synthesis of some naturally occurring quinones
TRANSCRIPT
Synthesis of Some Naturally Occurring
Quinones
Linda Birgitta Nielsen B.A., B.Sc. (Hons)
This thesis is presented for the degree of Doctor of Philosophy of
the University of Western Australia
Discipline of Chemistry
School of Biomedical, Biomolecular and Chemical Sciences
2008
DECLARATION FOR THESES CONTAINING PUBLISHED WORK AND/OR WORK PREPARED FOR PUBLICATION The examination of the thesis is an examination of the work of the student. The work must have been substantially conducted by the student during enrolment in the degree. Where the thesis includes work to which others have contributed, the thesis must include a statement that makes the student’s contribution clear to the examiners. This may be in the form of a description of the precise contribution of the student to the work presented for examination and/or a statement of the percentage of the work that was done by the student. In addition, in the case of co-authored publications included in the thesis, each author must give their signed permission for the work to be included. If signatures from all the authors cannot be obtained, the statement detailing the student’s contribution to the work must be signed by the coordinating supervisor. Please sign one of the statements below. 1. This thesis does not contain work that I have published, nor work under review for publication. Signature......................................................................................................................................................... 2. This thesis contains only sole-authored work, some of which has been published and/or prepared for publication under sole authorship. The bibliographical details of the work and where it appears in the thesis are outlined below. Signature......................................................................................................................................................... 3. This thesis contains published work and/or work prepared for publication, some of which has been co-authored. The bibliographical details of the work and where it appears in the thesis are outlined below.The student must attach to this declaration a statement for each publication that clarifies the contribution of the student to the work. This may be in the form of a description of the precise contributions of the student to the published work and/or a statement of percent contribution by the student. This statement must be signed by all authors. If signatures from all the authors cannot be obtained, the statement detailing the student’s contribution to the published work must be signed by the coordinating supervisor.
Chapter 2 and Chapter 4 include work that has been published. Details of the publication,
together with an estimate of the percentage contribution of each of the authors, appear below:
Linda B. Nielsen (90%) and Dieter Wege (10%), ‘The enantioselective synthesis of elecanacin through an
intramolecular naphthoquinone-vinyl ether photochemical cycloaddition’, Org. Biomol. Chem., 2006, 4,
868.
The corresponding author Assoc. Prof. Dieter Wege has given permission for the results presented in this
publication to be included in this thesis.
Signatures......................................................................................................................................................... Signatures.........................................................................................................................................................
i
Summary
Naturally occurring quinones have attracted considerable interest due to their
widespread occurrence, structural diversity and often potent biological activities. The
research outlined in this thesis involves the development of synthetic approaches to two
novel naphthoquinone derivatives, both of which were discovered during investigations
into the bioactive constituents of tropical plant species. Chapter 1 introduces the family
of quinonoid compounds and also considers the important role that natural product
synthesis can play in structural confirmation and in providing an adequate supply of
compounds for further research.
Chapter 2 describes the synthesis of elecanacin 36, an unusual cyclobuta-fused
naphthalene-1,4-dione derivative which has been isolated from the bulbs of the iris
Eleutherine americana Merr. et Heyne (Iridaceae), along with the isomeric and well-
known pyranonaphthoquinones eleutherin 38 and isoeleutherin 39.
O
OO
HMeO
Me H
O
O
O
Me
Me
MeO
O
O
O
Me
Me
MeO
36 38 39
(±)-Elecanacin 36 was prepared, together with its epimer (±)-isoelecanacin 151, by an
intramolecular [2 + 2] photocycloaddition resulting from irradiation of 5-methoxy-2-(2-
vinyloxypropyl)naphthalene-1,4-dione 138.
ii
O
O
MeO
O
Me
O
O O
H
MeO
Me
O
O
MeO
O
H
Me
CH2Cl2hv, 350 nm
(±)-elecanacin
15136138(±)-isoelecanacin
(one enantiomer of each product is depicted)
The synthesis of enantiopure elecanacin 36 starting with (R)-propylene oxide was also
achieved. This established the absolute configuration of the natural product and revealed
that the sample isolated from the bulbs possessed an enantiomeric excess of only 14%.
A possible biosynthetic pathway which relates elecanacin 36 to its co-metabolites
eleutherin 38 and isoeleutherin 39 is also discussed.
Chapter 3 focuses on an approach to 3-hydroxymethylfuro[3,2-b]naphtho[2,3-
d]furan-5,10-dione 37, which has been isolated from the wood of the tropical tree
Crescentia cujete L. (Bignoniaceae) and incorporates a rare fully aromatic furofuran
moiety.
O
O
O
O
OH
37
The route to the furofuranonaphthoquinone 37 commenced with the synthesis of
ethyl 3-[3-(2-furyl)-1,4-dimethoxynaphthalen-2-yloxy]propynoate 263, which proved to
be highly unstable and could not be isolated. However, the pendant acetylenic ether
chain within 263 could be trapped intramolecularly by the attached furan moiety. Thus
iii
263 was instead converted directly into an advanced intermediate ethyl 5,10-
dimethoxyfuro[3,2-b]naphtho[2,3-d]furan-3-carboxylate 304 by way of a tandem
intramolecular cycloaddition-cycloreversion sequence. The key ester 304 was then
elaborated via a series of standard oxidation and reduction reactions to give the target
quinone 37.
OMe
OMe
O
O
CO2Et O
O
OMe
OMe
CO2Et
NN N
N
py
py
OMe
OMe
O
O
CO2Et
toluene, reflux
299263
304
heat
O
O
O
O
OH
37
1. CAN, MeCN/H2O2. LiAlH4, THF3. ON(SO3K)2
The synthetic routes to elecanacin 36 and furofuranonaphthoquinone 37 arising
from this work represent the first total syntheses of both compounds and have enabled
confirmation of their novel ring systems.
iv
Statement of Candidate Contribution
Except where specific acknowledgement of others is made, the work described
in this thesis is original and was carried out by the author in the Discipline of Chemistry
(School of Biomedical, Biomolecular and Chemical Sciences) at the University of
Western Australia, under the supervision of Assoc. Prof. Dieter Wege.
Chapter 2 and Chapter 4 include work that has been published. Details of the
publication, together with an estimate of the percentage contribution of each of the
authors, appear below:
Linda B. Nielsen (90%) and Dieter Wege (10%), ‘The enantioselective synthesis of
elecanacin through an intramolecular naphthoquinone-vinyl ether photochemical
cycloaddition’, Org. Biomol. Chem., 2006, 4, 868.
The corresponding author Assoc. Prof. Dieter Wege has given permission for the results
presented in this publication to be included in this thesis.
Assoc. Prof. Dieter Wege Linda B. Nielsen
v
Acknowledgements
First I would like to thank my supervisor Associate Professor Dieter Wege for
all his guidance, support and encouragement. I was lucky enough to be Dieter’s final
PhD student and he very kindly continued to oversee my work after he retired. I have
benefitted greatly from my supervisor’s wisdom, insight and years of experience
solving interesting problems, working at the bench and finding all the best sources in
the library, as well as his super stories. For this I am deeply grateful.
I would also like to give a special thank you to a number of people who helped
me throughout the course of this project. They include Dr Lindsay Byrne who assisted
with the 2D NMR spectra and chiral shift reagent experiments and gave me many
invaluable and enthusiastic NMR lessons, as well as Dr Anthony Reeder who recorded
the mass spectra. I would like to thank Professor Robin Giles (Murdoch University,
Western Australia) who kindly provided the chiral HPLC column, Dr Gavin Flematti
who assisted with HPLC analyses and Professor Y. Imakura (Naruto University,
Takashima) who generously supplied the 13C and 1H NMR spectra of natural
elecanacin. Nicole Hondow’s help with the IR machines was also greatly appreciated. In
addition, I am grateful to the department’s many present and former technical and
administrative staff, including Sarah Davies (store and glass workshop), Greg Cole
(glass workshop), George Sjepcevich (workshop), Kim Foo (first year labs) and Ingrid
Buschmann (office), for all their friendly assistance and expertise.
Thanks must also go to the last members of the Wege Group for many coffees
and much enthusiastic conversation. I would especially like to thank Alan Payne who
made sure that I became well-versed in almost all the lab techniques that I was to face
during my PhD. I would also like to thank Rosenani Haque, along with the members of
vi
the Bucat group (especially Janette Head), the Theoretical Chemistry group (including
Daniel Grimwood and Dylan Jayatilaka) and the Berners-Price group (including
Anthony Humphries, Donald Thomas, Joseph Moniodis, Peter Barnard, James Hickey,
Louise Wedlock, Scott McPhee, Junyong Zhang and Mikie Farmer) who all ensured
that I was never lonely and continued to have a great time during the years I spent
working in the Wege lab alone. I express my deepest gratitude to Associate Professor
Emilio Ghisalberti and the full- and part-time members of his group: my office buddy
Gavin Flematti, Laura Clayson and Stuart Ingham (the two nicest honours students
anyone could ever hope to work with), Chuck Heath, Chris Jones, Jon See and Katie
Punch for welcoming me into their lab when we moved into the new chemistry building
and for their continuing friendship over the last couple of years. Thank you also to Dr
Allan McKinley who kindly provided me with a desk and plently of space to write in
his lab during my final year.
Many thanks to my friends from beyond the lab, especially Junming Ho, Alistair
Usher and Nicole Hondow for their long and inspiring letters and my musical friends
Silvia Sze, Birger Dittrich and Helen Roberts who came with me to lots of concerts and
joined me for more than a few coffees afterwards.
Finally I would like to thank my family: Ing-Marie, John and Peter, who have
given me enormous support and encouragement and still continue to take an interest in
my studies after so many years.
vii
Table of Contents
Summary ii
Statement of Candidate Contribution v
Acknowledgements vi
Chapter 1: Introduction to Naturally Occurring Quinones 1
1.1 Introduction to Quinones 2
1.2 Naturally Occurring Quinones 4
1.3 Naturally Occurring Quinones as Pharmaceutical Targets 7
1.4 Natural Product Synthesis 13
1.5 Aim of Research 15
Chapter 2: The Synthesis of Elecanacin 17
2.1 Introduction 18
2.1.1 Elecanacin 36 and Other Naphthoquinones from Eleutherine
americana and Eleutherine bulbosa 18
2.1.2 Syntheses of Eleutherin 38 and Isoeleutherin 39 20
2.1.3 Elecanacin 36 as a Synthetic Target 34
2.2 [2 + 2] Photocycloadditions for the Synthesis of Cyclobutane Rings 35
2.2.1 Mechanism of the Enone-Alkene [2 + 2] Photocycloaddition 37
2.2.2 Intermolecular [2 + 2] Photocycloadditions 39
2.2.3 Intramolecular [2 + 2] Photocycloadditions 40
2.2.4 [2 + 2] Photocycloadditions of 1,4-Naphthoquinones 41
2.3 An Approach to Elecanacin 36 44
viii
2.4 Preparation of (±)-Elecanacin 36 46
2.4.1 Synthesis of 2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-
dione 46 46
2.4.2 Synthesis of 5-Methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-
dione 138 52
2.4.3 Synthesis of (±)-Elecanacin 36 54
2.5 The Enantioselective Synthesis of Elecanacin 36 61
2.5.1 An Approach to Chiral 1-(1-Hydroxy-5-methoxynaphthalen-
2-yl)propan-2-ol 152 using Jacobsen’s Catalyst 61
2.5.2 Synthesis of Epoxides 155, 156 and 168 and Attempted Hydrolytic
Kinetic Resolution 64
2.5.3 A Directed Metallation Approach to (2R)-1-(1-Hydroxy-5-methoxy-
2-naphthalenyl)propan-2-ol 152 70
2.5.4 Final Steps in the Preparation of Enantiopure Elecanacin 36 76
2.6 On the Possible Biosynthesis of Elecanacin 36 77
2.7 Concluding Remarks 82
Chapter 3: The Synthesis of 3-Hydroxymethylfuro[3,2-b]naphtho[2,3-
d]furan-5,10-dione 83
3.1 Introduction to 3-Hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-
dione 37 84
3.2 A Synthetic Approach to 3-Hydroxymethylfuro[3,2-b]naphtho[2,3-
d]furan-5,10-dione 37 90
3.3 Previous Work Towards the Synthesis of 3-Hydroxymethylfuro[3,2-
b]naphtho[2,3-d]furan-5,10-dione 37 93
3.4 An Alternative Approach to an Intermediate Acetylenic Ether 100
ix
x
3.5 Attempted Synthesis of Acetylenic Ether 263 104
3.6 Synthesis of Key Intermediate Ethyl 5,10-Dimethoxyfuro[3,2-
b]naphtho[2,3-d]furan-3-carboxylate 304 114
3.7 Final Steps in the Synthesis of 3-Hydroxymethylfuro[3,2-b]naphtho[2,3-
d]furan-5,10-dione 37 125
3.8 Concluding Remarks 128
Chapter 4: Experimental 133
4.1 General Details 134
4.1.1 Solvents and Reagents 134
4.1.2 Reactions and Chromatography 135
4.1.3 Characterisation 136
4.2 Experimental for Chapter 2 138
4.3 Experimental for Chapter 3 156
References 167
Chapter 1
Introduction to Naturally Occurring Quinones
1
1.1 Introduction to Quinones
Quinones are one of the oldest recognized classes of organic compounds and
have fascinated chemists since the early days of modern chemistry. The name
“quinone” (“chinon” in German) originates from the name given in the 1830s to a bright
yellow compound obtained by oxidation of quinic acid in Liebig’s laboratory by
Woskresensky, who referred to the product as “chinoyl” (Scheme 1).1 Quinic acid was
obtained from chinona bark and now is known to have structure 1 and “chinoyl” is 1,4-
benzoquinone 2.
