CALIFORNIA STATE UNIVERSITY, NORTHRIDGE
TOWARDS THE SYNTHESIS OF DIANDRAFLAVONE
A thesis submitted in partial fulfillment of the requirements
For the degree of Master of Science
in Chemistry
By
Christine Ani Dimirjian
August 2015
The thesis of Christine Ani Dimirjian is approved by:
_______________________________________
Dr. Daniel Curtis
___________________
Date
_______________________________________
Dr. Yann Schrodi
___________________
Date
_______________________________________
Dr. Thomas G. Minehan, Chair
___________________
Date
California State University, Northridge
ii
ACKNOWLEDGEMENTS
I would like to express my deepest gratitude to Dr. Thomas Minehan for giving
me the opportunity to work as part of his laboratory group. From my first organic
chemistry lecture taught by Dr. Minehan, it was easy to see his genuine enthusiasm for
the subject, which is only magnified in the laboratory. Thank you for your patience and
understanding when experiments failed, and giving me encouragement to keep going
with a different approach.
I also thank my thesis committee, Dr. Daniel Curtis and Dr. Yann Schrodi for
their feedback and input on this work. Thank you Dr. Curtis for all the support you have
shown me during my time at CSUN. Thank you Dr. Schrodi for being present at the
Graduate Recruitment event, it was only after talking with you during lunch that I even
considered applying to the program.
A thank you to past members of the Minehan group, especially Akop Yepremyan,
Miran Mavlan and Xiao Cai, for paving the way for the chemistry serving as a foundation
for my project. Thank you to current members who come in on a regular basis and keep
the research alive.
Thank you to the Chemistry Department faculty and staff. A special thank you to
Dr. Simon Garrett for his encouragement to continue on in my academic career. Thank
you to Irene, Sonia and Riccia in the Chemistry Office who help keep the department
running! Thank you Dr. Karin Crowhurst as the graduate coordinator, Dr. Mike Kaiser
for help with the NMR, and the Chemistry Stockroom for their efficient fullfillment of
orders.
iii
DEDICATION
I would like to dedicate this work to my parents who have been supportive of me
throughout my academic career. I am so thankful for the value they have placed on
education and providing us with all the resources my sister and I need so that we may
continue in our studies. My father fueled my interest and curiosity in seeing how things
work by allowing me to help fix things around the house. My mother always pushed me
to stand up for myself and demand my rights. Most of all, they have shown me how to
use my strengths to help others. It is their kindness and willingness to help others with no
expectation or desire of repayment that makes me admire them the most and is something
I hope to be able to do now and in the future.
To my sister and younger cousins, hard work and patience will pay off. Follow
your passions and chase your dreams.
iv
TABLE OF CONTENTS
Signature Page…………………………………………………………………………….ii
Acknowledgements…………………………………………………………………...….iii
Dedication………………………………………………………………………………...iv
List of Figures………………………………………………………………………...….vii
List of Schemes…………………………………………………………………………viii
List of Tables…………………………………………………………………………..….x
List of Equations………………………………………………………………….………xi
List of Abbreviations………………………………………………………..…...……...xii
Abstract…………………………………………………………………………….....…xiv
CHAPTER 1: CHEMICAL AND BIOLOGICAL SIGNIFICANCE OF C-ARYL
GLYCOSIDES AND FLAVONES
1.1
Introduction………………………………………………………………..1
1.2
Flavones…………………………………………………………………...2
1.3
C-Aryl Glycosides………………………………………………………...9
1.4
DNA Interaction………………………………………………………….13
CHAPTER 2: METHODOLOGY IN C-GLYCOSIDE SYNTHESIS
2.1
Introduction………………………………………………………………15
2.2
Electrophilic Substitutions……………………………………………….15
2.3
Nucleophilic Addition to Electrophilic Aromatics………………………22
2.4
Transition Metals………………………………………………………...23
2.5
Examples of C-Aryl Glycoside Synthesis………………………….…...29
v
CHAPTER 3: METHODOLOGY IN FLAVONE SYNTHESIS
3.1
Introduction………………………………………………………………36
3.2
Synthesis of C-Glycosylflavonoids………………………………………36
3.3
Cyclization……………………….………………………………………39
CHAPTER 4: SYNTHESIS OF DIANDRAFLAVONE
4.1
Introduction………………………………………………………………41
4.2
Structure and Retrosynthetic Analysis ……………………….….………41
4.3
Glucose moiety and first coupling……………………………….………42
4.4
Galactose Sugar Manipulations………………………………….………48
4.5
Preparation of the Chromophore .……………………………….………50
4.6
Model System for Chromophore Cyclization…………….…….…...…..54
CHAPTER 5: CONCLUSION …………………………………….……………………57
CHAPTER 6: EXPERIMENTAL ………………………………………………………58
REFERENCES………………………..…………………………………………………77
APPENDIX………………………..…………….……………………………………….83
vi
LIST OF FIGURES
Figure 1.1
The C-aryl Glycoside Kidamycin
Figure 1.2
Flavonoid Core
Figure 1.3
Flavonoid Classes
Figure 1.4
Strucutres of Apigenin and Diandraflavone
Figure 1.5
Kidamycin and the C10 Epimer, Isokidamycin
Figure 1.6
Interaction of pluramycin and DNA backbone
Figure 2.1
Oxocarbenium Ion Attack
Figure 2.2
β-selective Mechanism of Trichloroacetimidates
Figure 2.3
O→C Rearrangement
Figure 2.4
Ferrier Rearrangement
Figure 2.5
Orbitals Used During π-Complexation
Figure 2.6
Glycosylation via Stannylation
Figure 2.7
β-C-Glycosides from α Attack
Figure 2.8
Dexcarboylative Coupling
Figure 4.1
Diandraflavone
Figure 4.2
Coupling of Chromophore
vii
LIST OF SCHEMES
Scheme 1.1
Flavonoid Oxidation
Scheme 1.2
Biosynthesis of Flavones
Scheme 1.3
General Enzyme Degradation Mechanism
Scheme 2.1
O→C Rearrangement in Vineomycinone B2 Methyl Ester
Scheme 2.2
Lactone Mechanism
Scheme 2.3
Reductive Aromatization
Scheme 2.4
Mechanism of Palladium Mediated Glycosylation
Scheme 2.5
Total Synthesis of Salmochelin SX
Scheme 2.6
Organoindium Mediate Cross-Coupling
Scheme 2.7
Diels-Alder Pathway to C-Aryl Glycosides
Scheme 2.8
Regioselective Cycloadducts Using Silicon Tether
Scheme 2.9
Palladium Catalyzed Ring Opening
Scheme 2.10
Synthesis of Galtamycinone
Scheme 2.11
O→C Glycoside Rearrangement for Bis-C-Glycosyl Synthesis
Scheme 2.12
Synthesis of Isokidamycin
Scheme 3.1
Fries-Type Rearrangement
Scheme 3.2
O→C glycoside Rearrangement
Scheme 3.3
Regioselective Rearrangement of Glycosyl Moiety
Scheme 3.4
Cyclization via Baker-Venkataraman Rearrangement
Scheme 4.1
Retroanalysis of Diandraflavone
Scheme 4.2
Synthesis of Glucolactone
Scheme 4.3
Sonagshira Palladium Cross-Coupling
viii
Scheme 4.4
Coupled Sugar Lactone and Phenylacetylene
Scheme 4.5
Synthesis of Galactopyranose 6g
Scheme 4.6
One-Pot Cyclization via Carbonylation
Scheme 4.7
Preparation of Chromophore Through Selective Methylation
Scheme 4.8
Two-step preparation of Chromophore
Scheme 4.9
Model Cyclization
ix
LIST OF TABLES
Table 1.1
Classification of C-Aryl Glycosides
Table 4.1
Reaction Conditions for Lactol Reduction
x
LIST OF EQUATIONS
Equation 3.1
Oxidative Cyclization of a Chalcone
xi
LIST OF ABBREVIATIONS
Ac
acetyl
aq
aqueous
BF3•OEt2
boron trifluoride etherate
Bn
benzyl
BnBr
benzyl bromide
d
doublet
DBU
1,8-Diazabicycloundec-7-ene
DCM
dichloromethane
DIPEA
diisopropyl ethyl amine
DMAP
4-dimethylaminopyridine
DMF
dimethylformamide
DMSO
dimethyl sulfoxide
DDQ
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DNA
deoxyribonucleic acid
equiv
equivalent
Et2O
diethyl ether
Et3N
triethylamine
EOM
ethyl methyl ether
EtOH
ethanol
imid.
imidazole
iPr3SiH
triisopropyl silane
m
multiplet
MeOH
methanol
xii
mL
milliliter
mmol
millimole
nBuLi
n-butyllithium
NMR
nuclear magnetic resonance
Pd(PPh3)2Cl2
bis(triphenylphosphine)palladium(II) dichloride
Ph
Phenyl
POCl3
phosphoryl chloride
PPh3
triphenylphosphine
p-TsOH
para-toluenesulfonic acid
pyr
pyridine
q
quartet
Rf
retention factor
rt
room temperature
s
singlet
t
triplet
TBAF
tetrabutyl ammonium fluoride
TBAI
tetrabutylammonium iodide
TBS
tert-butyldimethylsilyl
THF
tetrahydrofuran
TIPS
triisopropylsilyl
TLC
thin layer chromatography
TMSOTf
trimethylsilyl trifluoromethanesulfonate
TsCl
4-toluenesulfonyl chloride
TTMSS
tris(trimethylsilyl)silane
TTN
thallium (III) nitrate
xiii
ABSTRACT
Towards the Synthesis of Diandraflavone
By
Christine Ani Dimirjian
Master of Science in Chemistry
Diandraflavone is a natural product isolated and characterized from the Drymaria
diandra plant native to Taiwan. It has been used in traditional medicine to treat a wide
range of ailments from fevers to cancers. Considering the inefficient and cumbersome
process of isolating diandraflavone, a synthetic route to the C-glycoside flavanoid is
designed. The structure of diandraflavone shows potential for antitumor and antibacterial
applications through DNA interactions. First, diandraflavone consists of two
carbohydrate moieties on opposite sides of the molecule, one derived from glucose and
the other from galactose, both of which contribute to DNA binding specificity. Second, a
flavone chromophore (derived from an aromatic aldehyde) comprises a planar structure
needed for possible DNA intercalation between base pairs. In our efforts to synthesize
diandraflavone, the protected glucose and 2-deoxy galactose moieties have been
synthesized. A glucose derived sugar residue has been attached to a phenyl acetylene
moiety via β-C-glycosidic linkage. A second sugar, derived from galactose, has been
xiv
modified to match the natural product. The chromophore has also been prepared in a
model system to ensure that future coupling and cyclization between the β-C aryl
glycoside piece and the chromophore can occur.
