Towards Organoboron-mediated Functionalization of Erythromycin A and Synthesis of its Aglycon

105 Pages·2014·4.99 MB·English

by  Christopher Adair

Towards Organoboron-mediated Functionalization of
Erythromycin A and Synthesis of its Aglycon
by
Christopher D. Adair
A thesis submitted in conformity with the requirements
for the degree of Master of Science
Department of Chemistry
University of Toronto
© Copyright by Christopher D. Adair 2014
Towards Organoboron-mediated Functionalization of
Erythromycin A and Synthesis of its Aglycon
Christopher D. Adair
Master of Science
Department of Chemistry
University of Toronto
2014
Abstract

Many natural products, including antibiotics, are structurally complex and contain a wide
variety of functional groups. As a consequence, the selective functionalization of these
molecules often requires the use of inefficient protecting group strategies. Inspired by this
obstacle, our group recently developed a borinic acid-catalyzed method to
regioselectively functionalize the equatorial position of cis-vicinal diols in carbohydrates
with limited use of protecting groups.

The work presented in this thesis describes progress made towards selective
functionalization of the cis-vicinal diol present in the macrolide antibiotic erythromycin
A. This was attempted using the boronic and borinic acid-mediated methodologies
developed previously in our group. Finally, a semisynthesis of erythronolide A was
carried out with the goal of using our methodology to prepare novel analogues for
biological evaluation.

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Acknowledgements

There was a time when I believed that personal success was driven solely by hard work
and perseverance. While the definition of success is dependent on whom you ask, I think
that many will agree that it is very difficult to be successful without the love and support
from others.

Firstly, I would like to acknowledge my parents. They continue to serve as my primary
inspiration and always will. Perhaps unknowingly, they’ve instilled within me a sense of
ambition, pride and humbleness that I will always cherish. My mother has always been
there to support me through the toughest times of my academic career and, for that, I am
forever grateful. My father has served a complementary role, pushing me to realize that I
have the potential to accomplish anything that I desire.

I should note that my choice to pursue synthetic organic chemistry wasn’t made until the
fourth year of my undergraduate career. As such, I have to thank to Professor France-
Isabelle Auzanneau for taking a chance on a student with limited synthesis experience.
She provided me with a wonderful introduction to carbohydrate chemistry and catalyzed
my passion for a very interesting branch of synthesis. I would also like to thank Professor
Mark S. Taylor. He taught me how to think like a scientist and suggested a project that
challenged me to go above and beyond what I thought possible.

A big thank you to the Taylor group! Being a part of such a smart and talented group of
people was truly a pleasure. A special thank you to Kyan D’Angelo and Kashif Tanveer
for sharing their vast knowledge of chemistry and contributing to many insightful
conversations about my work over the year.

And of course, I’m thankful for my brother and friends. There were times when I had to
make sacrifices to succeed academically and they were always supportive. Lastly, thank
you to Craig McDougall for being the best
 friend
 anyone
 could
 ask
 for.

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Table of Contents

Abstract .................................................................................................................................... ii
Acknowledgements .................................................................................................................. iii
Table of Contents ..................................................................................................................... iv
List of Tables ........................................................................................................................... vi
List of Figures .......................................................................................................................... vii
List of Schemes ........................................................................................................................ viii
Abbreviations ........................................................................................................................... xi

Chapter 1: Boron-Diol Interactions
1.0 Introduction ...................................................................................................... 1
1.1 Organoboron methodology in carbohydrate synthesis .................................... 3
1.2 Application of organoboron methodology to natural products ........................ 5
1.3 Conclusions ...................................................................................................... 8

Chapter 2: The Evolution of Antibiotics
2.0 Introduction ...................................................................................................... 10
2.1 Historical overview .......................................................................................... 10
2.2 Antibiotic resistance ......................................................................................... 13
2.3 Exploring new antibiotic landscape with chemical synthesis .......................... 14
2.4 Biosynthesis of novel antibiotic analogues ...................................................... 17
2.5 Conclusions and outlook .................................................................................. 19