OO
"chinoyl"
2
quinic acid
OHOH
OHOH
HO2C
1
MnO2H2SO4
Scheme 1
Structurally, quinones can be considered to be cross-conjugated systems, which
incorporate alternating double bonds including exocyclic oxygens, as exemplified by
the simplest members of the class 1,4-benzoquinone 2 and 1,2-benzoquinone 3 (Figure
1).
O
O
2
1,4-benzoquinone(p-benzoquinone)
O
O
1,2-benzoquinone(o-benzoquinone)
3
Figure 1
2
However, looking beyond these parent compounds, the quinone class encompasses a
remarkable array of molecular structures. Fusion of benzene rings to the parent
structures 2 and 3 generates polycyclic quinones. Some representative compounds are
shown in Figure 2, which includes simple derivatives such as the naphthoquinones 4
and 5, as well as more complex extended compounds such as 7 and 9.
O
O
O
O
O
O
O
O
O O
O O
1,4-naphthoquinone
4 5
1,2-naphthoquinone
6
benzo[a]pyrene-6,12-quinone
8violanthrone 9,10-anthraquinone
9
9,10-anthraquinone
7
Figure 2
One of the important characteristic properties of quinones is the facility with
which they undergo reversible reduction to hydroquinones via a semiquinone
intermediate, as shown in Scheme 2.
3
O
O O
OH
OH
OH
2 10 11quinone semiquinone hydroquinone
e- + H+
- ( e- + H+ )
e- + H+
- ( e- + H+ )
Scheme 2
This redox chemistry appears to play a role in the biological function of many naturally
occurring quinones,2 which are introduced in the following section.
1.2 Naturally Occurring Quinones
Quinones occur widely in nature and are most commonly found in plants, fungi
and bacteria. Other naturally occurring quinones are encountered in the animal
kingdom, where they are especially prevalent among arthropods and some marine
organisms, including sea urchins and other echinoderms.3 Several members of the
quinonoid family are of importance due to their involvement in key physiological
processes. In addition, many quinones are of medicinal interest, exhibiting a broad
range of pharmacological activities.
Some quinones have an essential biochemical function, which reflects their
characteristic oxidation/reduction chemistry. These include the widely distributed
ubiquinone 12, also known as coenzyme Q, which plays a vital role in cellular
respiration as an electron carrier (Figure 3).4-6 Coenzyme Q has also been proposed to
function as an anti-oxidant, with the hydroquinone form behaving as an effective free
radical scavenger.5
4
O
O
MeO
MeO H
Me
n n = 6-10
12
Me
Figure 3
Other naturally occurring quinones appear to have a defensive role, exhibiting
toxic or unpalatable properties which deter predators or competing species. A well-
known example is the naphthoquinone juglone 15, a plant growth inhibitor which
originates from the walnut tree Juglans nigra. Within the tree, a precursor to juglone
exists in a reduced bound form as a glycoside 13 (Scheme 3).7
OH
OGlcOH
OH
OHOH
O
OOH
oxidationhydrolysis
151413juglone
Scheme 3
Upon release from the leaves, fruit and roots and subsequent exposure to the air, the
hydroquinone 14 undergoes oxidation to the corresponding quinone 15,7, 8 which
accumulates in the soil under walnut trees.9 Juglone 15 has been shown to effectively
inhibit the growth of numerous plant species, even at micromolar concentrations,8, 10
and can reach toxic levels in the soil which eventually causes the death of neighbouring
plant species.9, 11
5
Numerous quinones have been isolated which possess a variety of potentially
useful biological properties, including antifungal, antiviral, antibiotic and antitumour
activities. Several bioactive quinone derivatives are shown in Figure 4, which illustrates
the wide-ranging biological properties and structural diversity that exist within the
quinonoid class of compounds.
OH
HO
O
O
O
H OH
HMe
O
OH
Me
HO
Me
OH
Me Me
O
MeO
O
MeMe
N
O
O
Me
MeO Me
O
thysanone, a fungal metabolite from Thysanophora penicilloides)
antiviral properties12
16
18
17
a plant metabolite from Bobgunnia madagascariensis
antifungal properties13
Cryptotanshinone, a plant metabolitefrom Salvia miltiorrhiza
antibacterial,14 and anti-inflammatory15
properties
19
mimosamycin, a marine sponge metabolite from Cribrochalina sp.
antitumour properties16
Figure 4
6
The overall importance of quinones in chemistry can be gleaned from a recent
monograph of over 1000 pages which summarizes modern synthetic methods for the
synthesis of quinones and their heteroatom analogues.17
1.3 Naturally Occurring Quinones as Pharmaceutical Targets
Given the often potent biological activity associated with many naturally
occurring quinones, it is not surprising that a considerable effort has been expended in
isolating, evaluating and synthesising novel quinones in the search for compounds with
potentially useful and selective pharmacological properties. In particular, quinones
constitute one of the largest classes of antitumour agents known and several naturally
occurring quinones, as well as a number of synthetic derivatives, have been developed
as important anticancer therapies.2 The quinone moiety and its associated redox
properties appear to be involved in the mechanism of action for cytotoxicity in many
quinones,2, 18 including the powerful antitumour agents mitomycin C 20 and the
anthracycline antibiotics doxorubicin 21 and daunorubicin 22.
The antibiotic mitomycin C 20 was first isolated in 1958 from the soil
microorganism Streptomyces caespitosus and became the first naturally occurring
quinone to be adopted in the clinic as an anticancer therapy (Figure 5).19 Even before
the structure was elucidated in the early 1960s,20-22 mitomycin C 20 received
considerable attention as it became quickly apparent that the compound exhibited
promising broad-spectrum antitumour activity.19, 21, 23
7
N NH
O
O
H2N
Me
O
ONH2
OMe
20
Figure 5
Mitomycin C 20 appears to target tumour cells via damage caused by DNA alkylation.
The most widely accepted mode of action for the drug is proposed to operate according
to the pathway in Scheme 4.2, 19, 23 Mitomycin C 20 first requires activation during a
bioreduction step in which 20 is transformed into the corresponding hydroquinone 23,
which is highly unstable and undergoes a spontaneous loss of methanol. Subsequent
protonation and opening of the aziridine ring of 24 generates a highly reactive o-
quinone methide 25, which is susceptible to nucleophilic attack by DNA to give a
covalently bonded drug-DNA complex 26. X-ray crystallography has revealed that
attack on 25 by DNA occurs primarily via the N2 position of a guanine residue.24 This
resulting drug-DNA intermediate 26 is then able to form a cross-linkage to the N2 of
another guanine residue. Such covalent cross-linkages are believed to cause a structural
distortion of the DNA helix, which prevents normal uncoiling and participation in
replication and cell division, hence stopping the growth of tumour cells.25
8
N NH
O
O
H2N
Me
O
ONH2
OMe
N
O
OH
H2N
Me
O
ONH2
NH2
H
N
OH
OH
H2N
Me
O
ONH2
NH2
DNA OCONH2
DNAN NH
OH
OH
H2N
Me
O
ONH2
N NH
OH
OH
H2N
Me
O
ONH2
OMe
N
OH
OH
H2N
Me
DNA
NH2
DNA
N
OH
OH
H2N
MeNH2
DNA
MeOH
H
20
28
2726
2425
23
reduction
Scheme 4
9
Unfortunately, the high reactivity associated with mitomycin C 20 has also proven to be
destructive towards the constituents of normal cells and produces severe side effects
including vomiting, liver and kidney toxicity, heart damage and bone marrow
depression.19 Although the use of mitomycin C 20 was popular during the 1960s,
especially in Japan where approximately half of all cancer patients received the drug as
part of their treatment, the associated side effects have largely limited mitomycin C’s
utility and the drug has generally fallen out of favour.19 Nevertheless, mitomycin C 20
remains an important component of several combination chemotherapeutic treatments
for breast, lung and prostate cancer.23 A similar bioreductive alkylation mechanism is
believed to play a role in the toxic and in particular antitumour properties of many
quinones, including dehydro-α-lapachone 29 and the alkannin derivative 30 (Figure
6).26
O
O
O Me
Me
O
O OAc
Me
Me
OH
OH
29 30
Figure 6
Doxorubicin (adriamycin) 21 and daunorubicin (daunomycin) 22 are also
naturally occurring quinones that are employed as anticancer drugs (Figure 7). They
were first isolated in the 1960s from Streptomyces peucetius and belong to the large
class of structurally related compounds known as the anthracycline antibiotics.27, 28
10
OMeO
O
O
OH
OH
O
OH
O
NH2OH
Me
OH
OMeO
O
O
OH
OH
O
CH3
O
NH2OH
Me
OH
2221
Figure 7
Doxorubicin 21 has proven to be a particularly important drug, possessing potent broad-
spectrum antitumour activity, and it continues to be used widely for the treatment of
acute leukaemias and many solid tumours.2, 27 Daunorubicin 22 has more limited
activity but is an effective treatment in combination with the drug cytarabine for adult
leukaemias.27 Although the exact mode of action for 21 and 22 is not yet understood,
the antitumour activity associated with the anthracycline antibiotics has been proposed
to arise from a combination of several different pathways. First, the planar disk-like
anthracyclines are known to target DNA through intercalation. X-ray crystallography
has revealed that the drugs associate closely with various base pairs, which distorts the
DNA helix.29 This tight binding appears to disrupt normal DNA replication and
transcription, thus halting cell division and the growth of tumours.29, 30 Second, both
doxorubicin 21 and daunorubicin 22 appear to inhibit the action of the enzyme
topoisomerase II, which has an essential function in cleaving and resealing DNA strands
during replication and transcription.31 It has been proposed that the anthracyclines are
able to stabilize the topoisomerase II-cleaved DNA complex. This leads to a large
increase in the number of DNA strand breaks, which disrupts replication and eventually
results in cell death.32 Proliferating cells, including tumour cells, have a particularly
high concentration of topoisomerase II and are therefore very vulnerable to compounds
11
which interfere with the enzyme.31, 32 A third likely mode of action for DNA damage
involves a radical based pathway, which is illustrated for doxorubicin 21 in Scheme 5.27
OMeO
O
O
OH
OH
O
OH
O
NH2OH
Me
OH
OMeO
O
O
OH
OH
O
OH
O
NH2OH
Me
OH
OMeO
O
O
OH
OH
O
OH
O
NH2OH
Me
OH
O2O2
O2
O2
one electron reduction
one electron reduction
21
32
31
Scheme 5
This pathway commences with a one electron reduction of the quinonoid drug 21 to
give a semiquinone derivative 31, which is able to react with molecular oxygen to
generate a superoxide radical anion. These radicals are unstable in the aqueous cell
environment and dismutase to hydrogen peroxide, which decomposes on reaction with
metal ions (via Fenton-type chemistry) to give hydroxyl radicals. The hydroxyl radicals
12
are highly reactive and can damage DNA and other cell components.2, 18 Unfortunately,
the oxidative damage caused by the generation of superoxide radicals also seems to be
largely responsible for the cardiotoxicity and potentially severe heart damage associated
with the use of anthracycline antibiotics, which greatly limits the dose able to be
administered during chemotherapy.27, 33, 34 Despite this serious side effect, the
anthracycline antibiotics, especially doxorubicin 21, are amongst the most effective and
widely used anticancer pharmaceuticals ever developed.2, 28
1.4 Natural Product Synthesis
Given the wide-spread occurrence and biological activity of naturally occurring
quinones and especially their potential as pharmaceuticals and pharmaceutical leads, it
is important to have a thorough understanding of their properties. This is particularly
true in the area of medicinal chemistry where an understanding of natural product
structure-activity relationships may enable the design of analogues, which exhibit less
toxicity and more selective and potent pharmacological activity.35-37 One of the things
that hampers natural product research is the supply of the compounds of interest as they
are often isolated in only milligram amounts from their source. While these small
amounts are often sufficient for structural elucidation, they do not allow for a thorough
biological evaluation.37 Total synthesis can play an important role in structural
confirmation and in providing an adequate supply of compounds for further research.
