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University of Groningen Total Synthesis of Enantiopure University of Groningen Total Synthesis of Enantiopure Biomolecules van Summeren, Ruben Petrus IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2006 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): van Summeren, R. P. (2006). Total Synthesis of Enantiopure Biomolecules: on mycolactones, saturated isoprenoid building blocks and ß-mannosyl phosphomycoketides. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 26-09-2021 Total Synthesis of Enantiopure Biomolecules On mycolactones, saturated isoprenoid building blocks and -mannosyl phosphomycoketides Ruben Petrus van Summeren The work described in this thesis was carried out at the Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen, The Netherlands. The work described in this thesis was financially supported by the Dutch Organization for Scientific Research (NWO). RIJKSUNIVERSITEIT GRONINGEN Total Synthesis of Enantiopure Biomolecules On mycolactones, saturated isoprenoid building blocks and -mannosyl phosphomycoketides Proefschrift ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op maandag 27 maart 2006 om 16.15 uur door Ruben Petrus van Summeren geboren op 10 november 1977 te Veghel Promotores : Prof. Dr. B.L. Feringa Prof. Dr. Ir. A. J. Minnaard Beoordelingscommissie: Prof. Dr. J.B.F.N. Engberts Prof. Dr. J.G. de Vries Prof. Dr. H.S. Overkleeft ISBN: 90-367-2545-3 Voorwoord Dat was het dan. De vier jaar van mijn promotieonderzoek zijn werkelijk voorbij gevlogen. En….? Wat heb je nou geleerd? Veel als chemicus, maar nog meer als persoon. Dat heeft natuurlijk alles te maken met de mensen om je heen en die wil ik op deze plaats dan ook bedanken. Allereerst wil ik mijn promotores prof. dr. B. L. Feringa en prof. dr. A. J. Minnaard bedanken voor de gelegenheid om mijn onderzoek uit te voeren. Ben, jouw enthousiasme voor chemie is inmiddels bijna spreekwoordelijk. Adri, ik ben vereerd om jouw eerste promovendus te mogen zijn. Jij stond altijd klaar met advies en zonodig met bemoedigende woorden en dat was van groot belang met name in de eerste twee jaar. Daarnaast toonde je ook interesse in mij als persoon, bijvoorbeeld toen ik aan mijn knie geopereerd werd. Niets veranderen, al zal dat moeilijk zijn nu je een steeds grotere groep krijgt en bovendien binnenkort naar Duitsland gaat. Succes! De leden van de beoordelingscommissie prof. dr. J. B. F. N. Engberts, prof. dr. J. G. de Vries en prof. dr. H. S. Overkleeft wil ik bedanken voor de snelle correctie van het manuscript. MD T. S. van der Werf en collegae ben ik dankbaar voor de prettige samenwerking met betrekking tot het Buruli ulcer project. Furthermore, I would like to express my gratitude to Dr. Moody and co-workers in Boston for the successful collaboration on the -mannosyl phosphomycoketide project. Pieter Bos ben ik veel dank verschuldigd voor zijn werk als bijvak- en later als hoofdvakstudent. Een gedeelte van dit werk is opgenomen in hoofdstuk 3 van dit proefschrift. Zijn huidige project hoop ik binnenkort te begroeten in artikelvorm. Pieter, je hebt aan den lijve ondervonden dat totaalsynthese niet de makkelijkste weg is naar snelle resultaten. Je hebt echter veel vaardigheden opgedaan als organisch syntheticus en ik heb dan ook alle vertrouwen in de promotie die je hierna wilt gaan doen. Daarnaast hebben mijn labgenoten: Martin Klopstra, Pedro Pinho, Diego Peña, Richard Jagt, Francesca Gini en Fernando López enorm bijgedragen aan een aangename werkomgeving. Nothing beats a Spanish postdoc as a neighbour. Especially when they also provide all arranged holidays to Galicia. Francesca, dit is mijn laatste poging als ambassadeur van de Nederlandse taal. Ik vond het leuk om met je samen te werken. Je bent, één van de meest sociale personen die ik ken. Die keren dat je niet zeker wist of ik serieus was: het was een grapje. Ik draag hierbij de radio aan jou over. Richard, jij bent me d’r eentje. Op veel vlakken zijn wij absolute tegenpolen, maar dat heeft het eigenlijk alleen maar interessanter gemaakt. Veel succes met je verdere ondernemingen op mikado-gebied. Verder zijn er natuurlijk een groot aantal mensen die voor gezelligheid zorgden bij diverse gelegenheden zoals lunches, borrels, etentjes, voetbalwedstrijden, vakanties en wat al niet meer. In