Chapter 3: Application of Organoboron-mediated Transformations to Erythromycin A
3.0 Introduction ...................................................................................................... 20
3.1 Biosynthesis of erythromycin A ...................................................................... 21
3.2 Total synthesis of the erythromycins ............................................................... 25
3.3 Acid-catalyzed rearrangements of erythromycin A ......................................... 28
3.4 Semisynthetic analogues of erythromycin A ................................................... 30
3.5 Regioselective functionalization of erythromycin A ....................................... 31
3.6 Research goals ................................................................................................. 33
3.7 Results and discussion ..................................................................................... 34

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3.7.1 Organoboron-mediated glycosylation of erythromycin A ................... 34
3.7.2 Organoboron-mediated benzoylation of erythromycin A .................... 37
3.7.3 NMR experiments with erythromycin A ............................................. 44

3.8 Conclusions and outlook .................................................................................. 48
3.9 Experimental details ......................................................................................... 49
3.10 Characterization data ....................................................................................... 50

Chapter 4: Semisynthesis of Erythronolide A
4.0 Introduction ...................................................................................................... 57
4.1 Semisynthesis of erythronolide A .................................................................... 57
4.2 Research goals ................................................................................................. 60
4.3 Results and discussion ..................................................................................... 60
4.4 Conclusions and outlook .................................................................................. 65
4.5 Experimental details ......................................................................................... 67
4.6 Characterization data ....................................................................................... 68

Appendix A: NMR spectra ..................................................................................................... 75

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List of Tables

Table 3.1 – Borinic acid-mediated glycosylationa .................................................................. 35

Table 3.2 – Boronic acid-mediated glycosylationa ................................................................. 36

Table 3.3 – Organoboron-mediated benzoylation at 23 °Ca ................................................... 39

Table 3.4 – Organoboron-mediated benzoylation at 80 °Ca ................................................... 41

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List of Figures

Figure 1.1 – Deprotected pentasaccharide target of our synthesis (1.1) and
pentasaccharide derived target of the Du synthesis (1.2) ........................................................ 7

Figure 2.1 – Dimer, trimer and pentamer forms of arsphenamine (Salvarsan) effective for
treating syphilis ........................................................................................................................ 11

Figure 2.2 – Selected antibiotics discovered in the 20th century of historical importance ..... 12

Figure 2.3 – Overview of the cephalosporin scaffold and examples of modern
adaptations ............................................................................................................................... 15

Figure 3.1 – Components of the macrolide antibiotic erythromycin A .................................. 20

Figure 3.2 – Polyketide synthase-mediated chain elongation process to form 6-
deoxyerythronolide B [adopted from (47)] .............................................................................. 22

Figure 3.3 – Select examples of 6-deoxyerythronolide B analogues generated by site-
directed mutagenesis of polyketide synthase domains (McDaniel, 1999) ............................... 24

Figure 3.4 – Total syntheses of erythromycin derivatives ...................................................... 25

Figure 3.5 – Seco acid derivative for erythromycin A synthesis (Woodward, 1981) ............. 26

Figure 3.6 – Erythromycin A enol ether and anhydroerythromycin A ................................... 28

Figure 3.7 – Inherent reactivity of the hydroxyl groups in erythromycin A ........................... 32

Figure 3.8 – (a) 11B NMR (128 MHz, decouple 1H 400 MHz, CD CN, 295 K) of
3
Ph BOH (3.37) (b) 11B NMR (128 MHz, decouple 1H 400 MHz, CD CN, 295 K) of
2 3
erythromycin A (3.1) upon addition of Ph BOH (3.37) .......................................................... 45
2

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List of Schemes

Scheme 1.1 – Boronic acid-diol complexation equilibria in aqueous media .......................... 2

Scheme 1.2 – Boronic acid-mediated monoalkylation of methyl α-L-fucopyranoside with
Lewis base activation ............................................................................................................... 3

Scheme 1.3 – Borinic acid-catalyzed regioselective monoacylation of carbohydrate
derivatives ................................................................................................................................ 4

Scheme 1.4 – Borinic acid-catalyzed regioselective glycosylation of carbohydrate
derivatives ................................................................................................................................ 4

Scheme 1.5 – Organoboron-catalyzed regio- and stereoselective formation of β-2-
deoxyglycosidic linkages ......................................................................................................... 5

Scheme 1.6 – Synthesis of cardiac glycoside analogs by catalyst-controlled,
regioselective glycosylation of digitoxin ................................................................................. 6

