VU Research Portal Biocatalysis & Multicomponent Reactions: The Ideal Synergy Znabet, A. 2012 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Znabet, A. (2012). Biocatalysis & Multicomponent Reactions: The Ideal Synergy: Asymmetric Synthesis of Substituted Proline Derivatives. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? 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Oct. 2021 Biocatalysis & Multicomponent Reactions: The Ideal Synergy Asymmetric Synthesis of Substituted Proline Derivatives Anass Znabet 2012 This Research was supported by the Netherlands Organisation for Scientific Research (NWO) under project number: 017.004.008 Printed by: Ridderprint BV, Ridderkerk, the Netherlands Lay out: Simone Vinke, Ridderprint BV, Ridderkerk, the Netherlands Cover Design: Nikki Vermeulen, Ridderprint BV, Ridderkerk, the Netherlands ISBN: 978-90-5335-497-1 VRIJE UNIVERSITEIT Biocatalysis & Multicomponent Reactions: The Ideal Synergy Asymmetric Synthesis of Substituted Proline Derivatives ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Exacte Wetenschappen op donderdag 26 januari 2012 om 13.45 uur in de aula van de universiteit, De Boelelaan 1105 door Anass Znabet geboren te Amsterdam promotoren: prof.dr. ir. R.V.A. Orru prof.dr. M.B. Groen copromotor: dr. E. Ruijter إ وادي Table of Contents Chapter 1 General Introduction: 9 Biocatalysis & Multicomponent Reactions Chapter 2 Monoamine Oxidase N: 41 A Promising Biocatalyst for Asymmetric Synthesis Chapter 3 Highly Stereoselective Synthesis of Substituted Prolyl Peptides 53 Using a Combination of Biocatalytic Desymmetrization and Multicomponent Reactions Chapter 4 Asymmetric Synthesis of Synthetic Alkaloids by a Tandem 77 Biocatalysis/Ugi/Pictet–Spengler-Type Cyclization Sequence Chapter 5 A Highly Efficient Synthesis of Telaprevir® by Strategic use of 99 Biocatalysis and Multicomponent Reactions Chapter 6 Stereoselective Synthesis of Substituted N-Aryl Proline Amides 125 by Biotransformation/Ugi-Smiles Sequence Chapter 7 Reflections & Outlook 145 Summary 159 Samenvatting (Summary in Dutch) 165 Dankwoord 173 List of Publications/Patents 179 Chapter 1 General Introduction: Biocatalysis & Multicomponent Reactions General Introduction 1.1 Introduction The chemical and pharmaceutical industry provides us with a myriad of useful products without which our standard of living would not be what it is now. However, the industry is also one of the major contributors to environmental pollution, due to the use of hazardous chemicals and in particular large amounts of flammable, volatile and often toxic organic solvents and reagents. For the production of fine chemicals, the waste/product ratio ranges between 5 and 50, while for pharmaceuticals this ratio may even be as high as 100.[1] The problems posed by this, including the inefficient use of resources, energy and capital, together with the risk to welfare and the environment are widely recognized throughout society. Although we have reaped many benefits from our fossil fuel-based economies, man faces an urgent environmental crisis. In recent decades, a growing consensus has risen about the negative influences of the increase of various gases on the global climate, such as CO2 and CH4. For example, since th the start of the industrial revolution in the 18 century, the CO2-concentration in the air has increased from roughly 100 ppm to more or less 400 ppm.[2-3] These gases, also called greenhouse gases, share a common feature that they tend to absorb heat and keep earth’s atmosphere at a comfortable average temperature of 15 °C. Without these greenhouse gases, the earth would lose too much heat to space and would be too cold to be habitable. But the increasing amount of these gases in the atmosphere will isolate the earth too much, resulting in elevated temperatures and the melting of vast amounts of ice on both poles and various high mountain ranges. Beside ecological destruction of these areas, the oceans will also rise and flood low-lying areas around the globe. Since many large cities, such as Amsterdam, New York City, harbors, such as Rotterdam, Singapore, and historical treasures, such as Venice, are situated at sea level, these will be lost if the sea level rises substantial due to melt water. These issues were emphasized when Al Gore’s documentary film “An inconvenient truth” was aired drawing the attention of politicians as well as that of the general public, which has put global warming and environmental issues high on the political and socio-economic agenda. In order to fight environmental decay, rising sea levels and increasing toxic waste piles development of new technologies for the production of energy, chemicals and products is vital. Among others, synthetic chemists are challenged to find solutions that maintain our standard of living but spare earth’s resources. The focus is set on developing novel, clean, atom-and step-efficient procedures for sustainable production for valuable fine chemicals and pharmaceuticals. The “ideal synthesis” should lead to the desired product from readily available starting materials in one or two reaction steps, in good overall yield and using environmentally benign reagents.[4] This minimizes energy consumption and waste 11 Chapter 1 production. A powerful strategy would be combining two methodologies which have proven to be efficient and environmentally benign: (i) biocatalysis and (ii) multicomponent reaction (MCR) methodology. 1.2 Biocatalysis 1.2.1 Enzymes as Catalysts In chemistry, a catalyst is a substance that decreases the activation energy of a chemical reaction without itself being changed at the end of the reaction. Catalysts participate in reactions but are neither reactants nor products of the reaction they catalyze (a strange ‘exception’ is the process of autocatalysis). They work by providing an alternative pathway for the reaction to occur, thus reducing the activation energy and increasing the reaction rate (Figure 1). Figure 1: Generic graph showing the effect of a catalyst in a hypothetical exothermic chemical reaction. The catalyzed pathway, despite having a lower activation energy, produces the same final result. In biocatalysis, natural catalysts, mostly enzymes, are used to perform chemical transformation of organic compounds. Biocatalysis is one of the oldest chemical transformations known to man; 6000 years ago it was already used for e.g. brewing beverages or cheese making. A brief historical background is depicted in Table 1. 12 General Introduction Table 1: Brief history of enzyme engineering and their application. Year Milestones Discoverer Chymosin from the stomach of cattle employed for the 6000 B. C. production of cheese 1783 Hydrolysis of meat by gastric juice (digestion) demonstrated Spallazani 1846 Invertase activity observed Dubonfout 1893 Definition of a catalyst including enzymes is postulated Ostwald Discovery of enzyme stereospecificity. “Lock-and-key” 1894 E. Fischer[5] model was proposed Cell free extract form yeast was employed for the 1897 Büchner[6] conversion of glucose to ethanol 1908 Application of pancreatic enzymes in the leather industry Röhm Application of pancreatic enzymes to clean laundry. 1913-1915 Röhm Commercialized as “Burnus” 1926 Enzymes are proven to be proteins Sumner[7] The first amino acid sequence of a protein (Insulin) 1953 Sanger[8] established, proving the chemical identity of proteins 1965 “Allosteric model” of enzyme was proposed Monod[9] Protein engineering developed for the improvement of After 1980 Many enzyme production and properties Since the pioneering work of Büchner[6] (Table 1), it has been demonstrated that enzymes do not require the environment of a living cell to perform catalysis. From those findings, the use of enzymes has been increasing in importance and has been employed by the industry in several applications in food technology, for example in bread, beer, wine, cheese, yoghurt. Last but not least, also in the production of washing powder, textiles and paper. Biocatalysis can offer several advantages over conventional chemical catalysis since enzymes show great chemoselectivity, regioselectivity and enantioselectivity. Furthermore, enzymes show higher substrate selectivity, milder reaction conditions, lower energy requirements and fewer side reactions, such as isomerization, racemization and rearrangement than conventional chemical catalysis. In addition, biocatalytic processes often provide products of high purity in one reaction step.