willekeurige vollegorde: Hans, Niek, Jaap, Joost, Wesley, Michel, Tieme, Bas, Chris, Rob, Bjorn, Heiko, Lavinia, Suzy, Gabriella, Javier, Edzard en iedereen die ik nog vergeet…bedankt. De mensen van de subgroep asymmetrische katalyse ben ik dankbaar voor hun suggesties en voor hun geduld wanneer ik het weer eens niet over asymmetrische katalyse had. Theodora Tiemersma-Wegman ben ik veel dank verschuldigd voor hulp bij de analyse van chirale verbindingen. Wim Kruizinga wil ik bedanken voor de NMR-metingen die hij voor mij heeft verricht en Albert Kiewiet voor het bepalen van een enorm aantal massa’s. Een speciaal woord van waardering wil ik richten tot mijn beste vrienden: Erik, Leon, Maarten en Ruud. Samen doorlopen wij nu al ruim 15 jaar de universiteit van het leven. Over oude verhalen en nieuwe bespiegelingen. De discussies, de hilariteit, het geneuzel en het gerommel in de marge. Alles heeft zijn functie. Wanneer is het volgende avondje? Mijn familie wil ik bedanken voor hun begrip. Groningen? Kan dat niet in Nijmegen dan? Bedankt voor jullie geduld en voor jullie interesse in wat ik doe. Anne, bedankt voor het ontwerpen van de voorkant van o.a. dit boekje. Philana, jij brengt het beste in mij boven en alleen bij jou kan ik zijn op mijn slechtste momenten. Dank je wel. Contents Chapter 1 Introduction 1 1.1 Organic synthesis 1 1.2 Objectives of total synthesis and target selection 2 1.2.1 Structure elucidation 2 1.2.2 Privileged structures 4 1.2.2.1 Natural product synthesis and drug development; the case of discodermolide 5 1.2.2.2 Structure-activity relationship (SAR) 5 1.2.3 Synthetic challenges 8 1.2.4 Method-inspired targets 10 1.3 Asymmetric catalysis in total synthesis 11 1.3.1 Trends in methodology 12 1.3.2 Considerations in total synthesis 13 1.3.2.1 Total synthesis of libraries of stereoisomers 14 1.3.2.2 Synthesis of a single stereoisomer 15 1.3.2.3 Commercial considerations 17 1.3.3 Conclusion 19 1.4 Aims and ouline of this thesis 19 1.5 References 20 Chapter 2 Total Synthesis of Mycolactones 25 2.1 Introduction 25 2.2 Biological context 25 2.2.1 Infection 26 2.2.2 Treatment 26 2.2.3 Structure of mycolactones 26 2.2.4 Biosynthesis of mycolactones A and B 27 2.2.5 Production of mycolactones 29 2.3 Previous total syntheses of mycolactones 30 2.3.1 Synthesis of the mycolactone core by Kishi 30 2.3.2 Synthesis of a side chain epimer 33 2.3.3 Synthesis of the side chain of mycolactones A, B and C 34 2.4 New approaches towards the side chain of mycolactones A and B 36 2.4.1 Retrosynthesis 37 2.4.2 Synthesis of the conjugated building block (2.37) 38 2.4.3 Synthesis of the chiral building block from D-glucose (2.38) 40 2.4.4 Synthesis of a chiral building block from L-rhamnose 45 2.4.5 Coupling and partial hydrogenation 47 2.4.6 Alternative strategies 49 2.5 Summary and concluding remarks 51 2.6 Experimental section 52 2.7 References 70 Chapter 3 Enantiopure Saturated Isoprenoid Building Blocks 75 3.1 Introduction 75 3.2 Previously reported strategies 76 3.2.1 Chiral pool and substrate control strategies 76 3.2.2 Chiral auxiliary methods 79 3.2.3 Enzymatic approaches 81 3.2.4 Catalytic asymmetric methods 82 3.3 A general catalytic asymmetric method 83 3.3.1 Strategy 83 3.3.2 Synthesis 84 3.3.3 Determination of the relative and absolute stereochemistry 87 3.4 Application in the total synthesis of apple leafminer pheromones 88 3.5 Limitations of the catalytic system 91 3.6 Summary and concluding remarks 92 3.7 Experimental section 93 3.8 References 106 Chapter 4 -D-Mannosyl Phosphomycoketides 109 4.1 Introduction 109 4.2 Lipid-antigen mediated immune response 110 4.2.1 CD1 proteins and lipid-antigen presentation 112 4.2.2 Recognition of CD1-lipid complexes by T-cell antigen receptors 113 4.2.3 Effector functions of T-cells 114 4.2.4 Rationale for a lipid-antigen mediated immune response 115 4.3 CD1c-mediated T-cell recognition of isoprenoid glycolipids 115 4.4 Biosynthesis of mycoketides 117 4.5 Synthesis of stereorandom -D-mannosyl phosphomycoketides 118 4.6 Total Synthesis of enantiopure -D-mannosyl phosphomycoketides 119 4.6.1 Retrosynthesis 119 4.6.2 Synthesis of diisoprenoids 120 4.6.2.1 Copper-catalyzed Grignard and SmI2-assisted cross-couplings 121 4.6.2.2 Cross-couplings via formation of an olefin 122 4.6.3 Completion
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