This is especially true of natural products that are obtained from hard to access
environments, such as the ocean, or those that are only present in tiny quantities.36, 37
Throughout the 19th Century and for most of the first half of the 20th Century,
total synthesis of a natural product served as the final proof of the proposed structural
13
assignment. The latter was formulated on the basis of an often painstaking series of
chemical degradations.38 The period after the Second World War saw rapid advances in
the development of powerful analytical methods including spectroscopy (UV, NMR,
IR), X-ray crystallography and mass spectrometry so that by the late 1960s, the classical
methods of structure determination had been largely replaced by these modern
techniques.38 Today, a combination of these techniques often allows for the correct
structural formulation of quite complex compounds, even before the advent of any
synthetic work.38, 39 However, synthesis continues to play an important role in the area
of structural elucidation. In particular, synthesis maybe necessary for providing
stereochemical information about a natural product, which is often beyond the reach of
X-ray and spectroscopic techniques alone.38, 40 For example, only in occasional cases
when a suitable crystalline sample exists can X-ray analysis be used to establish the
absolute configuration of a natural product.40 More often, at least one or more
stereoisomers will need to be synthesised in order to determine the correct
configuration.38, 40 Moreover, total synthesis remains an important method for verifying
a proposed structure as structural misassignment can occur. As numerous examples
highlighted by Mori41 and by Nicolaou and Snyder38 have demonstrated, it is not
entirely uncommon to complete a synthesis and discover that the original structural
assignment of a natural product is incorrect. One example from the field of quinone
research involves the discovery of the longstanding incorrect structure proposed for the
kinamycin antibiotics. The first members of the family kinamycin A-D were isolated in
the early 1970s from Streptomyces murayamaenis. The compounds were originally
formulated as N-cyanobenzo[b]carbazole derivatives, as exemplified by the postulated
structure for kinamycin C 33, on the basis of spectroscopic, X-ray and chemical
evidence (Figure 8).42 However, the structural assignment was called into question after
14
spectroscopic data obtained from several synthetic N-cyano derivatives, including
compound 34, were inconsistent with those of the natural products.43, 44
N
O
O C
AcO
CH3
OAc
OH
OAc
OH
3433
C
O
O N
AcO
CH3
OAc
OH
OAc
OH
35
N
N
O
O CMeO
AcO
CH3
N N
Figure 8
Structural revision in 1994 based on reconsideration of the original X-ray and
spectroscopic evidence, as well as further NMR studies, resulted in the kinamycin
antibiotics being reassigned a diazobenzo[b]fluorene skeleton.44, 45 This revised
structure has recently been confirmed through the first total synthesis of (-)-kinamycin
C 35 by Lei and Porco.46
1.5 Aim of Research
The aim of the research described in this thesis was to develop synthetic
approaches to two novel naturally occurring naphthoquinone derivatives, both of which
were isolated during investigations into the bioactive constituents of tropical plant
species. The first target compound to be considered is a cyclobuta-fused dione 36,
which was isolated from the bulbs of the iris Eleutherine americana Merr. et Heyne
(Iridaceae) and was named elecanacin.47 This compound was deduced as 36 by means
of NMR spectroscopy (Figure 9). However, the absolute stereochemistry was not
determined and the compound was arbitrarily depicted as shown in Figure 9. The
15
second compound of interest was isolated from the tropical American tree Crescentia
cujete L. (Bignoniaceae) and was formulated as the furofuranonaphthoquinone 37, again
largely on the basis of NMR spectroscopy (Figure 9).48
O
OO
MeO
HMe
HO
O
O
O
OH
3736
Figure 9
The ring skeletons of both compounds are rather unusual for natural products and have
never previously been reported. Thus, it was felt that confirmation of the structures of
36 and 37 by synthesis was desirable. In addition, it was thought that the development
of an asymmetric approach to elecanacin 36 would possibly allow the absolute
configuration to be established. Work carried out to achieve the synthesis of elecanacin
36 is described in Chapter 2. The naphthoquinone 37 is of particular interest because it
exhibits selective cytotoxic properties and therefore may provide a possible lead
compound in the development of therapeutic anticancer agents. Thus it was thought that
devising a viable route to 37 should not only allow confirmation of the unusual
structure, but may also enable the synthesis of sufficient quantities of the compound for
further investigation into the potentially useful biological activity. Chapter 3 discusses
the development of a synthetic approach to furofuranonaphthoquinone 37.
16
Chapter 2
The Synthesis of Elecanacin
17
2.1 Introduction
2.1.1 Elecanacin 36 and Other Naphthoquinones from Eleutherine americana and
Eleutherine bulbosa
Extracts from the bulbs of members of the Iridaceae family have long been used
as a traditional medicine by a number of cultures,49-53 and this has led to investigations
into their potential bioactive constituents. In recent years a variety of related
naphthoquinone derivatives, isolated from the bulbs of the Iridaceae species Eleutherine
americana Merr. et Heyne and Eleutherine bulbosa (Miller) Urb., have been a subject
of interest because a number of them exhibit interesting and potentially useful
biological activity.
The white-flowered iris Eleutherine americana is cultivated on the Southern
Chinese island Hainan, and extracts of the bulbs have been used as a traditional
treatment for coronary disorders.49 During a search for bioactive constituents from the
bulbs, Hara and coworkers isolated a novel cyclobuta-fused dione, which they named
elecanacin.47 Elecanacin was assigned the structure 36 on the basis of NMR
spectroscopy and has a tetracyclic ring skeleton, composed of a naphthoquinone ring
fused to a cyclobuta[1,2-b]furan-derived moiety (Figure 10). Along with elecanacin 36,
Hara and coworkers also isolated two known pyranonaphthoquinones, eleutherin 38 and
isoeleutherin 39, which had been isolated previously from Eleutherine americana by
Chen and coworkers49 and are also important constituents of the bulbs of the related iris
Eleutherine bulbosa (Figure 10).
18
O
OO
HMeO
Me H
O
O
O
Me
Me
MeO
O
O
O
Me
Me
MeO
36 38 39
Figure 10
Eleutherine bulbosa originates from tropical Central America, South America
and the West Indies,54 where the bulbs have been used traditionally as an antifertility
agent55 and for the promotion of wound healing.51 The bulbs of Eleutherine bulbosa are
also used in Java as a diuretic and purgative, as well as for the treatment of jaundice,56
and have more recently been reported as a South African folk medicine for the treatment
of burns and gastro-intestinal disorders.52
Early work on the chemical constituents of the bulbs of Eleutherine bulbosa was
carried out by Schmid and coworkers who first isolated the pyranonaphthoquinone (+)-
eleutherin 38, along with its diastereomer (-)-isoeleutherin 39.57 The structures of these
compounds were assigned on the basis of chemical degradation and derivatisation
studies,57, 58 and later confirmed by synthesis.59 Eleutherin 38 displays slight
antibacterial activity against Pyococcus aureus, Streptococcus haemolyticus A60 and
Bacillus subtalis61 and also has anticancer properties, inhibiting topoisomerase II
activity.47, 62 Isoeleutherin 39 has been found to have inhibitory activity against HIV,47
and both eleutherin 38 and isoeleutherin 39 possess antifungal activity.53
Further work on the constituents of the bulbs of Eleutherine bulbosa by Alves
and coworkers uncovered another naphthoquinone derivative, (+)-eleutherinone, which
was assigned structure 40 on the basis of spectroscopic evidence (Figure 11).53 The
19
absolute stereochemistry was not determined and remains unknown. Biological testing
revealed that (+)-eleutherinone 40 exhibits antifungal activity.
O
O
MeO
O
Me
40
Figure 11
2.1.2 Syntheses of Eleutherin 38 and Isoeleutherin 39
Eleutherin 38 and isoeleutherin 39 have been a particular focus of attention
because they are members of the class of compounds known as the
pyranonaphthoquinone antibiotics, which have the naphtho[2,3-c]pyran-5,10-dione ring
system in common. Like eleutherin 38 and isoeleutherin 39, many
pyranonaphthoquinones exhibit potentially useful biological properties, including
activity against gram-positive bacteria, pathogenic fungi and yeasts, and a number of
them possess antiviral activity.63, 64 It has also been suggested that many
pyranonaphthoquinones, including eleutherin 38 and isoeleutherin 39, may act as
bioreductive alkylating agents with a mechanism of action similar to that of the
antitumour agent mitomycin C 20 discussed in Chapter One (p. 8).26, 63
Eleutherin 38 and isoeleutherin 39 are amongst the simplest members of the
pyranonaphthoquinone family and consequently their syntheses have attracted a
considerable amount of interest.65 A number of different approaches for the construction
of the naphthopyran rings of 38 and 39 have been developed.
20
The first reported synthesis of (±)-eleutherin 38 and (±)-isoeleutherin 39 was
devised by Schmid and Eisenhuth,59 and it begins with 5-methoxynaphthalen-1-ol 41
(Scheme 6). Treatment of 41 with allyl bromide gave the allyl ether 42 and a subsequent
Claisen rearrangement produced the naphthol 43, which was oxidised to the
corresponding 1,4-naphthoquinone 44 by treatment with Fremy’s salt. Reductive
cyclisation of 44, followed by oxidative ring-opening then afforded the alcohol
derivative 46. Finally, construction of the pyran ring was effected by condensation with
acetaldehyde under acidic conditions and gave a mixture of (±)-eleutherin 38 and (±)-
isoeleutherin 39.
ON(SO3K)2
O
O
MeO
MeO
OH
O
Me
MeO OH
MeO
O
O
O
O
Me
Me
MeO
Br
K2CO3, Me2CO
CH3CHO
H3PO4
O
O
O
Me
Me
MeO
MeO
O
Me
OH
O
MeO
OH
2. aq. HBr
+
1. SnCl2/ HCl EtOH
FeCl3aq. Me2CO
41
44
42 43
3938
46 45
Scheme 6
21
The generation of the pyranonaphthoquinone ring system in the final step of this
synthesis is, at first sight, mechanistically puzzling. Eisenhuth and Schmid have
suggested that the formation of the pyran ring does in fact proceed via the hydroquinone
47, generated by some H donor in the reaction medium, and subsequent intramolecular
electrophilic substitution within the oxacarbenium ion 49, derived from the hemiacetal
48 (Scheme 7). Oxidation of 50 then delivers eleutherin 38 and isoeleutherin 39.
MeO
O
Me
OH
O
O
O
O
Me
Me
MeO
O
O
O
Me
Me
MeO
MeO
OH
Me
OH
OH MeO
OH
Me
O
OH
Me
OH
MeO
OH
Me
O
OH Me
O
OH MeMeO
Me
OH
[H] MeCHO
H+
[O]
+
39
38 50 49
484746
Scheme 7
Support for this sequence comes from the observation that pre-reduction of 46 and later
addition of benzoquinone to the reaction mixture increased the yield of eleutherin 38
and isoeleutherin 39, presumably by facilitating the oxidation step in the generation of
eleutherin 38 and isoeleutherin 39 from 50.
