PART I – SYNTHESIS OF PHOTOCHROMIC FULGIDES
PART II – SYNTHETIC STUDIES TOWARDS ANTI-SARS
AGENT AG7088

W
AYNE LEE WEI WOON
NATIONAL UNIVERSITY OF SINGAPORE
2006
PART I – SYNTHESIS OF PHOTOCHROMIC FULGIDES
PART II – SYNTHETIC STUDIES TOWARDS ANTI-SARS
AGENT AG7088

W

Finally I would like to thank the love of my life, my wife, Constance, for her
constant support, patience and for being so understanding, during the course of my
candidature, without which I would not have the courage to carry out. Last but most
importantly, I would like to thank God, the almighty, for blessing me and giving me the
opportunity to complete my course.

i
TABLE OF CONTENTS

ACKNOWLEDGEMENTS i
T
ABLE OF CONTENTS ii
S
UMMARY vi
L
IST OF ABBREVIATIONS vii

PART I – SYNTHESIS OF PHOTOCHROMIC FULGIDES
CHAPTER 1 : INTRODUCTION TO PHOTOCHROMISM
1.1. Introduction to Photochromism 1
1.2.
Introduction to Fulgides – A Historical review of fulgides
chemistry
2
1.3. Photochromism of Fulgides 12
1.4. The Stobbe Condensation 13
1.5. The Stobbe Condensation mechanism 15
1.6. Strategy of modification of fulgide core structure 16

CHAPTER 2 : SYNTHESIS OF MODEL FULGIDES

5.1. Exploration of the Synthesis of other Potential Fulgides 64
5.2.
Possible extension of fulgide chemistry – Incorporation of
Polyhedral Oligomeric Silsesquioxanes (POSS)
67
5.3
Conclusion and Future work – Exploration of photochromic
nanoparticles
75

PART II – SYNTHETIC STUDIES TOWARDS ANTI-SARS AGENT AG7088
CHAPTER 1 : INTRODUCTION TO SARS
1.1. Introduction to Severe Acute Respiratory Syndrome (SARS) 76
1.2. SARS-CoV 3CL Protease (3CL
Pro
) Background 77
1.3.
Active site and binding pocket of SARS-CoV 3CL
Pro
for
inhibitors
80
1.3.1. Peptide SARS-CoV 3CL
Pro
inhibitors 81
1.4. Formal Synthesis of AG7088 – Retrosynthetic Strategy 84

iii
CHAPTER 2 : SYNTHESIS OF LACTONE 2
2.1. Introduction – Synthesis of Lactone 2 86


CHAPTER 6: EXPERIMENTAL SECTION
P
ART I – DESIGN AND SYNTHESIS OF PHOTOCHROMIC FULGIDES
6.1. General Information 112
6.2. Materials 112
6.3. Chromatography 113
6.4. Instruments and Equipment 114
6.5. Procedures and Supporting Information for Part I 116

PART II – SYNTHETIC STUDIES TOWARDS ANTI-SARS AGENT AG7088
6.6. General Information 183
6.7. Materials 183
6.8. Chromatography 184
6.9. Instruments and Equipment 185
6.10. Procedures and Supporting Information for Part II 187

APPENDIX - FORWARD CHEMICAL GENETICS USING ZEBRAFISH EMBRYOS
- F
ORWARD CHEMICAL GENETICS USING ZEBRAFISH EMBRYO (DANIO RERIO) A1-A10

PUBLICATION LIST
PL1

v
SUMMARY

Photochromism is defined as a light-induced reversible change of colour. It is a
process whereby, a reversible transformation of a single chemical species is being
induced in one or both directions, by the absorption of electromagnetic radiation between