xv
Chapter 1: Chemical and Biological Significance of C-Aryl Glycosides and Flavones
1.1 Introduction
Nature offers a large library of compounds with a variety of biological activities
such as antibacterial and antitumor properties.1 For example, the extracts of bacterial
secondary metabolites are used as antibiotics. Some antibiotics such as hedamycin and
rubiflavin have been shown to bind to DNA. Structurally, many natural products contain
a carbohydrate moiety linked to an aromatic (non-carbohydrate) moiety through a
glycosidic bond.2 While natural products containing oxygen-carbon linkages are
common, these O-aryl linkages are subject to acidic hydrolysis and enzymatic
degradation. 3,4 Replacing the oxygen-carbon bond with a carbon-carbon bond to link the
carbohydrate to an aromatic moiety affords a new class of structures called C-glycosides
(Figure 1.1). C-glycosides have been important targets for natural product synthesis,
because unlike O-glycosides, they are more resistant to cleavage and thus both an
aromatic portion and carbohydrate portion are allowed to interact with the DNA,
providing both intercalation and binding specificity.
1
Figure 1.1 The C-aryl glycoside kidamycin
1.2 Flavones
1.2.1 Structure
Flavonoids are a group of plant metabolites produced during photosynthesis
known as benzo-γ-pyrone derivatives.5,6 Flavonoids consist of three rings formed by a 15
carbon skeleton: a benzene ring (A), a fused heterocyclic ring (C), and a phenyl ring (B)
at the C2 or C3 position (Figure 1.2).
2
Figure 1.2 Flavonoid core
This core structure of flavonoids is an aglycone structure (lacking sugars) but the
glycoside, methyl and hydroxyl derivatives exist as well.5 The presence of phenolic
hydroxyl groups in flavonoids classifies them as polyphenols, which have been
extensively studied for the antioxidant effects they provide.7 Flavonoids can be further
classified as flavonols, flavones, and flavanones if the B ring serves as a C2 substituent,
or as isoflavonoids when the B ring is on the C3 position (Figure 1.3). Flavonols contain
a hydroyl group at the C3 position, while flavones contain alkyl groups instead. Whereas
the flavonols and flavones have an unsaturated C2-C3 bond, in the flavanones this bond
is saturated. Additionally, both flavanols and anthocyanins fall under the flavonoid
category, but lack the C4 keto functional group.8
3
Figure 1.3 Flavonoid classes
The abundance of flavonoids in plants serves a practical purpose in absorbing
UV-B radiation for leaf protection.9,10 The chemical structure of the flavonoids also
allows for the scavenging and quenching of free radicals (Scheme 1.1). Electron donating
groups on the B ring reduce the O-H bond dissociation energy, allowing the hydroxyl to
donate a hydrogen atom and an electron to an intruding radical to stabilize the species.11
It has been shown that hydroxy or methyl substitutions on the 2',3' or 4' positions on the
4
B ring play a critical role as radical scavengers.10, 12 The newly created flavone radical
may be stabilized through electron delocalization of the B ring from the C2-C3 double
bond conjugation with the C4-keto group.11,6
In addition to providing reducing power, flavones and flavonols have compatible
structures which allow for protein-binding.13 The planar conjugated rings allow for
electron delocalization and polarizability. The 4-keto group influences the acidity of the
7-OH group, making it partially deprotonated at neutral pH and available for electrostatic
interactions.13
Scheme 1.1 Flavonoid oxidation
1.2.2 Biosynthesis of Flavones
Flavones from plant sources are commonly found as O-glycosides or Cglycosides, aiding in water solubility in cell vacuoles.10,6 While flavonoids can be in
present in a variety of fruits, the flavones apigenin and luteolin are restricted to citrus
fruits.14 However, flavones can also be found in vegetables such as sweet peppers and
parsley.14,15
5
In plants, the precursor for flavonoids is chalcone.11 In just a few steps and with
the involvement of specific enzymes, phenylalanine is converted into the chalcone
(Scheme 1.2).11 Phenylalanine ammonia lyase (PAL) converts phenylalanine into transcinnamate, which in turn is hydroxylated to trans-4-coumarate by cinnamate 4hydroxylase (C4H).16 Trans-4-coumarate is then activated by 4-coumarate:CoA ligase
(4CL).16 The resulting 4-coumaroyl-CoA is condensed with three molecules of malonylCoA with the help of chalcone synthase (CHS) to yield the chalcone, in this case
naringenin chalcone.16 With the backbone assembled, the chalcone isomerase enzyme
(CHI) isomerizes the chalcone into the corresponding naringenin flavanone, which
through different enzymes and modifications can provide the plant with various
flavonoids.16,9 In plants, flavone synthases (FNSI and FNSII) are responsible for
desaturating the C2-C3 bond of naringenin to yield apigenin, or 4', 5, 7, trihydroxyflavone.7,8
6
Scheme 1.2 Biosynthesis of Flavones
7
1.2.3 Flavones and Cancer
Apigenin, like many other flavones, is a yellow crystalline compound.8,
11
Apigenin can be found in citrus fruits and different herbs including parsley and
chamomile.8 As the pure form of apigenin is unstable, apigenin is usually obtained with
glycosidic moieties attached.8 Since diandraflavone is a glycone O-methyl analogue of
apigenin, it is worthwhile to consider the biological properties of apigenin here.
Figure 1.4 Structures of Apiginin and diandraflavone
Over the past several decades, apigenin has been widely studied for its antiinflammatory, antioxidant and anti-carcinogenic properties.8 A study by Koganov et al
showed that apigenin in concentrations ranging from 0.001 to 100 mg/mL inhibits
fibroblast growth, which in turn speeds the healing of skin injuries.10,
17
In fact,
chamomile, an herb high in apigenin, has been used specifically for antibacterial and antiinflammatory purposes.8 The flavone's antioxidant effect preventing UV damage in plants
has also been exhibited in mice. When applied topically in mice, apigenin showed that
the incidence of chemically induced tumors decreased from 76.7 to 16.7 percent.18
8
What makes apigenin an attractive choice for medicine is that although natural
sources are limited, about a quarter of ingested apigenin remained in the body up to 10
days.8 Such accumulation of this flavone may be a factor in its effectiveness as a
chemopreventive agent. Apigenin serves to induce apoptosis in a variety of cancer cells
including breast HER2/neu cells, cervical carcinoma HeLa cells, colon cancer cells,
prostate PC-3 cells, and leukemia HL-60 cells.8
1.3 C-Aryl Glycosides
1.3.1 Classification
As previously mentioned, flavones occur naturally as glycosides. C-aryl
glycosides can be classified into four groups, based on the substitution pattern of the
glycoside relative to the hydroxyl group on the aromatic ring (Table 1.1).2 In group 1, the
glycoside is para to the phenolic hydroxyl, while in group 2, it is ortho. Compounds of
group 3 have sugar moieties in both the para and ortho positions of the aromatic
hydroxyl. Group 4 compounds are unique in that one glycoside is ortho to one hydroxyl
group and meta to a second hydroxyl group. Examples of compounds of each of the four
classes are shown below. The classification of these compounds becomes important
during synthesis as the methods in creating the glycosidic linkage directly effects
regioselectivity. While some methods of synthesis can be applied to more than one class,
there still does not exist a unified approach for all substitution patterns.
9
Table 1.1 Classification of C-aryl glycosides
10
1.3.2 The Group III bis-c-aryl glycosides
While C-aryl glycosides have been studied a great deal, there have been only a
handful of attempts to synthesize the bis-C-aryl glycosides of Group 3. As Group 3 type
glycosides, the pluramycin family has gained attention due to antibiotic and antitumor
activities.
