April 18, 2007
The search for new methods to prepare new chiral compounds has been a hot topic among chemists in both academia and industry for years. A recent trend is to employ small chiral organic molecules as catalysts for asymmetric transformations – a method that had been forgotten for some time – enantioselective organocatalysis.
Scientists from the US, the UK, Italy and Germany discussed the capacities of organocatalysis for developing new syntheses as well as clarifying reaction mechanisms on the scientific symposium „Organocatalysis“, organized by the Schering Stiftung in Berlin, Germany.
The first descriptions of the use of simple organic molecules as catalysts in asymmetric syntheses, date back to the last century. In the early seventies two research teams discovered, independently of each other, asymmetrical synthesis of steroid structures, catalyzed through the amino acid L-proline. One of these teams was part of the research labs of Schering AG in Berlin. Their pioneering contribution made history as the Hajos-Parrish-Eder-Sauer-Wiechert-reaction, being named after the discoverers both at Schering and Roche. However it seems the world was not ready for it yet. The field of organocatalysis only took off some thirty years later. „We had no idea at the time of how important our work was going to be for enantioselective organocatalysis“, says Dr. Ulrich Eder at the ESF-workshop. He and his fellow colleagues of the Schering team, Dr. Gerhard Sauer and Professor Rudolf Wiechert were honorary guests at the symposium. „The zeitgeist back then was a different one“, recalls Eder. „It was trendy to do catalytic synthesis with transition metals or enzymes.“
During his opening lecture Professor Benjamin List from Max-Planck-Institute for Coal Research in Mülheim, Germany, gave an overview over the broad spectrum of enantioselective, organocatalyzed reactions. He presented some of the latest research results and strategies like the concept of asymmetric counteranion-directed catalysis. „Why we organic chemists have mostly been using catalysts that are not from our own discipline is beyond me,“ says Professor List. „Amines and ketones are so familiar and they are easy to handle, cheap and readily available. Thus organocatalysts are so much more attractive compared to biological catalysts like enzymes and inorganic transition metal catalysts. I think that organocatalysts are going to revolutionize asymmetric synthesis.“
Organocatalysts are lower molecular weight, purely organic catalysts that are easy to synthesize, as well as cheap, stable and often non-toxic. They enable reactions in water, at room temperature and under normal atmospheric conditions. They are highly selective and efficient. In cascade reactions with simple organocatalysts several stereo centers can be established in one pot. Hence, organocatalysts have proven their versatility in the synthesis of natural products and biologically active compounds. They are not only attractive for lab research, but, due to their “green” properties and handiness, also suitable for larger scale reactions.
Prof. Yian Shi of Colorado State University, Colorado, USA reported on the first industrial scale use of an organocatalyst for asymmetric epoxidation as well as its 2nd and 3rd generation successors discovered in his lab. The so called „Shi-epoxidation“ is used in a process to access chiral lactones. This reaction type generates epoxides with high enantiomeric excesses from trans-disubstituted and trisubstituted alkenes. Shi and his team could show the great potential of the new, fructose derived chiral ketone D-epoxone. First results of using this method on an industrial scale showed useful enantiomeric excess (ee=88%), high yields, and high chemical purity of the reaction product.
Enantioselective organocatalysts that have already made the transition from lab to industrial production were the topic of the talk given by Professor Harald Gröger from the Institute of Organic Chemistry of the University of Erlangen-Nuremberg, Germany. Companies like F. Hofmann-La Roche AG, Merck, Nagase, Rhodia ChiRex, Firmenich, Bayer AG, Degussa AG and DSM are experimenting with or using organocatalysts on a larger scale already. Using an alkylation reaction as an example, Gröger was able to show how production costs can be cut considerably using organocatalysts. „It is interesting to notice how many new organocatalytic syntheses come from industrial research groups“, says Gröger. „This leaves us thinking that we will have to expect an even greater use of these new syntheses in industrial production in the future.“ Professor Gröger, who has extensive experience in working in the industry, would like to see more co-operations between academic research projects and big chemical companies. „There will never be a timetable that states exactly up to where the academic part will extend and where and when industry should start getting involved“, thinks Gröger. „However cross-checks on a regular basis according to previously agreed criteria are important.“
Professor Thorsten Bach from the Technical University of Munich, Germany is interested in a rather novel area of enantioselective organocatalysis. He and his team were the first to report on radical reactions accelerated by enantioselective organocatalysis. Bach is currently assessing the impact of chiral additives on enantiomeric excess in photochemical reactions. Furthermore he works on immobilizing organocatalysts in order to enable easier recycling of catalysts. „The aim is to eventually work in a continuous flow reactor with immobilized catalysts“, explains Bach. In his talk given in Berlin, he asked to what degree the principles of asymmetric organocatalytic photoreaction might be exploited for the synthesis of complex molecules such as the pentacyclic alkaloid (+)-meloscine. While the current racemic and low -yielding synthesis requires 26 reaction steps, Bach pursues a shorter approach with an enantionselective, organocatalytic step as key step. He is only a few steps away from obtaining the naturally occurring enantiomer (+)-meloscine.
Professor Varinder K. Aggarwal of Bristol University, UK together with his college Professor Kevin Booker-Milburn developed a single pass continuous flow photochemical reactor for synthesizing bicyclic chiral sulfides on a large scale. These chiral sulfides are being used as organocatalysts in the synthesis of complex chiral target structures via sulfure ylide methodology or Morita-Baylis-Hillman-reaction. Apart from developing new synthesis pathways Aggarwal is further interested in shedding light on the mechanical aspects of organocatalysis.
Dr. Maurizio Benaglia of Milan University, Italy and Professor Scott J. Miller of Boston College, Massachusetts, USA both elaborated on another topic of organocatalysis – employing larger molecules. While Benaglia is working on immobilizing organocatalysts on a polyethylene glycol matrix, Miller examines the potentials of peptide catalysts for selective synthesis of complex molecules. The scientific part of the symposium was brought to an end by the talk of Professor Manfred Reetz of the Max-Planck-Institute for Coal Research in Mülheim, Germany, who elaborated on new methods of target-oriented evolution of more selective and stable enzymes. During the final discussion the co-organizer of the symposium Professor Reetz concluded „In science it’s a bit like in soccer: if you don’t train your players properly and more over, if you do not put them in their appropriate positions you won’t get any goals and you won’t succeed as a team.“
„The intensive exchange on the latest developments in the long neglected field of organocatalysis, at this years Schering Stiftung symposium, has shown to us the great potential of this methodology in chemical synthesis.“, concluded Prof. Eckhard Ottow, head of medicinal chemistry of the Berlin Bayer Schering Pharma AG, as he ended the workshop. „I am especially pleased at the fact that so many young scientists from academia have presented their work at this symposium.“ His colleagues and workshop organizers, Dr. Hilmar Weinmann and Dr. Stefan Jaroch agreed and added that the interesting discussions and new impulses gained here will be very useful and inspiring for organocatalytic research.
Dr. Hilmar Weinmann, Dr. Stefan Jaroch, Med. Chemistry 1, Bayer Schering Pharma AG, Berlin, Germany
Prof. Manfred T. Reetz, Dr. Benjamin List, Max Planck Institute for Coal Research, Mühlheim/Ruhr
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