Bp Boiling point
br Broad
C Closed-form / Coloured form
Calcd Calculated
d Doublet
dd Doublet of doublets
ddd Doublet of doublet of doublets
ddt Doublet of doublet of triplets
de Diastereomeric excess
dq Doublet of quartet
dt Doublet of triplets
DMF N,N-dimethyl formamide
DMSO Dimethyl sulfoxide
ee Enantiomeric excess
EI Electron impact
equiv Equivalent(s)
ESI Electro-spray ionization
Expt Experiment
FAB Fast-atom bombardment

vii
FGI Functional group interconversion
FTIR Fourier transform infrared spectrometry
h / hr Hour(s)
hept heptet
Hex Hexane
HRMS High resolution mass spectrometry
Hz Hertz
iPr Isopropyl
IUPAC International Union of Pure and Applied Chemistry


ix
PART I
PART I – SYNTHESIS OF PHOTOCHROMIC
FULGIDES PART I
CHAPTER 1

b
s
o
r
b
a
n
c
e

Wavelength
Figure 1. Diagram depicting photochromism of molecule A, converting to molecule B

1
Photochromism: Molecules and Systems; Dürr, H.; Bouas-Laurent, H.; Eds. Elsevier, Amsterdam,
1990.
PART I – SYNTHESIS OF PHOTOCHROMIC FULGIDES
1
CHAPTER 1 – INTRODUCTION TO PHOTOCHROMISM
The most prevalent organic photochromic systems involve unimolecular
reactions. Most common photochromic molecules have a colourless or pale yellow
form A and a coloured form B (e.g., red or blue). This phenomenon is referred to as
positive photochromism. Other systems are bimolecular, such as those involving
photocycloaddition reactions. When
λ
max
(A) >
λ
max
(B), photochromism is negative
2
Stobbe, H. Die Fulgide, Annalen 1911, 380, 1-129.
3
Stobbe, H. Ber. 1904, 37, 2236.
4
Org. Reactions. 6; Johnson, W. S.; Daub, G. H.; 1951.
5
Stobbe, H. Ber. Dtsch. Chem. Ges. 1905, 40, 3372-3382.
6
Latin word “fulgere” means to glitter or shine.
PART I – SYNTHESIS OF PHOTOCHROMIC FULGIDES
2
CHAPTER 1 – INTRODUCTION TO PHOTOCHROMISM

O
O
O
R
2
R
1
R
4
R
3
O
O
R

7
for the
succinimide of the corresponding fulgide (Figure 2), though fulgimides had been
synthesized earlier by Goldschmidt and co-workers in 1957.
8
Fulgimides have been
widely prepared so far, because it is convenient to attach another substituent onto the
fulgide core without a significant change of photochromic properties. Such molecular
tailoring of the original fulgide moiety have been carried out by several groups (e.g.,
Tomoda et al. and Matsushima et al.)
9a, b
and many articles have also been published
in the 1990s.
10a-e
As an illustration, fulgimides were used for the attachment of the
fulgide core to side chains of polymers,
10a, b
attachment of a fluorescent group for
control of fluorescence
10c
and binding to proteins for regulation of substrate
binding.
10d, e
7
Heller, H. G.; Hart, R. J.; Salisbury, K. J. Chem. Soc., Chem. Commun. 1968, 1627-1628.
8
Goldschmidt S.; Riedle, R.; Reichardt, A. Justus Liebigs Ann. Chem. 1957, 604, 121-132.

9a, b
For example, N-benzylfulgimide 1
(Figure 3) was shown to be more resistant to fatigue when compared to the
corresponding furyl-fulgide 2.

O
O
O
Ph
Ph
O
O
O
Ph
hv, I
2
3 4Scheme 1. Photocyclization of bisbenzylidenefulgide 3

The chemistry of the fulgides was reported in an article by Hans Stobbe in
1907.
11
At that time, the photocolouration mechanism of fulgides was not known.
However, Stobbe noticed that 1-phenylnaphthalene-2,3-dicarboxylic anhydride, 4,
was formed from photoirradiation of bisbenzylidenefulgide, 3, in a benzene or
chloroform solution, in the presence of iodine (Scheme 1).
11