3, 19
Many syntheses have been completed for the aglycone of the pluramycin
family, yet the glycosylated derivatives have proved difficult to prepare. Hauser and Rhee
were able to synthesize the aglycone O-methyl ether of kidamycin in 1980.20 Since then,
there have been a few attempts to synthesize the bis-C-glycoside of kidamycin, and while
they are able to achieve the desired regioselectivity, none have been able to use the
natural glycosides.19, 21 It was not until five years ago that the first complete synthesis of a
bis-C-arylglycoside from the pluramycin family was synthesized (Figure 1.5).3 Martin et
al. were able to make isokidamycin, the C10 anomer of kidamycin.3 It was previously
shown that when kidamycin is exposed to acid and heat, it forms the isokidamycin
anomer.22
Figure 1.5 Kidamycin and the C10 epimer, isokidamycin
11
1.3.3 Properties
Polysaccarides are polymers of sugar monomers linked together through oxygen
atoms. Typical carbohydrates are O-glycosides, but by replacing the oxygen atom with
carbon, most physical properties such as bond length and coupling constants remain
similar.23 However, one important difference is that the C-glycosides are more stable to
acid hydrolysis, making them an attractive target in medicine.23 In the presence of a
proton donor from the enzyme, the exocyclic oxygen in O-glycosides partakes in
hydrogen bonding to create a better leaving group (Scheme 1.3). Once the exocyclic
oxygen bond is broken, an oxocarbenium ion is formed, and one of two mechanistic
pathways is taken, resulting in either a retention or inversion at the anomeric center.24 In
a retention pathway, the departure of the leaving group is assisted by a nucleophilic base
in close proximity. The presence of a water molecule hydrolyzes the glycosyl-enzyme
bond by substitution and the original stereochemistry is retained.25 An inversion will
occur when the nucelophilic base is further away from the glycoside and the water
molecule acts as the nucleophile. The base residue on the enzyme acts to deprotonate the
water molecule and now the inversion product is obtained. In both pathways, the distance
between the proton donor and sugar is the same, so it is only the distance of the catalytic
base and sugar that determines the mechanism.24
12
Scheme 1.3 General enzyme degradation of O-glycosides
1.4 DNA Interaction
Research on C-aryl glycosides has been driven by their biological properties,
particularly as potential anticancer agents. Since DNA is responsible for important
cellular processes necessary for cell growth and replication, it is a desirable target for
drugs. Many DNA targeting drugs are responsible for single strand breakage due to
inhibition of unwinding by topoisomerase.3,
26
Pluramycins, a group of compounds
isolated from Streptomyces derived bacteria, have exhibited strong interactions with
DNA.19 The carbohydrate moieties on the molecule can bind to the major or minor
grooves formed by the nucleic acid backbone of DNA.27 The binding of the sugar
moieties allow the molecule to direct the chromophore between the base pairs of DNA.
This noncovalent stacking interaction of the aromatic base pairs and aromatic portion of
the molecule is known as intercalation.28 The pluramycins hedamycin, kidamycin, and
altromycin have been shown to intercalate through DNA coiling studies which can be
13
visually observed.29 Intercalation by a drug will unwind supercoiled DNA and retard
migration on gel electrophresis, resulting in streaking bands. Thus, it was shown that
intercalation can occur with molecules such as the pluramycins.29 In addition to
intercalation, molecules may also covalently modify DNA through alkylation. For
example, the epoxide of altromycin B can interact with the N7 residue on guanine bases,
causing cleavage of DNA (Figure 1.6).27
Figure 1.6 Interaction of Altromycin B with DNA backbone
14
Chapter 2: Methodology in C-Glycoside Synthesis
2.1 Introduction
C-glycosides have been a target for many researchers due to their resistance to
acidic and enzymatic hydrolysis. Postema, and separately Levy and Tang, have both
published comprehensive reviews of the available methods for synthesizing C-glycosides
up to 1995.23,30 A more recent review emphasizing methods for β-C-glycosides was
compiled by Nagarajan.31 The methods for synthesis can be classified into one of five
groups: electrophilic substitutions at the anomeric center, nucleophilic substitutions by
the sugar, transition metal mediated reactions, cycloadditions, or benzannulations.
Representative examples from the first three groups will be presented.
2.2 Electrophilic Substitutions
Electrophilic substitutions on the anomeric carbon of the carbohydrate are
commonly used for carbon-carbon bond formation due to the variety of available sugars,
Lewis acids and nucleophiles. Early examples created an oxocarbenium ion intermediate
that would allow for a mixture of anomers, but by using different activating groups or
Lewis acids, these reactions have experienced higher stereoselectivity.
2.2.1 Friedel-Crafts Approach
Early examples of C-glycosylation relied on Friedel-Crafts type methods where a
glycosyl donor is activated by a Lewis acid. Common Lewis acids used for this
transformation include TMSOTf, BF3•OEt2 and SnCl4.23,32 The glycosyl donor may
15
contain acetyl, alkyl, halogen or trichloracetimidate leaving groups, which are acted on
by the Lewis acid promoter. The glycoside is transformed into an oxocarbenium ion,
allowing attack by an electron rich moiety at either the top or bottom face, resulting in
either the α or β anomer (Figure 2.1). It is thought that the presence of the oxocarbenium
ion would primarily afford the α anomer, as dictated by the stereoelectronics at the axial
position, referred to as the anomeric effect.33 However, under different reaction
conditions, a mixture of anomers are obtained, leading to a need for stereoselective
methods.
Figure 2.1 Oxocarbenium ion attack
β
α
There have been several methods in efforts to control the stereochemistry of Cglycosides in favor of the β anomer. Schmidt et al. showed that trichloroacetimidates
preferentially gave the β anomer in high yields when coupled with aromatic rings.34 In
this case, the axial trichloroacetimidate coordinates the Lewis acid and the oxocarbenium
ion is not formed (Figure 2.2). This forces the nucleophile to attack in SN2 fashion from
the equatorial position.
16
Figure 2.2 β-selective mechanism of trichloroacetimidates
Suzuki et al. found that glycosyl fluorides could be activated in benzene with
Group IV metallocene complexes Cp2MCl2 (M=Zr, Hf) with AgClO4, to result in high
stereoselectivity for the β anomer.35 This methodology was later employed to synthesize
the C-glycoside antibiotics mycinamicin IV and mycinamicin VII.36
Suzuki's metallocene complex was also shown to promote a rearrangement of Oglycoside to C-glycoside.37 By using the same glycosyl fluorides as before, or switching
to a more stable 1-O-acetyl sugar, a two-step process yields mostly β-C-glycosides.37 In
the first step, the anomeric carbon undergoes an O-glycosidation with a phenol species
(Figure 2.3). Once the O-glycosyl is formed, the temperature is slowly increased and the
O→C rearrangement takes place, resulting with the new bond formed ortho to the
phenolic hydroxyl group.38 The formation of the C-glycoside was explained through the
idea of the oxonium-phenolate ion-pair.39
17
Figure 2.3 O→C rearrangement
The O→C rearrangement has proved to be a critical tool in the synthesis of
antibiotics such as vineomycinone B2 methyl ester (Scheme 2.1).40 Due to the formation
of the oxocarbenium intermediate, a mixture of anomers was obtained, however choice of
Lewis acid influenced the ratio. It was shown that using BF3•OEt2 favored the kinetically
stable α anomer, but the Cp2HfCl2-AgClO4 complex yielded solely the β anomer.
Altering the stereoelectronic effects help to direct the nucleophile to add at the axial
position, whereas steric effects favor the equatorial position to yield β-glycosides.41
18
Scheme 2.1 O→C rearrangement in Vineomycinone B2 methyl ester
2.2.2 Glycals
The O→C rearrangement has also been observed in 2,3-unsaturated glycals.42
Glycals are the cyclic enol ether derivatives of carbohydrates with a double bond at the
1,2 positions. In the presence of Lewis acids, the glycal with a 1,2 unsaturation undergoes
a Ferrier rearrangement which shifts the double bond to a 2,3 position (Figure 2.4). The
Lewis acid is responsible for the departure of the group at the allylic position, C3, which
subsequently causes an allylic shift. If there is a nucleophile present, substitution occurs
at the newly allylic position, which is now also the anomeric center. Again, it was
observed that addition to the axial position by the nucleophile was kinetically preferred.
However, in cases where electron-rich nucleophiles were used, addition to the β-face was
preferred, due to competition with solvent for a less sterically hindered environment.43
19
Figure 2.4 Ferrier rearrangement
2.2.3 Lactones
So far, the reactions discussed have resulted in a mixture of anomers. One method
that is selective for β-C-glycosides is through the use of sugar lactones and alkyl or aryl
organometallics. Kishi showed a lactone treated with allylmagnesium bromide resulted in
a hemiketal, which could be further reduced using known methods.33 This method left the
aliphatic group in the desired equatorial position. Kraus further explored the hemiketal
route and found that benzyated lactones were able to survive under the harsh environment
produced by the BF3•OEt2 and triethylsilane reducing agents.44 While Kraus
demonstrated the versatility of aryl Grignards and aryllithium reagents, Czernecki
displayed further extension to heterocyclic rings like furyllithum.44, 45
20
Scheme 2.2 Lactone Mechanism
The products obtained through these reductions have been shown to have high
stereospecificity. Several groups have reported spin-spin coupling constants of 9.6-9.7
Hz, in agreement with literature values for the β anomer.44,33,45 This result is partly due
to the stabilization of the oxocarbenium intermediate by the anomeric effect mentioned
before. The oxocarbenium intermediate has a preference to accept nucleophiles axially,
and in this reduction, the hydride attacks from the α face, leaving the β face open for the
aryl system (Scheme 2.2).33
21
2.3 Nucleophilic Addition to Electrophilic Aromatics
The glycoside is not limited to its role as the electrophile; it can also act as a
nucleophile. Parker demonstrated the use of this umpolung, or reverse polarity, strategy
for the synthesis of C-aryl glycosides.2,46 In this method, a lithiated glycal is added to a
quinone and the resulting quinol ketal undergoes reductive aromatization (Scheme 2.3).46
The standard aluminum or borane hydrides reagents used for reducing ketals to ethers did
not work for reductive aromatization, so borane-methyl sulfide was used instead.46
Scheme 2.3 Reductive aromatization
While the umpolung strategy was developed primarily for Group 1 glycosides, the
borane-methyl sulfide reagent also opened the door to expanding the strategy to Group 4
compounds through rearrangement.2 To optimize the rearrangement, zinc chloride was
used so that the Lewis acid would not act as a hydride donor.2
22
2.4 Transition Metals
2.4.1 Introduction
An alternative method to creating C-glycosides uses transition metals in order to
avoid the epimerization problem encountered when using acid or base in the presence of
a stereogenic center.23 Common couplings done in this manner involve glycals with aryl
or similar π-conjugated systems mediated by palladium acetate.