22
A biomimetic synthesis of (±)-eleutherin 38 and (±)-isoeleutherin 39 from a
polyketide chain has been achieved by Webb and Harris (Scheme 8).66, 67
Me Me
O O
N
OEt
OEt
O
O
O
OH O
Me
MeOH OH
O
Me
Me
OH
O
Me
Me
MeO MeO OH
O
Me
Me
ON(SO3K)2
N
Me
O O O
Me
O OO
MeO O
O
Me
Me
O
MeO O
O
Me
Me
O
Me
Me
OHOH O
O
1. LDA, THF
2.
H2 , 5% Pd/CEtOH
CH2N2Et2O
cat. CF3CO2HEtOH
39
385857
56 55 54
53
52
51
Scheme 8
23
Treatment of diethyl 3-pyrrolidinylglutarate 52 with two equivalents of the
acetylacetone dianion generated the polyketide intermediate 53, which underwent
cyclisation to give the naphthyl diketone 54. Acid-catalysed cyclisation then yielded the
naphthopyran 55. Hydrogenation, followed by monomethylation of 56, by treatment
with diazomethane in the absence of light, gave a 9 : 1 mixture of cis and trans isomers
57 and 58. Finally, oxidation with Fremy’s salt afforded mainly (±)-eleutherin 38, with
(±)-isoeleutherin 39 as the minor product.
A series of three related syntheses of (±)-eleutherin 38 and (±)-isoeleutherin 39
has also been reported. All of them involve construction of the pyran rings of 38 and 39
by way of an intramolecular cyclisation of a key alcohol intermediate 62. The first of
these syntheses was carried out by Kometani and coworkers (Scheme 9).68 Allylation of
2-bromo-8-methoxy-1,4-naphthoquinone 59 with vinylacetic acid, followed by
reductive methylation gave the bromonaphthalene 61. Lithiation, followed by treatment
with acetaldehyde then furnished the key alcohol 62, which participated in an
intramolecular oxymercuration to form the pyran ring, yielding a 1 : 0.9 mixture of cis
and trans isomers 65. The isomers were separated and individually subjected to
oxidative demethylation with ceric ammonium nitrate, giving (±)-eleutherin 38 and (±)-
isoeleutherin 39.
24
O
O
MeO
Br CO2H
MeO O
O
Me
Me
O
SnMe3O
O
MeO
Me
OBF3.Et2OCH2Cl2
O
O
MeO
Br
MeO MeO
MeO
Me
O
MeO O
O
Me
Me
O
LiAlH4Et2O
MeO
MeO
O
Me
Me
MeO
MeO MeO
Br
MeO
MeO MeO
MeO
Me
OH
AgNO3, aq. MeCNH2O, (NH4)2S2O8
1. aq. NaHSO3 Et2O
2. KOH, Me2SO4
BuLi, THFMeCHO
1.
2. MeI, K2CO3 Me2CO
1. Hg(OAc)2 THF, H2O2. 3M NaOH NaBH4
CANaq. MeCN
653938
626463
616059
Scheme 9
Uno and coworkers adapted this sequence with an alternative method for
preparing the key alcohol 62 (Scheme 9).69, 70 Nucleophilic addition of
allyltrimethylstannane to the quinone 63, in the presence of the Lewis acid BF3.Et2O,
followed by methylation gave the trimethoxynaphthalene derivative 64. Reduction of 64
then provided the alcohol 62, which was subjected to the operations outlined above to
give (±)-eleutherin 38 and (±)-isoeleutherin 39.
25
The final synthesis employing the key alcohol intermediate 62 was carried out
by Giles and coworkers,71, 72 who developed a sequence allowing the selective
preparation of (±)-isoeleutherin 39 (Scheme 10). A stereospecific base-induced
intramolecular cyclisation of the alcohol 62 by brief treatment with potassium tert-
butoxide under anaerobic conditions gave the trans-pyranonaphthalene 66, with only a
trace amount of the cis isomer being produced. Finally, oxidation of 66 gave (±)-
isoeleutherin 39.
MeO MeO
MeO
Me
OH
MeO MeO
MeO
O
Me
Me
MeO O
O
Me
Me
O
39
KOBut
DMFCANaq. MeCN
6662
Scheme 10
Giles and coworkers have accounted for the completely stereoselective nature of
the cyclisation with a mechanistic rationale for a similar system in which a related
alcohol derivative 68 was converted to the trans-pyranonaphthalene 73 (Scheme 11).73
It was noted that a short reaction time (ca 5 min) resulted in the sole formation of 73 in
almost quantitative yield, but that longer reaction times led to the formation of
increasing amounts of the cis isomer 71. After 1.25 h, the trans-pyranonaphthalene 73
and the cis-pyranonaphthalene 71 were formed in 53% and 40% yields respectively.
26
OMe
OMe
OH
Me OMe
OMe
O
Me
OMe
OMe
OH
Me
O
Me
Me
OMe
OMe
O
Me
Me
OMe
OMe
O
Me
Me
OMe
OMe
O
Me
Me
OMe
OMe
73
KOBut, DMF
60ºC
KOBut, DMF60ºC
7172
706968
67
Scheme 11
Mechanistically it has been suggested that the reaction commences with deprotonation
of the alcohol 68 and isomerisation of the allyl substituent under the strongly basic
27
conditions to give the 2-propenyl intermediate 69. The resultant alkoxide then adds to
the double bond of the alkenyl moiety so that the trans-dimethylpyran anion 72 is
formed. It has been speculated that the formation of the trans compound is favoured
kinetically because the methyl group at C3 adopts the less crowded equatorial position,
avoiding a 1,3 diaxial interaction with the methyl group at C1, which itself adopts a
pseudoaxial configuration thereby avoiding a peri interaction with the methoxy
substituent on the naphthalene ring. Protonation of the anion 72 then delivers the trans-
dimethylpyran derivative 73. Evidence for the initial isomerisation of 68 to 69 comes
from the observation that the alcohol 67 can be substituted for 68 in the above reaction
and also results in the formation of the trans-dimethylpyran derivative 73. It has been
suggested that the cis-dimethylpyranonaphthalene 71 is the thermodynamically
preferred product and that the conversion of the trans-dimethylpyranonaphthalene 73 to
the cis isomer after longer reaction times arises through deprotonation at C4 of the
pyran ring of 73, reforming the anion 72 which undergoes ring opening to give the
alkoxide 69. This can then cyclise to form the cis-pyranonaphthalene anion 70.
Protonation of 70 would then form the cis-pyranonaphthalene 71. The cyclisation of the
alcohol 62 to give the naphthopyran precursor 66 to isoeleutherin 39 presumably occurs
in a similar fashion to that described above and a mechanism for the transformation is
outlined in Scheme 12.
28
MeO
MeO
OH
MeMeO
O
Me
Me
MeO
MeO
MeO
MeO
MeO
O
MeMeO
O
Me
Me
MeO
MeO
MeO
O
Me
Me
MeO
MeO
MeO
O
Me
Me
MeO
MeO
MeO
66
KOBut, DMF
60ºC, 15 min
trace
87%
7677
757462
Scheme 12
The addition of alcohol 62 to the unactivated double bond of the alkenyl
substituent to form the pyran ring of 66 is unusual (Scheme 12). Giles and coworkers
have suggested that this novel reaction might be driven by steric effects.74 Studies on
related systems have revealed that such a transformation will only occur if there are two
methoxy substituents at C1 and C4 of the naphthalene moiety, and it has been argued
that the two methoxy groups flanking the hydroxymethyl and alkenyl substituents may
be forcing the two reaction centres together, thereby facilitating the addition to form a
pyran ring.
29
A different approach to (±)-eleutherin 38 and (±)-isoeleutherin 39 has been
described by Kobayashi and coworkers,64, 75 who generated the pyran ring of the key
precursor 83 in a single pot via a tandem conjugate addition-cyclisation sequence
(Scheme 13).
O
O
N
Me
iPr
H
Me OHMeO
MeO OH
O
Me
OH
Me
NH
iPr
MeO O
O
Me
Me
O
MeO O
O
Me
Me
O
Et3SiHTFA
N
Me
iPrH
O
O
Me
O
Me
NH
iPr
MeO
MeO O
O
Me
Me
O
O
O
MeO
OH
Me
39
air
NH2iPr
3883
82 81
8078 79
Scheme 13
It has been suggested that the sequence commences with the addition of the enamine 79
to the naphthoquinone 78. Intramolecular cyclisation of 80 and subsequent oxidation,
upon exposure to the air, then gave the naphthoquinone 82. Elimination of the amine,
30
during workup and purification on silica gel, provided the key precursor
pyranonaphthoquinone 83. Finally, reduction at room temperature gave a 1 : 5 mixture
of (±)-eleutherin 38 and (±)-isoeleutherin 39. The authors concluded that (±)-eleutherin
38 was the initially formed product, which isomerised to 39 under the reaction
conditions. Repeating the reaction at –20 ºC suppressed the isomerisation resulting in
the selective formation of (±)-eleutherin 38.
Recently, Tewierik and coworkers reported the first enantioselective synthesis of
eleutherin 38 (Scheme 14).76
O
OH O
Me
O
O Me
Me
O
MeO
O
O Me
Me
O
MeONEt3CH2Cl2 O
O Me
Me
O
MeOBr
O
OH Me
Me
MeO
O
OH Me
Me
Br
Br
O
O Me
Me
Br
O
1. MeLi, THF or MeMgBr, ether
2. Et3SiH CF3CO2H CH2Cl2
2 eq. NBSDMF
CANMeCN, H2O
benzene, 80 ºC
150 ºC CH2=CH2
84
89 88 87
8685
(1R, 3S)-38
Scheme 14
31
Unlike most of the previous syntheses of (±)-eleutherin 38 and (±)-isoeleutherin 39
described above where the key step involves construction of the pyran rings, this
synthesis takes advantage of the pyran ring already present in the starting lactone (S)-
mellein 84. An important part of the sequence involves formation of the
naphthoquinone moiety of eleutherin 38 via a Diels-Alder cycloaddition. (S)-Mellein 84
is itself a natural product and was prepared following a six step sequence from (S)-
propylene oxide.77 Methylation of 84, followed by stereospecific reduction with
triethylsilane and trifluoroacetic acid yielded the 1,3-dimethylpyran 85. Bromination of
85, followed by oxidaton with ceric ammonium nitrate then generated the
bromonaphthoquinone 87. A Diels-Alder addition of 87 and 1-methoxy-1,3-
cyclohexadiene, followed by treatment with triethylamine and heating to 150 ºC
afforded (1R, 3S)-eleutherin 38 in low yield (13%). This final sequence presumably
occurs by way of dehydrobromination of the Diels-Alder adduct 88 upon treatment with
base, followed by a pyrolysis-induced loss of ethylene to effect aromatisation and
deliver 38.
This recent synthesis has been followed closely by a second enantioselective
route to (1R, 3S)-eleutherin 38, which was devised by Gibson, Andrey and Brimble and
incorporates a key Hauser-Kraus annulation strategy for constructing the naphthopyran
ring of 38 (Scheme 15).78
32
O
O
CN
MeO
O
MeO
Me
HO MeMeO
MeO
MeO
MeO
Me
O
OTBDPS
Me
MeO
O
Me
Me
OTBDPS
O
O Me
Me
O
MeO
O
MeO Me
Me
MeO
MeO
OH
OH
Me
O
OTBDPS
Me
MeO
O
O
Me
O
OTBDPS
Me
MeO
(1R, 3S)-38
2. Na2S2O4 tetra-n-butylammonium bromide, H2O, THF; then NaOH, Me2SO4
1. t-BuOK DMSO
90
94 93
9291
95
Et3SiH CF3CO2H CH2Cl2-78 ºC to RT
tetra-n-butylammoniumfluoride, THF
96
CANMeCN/H2O
Scheme 15
The annulation reaction of the known 3-cyanophthalide 90 with a chiral Michael
acceptor 91, followed by a one pot reduction/methylation of the crude reaction product
33
gave the naphthalene 94 in 67% yield. Deprotection of the tert-butyldiphenylsilyl ether
with tetra-n-butylammonium fluoride and subsequent intramolecular addition of the
liberated hydroxy group at the ketone moiety then afforded the cyclic hemiacetal 95. A
stereospecific reduction of 95 with triethylsilane and trifluoroacetic acid provided (1R,
3S)-dimethyl benzo[g]isochromene 96, which was converted into the target (1R, 3S)-
eleutherin 38 in excellent yield via an oxidative demethylation reaction with ceric
ammonium nitrate.
