University of Groningen
Total synthesis of mycolic acids and site-selective functionalization of aminoglycoside
antibiotics
Tahiri, Nabil
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Publication date: 2019
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Tahiri, N. (2019). Total synthesis of mycolic acids and site-selective functionalization of aminoglycoside antibiotics. University of Groningen.
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Total Synthesis of Mycolic Acids and
Site-Selective Functionalization of
Aminoglycoside Antibiotics
Nabil Tahiri
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Processed on: 3-5-2019 PDF page: 2PDF page: 2PDF page: 2PDF page: 2 The work described in this thesis was executed at the Stratingh Institute for Chemistry,
University of Groningen, The Netherlands.
The authors of this thesis wish to thank the Nederlands Organization for Scientific Research for funding.
Cover design by Leonardo Miluccio (website: www.leonardomiluccio.myportfolio.com email: leonardomiluccio@gmail.com)
Printed by Ipskamp Printing BV, Enschede, The Netherlands ISBN: 978-94-034-1684-7 (print)
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Total Synthesis of Mycolic Acids and Site-Selective
Functionalization of Aminoglycoside Antibiotics
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties
De openbare verdediging zal plaatsvinden op vrijdag 7 juni 2019 om 16:15 uur
door
Nabil Tahiri
geboren op 13 juli 1989 te Breda
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Processed on: 3-5-2019 PDF page: 4PDF page: 4PDF page: 4PDF page: 4 Promotores Prof. dr. A. J. Minnaard Prof. dr. M. D. Witte Beoordelingscommissie Prof. dr. B. L. Feringa Prof. dr. S. R. Harutyunyan Prof. dr. H. Hiemstra
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“People should continue to work hard at organic synthesis – it’s hard,
exacting, frustrating, but always fascinating….
synthesis can create whole new worlds.”
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Table of Contents
Chapter 1. Mycolic Acids from Mycobacterium tuberculosis ... 1
1.1 Mycobacterium tuberculosis ... 2
1.1.1 Basic facts ... 2
1.1.2 Treatment and detection ... 3
1.2 The cell envelope ... 4
1.3 Mycolic acids ... 7
1.3.1 Structures and classes ... 7
1.3.2 Biosynthesis ... 8
1.3.3 Stereochemical elucidation ... 13
1.3.4 Previous total synthesis ... 15
1.4 Outline of the thesis ... 18
1.5 References ... 19
Chapter 2. Synthesis of the Methoxymycolic Acid Fragments ... 21
2.1 Introduction ... 22
2.2 Fragment A ... 23
2.2.1 Retrosynthetic analysis ... 23
2.2.2 Synthesis of the aldehyde spacer ... 24
2.2.3 Completion of fragment A ... 25
2.3 Fragment B ... 26
2.3.1 Retrosynthetic analysis ... 26
2.3.2 Route 1 ... 27
2.3.3 Route 2 ... 28
2.3.4 Route 3 and completion of fragment B ... 29
2.4 Fragment C ... 30
2.4.1 Retrosynthetic analysis ... 30
2.4.2 Synthesis of 37 ... 31
2.4.3 Completion of the fragment ... 33
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2.6 Possible points of improvement ... 36
2.7 Experimental section... 39
2.7.1 Fragment A: ... 40
2.7.2 Fragment B: ... 46
2.7.3 Fragment C: ... 54
2.8 References... 64
Chapter 3. Completion of the Methoxymycolic Acid Total Synthesis ... 67
3.1 Introduction... 68
3.2 Coupling of fragments B and C ... 68
3.3 Julia-Kocienski coupling of fragments BC and A ... 71
3.4 Finalization of the synthesis ... 73
3.5 Synthesis of R- and S-GroMMs, and GMMs ... 75
3.6 Comparison of [α]D and[Φ]Dvalues ... 77
3.7 Biological assays ... 78
3.8 Conclusion ... 80
3.9 Future prospects ... 81
3. 10 Experimental section ... 82
3.11 References... 111
Chapter 4. Deuteration Enhances Catalyst Lifetime in Aerobic Palladium-Catalyzed Alcohol Oxidation ... 113
4.1 Introduction... 114
4.1.1 Goal ... 115
4. 2 Results and discussion ... 116
4.2.1 Preparation of the catalyst ... 116
4.2.2 Aerobic oxidation of 2-heptanol ... 116
4.2.3 Aerobic oxidation of methyl α-D-glucopyranoside ... 118
4.3 Conclusion ... 119
4.4 Experimental section... 120
4.5 References... 125
Chapter 5. Synthesis of a Library of Neomycin B Amphiphiles for the Development of Novel Antimicrobial Agents ... 127
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5.1 Introduction ... 128
5.1.1 Aminoglycosides: structural composition, mode of action and toxicity ... 128
5.1.2 Amphiphilic aminoglycosides: structural features, mode of action and toxicity ... 130
5.1.3 Goal of the project ... 132
5.2 Results and discussion... 134
5.2.1 Synthesis of the amphiphiles ... 134
5.2.1 Viability assay ... 140
5.3 Conclusion ... 141
5.4 Experimental section ... 142
5.5 References ... 156
Chapter 6. Summary and future perspectives ... 159
6.1 Summary ... 160
6.2 Work in progress, and future perspectives ... 163
6.2.1 Mycolic acid research ... 163
6.2.2 Development of novel AGAs for targeting APH(3’) ... 166
6.3 Experimental ... 169
6.4 References ... 174
Nederlandse Samenvatting ... 177
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