2.4.2 Palladium cross-couplings
Shortly after Heck's discovery of palladium mediated cross-couplings, Daves was
able to apply the method to glycals. The first examples featured a pyrimidine mercuric
acetate species as the aglycon to be coupled with 1,2 unsaturated sugars.47 The coupling
process is thought to undergo four stages, the first of which is transmetalation of the
mercuric acetate with palladium acetate (Scheme 2.4).47,
48
Following that, a
stereospecific π-complexation of the palladium with the enol ether (glycal) occurs. Next,
a regioselective insertion of the enol ether double bond into the Pd-C bond allows for the
formation of the σ-adduct. Finally, a σ-adduct decomposition eliminates palladium
hydride in a β-hydride elimination and forms the product. For cyclic enol ethers, the
regiochemistry is dictated by the electronics of the π-complex, which forms from the
highest occupied molecular orbital (HOMO) of the enol ether with the antibonding (σ*)
orbitals of the Pd-aglycon species (Figure 2.5).48 The large electron density on the βcarbon attracts the electron deficient palladium(II) center, while the α-carbon on the enol
ether gravitates toward the electron-rich aglycon, simultaneously forming two σ-bonds. 48
23
Scheme 2.4 Mechanism of Palladium Mediated Glycosylation
transmetalation
β-hydride
elimination
π -complexation
σ-adduct
formation
Figure 2.5 Orbitals used during π-complexation
In addition to controlling regiochemistry, the use of palladium species also
influences the stereochemistry based on the π-complex formation. When the three
hydroxyl groups on the enol ether remain as free hydroxyls, a mixture of α and β products
24
is obtained, but if only one hydroxyl is substituted, the π-complex will favor the side
opposite the large group. However, when both hydroxyl groups are substituted, almost
exclusive β product is obtained, as the closer substituent to the enol ether interferes with
π-complex formation.48
Beau showed that Stille type coupling could be applied to stannylated glycals, and
could be more useful than tin-lithium couplings in base sensitive protecting group.49,50
Phenylsulfonyl glucals are used to undergo stannylation and are then refluxed with a
palladium catalyst and desired aryl halide to produce the corresponding C-glycal (Figure
2.6).49 The system was initially tested with aromatic bromides and after yields greater
than 80 percent, other substituents such as benzyl, acyl and allyl were found to have
similar results. An advantage of this coupling is that is leaves the enol ether group
unchanged so it can be manipulated into regioselective and stereoselective
hydrogenations, hydroboration-oxidations or epoxidations.49, 51
Figure 2.6 Glycosylation via stannylation
The coupling of these tributylstannyl-D-glucals can be applied even further by
using 1,3-dibromobenzene in order to obtain meta-substituted aromatics.49,
51
The
formation of bis-C-glycosides has been an important step in the synthesis of the
antifungal antibiotics such as papulacandins and chaetiacandin.50 Once coupled,
25
modifications such as oxidizing agents would attack at the α-face, yielding the β-Cglycosides (Figure 2.7).
Figure 2.7 β-C-glycosides from α attack
α face
Building on the use of palladium catalysts, an arylborane system was used by
Suzuki. In addition to being less toxic, arylboronic acids have gained popularity in
catalysis due to the stability in air and moisture.52 The reaction is proposed to be
mechanistically similar to the previous mercuric acetate, but now the transmetallation
step involves the phenyl-boronic acid and Pd(OAc)2.53 While this catalyst may seem
advantageous, it has been noted that a second transmetalation can occur, resulting in
PdPh2 which can reductively eliminate to Pd(0) and biphenyl in β-elimination.52 In
addition,
the aqueous conditions used for the reaction results in competitive
deboronation of the boronic acids.54
In order to overcome low yields due to steric hinderance from the arylboronic
acids and electron withdrawing compounds, a Negishi coupling using zinc and nickel was
pursued.54 Gange et al. realized that pincer ligands could be used on sp3 carbons in order
to avoid β-elimination.55 Using the optimized conditions of Ni(COD)2 with tBu-Terpy
26
ligands to cross-couple with ArZnI·LiCl in DMF, the β-C-aryl glucoside, salmochelin
SX, was synthesized in high β-selectivity (1:20 α:β) in 55% yield (Scheme 2.5).55
Scheme 2.5 Total Synthesis of Salmochelin SX
The Minehan group presented a recent environmentally benign organoindum
reagent that could also be used in cross-couplings (Scheme 2.6).56 After first being
subjected to an indium mediated aldehyde allylation, the glycoside undergoes crosscoupling with the respective triarylindium reagent.
27
Scheme 2.6 Organoindium mediated cross-coupling
Similar to the aryl halides, it has been demonstrated that carboxylic acids can be
used in the presence of palladium catalysts for Heck-type reactions.57 Xiang adapted the
method of decarboxylative coupling to glycals. Using Pd(OAc)2 with ligands such as
PPh3 in addition to Ag2CO3 catalyst, the corresponding C-aryl glycosides can be obtained
by using a variety of glycal derivatives in good yield with stereochemical control (Figure
2.8).
Figure 2.8 Decarboxylative Coupling
28
2.5 Examples of C-Aryl Glycoside Synthesis
2.5.1 General Strategies
Martin et. al worked on strategies to generalize the synthesis of the four groups of
C-glycosides.1,58 Group I C-aryl glycosides were obtained by Diels-Alder reaction
between 2-glycosyl furan and benzyne. The formed oxabicyclic compound would then be
treated with an acid to undergo a ring opening to give the C-aryl glycoside. (Scheme
2.7).58
Scheme 2.7 Diels-Alder Pathway to C-aryl glycosides
The same method could be applied to 3-glycosyl furan to obtain Group II C-aryl
glycosides, which in turn could be oxidized to yield Group IV C-aryl glycosides.58
29
Taking the same pathway one step further, a second sugar can be introduced to the
glycosyl furan compound, to give a 2,4 diglycosyl furan, before partaking in a DielsAlder reaction. Upon treatment with acid, the Group III glycosides are obtained (Scheme
2.8).58 It was later shown that these reactions could be regioselective by building a silicon
tether between the furan and phenol.59
Scheme 2.8 Regioselective Cycloadducts Using Silicon Tether
30
An alternative pathway to prepare Group II, III and IV C-aryl glycosides is
through palladium catalyzed coupling of a sugar nucleophile with benzyne-furan
cycloadduct.60 The palladium aids in opening of the cycloadduct through a SN2' type
fashion and an iodo glycal is able to add ortho to the bridging oxygen (Scheme 2.9).
Scheme 2.9 Palladium catalyzed ring opening
2.5.2 Galtamycinone
Suzuki had the first recorded synthesis of galtmycinone, a linear tetracycle of the
angucycline family, through a two cycloaddition synthesis.61 The first cycloaddition of Colivosyl benzyne to furan resulted in the key intermediate C-olivosyl juglone (Scheme
2.10a). With the first half of galtmycinone in hand, it was exposed to the base-induced
cycloaddition with homophtalic anhydride via the Tamura protocol, leading to the desired
tetracycle (Scheme 2.10b).
31
Scheme 2.10 Synthesis of Galtamycinone
a) Cycloaddition of glycosylbenzyne and furan
b) Tamura cycloaddtion
Martin proposed an alternative cycloaddition to prepare C-olivosyl juglone via the
Diels-Alder reaction proposed earlier, which would add an olivosyl furan to the
benzyne.60 A second method of a palladium-catalyzed ring opening of a furan-benzyne
cycloadduct coupled with an iodo glycosyl would also result in the juglone intermediate.1
This pathway would allow for greater versatility as the carbohydrate can be added later in
the synthesis and allow for more variation in products.
32
2.5.3 Pluramycin
The total synthesis of members of the pluramycin family of antibiotics, which
follow the Group III C-aryl glycoside pattern, has proven challenging. 3,20,62 Danishefsky,
et al. studied possible strategies into making pluraflavins, one of the bis-C-aryl
glycosides from the pluramycin family.62 The approach required that the aromatic core be
made first and then the glycosides could be introduced through Stille cross-coupling.
Interesting to note is that pluraflavin A requires α glycosidic linkages, but the β Cglycoside is obtained as thermodynamic product so special conditions for the
hydrogenation of the C-aryl glycal were needed to result in the desired α isomer.
There have been many attempts at another member, kidamycin, but only recently
has synthesis of its stereoisomer been fruitful.3 While some groups have had success in
synthesizing the aglycon core of kidamycin, incorporating the carbohydrate moieties has
proven difficult.20,
63
Suzuki was able to obtain the desired bis-C-glycosyl substitution
pattern by subjecting the chromophore to the O→C glycoside rearrangement twice
(Scheme 2.11).64 While the sugars were only introduced to a model system with one ring,
instead of the tetracyclic chromophore, it was shown that the sugars were present as the β
isomer.64
33
Scheme 2.11 O→C Glycoside Rearrangement for Bis-C-Glycosyl Synthesis
Shortly after, Martin et al. provided the first total synthesis of a bis-C-aryl
glycoside with isokidamycin, the C10 anomer of kidamycin (Scheme 2.12).3 This was
done by extending previous works to create adducts between naphthyne and glycosyl
furans. Once the aminoglycosyl furan was made, a silicon tether was added to aid in
regioselectivity. This piece was used in a Mitsubou etherification with a substituted
naphthol. A Diels-Alder reaction formed the third and final ring for the system, which
after a few modifications was ready for the introduction of a second aminoglycosyl
moiety.
34
Scheme 2.12 Synthesis of Isokidamycin
35
Chapter 3: Methodology in Flavone Synthesis
3.1 Introduction
As flavones contain a C-glycosidic linkage, many methods used to make them
have been encountered before.65 The most common method is utilizing the O→C
rearrangements on the aromatic glycosyl acceptors after glycosidation. Once an
arylglycosyl is formed, other benzene derivatives can be introduced via aldol
condensations. After a final cyclization step, the C-glycosyl flavone is obtained.