Scheme 1.7 – Preparation of disaccharide fragment 1.4 using the borinic acid-catalyzed
methodology ............................................................................................................................ 7

Scheme 1.8 – Preparation of disaccharide fragment 1.6 using the catalytic borinic acid
and stoichiometric boronic acid methods ................................................................................ 8

Scheme 2.1 – Reductive removal of the C6-hydroxy group in 6-demethyltetracycline to
give sancycline (Pfizer, 1958) .................................................................................................. 16

Scheme 2.2 – Semisynthesis of minocycline from sancycline (Lederle, 1967) ...................... 17

Scheme 2.3 – Semisynthesis of tigecycline from minocycline (Wyeth, 1994) ....................... 17

Scheme 2.4 – Precursor-directed biosynthesis of 6-deoxyerythronolide B analogues by
genetically engineered polyketide synthase (Khosla, 1996) .................................................... 18

Scheme 2.5 – Biosynthesis of unnatural erythromycin A derivatives ..................................... 19

Scheme 3.1 – Formation of 6-deoxyerythronolide B from propionyl CoA and methyl
malonyl CoA ............................................................................................................................ 21

Scheme 3.2 – Post-PKS enzyme cascade to give erythromycin A .......................................... 23

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Scheme 3.3 – Key steps in Woodward’s total synthesis of erythromycin A .......................... 27

Scheme 3.4 – Acid degradation mechanism of erythromycin A in deuterated phosphate
buffer (pH = 3.0) at 37 °C ........................................................................................................ 29

Scheme 3.5 – Semisynthesis of clarithromycin (Taisho, 1980) .............................................. 30

Scheme 3.6 – Semisynthesis of azithromycin (Pliva, 1980) ................................................... 31

Scheme 3.7 – Site-selective acylation of erythromycin A using a peptide catalyst (Miller,
2006) ........................................................................................................................................ 33

Scheme 3.8 – Proposed regioselective monofunctionalization of erythromycin A
catalyzed by a diarylborinic acid ............................................................................................. 33

Scheme 3.9 – Monobenzoylation of erythromycin A using acetic anhydride in pyridine ...... 38

Scheme 3.10 – Monobenzoylation of erythromycin A enol ether under boron-free
conditions ................................................................................................................................. 42

Scheme 3.11 – Erythromycin A acid-catalyzed rearrangement products and their
molecular masses ..................................................................................................................... 43

Scheme 4.1 – Semisynthesis of erythronolide A (LeMahieu, 1974) ....................................... 58

Scheme 4.2 – Cope elimination procedure employed by Celmer for removal of the
tertiary amine from D-desosamine in oleandomycin ............................................................... 59

Scheme 4.3 – Synthesis of erythromycin A 9-oxime N-oxide (4.2) ....................................... 61

Scheme 4.4 – Synthesis of 3’-de(dimethylamino)-3’,4’-dehydroerythromycin A 9-oxime
(4.3) via Cope elimination ....................................................................................................... 61

Scheme 4.5 – Synthesis of erythronolide A 9-oxime (4.4) under acidic conditions ............... 62

Scheme 4.6 – Nitrous acid-mediated oxime cleavage to give erythronolide A 5,9-enol
ether (4.6) ................................................................................................................................. 63

Scheme 4.7 – Final steps of the erythronolide A total synthesis (Carreira, 2009) .................. 64

Scheme 4.8 – Oxime cleavage with Raney Nickel in the semisynthesis of erythronolide A
(4.5) .......................................................................................................................................... 65

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Abbreviations

1H proton (NMR spectroscopy)
13C carbon (NMR spectroscopy)
°C degrees Celsius
Å Ångstrom(s)
aq. aqueous
Ac acetyl
ACP acyl carrier protein
AT acyl transferase
Bn benzyl
Bz benzoyl
cat. catalytic or catalyst
d doublet
DCM dichloromethane
DEBS deoxyerythronolide B synthase
DIPEA N,N-diisopropylethylamine (Hünig’s base)
DMSO dimethylsulfoxide
equiv. equivalent(s)
ESI electrospray ionization
Et ethyl
EtOAc ethyl acetate
FTIR Fourier transform infrared spectroscopy
g gram(s)

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