The work outlined above illustrates some of the chemistry required to elaborate
the naphthoquinone and dimethyl-substituted pyran moieties of eleutherin 38 and
isoeleutherin 39. Some of this chemistry is relevant to the proposed synthesis of
elecanacin 36, which is one of the themes of this thesis.
2.1.3 Elecanacin 36 as a Synthetic Target
Unlike eleutherin 38 and isoeleutherin 39 which belong to the large family of
pyranonaphthoquinone antibiotics, the structural isomer elecanacin 36 has a unique and
previously unreported tetracyclic ring skeleton. Given this unusual structure, as well as
the continuing interest in naphthoquinones isolated from the Iridaceae Eleutherine
genus, it seemed of interest to develop an approach to the synthesis of elecanacin 36 in
order to confirm the structure of the novel ring skeleton, and to possibly determine its
absolute stereochemistry. The construction of the cyclobutane ring would be a key step
in this synthesis and it was envisaged that this might be possible by way of a [2 + 2]
photocycloaddition.
34
2.2 [2 + 2] Photocycloadditions for the Synthesis of Cyclobutane Rings
While there is a variety of methods available for the preparation of cyclobutane
derivatives,79 one of the most common methods for accessing the strained four-
membered ring is by way of a light-induced [2 + 2] cycloaddition between an excited
state enone and a ground state alkene. This reaction has been the subject of many
detailed reviews.80-85
The [2 + 2] photoaddition was discovered by Ciamician and Silber who reported
in 1908 that solutions of carvone 97 left in Italian sunlight for 1 year led to the
formation of an adduct formulated as structure 98 (Scheme 16).86 The resultant
cyclobutane derivative 98 was named carvonecamphor and arises by the intramolecular
cycloaddition of the carbon-carbon double bonds of the cyclohexenone moiety to the
tethered alkenyl side-chain within 97.
MeO
Me
OMe
O
Me
Me
hv (sunlight)1 yr
97 98
Me
Scheme 16
Ciamician and Silber’s observation gained little attention until the result was confirmed
in 1957 by Büchi and coworkers, who repeated the reaction by irradiating a solution of
carvone 97 with Californian sunlight for 6.5 months.87 The structure of 98 was
confirmed using a combination of IR and UV spectroscopy, as well as chemical
degradation and derivatisation techniques.
35
Since Büchi’s work in the late 1950s, the reaction has become an important part
of the organic synthetic methodology and has been a key step in the synthesis of a
number of cyclobutane-containing natural products,88 including caryophyllene 10289
and β-panasinene 10590, as well as some theoretically interesting compounds such as
cubane 109 (Scheme 17).91, 92
Br
O
OBr
Br
OBr
OO
H
HMe
MeMe
Me
Me
Me
O
MeMe
OMe
Me
O
Me
Me
Me
OMe
Me
Me
O
O
Br
Br
O Br
Br
O
O
COOH
HOOC
hvpentane
hv, MeOH, HCl
steps
steps
hvbenzene
1. (CH2OH)2 H+
2. aq. HCl
steps
steps50% aq. KOH
99 100 101 102
105104103
106 107 108
109111110
hvpentane
Scheme 17
36
The [2 + 2] photoaddition has also become increasingly important for the
preparation of useful synthetic intermediates because the strained cyclobutane ring can
be induced to undergo a number of transformations. These include ring-expansion for
the formation of five- to nine-membered rings, as well as ring-contraction for
cyclopropane rings and ring-opening for acyclic systems.93
2.2.1 Mechanism of the Enone-Alkene [2 + 2] Photocycloaddition
While many details about the mechanism of the [2 + 2] photocycloaddition are
not yet understood,80 the triplet mechanism based on work by Corey94 and de Mayo95, 96
for the addition of an excited state enone to a ground state alkene is now well accepted,
and this can be explained with the help of the figure set out below (Figure 12).
Irradiation results in excitation of the enone 99 to the singlet state S1 (n, π*) 113, which
is short-lived in enone systems. In the case of acyclic enones or large flexible
cycloalkenones (with seven or more members), the energy provided allows them to
undergo cis-trans isomerisation, and the substrate quickly reverts to the ground state
without further reaction. For this reason the [2 + 2] photoaddition is most commonly
carried out on five- or six-membered cycloalkenones and other conformationally
constrained systems because they will not undergo energy-wasting isomerisation around
the carbon-carbon double bond when subjected to irradiation.80-83 However, it should be
noted that this condition is less important for the intramolecular version of the reaction,
where trapping is particularly efficient due to the proximity of the excited state enone
and ground state alkene.80
37
O
O O
O O
O
S1 T1
O *
exciplex
intersystemcrossing
hv
and/or
99 112
113 112 112114 115
116 117
118
Figure 12. Mechanism for the enone-alkene [2 + 2] photocycloaddition, illustrated by
the addition of cyclohexenone 99 and ethylene 112 (adapted from a similar scheme by
Horspool)83
In the case of these smaller ring cycloalkenones, the singlet state 113 may
undergo intersystem crossing to the triplet state T1 (n, π* or π, π*) 114 (Figure 12),
which is a fast and efficient process for enones, and this triplet state is sufficiently long
lived for a reaction to occur. 80-84 According to this theory, the enone in its triplet state
forms a complex with the ground state alkene 112, known as an exciplex 115. The
exciplex 115 can decay back to starting materials or proceed to form a triplet 1,4-
diradical intermediate 116 and/or 117. The diradical intermediate then either fragments
38
back to starting materials or undergoes spin inversion to a singlet diradical which can
close to form a cyclobutane adduct 118.80, 82, 83 It should be noted that Schuster and
coworkers have presented evidence that the diradical intermediate may be formed
directly without the need for an exciplex precursor.97
2.2.2 Intermolecular [2 + 2] Photocycloadditions
The intermolecular [2 + 2] photoaddition is often of limited use in synthesis
because there are many systems where the regioselectivity of the reaction is
unpredictable.81, 82 When unsymmetrical enones and alkenes undergo photoaddition,
two possible regioisomers may form: the head-to-head and the head-to-tail adduct. The
regiochemical outcome of a reaction tends to be dependent upon the electronic and
steric character of the particular enone and alkene substrates, as well as other factors
such as the temperature and the solvent used in the reaction.80, 82, 84 There are also many
reports of intermolecular photoadditions where the regioselectivity is low and mixtures
of adducts arise.80 One example comes from White and Gupta’s synthesis of the
naturally occurring compound β-bourbonene 123,98, 99 where the key [2 + 2]
photoaddition of cyclopentenone 119 to 2-methyl-5-isopropylcyclopentene 120
proceeded in a non-regioselective fashion, affording a 1 : 1 mixture of two adducts 121
and 122 in 66% yield (Scheme 18).
39
O
Me
MeMe
H
H
H
Me
MeMe
O Me
H
H
H
O
MeMe
H
H
H
Me
MeMe
hvpentane
Ph3P=CH2,ether
119 120 121 122
123
Scheme 18
The two regioisomers were separated by chromatography and the sequence was
completed by treatment of the desired head-to-head isomer 121 with
methylenetriphenylphosphorane affording β-bourbonene 123.
2.2.3 Intramolecular [2 + 2] Photocycloadditions
The intramolecular [2 + 2] photoaddition is often more useful than the
intermolecular reaction because the former offers better regiochemical control due to
the constrained nature of such systems.80, 82, 84 These reactions also tend to be more
efficient due to the proximity of the excited state enone subunit and the tethered ground
state alkene.80, 84
40
For intramolecular [2 + 2] photoadditions, there is a preference for the formation
of adducts with the cyclobutane ring fused to a five-membered ring, rather than to a
four- or six-membered ring, because five-membered rings form more rapidly.80, 82, 84
This phenomenon has been termed the ‘Rule of Five’ and can be illustrated by Pirrung’s
synthesis of the naturally occurring sesquiterpene (±)-isocumene 126 (Scheme 19),100,
101 where an intramolecular enone-alkene [2 + 2] photoaddition within the
cyclohexenone derivative 124 gave the required cyclopentyl-fused intermediate 125 in
77% yield.
O
Me
Me
MeO
Me
Me
Me
Me
Me
Me
Me
stepshv, 350 nmhexane
124 125 126
Scheme 19
The stereoselectivity of the above photoaddition is also notable and results in the
formation of a single diastereomer. This arises by addition of the terminal alkene to one
of the diastereotopic faces of the cyclohexenone carbon-carbon double bond opposite to
the C4 methyl substituent within 124, thereby avoiding destabilizing steric interactions
(Scheme 19).
2.2.4 [2 + 2] Photocycloadditions of 1,4-Naphthoquinones
1,4-Naphthoquinones are amongst the variety of unsaturated carbonyl
compounds which are known to undergo [2 + 2] photocycloaddition to alkenes, making
them potentially useful substrates for the synthesis of cyclobuta-fused ring systems. The
41
intermolecular version of the reaction in particular has attracted some attention and
photoadditions between a variety of alkene and 1,4-naphthoquinone derivatives have
been reported, including the reactions shown in Scheme 20.
O
O
Cl
O
O
Cl
O
O
O
O
O
O
O
OOEt
O
O
OEt
OEt
hv benzene
hv benzene
hv benzene
127 112 128
4 112 130
4 131 132 133
Scheme 20
Naito and coworkers have found that irradiation of 2-chloro-1,4-naphthoquinone 127 in
the presence of ethylene 112 gives rise to the cyclobuta-fused dione 128 in 53%
yield.102 Some further examples come from an investigation carried out by Bryce-Smith
and coworkers who observed that 1,4-naphthoquinone 4 undergoes a similar
photoaddition to ethylene 112 to afford the cyclobutane derivative 130 (28%).103
However, in the case of the photoaddition of 1,4-naphthoquinone 4 to ethyl vinyl ether
131 both a cyclobutane 132 and a spirooxetane adduct 133 were generated in low yield
42
(8% total chemical yield). The spirooxetane 133 in this final example arises by way of a
Paterno-Büchi reaction, which involves the light-induced cycloaddition of a carbonyl
carbon-oxygen double bond to an alkene to form a four-membered oxetane ring104 and
is able to compete with cyclobutane formation in some systems.103, 105, 106
Examples of intramolecular [2 + 2] photoadditions of 1,4-naphthoquinones are
rare, but one reaction has been reported by Suzuki and coworkers who found that the
norbornadiene-fused naphthoquinone 134 underwent ready intramolecular cycloaddition
upon irradiation with visible light generating the quadricyclane derivative 135 in 63%
yield (Scheme 21).107 Interestingly, the quadricyclane product absorbs light near the
visible region and 135 was found to undergo a cycloreversion reaction when irradiated
at shorter wavelengths (≤ 370 nm) resulting in a 79 : 21 mixture of the norbornadiene
134 and quadricyclane 135 respectively.
O
O
O
O
hv (> 410 nm) dichloromethane
hv (< 370 nm)
134 135
Scheme 21
43
2.3 An Approach to Elecanacin 36
The ability of 1,4-naphthoquinones to undergo light-induced [2 + 2]
cycloaddition and form cyclobutane rings suggested that such a photoaddition may
provide a useful approach to the cyclobuta-fused ring skeleton of elecanacin 36.