3.2 Synthesis of C-Glycosylflavonoids
3.2.1 Fries-Type rearrangement
The Friedel-Crafts-type reactions between glycosyl donors and electron-rich
aromatic glycosyl acceptors explored previously have provided one method of Cglycoside formation. For flavones, a slightly different strategy involving Fries-type
rearrangements, has been used to form C-glycosylflavonoids.66 Glycosylation occurs with
a partially unprotected 2-acetyl phenol, made from 2,4,6-trihydroxyacetophenone, and an
O-benzylated glucosyl trichloroacetamide under Lewis acidic conditions. The formed Oglycoside undergoes a Fries-type rearrangement to transfer the glycosyl moiety from the
hydroxyl group to a position ortho on the aromatic ring (Scheme 3.1). This new Cglycosylacetophenone is then introduced to a benzaldehyde derivative in order to create a
chalcone, which can then be cyclized into the corresponding flavone.66
36
Scheme 3.1 Fries-Type Rearrangement
3.2.2 O→C glycoside rearrangement
The O→C glycoside rearrangement observed by Suzuki had first been applied to
the synthesis of C-glycosylflavones by Kumazawa et al.67 A glycosyl fluoride is
introduced to a phloroacetophenone derivative, acting as a glycosyl acceptor, in the
presence of a catalytic Lewis acid. While some phenolic hydroxyls may be protected, it is
important to keep the hydroxyl group ortho to the acetyl group unprotected to provide a
temporary site for O-glycosylation. The ortho hydroxyl returns to a free hydroxyl
immediately through the Lewis acid promoted O→C rearrangement (Scheme 3.2).68-70
Once the rearrangement takes place, the ortho hydroxyl can be protected and the
hydroxyl para to the glycosyl should be deprotected to allow for cyclization.
37
Scheme 3.2 O→C Glycoside Rearrangement
Several flavones have been synthesized by utilizing the O→C rearrangement. A
more sophisticated synthesis uses acetyl groups to protect the ortho free hydroxyl after
condensation, in order to allow for regioselective rearrangement to 8-C-glycosylflavones
(Scheme 3.3).70
Scheme 3.3 Regioselective Rearrangement of Glycosyl Moiety
38
3.3 Cyclization
Baker–Venkataraman transformation
A common method for forming flavones is by cyclization of the C ring by Baker–
Venkataraman rearrangement.71 The first step to synthesize flavones is to subject a
hydroxyacetophenone to an aldol condensation with a benzoyl chloride derivative. When
the resulting benzoyl ester is treated with base, it undergoes a Baker–Venkataraman
rearrangement, wherein a 1,3 diketone is formed. Exposure to strong acidic or basic
conditions promotes the cyclization into the flavone (Scheme 3.4).68
Scheme 3.4 Cyclization via Baker Venkataraman Rearrangement
39
A second method for cyclization involves the oxidation of a chalcone product.
Again, starting with an aldol condensation of a hydroacetophenone to a benzaldehyde
derivative, this time a chalcone was formed. Although free hydroxyls may be protected to
prevent side reactions from occurring, it is important for the phenolic hydroxyl group to
remain unprotected so that glycosylation and cyclization can occur.72 In order to prevent
oxidation of the protecting methylbenzyl groups, I2, a milder oxidative reagent was used
(Equation 3.1).
Equation 3.1 Oxidative Cyclization of a Chalcone
40
Chapter 4: Synthesis of Diandraflavone
4.1 Introduction
Since their discovery, the functional C-aryl glycosides are common in antibiotics
from bacteria. While not derived from a microbial source, the plant metabolite
diandraflavone still contains two important glycosidic linkages to a flavone core (Figure
4.1). Diandraflavone is bis-c-aryl glycoside flavone extracted from the plant species
Drymaria diandra Blume. Belonging to the genus Drymaria, this plant is native to
Southeast Asia has been used for treating many different ailments including hepatitis,
rheumatism and cancer.73
Figure 4.1 Diandraflavone
4.2 Structure and Retrosynthetic Analysis
Structurally, diandraflavone can be viewed as a flavone with carbohydrate
moieties on either side. These sugar moieties, one derived from galactose and one from
glucose, may contribute to DNA binding specificity. The flavone core gives rise to the
41
planar structure needed for possible DNA intercalation between base pairs. In order to be
able to bind and interact with DNA therefore, the goal in making diandraflavone is to
introduce the sugar groups to the flavone core and form the important C-aryl glycosidic
bonds (Scheme 4.1).
If the first glycosidic bond between the galactose sugar and flavone core is cut,
the galactose moiety 6f can be seen as the 2,6 dideoxy derivative of galactose. The
galactose sugar can be considered a Group IV C-aryl glycoside, ortho to a free hydroxyl
and para to a cyclic hydroxyl, which can then be introducted to the system through an
O→C rearrangement. The larger C-glycosylflavone fragment 7b can further be broken
down into a simpler aromatic derived from phloroglucinol 7a and the protected
glucophenylacetylene 5c. The fragment 5c can be made through an electrophilic
substitution of the glucolactone 2d by the phenylacetylene made from 3a.
4.3 Glucose moiety and first coupling
Although in the final product, the glucose moiety looks unchanged, a few
modifications were necessary to allow the formation of the C-glycosidic bond formation.
Following the protocol established by Yepremyan et al., a glucose lactone was made
starting from commercially available dextrose (Scheme 4.2).74 The hydroxyl at C1 was
first protected with an allyl ether under acidic conditions, and the remaining free
hydroxyls were benzylated. The allyl ether was removed by base mediated olefin
isomerization followed by enol ether hydrolysis. Instead of proceeding with the Swern
42
Scheme 4.1 Retroanalysis of Diandraflavone
oxidation to provide the lactone, an alternative Albright-Goldman oxidation was done.
This change allowed the reaction to take place at room temperature instead of -78°C and
produced the lactone in 80% yield and matched spectral data from the previous method.
43
Scheme 4.2 Synthesis of Glucolactone
The phenylacetylene piece was synthesized by Sonogashira coupling of trimethyl
silyl acetylene and 1-bromo-4-iodo benzene. The basic mechanism shows how palladium
and copper work together to couple the two pieces together (Scheme 4.3). First the
palladium inserts itself in between the aryl and halide groups. This step is called
oxidative addition because the palladium goes from oxidation state of 0 to 2+, so it is
being oxidized. In the transmetalation step, the copper displaces the terminal hydrogen by
increasing the acidity of the proton so that it is picked up by triethylamine. The resulting
copper acetylide can then undergo transmetalation with the palladium species. After
transmetalation, reductive elimination allows the two pieces separated by palladium to
join and palladium returns to its oxidation state of 0.
44
Scheme 4.3 Sonagshira Palladium Cross-Coupling
With both lactone and 1-bromo-4-(trimethylsilylethynyl)benzene in hand, a few
approaches were taken in coupling them. It has been shown that β-C-glycosyl linkages
between can be created between sugar lactones and TMS-acetylene.75, 76, 77 Although our
synthesis uses TMS-acetylene, the required linkage actually occurs between the
additional phenyl ring in a linkage that is truly a β-C-aryl glycosidic bond. Despite this
difference, the same mechanism was expected to occur, so the protocol set by others was
followed. First, the protected phenylacetylene was activated with butyllithium at -78°C,
and then added to cerium trichloride.75 Once this was allowed to react, the lactone was
added. This procedure only resulted in a 13% yield, but when repeated without the
45
cerium trichloride, the product yield was improved to 31%. The yield was further
improved when the protected phenylacetylene and butyllithium mixture was warmed
from -78°C to 0°C after 40 minutes of introduction, and then cooled back down to -78°C
before adding the lactone. Allowing time for activation by temperature manipulation gave
yields of 66%.
Once coupled, the resulting lactol needed reduction to afford the desired
compound. Several attempts were required before this was successful (Table 4.1). The
agent BF3◦OEt2 was used in combination with triethylsilane at various temperatures and
solvents. Another attempt came from using trimethylsilyl trifluoromethanesulfonate
(TMSOTf) instead of BF3◦OEt2. The reaction was allowed to take place at -78⁰C, but
again this attempt did not successfully reduce the compound. Since the sugar can convert
between the open chain and ring conformers, if an oxygen is present, it would result as a
ketone and would be apparent when analyzed through carbon NMR spectroscopy with a
peak around 180ppm.
Table 4.1 Reaction Conditions for Lactol Reduction with TMS-acetylene Intact
Lewis Acid
(eq)
Silane
(eq)
Solvent
Temperature
Yield
BF3◦OEt2
(4)
Et3SiH
(4)
MeCN: CH2Cl2
(2:1)
-10°C
decomposition
BF3◦OEt2
(3)
(TMS)3SiH
(5)
MeCN: CH2Cl2
(85:15)
0°C
13%
BF3◦OEt2
(3)
Et3SiH
(5)
MeCN: CH2Cl2
(85:15)
-40°C
no reaction
TMSOTf
(2)
Et3SiH
(3)
CH2Cl2
-78°C
decomposition
46
Thus, it was proposed to cleave the protecting trimethylsilane group from the
coupled product before reduction (Scheme 4.4). A solvent system of 5:1
methanol:methylene chloride and 1M NaOH was reacted at room temperature for 2-3
hours. The product was purified and subject to silane reduction using 5 equivalents of
triisopropyl silane and 3 equivalence of BF3◦OEt2 in a 3:1 acetonitrile: methylene
chloride solution. Based on other studies, triisopropylsilane was chosen instead of
triethylsilane in order to provide more steric bulk. Since the α-face of the oxocarbenium
cation is less sterically hindered, using larger silanes would improve the stereoselectivity
to favor the β anomer.76 After the silane reduction, a carbon NMR spectra was taken and
showed successful reduction with the absence of a carbon peak in the ketone region
(~180ppm).
Scheme 4.4 Coupled Sugar Lactone and Phenylacetylene
47
4.4 Galactose Sugar Manipulations
In order to make the 2,6 dideoxygalactopyranose formed by the synthesis, a
galactose starting material, 3,4,6-tri-O-acetyl-D-galactal was used. The acetyl groups
were cleaved and the C6 hydroxyl was converted to a tosyl leaving group. It was thought
that from this point, the tosyl could be cleaved to obtain 6 deoxygalacal, but the yields
were considerably low so an alternative starting point was devised.
