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  • 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

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    إ وادي

  • 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

  • General Introduction: Biocatalysis & Multicomponent Reactions

    Chapter 1

  • General Introduction

    11

    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

    the start of the industrial revolution in the 18th 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

  • Chapter 1

    12

    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).

     

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     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.

  • General Introduction

    13

    Table 1: Brief history of enzyme engineering and their application.

    Year Milestones Discoverer

    6000 B. C. Chymosin from the stomach of cattle employed for the

    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

    1894 Discovery of enzyme stereospecificity. “Lock-and-key”

    model was proposed E. Fischer[5]

    1897 Cell free extract form yeast was employed for the

    conversion of glucose to ethanol Büchner[6]

    1908 Application of pancreatic enzymes in the leather industry Röhm

    1913-1915 Application of pancreatic enzymes to clean laundry.

    Commercialized as “Burnus” Röhm

    1926 Enzymes are proven to be proteins Sumner[7]

    1953 The first amino acid sequence of a protein (Insulin)

    established, proving the chemical identity of proteins Sanger[8]

    1965 “Allosteric model” of enzyme was proposed Monod[9]

    After 1980 Protein engineering developed for the improvement of

    enzyme production and properties Many

    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