Although Suzuki and coworkers’ synthesis of the quadricyclane-fused naphthoquinone
135 appears to be the only reported example of an intramolecular [2 + 2]
photocycloaddition involving a 1,4-naphthoquinone (Scheme 21), intramolecular
photoadditions in cyclohexenone derivatives bearing an alkenyl-substituted side chain
are well known.108 One example is the intramolecular photoaddition reported by Cargill
and coworkers who found that irradiation of 136 in dichloromethane gave the adduct
137 in 83% yield (Scheme 22).109
O O
CH2Cl2
hv
136 137
Scheme 22
On this basis, it was expected that a similar photoaddition could provide access to the
cyclobuta[1,2-b]tetrahydrofuran moiety in elecanacin 36. Leaving aside for the moment
the question of the configuration of the methyl-substituted carbon of the tetrahydrofuran
ring, retrosynthetic cleavage of two cyclobutane bonds in 36 suggested 138 as a
potential key intermediate (Scheme 23).
44
O
O O
OMe
Me
O
O
O
MeO
Me
MeO O
O
OH
Me
O
O O
OMe
Me
36
13846
Scheme 23
Considering the synthetic direction, an intramolecular photoaddition of the vinyl ether
moiety to the double bond within the naphthoquinone 138 should in principle give
elecanacin 36, and would allow construction of the cyclobutane and tetrahydrofuran
rings to be achieved in a single reaction. The vinyl ether 138 should in turn be available
from the hydroxy-quinone 46. Although the intermolecular addition of 1,4-
naphthoquinone 4 with ethyl vinyl ether 131 proceeds in low yield (Scheme 20, p. 42),
it was expected that this related intramolecular version should be more efficient given
the proximity of the reaction centres within 138, which should result in a more
favourable entropy of activation.
In order to test the feasibility of the proposed intramolecular [2 + 2]
photoaddition, the synthesis of the racemic vinyl ether 138 was undertaken and
hydroxy-quinone 46 was set as the initial target.
45
2.4 Preparation of (±)-Elecanacin 36
2.4.1 Synthesis of 2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-dione 46
There have been two previous syntheses of 2-(2-hydroxypropyl)-5-
methoxynaphthalene-1,4-dione, one yielding the racemate 46 and the other giving one
enantiomer 146. However, it was felt that neither synthesis was particularly
straightforward.
As already mentioned, Eisenhuth and Schmid prepared 46 as an intermediate in
their synthesis of eleutherin 38 and isoeleutherin 39 (Scheme 6, p. 21).59 Although they
found that the hydroxy-quinone 46 could be obtained following a route involving an
oxidative ring-opening of the naphthofuran 45 by treatment with ferric chloride in
aqueous acetone (Scheme 6), it was noted that very exact experimental manipulations
were required or the reaction would result in the formation of polymeric material.
A more recent synthesis of the (S)-hydroxy-quinone 146 has been reported by
Tanada and Mori who found that 146 arose unexpectedly during oxidation of
naphthofuran 144 with Fremy’s salt (Scheme 24).110 However, this result was just
mentioned in passing and no experimental detail or yield was given. Although this route
could conceivably be shortened to give the hydroxy-quinone 146 at an earlier stage by
possible oxidation of intermediate 143, the use of tetralone 139 as the starting material
also makes the sequence undesirably expensive (current catalogue price of 139 :
$28/g).111
46
O
MeOO
Me
O
Me
OHMeO
O
Me
MeO O
O
ON(SO3K)2 ON(SO3K)2
MeO O
O
OH
Me
O
MeO
Me
OH
OH
MeO
Me
OH
OH
O
MeO
Me
OTroc
O
MeO
Me
OTroc
O
1. LHMDS, toluene
2. 10% Sc(OTf)3
Cl3CCH2OC(O)ClpyridineCH2Cl2
SeO21,4-dioxane
powdered ZnAcOH
DEAD, PPh3THF
139 140 141
142143144
146145
H H
HH
H
Scheme 24
Thus, rather than repeating either of these syntheses, it was envisaged that the
hydroxy-quinone 46 might be prepared more conveniently following a route involving
hydration of the terminal double bond in the allyl-substituted naphthalene 147 via an
oxymercuration-reduction (Scheme 25).
47
MeO
OH
Br
MeO O
O
OH
Me
ON(SO3K)2
MeO
O
MeO
OH
OH
Me
K2CO3MeOH
MeO
OAc
MeO
OAc
OH
Me
K2CO3, Me2CO
Ac2O, PhNEt2170 ºC
1. Hg(OAc)2, THF2. NaBH4, 2M NaOH
41 42 147
14814946
Scheme 25
Allylation of 5-methoxynaphthalen-1-ol 41, followed by a Claisen rearrangement and in
situ acetylation of 42 afforded the acetate 147 in 95% yield. While it was appreciated
that the acetate group was unlikely to be robust enough to survive the addition of dilute
base during the oxymercuration-reduction, any hydrolysis of 148 would be of no
consequence because the next step of the sequence would involve removal of the acetyl
group. Unfortunately treatment of 147 with mercuric acetate in aqueous tetrahydrofuran
according to the general method of Brown and Geoghegan,112 followed by sodium
borohydride reduction was unsuccessful and returned a 1 : 1 mixture of starting acetate
147 and hydrolysed starting material. There was no trace of the desired alcohol 148.
The oxymercuration of an alternative allyl-substituted precursor 44 to the key
hydroxy-quinone 46 was also briefly examined (Scheme 26).
48
MeO
O
MeO
OH
ON(SO3K)2
MeO O
O
MeO O
O
OH
Me
1. Hg(OAc)2, THF2. NaBH4, 2M NaOH
160-185 ºC
42 43 44
46
Scheme 26
The quinone 44 was prepared according to the procedure of Eisenhuth and Schmid.59 A
Claisen rearrangement of the allyl ether 42 provided the naphthol 43, which underwent
oxidation upon treatment with Fremy’s salt affording 44 in 91% yield. Attempted
oxymeruration of this compound was also unsuccessful and returned a complex mixture
of products which could not be identified.
As preparation of the hydroxy-quinone 46 by way of an oxymercuration reaction
could not be achieved, an alternative approach was investigated and is outlined in
Scheme 27. It begins with the previously prepared acetate 147.
49
MeO
OAc
MeO
OAc
H
O
MeO O
O
OH
Me
MeO
OH
OH
Me
ON(SO3K)2
2. (NH2)2CS NaHCO3
1. O3, CH2Cl2/MeOH -78 ºC
147 150
14946
MeMgITHF
Scheme 27
Careful ozonolysis of the acetate 147 followed by thiourea reduction gave the aldehyde
150. The reaction mixture did not turn blue to signify the consumption of the alkene and
it was necessary to monitor the disappearance of the starting material by TLC in order
to avoid over-oxidation of the electron-rich aromatic ring system. The aldehyde 150
proved to be unstable and decomposed on silica during attempted purification. The 1H
NMR spectrum of the crude aldehyde 150 includes a triplet at 9.69 ppm, consistent with
an aldehyde proton and this is coupled to the methylene protons in the formylmethyl
sidechain, which resonate as a doublet at 3.70 ppm. The spectrum also shows two
singlet signals at 4.00 ppm and 2.46 ppm, corresponding to the C5 methoxy group and
C1 acetate methyl group protons respectively.
The problem of the instability of aldehyde 150 was overcome by using the crude
compound directly in the subsequent Grignard reaction (Scheme 27). Immediate
50
treatment of 150 with an excess of methylmagnesium iodide gave the required alcohol
149. The molecular formula C14H16O3 of 149 was confirmed by combustion analysis
and mass spectrometry. The 1H NMR spectrum contains signals consistent with the
presence of the hydroxypropyl side chain, including a C3 methyl doublet at 1.27 ppm
and two doublet of doublets arising from the C1 methylene protons at 3.01 ppm and
2.90 ppm (Figure 13). The C2 methine proton appears as a multiplet at 4.36-4.27 ppm.
Figure 13. 1H NMR spectrum of 149 (300 MHz, CDCl3).
Finally, oxidation of 149 with Fremy’s Salt afforded the desired hydroxy-
quinone 46 as a bright yellow crystalline solid in 41% yield over three steps (Scheme
27). In the 1H NMR spectrum of 46, the C3 proton resonates as a triplet at 6.78 ppm due
to long range coupling to the methylene protons in the hydroxypropyl side chain, which
themselves occur as two doublet of doublet of doublets at 2.74 ppm and 2.59 ppm
51
(Figure 14). The methylene protons are also coupled to the adjacent methine proton,
which occurs as a multiplet at 4.15-4.03 ppm. A doublet at 1.29 ppm is associated with
the methyl protons in the hydroxypropyl side chain. The 13C NMR spectrum includes
two signals at 186.1 ppm and 184.3 ppm, corresponding to the quinonoid carbonyl
carbons. The electronic spectrum shows absorbances at 247, 268, 354 and 396 nm,
which are consistent with the presence of a naphthoquinone chromophore.113
Figure 14. 1H NMR spectrum of 46 (300 MHz, CDCl3).
2.4.2 Synthesis of 5-Methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-dione 138
With the hydroxy-quinone 46 in hand, the next step involved conversion of 46 to
the target vinyl ether 138. This was achieved in the usual fashion by heating the
52
hydroxy-quinone 46, ethyl vinyl ether and a catalytic amount of mercuric acetate under
reflux,114 which delivered 138 as a bright yellow oil (Scheme 28).
O
O
MeO
O
Me
MeO O
O
OH
Me
EtO
cat. Hg(OAc)2
13846
Scheme 28
The NMR spectral properties are in accord with the structure of the vinyl ether 138
(Figure 15). The 1H NMR spectrum shows a signal at 6.75 ppm due to the C3 proton,
which is split into a triplet due to long range coupling to the methylene protons in the
vinyloxypropyl side chain. These methylene protons occur as two doublet of doublets of
doublets at 2.79 ppm and 2.67 ppm. The methylene protons are also coupled to the
adjacent methine, which itself resonates as a multiplet at 4.26-4.15 ppm. In addition, the
spectrum shows a vinylic pattern with components centred at 6.27 ppm, 4.30 ppm and
3.99 ppm. This last signal overlaps with the C5 methoxy group singlet signal at 3.99
ppm.
53
Figure 15. 1H NMR spectrum of 138 (300 MHz, CDCl3).
2.4.3 Synthesis of (±)-Elecanacin 36
Having prepared the key vinyl ether 138, efforts were now directed towards
construction of the remaining cyclobutane and tetrahydrofuran rings in elecanacin 36
via the proposed [2 + 2] photocycloaddition. Irradiation at 350 nm of a 0.009 M solution
of vinyl ether 138 in dichloromethane cleanly gave two compounds, with very close Rf
values. An electronic spectrum of the reaction solution measured after irradiation shows
the disappearance of the characteristic long wavelength absorbance attributable to the
naphthoquinone chromophore,113 which occurs at 393 nm in the electronic spectrum of
138 (Figure 16).
54
Figure 16. Electronic spectrum of 5-methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-
dione 138 (solid line) and the photoaddition reaction product (broken line) in
dichloromethane.
O
O
MeO
O
Me
O
O O
H
MeO
Me
O
O
MeO
O
H
Me
CH2Cl2hv, 350 nm
(±)-elecanacin
15136138(±)-isoelecanacin
(one enantiomer of each product is depicted)
Scheme 29
55
The two compounds were separated by careful radial chromatography. The slightly
more polar compound, isolated in 25% yield, was (±)-elecanacin 36 (Scheme 29). The
1H and 13C NMR spectra were identical to those of the naturally occurring (+)-
enantiomer (provided by Prof. Yasuhiro Imakura of the Naruto University of Education
in Japan)47 and are shown in Figures 18 and 19. This result confirms the unusual
cyclobuta-fused ring skeleton of elecanacin 36.
The more mobile product, which we named isoelecanacin, was obtained in 38%
yield. The 1H and 13C NMR spectra closely resemble those recorded for elecanacin 36
with similar chemical shifts (Figures 20a and 20b), and isoelecanacin was assigned the
isomeric structure 151 on the basis of 2D-NMR (COSY, HMBC, HSQC and NOESY)
evidence. The NMR spectral data for 36 and 151 are collected in Table 1 and key
NOESY correlations within the oxabicyclo[3.2.0]heptyl framework are shown in Figure
17. It should be noted that the aromatic proton signals of both isomers show second
order characteristics, even at 500 MHz, rather than the first order pattern implied47 for
elecanacin 36.