Galactose was first protected at the C1 position with an allyl group, using the
same conditions as before with glucose. This galactoallyl pyranose was protected at the
C3 and C4 positions with an acetonide group and then cleave the oxygen at the C6 carbon
using lithium aluminum hydride. This cleavage did not work due to possible steric
hinderance from the acetonide group, which prevents the hydride from cleaving the C-O
bond and instead cleaves the S-O bond from the tosyl to reform the hydroxyl at C6. Thus,
a second method was tried in which after allyl protection, the C6 oxygen was cleaved
first, and then the acetonide group was added. After the successful reduction at C6, the
acetonide group was added to C3 and C4 with a procedure adapted from Steffan et al.78
The sugar was treated with 2,2dimethoxypropane and acetone in a 1:4 mixture and using
a catalytic amount (2% mol) of toluenesulfonic acid at room temperature.
With the C3 and C4 free hydroxyls protected, it was time to focus on the C2
hydroxyl. Reduction by forming the xanthate group was attempted using a procedure
Shafer et al.79 The xanthate source that was added to the oxygen at the C2 carbon came
from carbon disulfide, with catalytic imidazole, sodium hydride and methyl iodide. In a
1:1 solvent of EtOAc:hexanes, the Rf value for this compound was 0.87, slightly higher
than the acetonide starting product. The xanthate was dissolved in triethylamine and
48
degassed hypophosphoric acid, in addition to azobisisobutyronitrile (AIBN) was added at
100⁰C, but this resulted in decomposition of the reagents. A second trial was done using
freshly distilled triethyl amine, but still did not result in product. An alternative method
using tris(trimethylsilyl)silane, toluene and AIBN, however, proved successful.
Scheme 4.5 Synthesis of Galactopyranose 6g
49
4.5 Preparation of the Chromophore
Once the auxilary carbohydrates were made, we looked to assemble the
chromophore to hold the pieces together. It was proposed to use one aromatic ring, and
through coupling and cyclization of glycosyl acetylene 5c, the second ring of the core
could be formed (Figure 4.2). The key features of the chromophore is a single
methoxygroup in the para position to either a halogen or aldehyde that will allow for later
coupling. Phloroglucinol was used as the starting material due to the 2,4,6 substitution
pattern and ease of manipulation.
Figure 4.2 Coupling of Chromophore
50
In the first attempt at the chromophore, one of the hydroxyl groups on
phloroglucinol was converted into a methoxy group. With methoxy as a strong activating
group and electron donating substituent, it was perceived that halogenation or
formylation would occur ortho or para to the group. There was hope that due to steric
hinderance, only the para isomer would be obtained. Initially, it was thought to have an
iodine at the 4-position, so that it would be accessible to a one-pot palladium catalyzed
carbonylative annulation as had been demonstrated before by the Larcock group80
(Scheme 4.6).
Scheme 4.6 One-Pot Cyclization via Carbonylation
51
Using Mo(CO)6 as a carbonyl source, it was shown that iodo phenols would
cyclize with terminal alkynes at high heats. A test reaction with was performed o-iodo
phenol and phenyl acetylene to verify reaction conditions. Heating at 160°C for 2 hours
resulted in a 40% yield of UV active product. A second test using 1-methoxy 3,5hydroxy
4-iodo benzene was added to phenyl acetylene and showed conversion by TLC.
Encouraged by these results, phenyl acetylene was replaced by 5c, and exposed to the
same conditions as before, however there was little conversion and the compound had
polymerized due to subjection at high heat.
After unsuccessful carbonylation, the iodo substituent was abandoned in favor of
aldehyde. Formylation of 1-methoxy-3,5-dihydroxy-benzene would yield both para and
ortho isomers, which were unfortunately inseparable by flash chromatography. In our
effort to obtain one isomer, phloroglucinol was subjected to formylation first, followed
by methylation. Once again, however, both para and ortho regioisomers were obtained as
an inseparable mix. Characterization by NMR showed there to be a 3:1 mixture of para to
ortho. To try to solve the regioselectivity issue, a variety of ether and silyl protecting
groups were used in order to selectively place a methoxy para to the aldehyde. First,
triisopropylsilyl ether was used to protect the hydroxyl group para to the aldehyde
(Scheme 4.7). The remaining hydroxyls were protected by methyl ethyl ether, so that the
OTIPS group could be selectively removed to reveal a free hydroxyl which could then be
methylated. With the desired methoxy para to the aldehyde, direct coupling of the
terminal alkyne of the 5c using an organolithium was thought to occur with the aldehyde.
After three hours, little conversion had taken place, possibly due to overcrowding near
the aldehyde due to the EOM acetal. Protection using the ethyl methyl ether and the
52
deprotection of triisopropylsilyl ether gave inconsistent results due to incomplete
conversion, high solubility in the aqueous phase during workup, and high volatility.
Scheme 4.7 Preparation of Chromophore Through Selective Methylation
.
53
4.6 Model System for Chromophore Cyclization
With the troublesome protection of hydroxyls encountered, a new two step
procedure was proposed to formylate the phloroglucinol using Vilsmeier-Haack
conditions, and then methylate all three hydroxyl groups, which could be selectively
deprotected later (Scheme 4.8).
Scheme 4.8 Two-step Preparation of Chromophore
The benzaldehyde was coupled to phenyl acetylene under inert atmosphere using
n-butyllithium (Scheme 4.9). The terminal proton of phenyl acetylene was first allowed
to react with nBuLi to create a nucleophile. When the aldehyde is introduced, the
nucleophile attacks the carbonyl and results in a secondary alcohol.
Two methods of oxidation were attempted. The first oxidation added manganese
oxide over several portions at room temperature. Even when left stirring overnight, there
was only about 50% conversion. The second method used Dess-Martin periodinane and
under basic conditions, the reaction was complete within 2 to 3 hours and resulted in a
clean NMR spectra.
54
To cyclize the ynone, selective deprotection of the methoxy groups ortho to the
carbonyl was needed. For this, the Lewis acid aluminum trichloride was used to
coordinate with the methoxy group and promote leaving. Since the aromatic is
symmetric, both methoxy groups can be deprotected and result in the same cyclized
product. After one hour of being exposed to 2.2 equivalents of AlCl3 only one of the
methoxy groups was removed, but since cyclization was still possible, no extra effort was
taken to remove the second methoxy at this stage. This compound was dissolved in
acetonitrile and catalytic base was added. Heating at 60°C for one hour yielded the
desired cyclized product.
55
Scheme 4.9 Model Cyclization
56
Chapter 5: Conclusion
In efforts to synthesize diandraflavone, we have synthesized the protected glucose
and 2,6-deoxy galactose moieties. A glucose derived sugar residue has been attached to a
phenyl acetylene moiety via β-C-glycosidic linkage. The chromophore has also been
prepared in a model system. Using selective deprotection of methoxy groups, we are
hopeful that future coupling and cyclization between the β-C aryl glycoside fragment and
the chromophore can occur. A second sugar, derived from galactose, has been assembled
to match the natural product. Future work will be able to attach the galactose moiety onto
the aromatic chromophore by using an O→C glycoside rearrangement.
57
Chapter 6: Experimental
General Methods
Distilled water was used in all experiments. Inert atmosphere was created by
using argon gas unless otherwise specified. Combined organic extracts were dried over
anhydrous sodium sulfate and concentrated using a rotary evaporator. Flash
chromatography was carried out on SiO2 (silica gel 60, 230-400 mesh). 1H NMR and 13C
NMR were measured at 400MHz and 100 MHz, respectively. Chemical shifts are
reported in ppm downfield from the internal standard Si(Me)4.
Synthesis of 2d
Procedure
To alcohol 2c (2 g, 3.7 mmol) was added dimethylsulfoxide (18 mL, 0.2 M) and acetic
anhydride (7 mL, 20 eq) and allowed to stir at room temperature overnight. The reaction
was checked by TLC and allowed to stir for an additional hour with methanol to consume
excess acetic anhydride. The reaction was quenched with water and extracted with
58
CH2Cl2 (3 x 50 mL). The organic phase was washed with sodium bicarbonate (NaHCO3)
and brine, and then dried over Na2SO4 and concentrated under reduced pressure. The
crude oil was purified by flash chromatography (4:1 hexanes: ethyl acetate) affording 2d
(1.59 g, 2.9 mmol, 80%).
1
H NMR: (400 MHz, CDCl3):
7.41-7.20 (m, 20H); 5.01-4.96 (d,1H); 4.81-4.32 (m,8H); 4.14-4.10 (d,1H); 3.95-3.87 (d,
1H); 3.74-3.70 (m, 2H), 3.69-3.67 (m, 2H).
13
C NMR: (100 MHz, CDCl3):
169.4; 137.6; 137.0; 128.6; 128.5; 128.4; 128.2; 128.1; 128.0; 127.9; 127.8; 80.9; 78.2;
76.1; 76.0; 74.1; 73.9; 73.8; 73.7; 73.6; 73.5; 68.3.
Synthesis of 3b
Procedure
To triethylamine (15 mL, 0.35 M), 1-bromo-4-iodo benzene (3a, 1.5 g, 5.3 mmol) was
added. Upon addition of copper iodide (40 mg, 3 mol%), the solution was degassed with
argon. Palladium catalyst (60 mg, 1.2 mol%) was added and TMS acetylene immediately
followed. The solution was stirred at 50°C overnight. The solution changed from clear
59
red to cloudy brownish green. The solution was momentarily cooled to room temperature
and HCl (2.5 mL, 2 M) was added. A black precipitate formed and the clear liquid was
filtered off by Hirsh funnel. The crude liquid was flushed through silica gel with hexanes
and concentrated under reduced pressure. The resulting product 3b (1.0 g, 4.0 mmol,
77%) was obtained as a white powder.