O
O
O
Ph
H
O
O
O
Ph
O
2
hv, I
2
3 3c 4Scheme 2. Deduction of 1,8a-dihydro-1-phenylnaphthalene-2,3-dicarboxylic anhydride 3c

The reinvestigation by Heller et al. of the reactions of yellow E- and Z-
benzylidene (diphenylmethylene)-succinic anhydrides 5E and 5Z showed that they
underwent reversible photochemical conrotatory ring closure to form red cis- and
trans-1,8a-DHN intermediates (1,8a-DHNs) 5EC and 5ZC respectively. These
molecules showed that they also underwent ring opening by a disrotatory mode to
yield Z- and E-fulgides, 5Z and 5E respectively.
12
(a) Chakraborty, D. P.; Sleigh, T.; Stevenson, R.; Swoboda, G. A.; Weinstein, B. J. Org. Chem.
1966, 31, 3342-3345. (b) Brunow, G.; Tylli, H. Acta Chem. Scand. 1968, 22, 590-596.

H
H
O
O
O
H
H
UV
UV
[1,5]-H shift
5E 5EC 5EC'
5Z 5ZC 5ZC'
UV
UV
[1,5]-H shiftScheme 3. Heller et al. investigated and confirmed the presence of [1,5]-H shifts on prolonged UV-
irradiation of fulgides 5E and 5Z

Eventually, irreversible rearrangement occurs to lead to the colourless cis- and
trans-1,2-DHNs, 5EC’ and 5ZC’ in two competing thermal processes (Scheme 3).
16

Other related studies have also been reported.
17
On exposure to visible light, 1,8a-
DHNs undergo photochemical conrotatory ring opening to the corresponding fulgides.

Since then the colouration mechanism of fulgide has been well understood as

UV
UV
Vis, UVScheme 4. X-ray crystallographic analysis of the coloured form of 6C

In 1984, Kaftory succeeded in the X-ray crystallographic analysis of the
coloured form of a thienylfulgide, 6C (Scheme 4).
19
This result determined the
structure of the coloured form and the photocolouration mechanism unequivocally.

From the late 1960s through the 1970s Heller et al. published a series of
articles entitled “Overcrowded Molecules”,
20a-q
in which the chemistry of fulgides and
closely related compounds was dealt with. They clarified the thermal reactions of the
coloured form of fulgides as shown (Scheme 5).
20p, q, a, b 21

19
Kaftory, M. Acta Crystallogr. 1984, 40, 1015-1019.
20
(a) Heller, H. G.; Auld, D.; Salisbury, K. J. Chem. Soc. C 1967, 682-685. (b) Heller, H. G.; Auld, D.;
Salisbury, K. J. Chem. Soc. C 1967, 1552-1554. (c) Heller, H. G.; Auld, D.; Salisbury, K. J. Chem. Soc.
C 1967, 2457-2459. (d) Heller, H. G.; Salisbury, K. J. Chem. Soc. C 1970, 399-402. (e) Heller, H. G.;
Salisbury, K. J. Chem. Soc. C 1970, 873-874. (f) Heller, H. G.; Salisbury, K. J. Chem. Soc. C 1970,
1997-2000. (g) Hart, R. J.; Heller, H. G. J. Chem. Soc., Perkin Trans. 1 1972, 1321-1323. (h) Hastings,
J. S.; Heller, H. G. J. Chem. Soc., Perkin Trans. 1 1972, 1839-1842. (i) Heller, H. G.; Megit, R. M. J.

3
R
2
H
O
O
O
R
1
R
3
R
2
O
O
O
R
1
R
3
R
2
H
O
O
O
R
1
R
2/3

v
h
v
[
1
,
3
]
-
H

s
h
i
f
t
R
2
/R
3
: HScheme 5. Thermal reactions of fulgides as reported by Heller and co-workers

Other than the thermal ring opening, the major thermal reactions are hydrogen
rearrangement and (or followed by) dehydrogenative aromatization.