36
elecanacin isoelecanacin
151
O
HnHx
H
H
MeH
Hn
Hx
O
HnHx
H
Me
HH
Hn
Hx
Figure 17. Key NOESY correlations within the 2-oxabicyclo[3.2.0]heptyl framework
of elecanacin 36 (ref. 47) and isoelecanacin 151 (this work).
56
Figure 18a. 1H NMR spectrum of synthetic (±)-elecanacin 36 (300 MHz, CDCl3).
Figure 18b. 1H NMR spectrum of natural (+)-elecanacin 36 (300 MHz, CDCl3).
57
Figure 19a. 13C NMR spectrum of synthetic (±)-elecanacin 36 (75.5 MHz, CDCl3).
Figure 19b. 13C NMR spectrum of natural (+)-elecanacin 36 (75.5 MHz, CDCl3).
58
Figure 20a. 1H NMR spectrum of isoelecanacin 151 (300 MHz, CDCl3).
Figure 20b. 13C NMR spectrum of isoelecanacin 151 (75.5 MHz, CDCl3).
59
60
The formation of elecanacin 36 and isoelecanacin 151 is due to the addition of
the vinyl ether moiety to the two diastereotopic faces of the carbon-carbon double bond
of the naphthoquinone system of 138 (Scheme 29). Monitoring the photoaddition by
TLC and NMR revealed that both 36 and 151 were formed at the early stages of the
reaction, and control experiments established that both products were photostable and
not interconverted under the irradiation conditions. Interestingly, the vinyl ether 138
also underwent conversion to elecanacin 36 and isoelecanacin 151 when a solution of
vinyl ether 138 in dichloromethane was left exposed to ambient laboratory light for 5h.
2.5 The Enantioselective Synthesis of Elecanacin 36
Having developed a sequence for the synthesis of racemic elecanacin 36, we
decided to extend this approach to the preparation of the enantiopure compound to
establish the absolute configuration of the natural product. In order to do this, a new
asymmetric route to alcohol 149 depicted in Scheme 27 (p. 50) was needed.
2.5.1 An Approach to Chiral 1-(1-Hydroxy-5-methoxynaphthalen-2-yl)propan-2-
ol 152 using Jacobsen’s Catalyst
Epoxides are valuable compounds for the preparation of alcohols because the
strained three-membered ring undergoes ready ring-opening when attacked by a wide
range of nucleophiles, and they can often be conveniently prepared directly from
alkenes or aldehydes.115 Accordingly, it was decided to investigate a route to the chiral
alcohol 152 involving an epoxide precursor, as outlined in Scheme 30.
61
MeO
OH
OH
H
Me
MeO
OR
O
MeO
OR
O
153 R = Ac154 R = Bn
152 155 R = Ac156 R = Bn
Scheme 30
It was expected that reductive opening of a chiral epoxide such as 153 or 154, with
lithium aluminium hydride, and removal of the protecting group would provide one
enantiomer of alcohol 152. The enantiopure epoxides 153 and 154 should in turn be
available by resolution of the corresponding racemic epoxide using Jacobsen’s catalyst.
Hydrolytic kinetic resolution with Jacobsen’s catalyst 160 has proven to be a
useful method for accessing chiral terminal epoxides (Figure 21).
N NCo
O OOAc
HH
But
But
But
But
N NCo
O OOAc
HH
But
But
But
But
(R,R) - 160 (S,S) - 160
Figure 21
In this procedure the chiral (salen)-CoIII catalyst 160 promotes opening of the epoxide
ring of one enantiomer over the other in a racemic mixture of a terminal epoxide by
nucleophilic attack of water.116-118 The process is illustrated below for the resolution of
propylene oxide 157 (Scheme 31).
62
O
MeMe
OHHOO
Me
0.5 eq H20,(R,R)-160
157 159158
Scheme 31
The reaction results in a mixture of a 1,2-diol 159 and an enantio-enriched starting
epoxide 158. In view of the large boiling point and polarity differences of these
compounds, the desired chiral epoxide can be readily isolated.
Jacobsen’s hydrolytic kinetic resolution has become increasingly popular for
natural product synthesis as the resolved epoxides are often obtained in very high
enantiomeric excess and yield.118-120 A representative example is the recent synthesis of
epothilone A 165 carried out by Liu and coworkers, who used Jacobsen’s catalyst
methodology to introduce the chiral centre at the C3 position of 165 (Scheme 32).121
O
S
N
OHO O
OH
O
OO
OOOOH
HO
OOH
O
O3
3
steps
0.6 eq. H2O2 mol% Jacobsen's catalyst 160
5 mol% Co2(CO)810 mol% 3-hydroxypyridineTHF/MeOH, CO
epothilone A
161 162 163
164165
Scheme 32
63
Treatment of the racemic epoxide 161 with Jacobsen’s catalyst and 0.6 equivalents of
water returned the chiral epoxide 163 in 48.3% yield (maximum 50%) and greater than
99% ee. Ring-opening by carbomethoxylation then afforded the alcohol 164 with the
required stereochemistry.
With these considerations in mind, it was envisaged that hydrolytic kinetic
resolution may provide an effective strategy for obtaining the chiral epoxides 153 and
154. Thus, the first step in the enantioselective approach to elecanacin 36 was to prepare
the corresponding racemic epoxides 155 and 156.
2.5.2 Synthesis of Epoxides 155, 156 and 168 and Attempted Hydrolytic Kinetic
Resolution
An initial attempt to prepare 155 was made by epoxidation of the previously
prepared acetate 147 with m-chloroperoxybenzoic acid (Scheme 33a). The reaction
proceeded sluggishly at room temperature and returned mainly starting material, with
only a trace amount of the desired epoxide 155 forming over three days (1H NMR
analysis). An effort to increase the yield of 155 by gentle heating of the reaction
mixture, in the presence of 2,6-di-t-butyl-4-methylphenol, appeared to be accompanied
by degradation of the electron-rich naphthalene system. This resulted in a complex
mixture of products, including the epoxy acetate 155, which could not be isolated in a
pure state. Similarly, the synthesis of the alternative epoxide 156 was attempted. The
naphthol 43 was protected as a benzyl ether, but subsequent treatment of 166 with m-
chloroperoxybenzoic acid again returned starting material along with an unidentifiable
mixture of products (Scheme 33b).
64
MeO
OAc
MeO
OH
MeO
OBn
MeO
OBn
O
MeO
OAc
O
PhCH2BrK2CO3, acetone
m-CPBA, CH2Cl2 0 ºC to RT (or 35 ºC, with2,6-di-t-butyl-4-methylphenol)
a)
b)
m-CPBA, CH2Cl2 0 ºC to RT
156
16643
147 155
Scheme 33
Alternative reagents for preparing the epoxides were investigated. Dubois and
coworkers have suggested that peracetic acid accompanied by a ferric phenanthroline
catalyst can be particularly useful for the epoxidation of terminal alkenes.122 However,
no reaction was observed when 147 was subjected to the reaction conditions (Scheme
34).
65
MeO
OAc
MeO
OAc
O[((phen)2(H2O)FeIII)2(µ-O)](ClO4)4
CH3CO3HMeCN, 0 ºC
147 155
Scheme 34
More success was encountered using dimethyldioxirane and the epoxy acetate 155 was
synthesised in low yield (23%) by treatment of 147 with a cold solution of
dimethyldioxirane in acetone, prepared according to the general method of Murray and
Singh (Scheme 35).123
MeO
OAc
O O
Me MeMeO
OAc
O
147 155
Me2CO
Scheme 35
As the monosubstituted ethylene moiety of acetate 147 had proven to be quite
resistant to epoxidation with peroxy reagents, an alternative method for preparing the
related epoxide 156 was considered. Aldehydes can be directly converted into epoxides
with dimethylsulfoxonium methylide, following the general method developed by
Corey and Chaykovsky,124 and the required benzyl ether 156 was prepared satisfactorily
using this approach, as shown in Scheme 36.
66
MeO
OBn
MeO
OBn
O
MeO
OBn
H
O
1. O3, CH2Cl2-MeOH -78 ºC
trimethylsulfoxoniumiodideNaH, Me2SO
2. (NH2)2CS NaHCO3
166 167
156
Scheme 36
Careful ozonolysis of 166 gave the aldehyde 167. Formation of 167 was rapid but the
reaction mixture did not turn blue at any stage of the reaction and it was necessary to
carefully monitor the disappearance of starting material by TLC in order to avoid over-
oxidation of the electron-rich aromatic ring. Finally, treatment of 167 with
dimethylsulfoxonium methylide gave the desired terminal epoxide 156 in 69 % yield.
With epoxides 155 and 156 in hand, it was now possible to investigate the
proposed hydrolytic kinetic resolution. Unfortunately, treatment with the (salen)-CoIII
catalyst 160 and water (0.5 equivalents) according to standard methods116, 118 did not
lead to ring-opening and both 155 and 156 were recovered essentially unchanged, even
after long reaction times (Scheme 37).
67
MeO
OR
O
155 R = Ac156 R = Bn
0.5 eq H2OJacobsen's Catalyst 160THF, 0 ºC to RT no hydrolytic
kinetic resolution
Scheme 37
While the reason for this lack of reactivity is unclear, it was felt that the electron-rich
naphthalene moieties of 155 and 156 could possibly interfere with the catalytic
hydrolytic cycle. This suggested that a more electron-deficient system such as the
quinonoid epoxide 168 would perhaps be more responsive to the resolution process and
the synthesis of 168 was undertaken (Figure 22).
O
O
MeO
O
168
Figure 22
Perez-Sacau and coworkers have demonstrated that naphthoquinone 170 can be
prepared by epoxidation of the alkenyl side chain of 169 by treatment with m-
chloroperoxybenzoic acid (Scheme 38).125
68
O
O
Me
Me
OAc
O
O
OAc
O
Me
Me
m-CPBACH2Cl2, 0 ºC
169 170
Scheme 38
Application of the above procedure to the allyl-substituted naphthoquinone 44
proceeded smoothly and the orange crystalline epoxide 168 was obtained in 67% yield
(Scheme 39). However, attempted hydrolytic kinetic resolution with Jacobsen’s catalyst
was unsuccessful and epoxide 168 was also returned unchanged.
O
O
MeO O
O
MeO
O
m-CPBACH2Cl2, 0 ºC to RT
0.5 eq H2OJacobsen's Catalyst 160THF, 0 ºC to RT
no hydrolytickinetic resolution
44 168
Scheme 39
Control reactions using the same batch of catalyst showed that simple epoxides such as
epichlorohydrin and propylene oxide were readily resolved under these conditions, as
described in the literature.116, 118 Although hydrolytic kinetic resolution has been
successfully applied to a broad range of terminal epoxides,118, 119 Jacobsen and
coworkers have noted that careful optimisation of reaction conditions, including the
69
type of solvent, the catalyst loading and the nature of the (salen)-CoIII catalyst
counterion, has been required in order to resolve some particularly unreactive
epoxides.118 While resolution of epoxides 155, 156 and 168 may well be achievable
with further experimentation, it was decided to revise the planned route to the chiral
alcohol 152 and another approach was adopted instead.
2.5.3 A Directed Metallation Approach to (2R)-1-(1-Hydroxy-5-methoxy-2-
naphthalenyl)propan-2-ol 152
A possible alternative approach to chiral alcohol 152 involves a directed
metallation sequence. A methoxymethoxy (MOM) substituent is known to be a stronger
ortho director than a methoxy substituent in the lithiation of aromatic rings.126 For
example, methoxymethoxybenzene 172 has been found to undergo ortho lithiation at a
much greater rate than anisole 171 when treated with n-butyllithium in the presence of
TMEDA (Figure 23).127
OMe O OMe
relativerate
1 14
171 172
Figure 23. Relative rates for ortho lithiation of anisole 171 and
methoxymethoxybenzene 172 (n-BuLi/TMEDA, 0 ºC).127
70
Kamikawa and Kubo have employed a route to alcohol 175 which takes advantage of
this greater rate (Scheme 40).128 Lithiation of 1-methoxy-5-
methoxymethoxynaphthalene 173 was found to occur preferentially at the C6 position
ortho to the MOM group rather than at the C2 position ortho to the methoxy group.