1
H NMR: (400 MHz, CDCl3)
7.16-7.11 (m, 4H); 0.27 (s, 9H)
13
C NMR: (100 MHz, CDCl3)
133.4; 133.0; 132.0; 131.9; 131.5; 130.9; 128.5; 128.3; 128.2;
HRMS (LIFDI): calculated for C11H48BrSi+H+ = 251.9964, found 251.9956
Synthesis of 5a
Procedure
Compound 3b (0.19 g, 0.74 mmol) was dissolved in THF (2 mL) and cooled to -78°C.
After 5 minutes, n-butyllitium (0.30 mL, 0.59 mmol, 2M in cyclohexanes) was added
slowly and the solution was allowed to stir for 40 minutes. The solution was then warmed
60
to 0°C, where it stayed for an additional 40 minutes, after which it was cooled back to 78°C for 20 minutes. A solution of lactone 2d (0.20 g, 0.37 mmol) dissolved in THF (1.6
mL) was cannulated into the nBuLi mixture. The reaction continued to stir for 3.5 hours
at -78°C while monitored by TLC. A saturated aqueous solution of NaHCO3 (10 mL) was
added and the organic layer was extracted with ethyl acetate (3 x 10 mL). The combined
organic portions were washed with saturated NaCl solution, dried over sodium sulfate,
and concentrated under reduced pressure. The crude product was purified by flash
chromatography (90:10, then 85:15 hexanes:ethyl acetate) to obtain 5a (0.35 g, 0.49
mmol, 67%). Starting with 1 gram of product would decrease the yield to about 33-45%.
1
H NMR: (400 MHz, CDCl3)
7.45-7.28 (m, 24H); 6.77-6.74 (d, J=8.8 Hz, 2H); 5.02-4.99 (d, J=12.0 Hz, 1H); 4.764.4.71 (t, J=11.2 Hz, 2H); 4.67-4.49 (m, 5H); 4.16-4.14 (d, J=6.4 Hz, 1H); 3.98-3.93 (m,
1H); 3.77-3.67 (m, 2H); 1.60 (s, 1H); 0.26 (s, 9H).
13
C NMR: (100 MHz, CDCl3)
169.5; 156.1; 149.4; 145.4; 137.6; 137.5; 136.9; 132.1; 131.9; 128.5; 128.4; 128.1; 128.0;
127.9; 127.7; 127.6; 125.8; 124.3; 121.5; 105.1; 105.0; 93.9; 92.3; 80.9; 78.2; 76.1; 73.9;
73.8; 73.7; 73.6; 73.5; 72.6; 68.3; -1.28.
61
Synthesis of 5b
Procedure
Compound 5a (0.63 g, 0.89 mmol) was dissolved in a 5:1 methanol:methylene chloride
(40 mL, 0.02 M). A 1 M solution of sodium hydroxide (1.8 mL, 1.8 mmol) was added
dropwise and a color change was observed. The solution was allowed to stir for 2-3 hours
before it was quenched with water (20 mL). The organic phase was extracted with ethyl
acetate (3 x 30 mL), dried over sodium sulfate, and concentrated. Residue was purified
using 4:1 hexanes:ethyl acetate solvent, yielding 5b (0.54 g, 0.84 mmol, 94%).
1
H NMR: (400 MHz, CDCl3)
7.52-7.34 (m, 24H); 6.15-6.03 (m, 1H); 5.98-5.92 (m, 1H); 4.90-4.89 (d, J=4.4 Hz, 1H);
4.53-4.44 (t, J= 18.4 Hz, 2H); 4.43-4.41 (m, 5H); 3.97 (s, 1H); 3.82-3.80 (d, J=9.2 Hz
1H); 3.55-3.54 (d, J=4.6 Hz, 1H); 3.41-3.40 (d, J=5.3 Hz, 1H); 3.33-3.26 (m, 2H)
62
13
C NMR: (100 MHz, CDCl3)
192.9; 186.5; 172.1; 156.7; 156.6; 155.5; 155.2; 139.9; 139.1; 138.3; 138.1; 138.0; 136.9;
136.8; 136.7; 135.2; 133.9; 121.9; 121.6; 101.7; 101.4; 97.42; 74.1; 73.9; 73.8; 73.7;
73.6; 73.4; 72.4; 72.2; 70.9; 70.8; 70.6; 56.6; 49.0; 44.65
Synthesis of 5c
Procedure
Compound 5b (0.22 g, 0.35 mmol) was dissolved in 3:1 acetonitrile:methylene chloride
(7 mL, 0.05 M). Cool to 0°C and slowly add triisopropylsilyl silane (0.53 mL, 1.7 mmol)
and freshly distilled boron trifluoride etherate (0.13 mL, 1.0 mmol). The solution was
stirred for 3-4 hours and quenched with sodium bicarbonate (10 mL). The organic phase
was extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with
saturate brine solution (10 mL) and dried over sodium sulfate. The resulting orange-
63
brown residue was purified by flash chromatography (4:1 hexanes:ethyl acetate) to obtain
5c (0.13 g, 0.21 mmol, 60%) as a yellow oil.
1
H NMR: (400 MHz, CDCl3)
7.51-7.23 (m, 24H); 6.36-6.35 (d, J=1.2 Hz, 1H); 6.31-6.30 (d, J=1.6 Hz, 1H); 5.15-5.11
(m, 2H); 4.73-4.71 (m, 1H); 4.60-4.55 (m, 2H); 4.48-4.46 (m, 2H); 4.43-4.35 (m, 1H);
4.03-3.96 (m, 1H); 3.95-3.94 (m, 1H); 3.56-3.52 (m, 3H).
13
C NMR: (100 MHz, CDCl3)
135.6; 131.7; 129.0; 128.6; 128.5; 128.3; 128.3; 127.9; 127.9; 127.8; 127.7; 127.6; 127.6;
127.4; 126.9; 124.3; 107.54; 86.82; 82.0.
64
Synthesis of 6a
Procedure
D-galactose (4.00 g, 22.2 mmol) was dissolved in methanol (40 mL, 0.5 M) and a
catalytic amount of sulfuric acid (1mL) was added. The solution was heated at 85°C for 2
hours, or until galactose had fully dissolved. The solution was then allowed to cool to
room temperature, where it was neutralized with NH4OH. Evaporatation of solvent and
azeotropically drying with toluene (4x20mL) afforded 6a (4.12 g, 21.2 mmol, 95%) as
white sticky residue.
65
Synthesis of 6b
Procedure
Compound 6a (1.93 g, 9.9 mmol) was dissolved using pyridine (5 mL) and methylene
chloride (25 mL, 0.4 M). The solution was cooled to 0°C and p-toluenesulfonyl chloride
(2.8 g, 14.9 mmol) was slowly added. the solution was allowed to warm to room
temperature where it remained stirring for up to 18 hours. The solution was cooled back
to 0°C before quenching with deionized water (10 mL), stirred for an additional 30
minutes and diluted with additional 10mL water. The organic phase was extracted with
saturated aqueous sodium bicarbonate and methylene chloride (2 x 25 mL). After
washing with aqueous NaCl, the organic phase was dried over sodium sulfate.
Evaporating with toluene afforded 6b (2.58 g, 7.4 mmol, 75%) as white solid.
1
H NMR: (400 MHz, CDCl3)
7.83-7.82 (m, 2H); 7.39-7.25 (m, 2H); 7.23-7.15 (m, 1H); 5.03-4.49 (m, 1H); 4.33-3.87
(m, 4H); 3.56-3.20 (m, 3H); 3.17-2.61 (m, 2H); 2.51-2.41 (d, J=4.04 Hz, 3H); 2.37 (s,
1H).
66
13
C NMR: (100 MHz, CDCl3)
145.6; 145.1; 132.5; 130.0; 129.9; 128.1; 109.1; 88.9; 85.1; 83.1; 79.9; 70.4; 68.5; 55.1;
21.7.
Synthesis of 6c
Procedure
To 6b (1.00 g, 2.8 mmol) was added freshly distilled diethyl ether (6 mL, 0.5 M). The
solution was cooled to 0°C where lithium aluminum hydride (0.33 g, 8.4 mmol) was
carefully added over four portions. The mixture was allow to warm to room temperature
and then refluxed for 1 hour. The reaction was quenched with deionized H2O (0.3 mL)
and allowed to stir for 15 minutes. A 15% solution of aqueous NaOH (0.3 mL) was
added, followed by deionized H2O (1.2 mL). The solution was diluted with diethyl ether
(20 mL) and passed through a Celite plug. Product (Rf =0.16, 1:1 Hexane:Ethyl Acetate)
may be purified by short silica plug (1:1 Hex:EtOAc to 100% EtOAc) to obtain 6c (0.15
g, 0.8 mmol, 30%).
67
1
H NMR: (400 MHz, CDCl3)
4.92 (s, 1H); 4.61-4.58 (m, 2H); 4.04-3.83 (m, 5H); 3.41-3.39 (d, J=9.13 Hz, 3H); 1.291.28 (d, J=6.84 Hz, 3H).
13
C NMR: (100 MHz, CDCl3)
109.5; 87.9; 72.2; 68.5; 66.4; 54.9; 15.9
Synthesis of 6d
Procedure
Sugar 6c (0.3 g, 1.7 mmol) was dissolved in acetone (4 mL, 0.4 M) and 2,2
dimethoxypropane (1.0 mL,8.4 mmol). Catalytic toluenesulfonic acid (51 mg, 3 mol%)
was added and allowed to stir overnight. The excess acetone was evaporated and the
residue was washed with sodium bicarbonate (10 mL) and extracted with diethyl ether (3
x 15 mL). The organic phase was dried over sodium sulfate, concentrated and purified by
flash chromatography (3:1 to 1:1 Hex:EtOAc) to obtain 6d (0.21 g, 0.97 mmol, 57%).