O
O

O
O
H'
R
R
H
H'
R
R
O
O
O
H
R
R
O
O
O
H
R
R
O
O
O
9Z/10Z Pale yellow, 9E/10E
1,8a-DHN
(Red) 9C,
(blue) 10C
[1,5]-H shift
[1,7]-H shift

O
O
O
UV
UV
UV
UV
11Z 11E 11CScheme 8. Side reactions can be prevented by removing reactive hydrogens

Heller et al. also further reported that fulgide 11Z/11E, having a
mesitylmethylene group, instead of the benzylidene group and an isopropylidene
(IPP) group, prevented the side reactions in which the hydrogen atoms on the ring
closing carbon atoms were involved, since there was no hydrogen to rearrange or to
be removed (Scheme 8). Furthermore, the vicinal methyl groups on the ring closing
aromatic carbon atoms prevented the thermal ring opening of the C-form, 11C, which
should occur by way of, different from the photochemical ring opening, the
disrotatory pathway; by the steric repulsion between them.

Indeed, they observed that the colour did not fade at 160°C. Unfortunately, the
conversion ratio to the coloured form at the photostationary state (pss) was so low that
almost no coloured form remained when the solution of the colourless form of 11E
was irradiated with 366 nm light until it reached the photostationary state.
20i
PART I – SYNTHESIS OF PHOTOCHROMIC FULGIDES
10
CHAPTER 1 – INTRODUCTION TO PHOTOCHROMISM


photochromic fulgide has been realized for the first time with molecule 2.

This furyl-fulgide, 2, is the monument of the long research history of the
photochromism of fulgides, as one challenge faced by researchers in this field was to
design thermally stable, fatigue-resistant photochromic fulgides that would potentially
be suitable for commercial applications. This included optical recording and security
printing. The compounds should have high quantum efficiencies for colouring and
bleaching and also achieve high conversions into the coloured forms. The valuable
information for the molecular design to append thermal irreversibility, i.e., (1) 22
(a) Heller, H. G.; Oliver, S. J. Chem. Soc., Perkin Trans. 1 1981, 197-201. (b) Darcy, P. J.; Heller, H.
G.; Strydom, P. J.; Whittall, J. J. Chem.Soc., Perkin Trans. 1 1981, 202-205.
PART I – SYNTHESIS OF PHOTOCHROMIC FULGIDES
11
CHAPTER 1 – INTRODUCTION TO PHOTOCHROMISM
introduction of substituents other than hydrogen onto the ring-closing carbon atoms
and (2) employing a heteroaromatic ring, was thus brought about.

The possible application of thermally irreversible photochromic compounds
such as 2 is in rewritable optical recording media.
23a-c
The 1980s and early 1990s were
devoted to improve the properties of 2, while after the early 1990s to date,
development of new fulgides rather than improvement has been the main research
interest. In this aspect, our efforts have been directed towards the extension of current
fulgide chemistry, with the main aim, being the discovery of new photochromic
fulgides that might display interesting and possibly useful properties.


3
UV
UV
UV
vis UV
Ar
Z-form
(colorless)
E-form
(colorless)
C-form
(colored)Scheme 10. Photochromism of fulgide under UV irradiation

The photochromism of a fulgide occurs between one of the colourless open
forms (hereafter abbreviated as the “E-form” (E) (Scheme 10) because the geometry
of the double bond connecting the aromatic ring and the succinic anhydride is usually
E and the photocyclized coloured form (abbreviated as the C-form (C)). However, 23
(a) Heller, H. G. Spec. Publ., R. Soc. Chem., Fine Chem. Electron. Ind. 1986, 60, 120-135. (b)
Photochromics for the Future.; Heller, H. G.; Electronic Materials, from Silicon to Organics; Miller, L.
S., Mullin, J. B., Eds.; Plenum Publishing, New York, 1991, 471-483. (c) Feringa, B. L.; Jager, W. F.;
de Lange, B. Tetrahedron 1993, 49, 8267-8310.
PART I – SYNTHESIS OF PHOTOCHROMIC FULGIDES
12