person being able to separate a racemic mixture processes. The limitation of such types of ‘classic’ kinetic into the two enantiomers was Louis Pasteur, who as early as in resolutions (KR), however, is that both enantiomers can only 1849 physically separated tartaric acid crystals of opposite be obtained in a maximum theoretical yield of 50%. The wish of handedness. Ever since, the separation of a racemate into its the chemical industry to reduce costs and waste in the produc- tion of chiral building blocks led chemists to develop novel a Radboud University Nijmegen, Institute for Molecules and Materials, resolution procedures of racemic mixtures that proceed beyond Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands. the 50% yield. This is called deracemisation, which is defined as E-mail: [email protected]; Fax: +31 24 365 3393; Tel: +31 24 365 3202 b University of Ło´dz´, Faculty of Chemistry, Department of Organic and Applied the conversion of a racemate into one of the corresponding Chemistry, Tamka 12, 91-403 Ło´dz´, Poland. E-mail: [email protected]; enantiomers in theoretically 100% chemical yield and 100% Fax: +48 042 665 5162; Tel: +48 042 635 5767 optical purity without isolation of intermediates. 9268 Chem.Soc.Rev.,2013, 42, 9268--9282 This journal is c The Royal Society of Chemistry 2013 View Article Online Tutorial Review Chem Soc Rev The existing different deracemisation techniques have been classified by the mechanism of action as proposed by Faber (Scheme 1).1 Inspired by the fact that deracemisation strategies continue to be discovered, we herewith provide an overview of deracemisation methods, based on the classification by Faber, with a strong focus on new and innovative approaches that have appeared in recent literature. 2 Dynamic kinetic resolution (DKR) Dynamic kinetic resolution (DKR) is the most widely used technique for deracemisation. It is a combination of ‘classic’ kinetic resolution, in which a racemate (SS and SR) is resolved by chemical transformation of one single enantiomer into a product (PR), with in situ racemisation of the ‘unwanted’ enantiomer (SS) of the starting material (Scheme 1). Many examples have been revealed combining metal-catalysed Dr Michał Rachwalski (1979, Scheme 1 Deracemisation mechanisms proposed by Faber. Cze˛stochowa, PL) received his PhD at the Centre of Molecular Creative Commons Attribution 3.0 Unported Licence. and Macromolecular Studies, racemisation with enzymatic kinetic resolution. Since such Polish Academy of Sciences in chemoenzymatic DKRs have already been extensively reviewed,2,3 Ło´dz´ (PL) under the supervision in this review, we will focus on DKR processes employing either of Prof. Piotr Kiełbasin´ski in organocatalysis, transition metal catalysis or enzymatic transforma- 2008. In 2012 he did his post- tions. DKR of atropoisomers and so-called attrition-enhanced doc with Prof. F. Rutjes (Radboud deracemisation will be also discussed. University Nijmegen, NL). Presently, he is assistant professor at the University of 2.1 Organocatalysed DKR This article is licensed under a Michał Rachwalski Ło´dz´ (PL). His research interests Organocatalysis has gained much interest from organic chemists include the synthesis and in recent years. Catalysis proceeds without metals using small application of chiral ligands in asymmetric synthesis, the use of organic molecules instead, thereby contributing to the sustainable enzymes in organic synthesis and the chemistry of aziridines. (green) nature of the given conversions. Not unimportantly, the Open Access Article. Published on 24 September 2013. Downloaded 9/27/2021 11:56:55 PM. Niek Vermue (1986, Oostburg, Prof. Floris Rutjes (1966, Heiloo, NL) studies chemistry at NL) received his PhD at the Radboud University Nijmegen, University of Amsterdam (NL) where he obtained his BSc in under the supervision of Prof. 2010. Currently studying to Nico Speckamp in 1993. He then obtain his MSc degree, he did did his post-doc with Prof. K. C. internships in both the synthetic Nicolaou (The Scripps Research organic chemistry group of Prof. Institute, La Jolla, USA) resulting Floris Rutjes, where he focussed in a total synthesis of brevetoxin on the synthesis of chiral B. In 1995, he became assistant heterocycles via the asymmetric professor at the University of Mannich reaction, and the Amsterdam and in 1999 full Niek Vermue bioorganic chemistry group of Floris P. J. T. Rutjes professor in synthetic organic Prof. Jan van Hest, working on chemistry at Radboud University biohybrid nanoparticles for drug- Nijmegen. His research interests include the application of delivery. asymmetric catalysis (bio-, transition metal- and organocatalysis) in the synthesis of biologically relevant molecules and synthesis of new molecular diagnostic tools for application in life sciences and flow chemistry. This journal is c The Royal Society of Chemistry 2013 Chem. Soc. Rev., 2013, 42, 9268--9282 9269 View Article Online Chem Soc Rev Tutorial Review Scheme 2 DKR of azlactones via BTM catalysis. small chiral molecules that are generally employed as organo- catalysts are often readily available at relatively low cost. Scheme 3 DKR of azlactones via Brønsted acid catalysis. In recent years the group of Birman reported several examples of DKR catalysed by small organic molecules. In 2010, they disclosed the use of benzotetramisole (BTM) as an enantio- group led to substantial improvement in ee (77% with R = Bn) selective acyl transfer catalyst in the DKR of azlactones.4 In initial (Scheme 3). Creative Commons Attribution 3.0 Unported Licence. experiments, different amidine-based catalysts were screened in The effect of the structure of the alcohol on enantioselectivity the alcoholysis of compound 1 (R = Me) using an equimolar was also examined. After screening, 1-naphthylmethanol (8)and proportion of catalyst and benzoic acid. Benzoic acid appeared to 1-pyrenylmethanol (9) were selected as being optimal leading to be an essential promotor in this reaction, since no conversion was 90% conversion, 100% ee and 91% conversion, 90% ee, respec- observed in its absence. The best results in terms of conversion tively. DKR of substituted 4-aryl azlactones under optimized and ee were obtained using (S)-BTM 3 as the catalyst (Scheme 2). conditions yielded the corresponding substituted a-arylglycine Under these slightly
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