68
1
H NMR: (400 MHz, CDCl3)
4.93 (s, 1H); 4.34-4.33 (t, J=7.2 Hz, 1H); 4.14-3.94 (m, 6H); 3.41 (s, 3H); 1.43 (s, 3H);
1.40 (s, 3H); 1.39 (s, 3H).
13
C NMR: (100 MHz, CDCl3)
206.9; 109.7; 85.6; 78.6; 78.2; 75.7; 55.0; 30.9; 25.6; 25.5.
Synthesis of 6e
Procedure
Sugar 6d (83.4 mg, 0.38 mmol) was dissolved in dry THF (2.0 mL, 0.2 mL) and cooled
to 0°C. NaH (15 mg, 0.57 mmol, in 60% oil dispersion) was slowly added along with
imidazole (0.6 mg, 1.5 mol%). The reaction was stirred for 2 hours at room temperature,
where upon carbon disulfide (0.1 mL, 1.5 mmol) was added. The solution was left
stirring for an additional 2 hours before methyl iodide (0.1 mL, 1.5 mmol) was added.
After an hour, the solution was cooled to 0°C and quenched with water (3 mL). The
organic phase was extracted with dichloromethane (3 x 5 mL) and dried over anhydrous
69
magnesium sulfate. Purification by silica (7:3 to 1:1 Hex:EtOAc, Rf=0.87, 1:1
Hex:EtOAc) afforded 6e (80 mg, 0.26 mmol, 68%).
1
H NMR: (400 MHz, CDCl3)
4.38-4.36 (d, J= Hz, 1H); 4.11-4.01 (m, 4H); 3.46-3.44 (d, 3H); 2.59-2.53 (s, 3H);1.411.39 (s, 6H);1.34-1.32 (d, J= Hz, 3H).
13
C NMR: (100 MHz, CDCl3)
129.8; 109.9; 82.6; 78.9; 77.7; 74.9; 55.5; 27.5; 27.4; 26.9; 18.6.
Synthesis of 6f
Procedure
Compound 6e (80 mg, 0.26 mmol) was dissolved in THF (0.85 mL, 0.3 M).
Tris(trimethylsilyl)silane (0.14 mL,0.44 mmol) and catalytic AIBN (4 mg, 0.03 mmol, 10
mol%) were added. The solution was refluxed at 85°C for 1.5 hours, or until TLC
showed completion (Rf=0.45 in 7:3 Hex: EtOAc). Solution was cooled and extracted
70
with saturated sodium bicarbonate solution (3 mL) and ethyl acetate (3 x 5 mL) to yield
6f (57.8 mg, 0.3 mmol, 10%).
Synthesis of 7b
Procedure
DMF (5.8mL, 75mmol) was added to a solution of phloroglucinol dihydrate (7a, 4.12g,
25mmol) and ethyl acetate (60mL, 0.4M). While cooled at 0°C, POCl3 (7.0mL, 75mmol)
was slowly added over a 40 minute period. The solution was allowed to warm to room
temperature and allowed to stir for 2-3 hours, or until a precipitate formed. The mixture
was vacuum filtered and the resulting solid was refluxed with water for 5 minutes. Once
cooled, the solution was extracted with ethyl acetate and concentrated to result in a
powder, which was recrystallized to obtain 7b as long orange spindles (3.1g, 80%).
1
H NMR: (400 MHz, MeOD)
10.03 (s, 1H); 5.79 (s, 2H); 4.93 (s, 9H).
71
13
C NMR: (100 MHz, MeOD)
191.3; 167.4; 164.5; 104.9; 93.77
Synthesis of 7c
Procedure
To 7b (0.50g, 3.2mmol) dissolved in acetone (8.0mL, 0.4M) was added potassium
carbonate (1.4g, 10.2mmol) and dimethyl sulfate (0.97mL, 10.2mmol). The solution was
heated at 60°C for 2-3 hours or until product had formed (Rf=0.18, 2:1 Hex:EtOAc). The
organic layer was extracted with ethyl acetate (3x15mL) and washed with saturated
sodium bicarbonate (10mL). The dried organic layer was concentrated under pressure to
yield 7c as a white solid (86%).
1
H NMR: (400 MHz, CDCl3)
10.37 (s, 1H); 6.10 (s,2 H); 3.90 (s, 6H); 3.89 (s, 3H)
13
C NMR: (100 MHz, CDCl3)
187.7; 166.2; 164.1; 108.7; 90.3; 55.9; 55.5
72
Synthesis of 8a
Procedure
To phenylacetylene (0.05 mL, 0.45 mmol) in THF (1.6 mL, 0.4 M), nBuLi (0.23 mL,
0.45 mmol, 2.0 M in cyclohexanes) was slowly added at -78°C. The solution was stirred
15 minutes before it was warmed to 0°C for 10 minutes. The solution was cool to -78°C
again and 7c (75 mg, 0.38 mmol, in 1M DCM) was added. The solution was stirred for
20 minutes until 7c was consumed (TLC Rr=0.5, 2:1 Hex:EtOAc). The solution was
extracted with sodium bicarbonate (5mL) and ethyl acetate (3x5mL) and then washed
with NaCl (5mL). The concentrated residue was purified (2:1 Hex:EtOAc) to obtain 8a
(56 mg, 0.19 mmol, 50%).
1
H NMR: (400 MHz, CDCl3)
7.42-7.39 (m, 2H); 7.28-7.27 (m, 3H); 6.20 (s, 2H); 6.12 (d, J=11.5 Hz, 1H); 3.89 (s,
6H), 3.83 (s, 3H); 3.78 (s, 1H).
13
C NMR: (100 MHz, CDCl3)
161.1; 158.3; 131.7; 128.1; 127.9; 123.4; 110.6; 91.3; 90.6; 90.3; 82.7; 56.7; 56.0; 55.4.
73
Synthesis of 8b
Procedure
To 8a (56 mg, 0.19 mmol) dissolved in dichloromethane (0.5 mL, 0.4 M), Dess-Martin
periodinate reagent (56 mg,1.3 mmol) and solid sodium bicarbonate (11 mg, 1.3 mmol)
were added. The solution was allowed to stir for 2 hours, or until the reaction was
complete as indicated by TLC. The solution was diluted with diethyl ether (5 mL) and
filtered through a short plug of Celite. After concentration, the crude sample was
analyzed by NMR spectra and assumed to have a near 100% conversion to 8b (0.19
mmol, >95%).
1
H NMR: (400 MHz, CDCl3)
7.58-7.55 (m, 2H); 7.43-7.37 (m, 3H); 6.15 (s, 1H); 3.87 (s, 9H).
13
C NMR: (100 MHz, CDCl3)
163.7; 160.4; 132.9; 130.0; 128.5; 121.1; 90.9; 56.1; 55.4; 1.0.
HRMS (ESI): calculated for C18H16O4+H+ = 297.1121, found 297.1124
74
Synthesis of 8c
Procedure
The crude product 8b (56 mg, 0.19 mmol) was dissolved in dichlormethane (0.2 mL, 1
M). Aluminum trichloride (55 mg, 0.42 mmol) was added to the solution at 0°C. The
solution was allowed to warm to room temperature, where it continued stirring for 1 hour.
Extraction with saturated sodium bicarbonate (5 mL) and dichloromethane (3 x 5mL)
followed by concentration and purification (2:1 Hex:EtOAc) yielded 8c (25.2 mg, 0.09
mmol, 47%).
1
H NMR: (400 MHz, CDCl3)
7.51-7.44 (m, 4H); 6.14 (d, 1H); 5.96 (d, 1H); 5.32 (s, 1H); 3.87 (s, 3H); 3.86 (s, 3H).
75
Synthesis of 8d
Procedure
Compound 8c (8.5 mg, 0.03 mmol) was dissolved in acetonitrile (0.05mL, 0.4M).
Anhydrous potassium carbonate (1mg, 35%mol) was added and the solution was heated
at 60°C for 1 hour. TLC showed a spot higher from starting material (Rf=0.8, 2:1
Hex:EtOAc). The solution was quenched with aqueous sodium bicarbonate (2mL) and
extracted with dichlormethane (3x5mL) to obtain 8d (5.6 mg, 0.02 mmol, 75%) after
purification (2:1 Hex:EtOAc).
1
H NMR: (400 MHz, CDCl3)
7.49-7.42 (m, 3H); 7.42-7.36 (m, 2H); 6.81 (d, 1H); 6.42 (d, 1H); 6.17 (s, 1H); 3.99 (s,
3H); 3.95 (s, 3H).
HRMS (ESI): calculated for C17H14O4 +H+=283.0965, found 283.0968
76
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APPENDIX
1
H NMR (400MHz) for 2d
83
1
H NMR (400MHz) for 3b
84
1
H NMR (400MHz) for 5a
85
13
C NMR (100MHz) for 5a
86
1
H NMR (400MHz) for 5b
87
13
C NMR (100MHz) for 5b
88
1
H NMR (400MHz) for 5c
89
13
C NMR (100MHz) for 5c
90
1
H NMR (400MHz) for 6b
91
13
C NMR (100MHz) for 6b
92
1
H NMR (400MHz) for 6c
93
13
C NMR (100MHz) for 6c
94
1
H NMR (400MHz) for 6d
95
13
C NMR (100MHz) for 6d
96
1
H NMR (400MHz) for 6e
97
13
C NMR (100MHz) for 6e
98
1
H NMR (400MHz) for 7b
99
13
C NMR (100MHz) for 7b
100
1
H NMR (400MHz) for 7c
101
13
C NMR (100MHz) for 7c
102
1
H NMR (400MHz) for 8a
103
13
C NMR (100MHz) for 8a
104
1
H NMR (400MHz) for 8b
105
13
C NMR (100MHz) for 8b
106
1
H NMR (400MHz) for 8c
107
1
H NMR (400MHz) for 8d
108