Subsequent quenching of 174 with n-decanal then afforded alcohol 175 in 77% yield.
MeO
O OMe
Li
MeO
O OMe
MeO
O OMe
CH(CH)8CH3
OH
CH3(CH2)8CHO
n-BuLi, TMEDATHF
173 174
175
Scheme 40
It was envisaged that a similar strategy involving nucleophilic attack of lithiated
naphthalene 174 on chiral propylene oxide 158, followed by deprotection would deliver
alcohol 152 with the required stereochemistry in the side chain (Scheme 42). An
advantage associated with this route is the ready availability of the starting materials.
Thus, 1-methoxy-5-methoxymethoxynaphthalene 173 was prepared in a straightforward
manner by deprotonation of naphthol 41 with sodium hydride, followed by treatment
with methoxymethyl chloride (Scheme 41).128
71
MeO
OH
MeO
O OMe
1. NaH, DMF
2. MOMCl
41 173
Scheme 41
(R)-(+)-propylene oxide 158 was also obtained conveniently by hydrolytic kinetic
resolution of racemic propylene oxide with Jacobsen’s catalyst (Scheme 31, p. 63),116
thereby avoiding the cost normally associated with this expensive reagent. Attention
was then turned to the rest of the sequence (Scheme 42).
MeO
O OMe
MeO
O OMe
H
OH H
Me OH
Me
MeO
OHH
OHMe
OMe
H
1. n-BuLi, THF
CBr42-propanol
MeO
O O
173
2. HMPA
158176 177
152
Me
Scheme 42
Lithiation of 173 in the presence of TMEDA, according to the method of Kamikawa
and Kubo,128 followed by addition of (R)-(+)-propylene oxide 158 returned only starting
material. However, lithiation followed by sequential addition of HMPA and 158 was
72
more successful and gave a 80 : 20 mixture of two compounds with very close Rf
values. The compounds could not be separated by silica gel filtration but small
analytical samples were isolated by careful radial chromatography. NMR and mass
spectral analysis indicated that both compounds were trisubstituted naphthalene
isomers, derived from nucleophilic attack on propylene oxide 158. The slightly less
polar component, being the major product, was identified as the target alcohol 176
([α]D21 + 8.7). The 1H NMR spectrum shows signals consistent with the presence of the
hydroxypropyl side chain (Figure 24). An ABX pattern is associated with the C1
methylene (3.10-2.94 ppm) and the C2 methine (4.23 ppm) protons. The methine proton
is further coupled to the adjacent hydroxy and methyl group protons, which resonate as
doublets at 2.32 and 1.30 ppm respectively. With the formation of the stereogenic centre
in 176, the methylene protons in the MOM moiety have become diastereotopic. This is
reflected in the 1H NMR spectrum where the methylene protons occur as an AB pattern
with JAB = 5.9 Hz.
Figure 24. 1H NMR spectrum of 176 (300 MHz, CDCl3).
73
The minor product was tentatively assigned structure 177 ([α]D21 –26.9), and arises due
to competitive metallation and alkylation ortho to the methoxy substituent. The 1H
NMR spectrum of 177 is similar to that of 176 (Figure 25). However, the MOM
methylene protons occur as a singlet at 5.39 ppm, despite being diastereotopic. An A2X
pattern is due to the C1 methylene and C2 methine protons in the hydroxypropyl side
chain, which resonate at 2.96 and 4.16 ppm respectively. The C2 methine is further
coupled to the C3 methyl protons, which occur as a doublet at 1.28 ppm. A broad
singlet at 2.29 ppm corresponds to the C2 hydroxy group.
Figure 25. 1H NMR spectrum of 177 (300 MHz, CDCl3).
Finally, removal of the MOM protecting group in 176 was achieved by the
action of carbon tetrabromide in refluxing 2-propanol (Scheme 42),129 and the target
alcohol 152 was easily isolated by chromatography at this stage as a white crystalline
solid with [α]D21 –6.7. The enantiomeric excess (ee) within the resulting alcohol 152
74
was determined by 1H NMR spectroscopy with the chiral shift reagent europium tris[3-
(heptafluoropropylhydroxymethylene)-(+)-camphorate]. Surprisingly, the chiral shift
reagent failed to induce significant chemical shift changes for protons near the
stereocentre and the only significant induced shift was observed for the H8 aromatic
proton. Treatment of the racemic alcohol 149 with 7.5% of the shift reagent was found
to separate the H8 doublet signal into two doublets in the 1H NMR spectrum (Figure
26). The enantiomeric ratio within the (2R)-alcohol 152 was estimated to be greater than
95 : 5 by examination of the corresponding H8 signal in the 1H NMR spectrum of a
sample of 152 in the presence of the chiral shift reagent (7.5%), indicating that the ee
was greater than 90%. A more precise upper limit for the ee could not be determined at
this stage due to some line-broadening of this signal.
Figure 26. Stacked plot showing the low-field region of the 1H NMR spectra of (2R,S)-
1-(1-hydroxy-5-methoxynaphthalen-2-yl)propan-2-ol 149 and (2R)-1-(1-hydroxy-5-
methoxynaphthalen-2-yl)propan-2-ol 152 in the presence of 7.5% europium tris[3-
(heptafluoropropylhydroxymethylene)-(+)-camphorate] (500 MHz, CDCl3).
75
2.5.4 Final Steps in the Preparation of Enantiopure Elecanacin 36
With the key alcohol 152 in hand, it was now possible to complete the synthesis
of chiral elecanacin 36 following the final steps developed for the racemic series
(Scheme 43).
O
O
MeO
H
O
Me
MeO O
O
OH
HMe
EtO
cat. Hg(OAc)2
O
O O
H
MeO
Me
O
O
MeO
O
H
Me
CH2Cl2
MeO
OH
HMe
OH
hv, 350 nm
(-)-elecanacin
15136
152 178 179
(+)-isoelecanacin
ON(SO3K)2
Scheme 43
Oxidation of 152 with Fremy’s salt gave the hydroxyquinone 178 ([α]D –25.3), which
was converted into vinyl ether 179 ([α]D –15.6). Finally, irradiation of 179 followed by
chromatographic separation afforded the target (2R, 3aR, 4aR, 10aR)-elecanacin 36
with [α]D -145.2 (CHCl3) after recrystallisation and an ee of 99.5% (as determined by
HPLC with a chiral stationary phase). The diastereomer (2R, 3aS, 4aS, 10aS)-
isoelecanacin 151 was obtained in 98% ee, with a specific rotation of +110.4.
76
The specific rotation reported for natural elecanacin is +20.7 (CHCl3)47 and
therefore the natural major enantiomer is the mirror image of 36, and the configuration
is (2S, 3aS, 4aS, 10aS). From the magnitude of the reported rotation, the enantiomeric
excess within the natural material is only 14%, and thus elecanacin 36 is an example of
a natural product that does not exist in an enantiomerically pure form. Although many
natural products occur as single enantiomers, others are known to exist as enantiomeric
mixtures.130 Another example of a naturally occurring quinone that occurs as an unequal
mixture of enantiomers has been noted by Cotterill and coworkers.131 Dermolactone 180
is an anthraquinone that has been isolated from the fruiting bodies of the Australian
toadstool Dermocybe sanguinea (Figure 27). A significant difference in the specific
rotation values of synthetic (S)-dermolactone 180 ([α]D +169.3) and the natural material
([α]D +45.9), along with chiral shift experiments and chiral HPLC analysis revealed that
natural dermolactone occurs as a 64 : 36 mixture of (S)- and (R)-enantiomers
respectively (28% ee).131
O
OH
MeO
O
O
OH O
H
Me
180
Figure 27
2.6 On the Possible Biosynthesis of Elecanacin 36
The structural similarities between elecanacin 36 and its isomeric co-metabolites
eleutherin 38 and isoeleutherin 38 suggest that these compounds may arise from a
related biosynthetic pathway. Although the biosynthesis of eleutherin 38 and
isoeleutherin 39 does not appear to have been investigated, it presumably involves a
77
polyketide pathway, as has been established for other pyranonaphthoquinones.63, 132 For
example, 13C labelling experiments have revealed that the bacterial metabolite
nanaomycin A 182 is assembled from an octaketide by a folding resulting from
orientation 181a, whereas cardinalin 2 183, a metabolite from the toadstool Dermocybe
cardinalis, has been shown to arise by cyclisation of the octaketide with the alternative
orientation 181b (Figure 28).132 It has been suggested that this also may be the pathway
for the synthesis of plant-derived pyranonaphthoquinones, such as eleutherin 38.132
O
HO
Me
O
OMe
OMe
O
Me
O
HO
OH
MeO
H
H
Me
Me
O
OO
OOO
CO2HO
O
OO
Me
OOO
O
CO2H
181a 181b
183
nanaomycin A cardinalin 2182
∗ ∗
∗
∗
∗
∗
O∗
HO O
O
Me
CO2H∗
Figure 28. Incorporation of 1-13C labelled acetate into nanaomycin A 182 and of 1,2-
13C2 labelled acetate into cardinalin 2 183 (identified units shown in bold).
Given that eleutherin 38 and isoeleutherin 39 are likely to arise from a
polyketide pathway, what is the biogenetic origin of elecanacin 36? Formally the vinyl
ether 138 can be derived from a Norrish type II cleavage of 184, the dihydro-derivative
78
of eleutherin 38 and isoeleutherin 39, followed by oxidation (Scheme 44). A subsequent
intramolecular [2 + 2] cycloaddition would then deliver elecanacin 36. The
enantiomeric ratio of the product 36 would be determined by the configurational ratio at
C3 inherent within 184. Since both eleutherin 38 and isoeleutherin 39 co-occur in the
plant, the involvement of a biosynthetic precursor such as 184 having both
configurations at the methyl-substituted carbon would explain the low ee observed for
elecanacin 36.
MeO OH
O
O
Me
O
MeO O
O
Me
CH2
HMeO
O
O
Me
O
O
HMe
O
O
MeOH
O
HMe
O
O
MeOH
185184
a
138
36 ent 36
b
Scheme 44
Of the pericyclic reactions possibly involved in biological systems,133 the Diels-Alder
reaction has attracted considerable attention and some evidence has been presented for
the existence of Diels-Alderases.134, 135 Although the suggestion that elecanacin 36
could possibly be generated in vivo by a sequence of pericyclic reactions as outlined in
Scheme 44 must be regarded as highly speculative, some evidence of such reactions in
79
other biological systems can be provided in support. For instance, ethylene has been
reported to arise from a Norrish type II fragmentation of enzymatically generated triplet
butanal 188, providing an example of a photobiochemical reaction without light
(Scheme 45).136
O
H
CH2H
CH2
CH2
OH
CH2H
O2H CH2
O
(CH2)2CH3HO C
HCH
O O
(CH2)2CH3
O
OHH
triplet butanal
horseradishperoxidase
112 188
186
189
Norrish type IIcleavage
187
Scheme 45
The cleavage step a in Scheme 44 therefore has some precedence. Furthermore, recent
evidence has been presented that the conversion of isochorismate 190 to salicylate 191
and pyruvate 192, catalysed by the enzyme isochorismate pyruvate lyase, involves a
one-step pericyclic retro-ene process (Scheme 46).137, 138
CO2OH
H
O CO2
CO2
OH
O2CCCH3
OIsochorismatePyruvate Lyase
190 192191
Scheme 46
80
Nevertheless, at this stage there appears to be no clear evidence of any enzyme-
mediated analogies for the [2 + 2] cycloaddition, although several such reactions have
been proposed. Hao and coworkers have suggested that the dimeric natural product
sceptrin 194, isolated from the sponge Agelas sceptrum, may arise from a biological [2
+ 2] cycloaddition involving the co-metabolite oroidin 193 (Scheme 47).139 Similarly, it
has been proposed that the plant metabolite Biyouyanagin A 197 from Hypercium
chinese L. var. salicifolium is biosynthesised via a [2 + 2] cycloaddition between the
sesquiterpene 195 and enone 196 (Scheme 47).140, 141 However, so far no enzyme has
been identified as a catalyst for either reaction.
N
NH
NH
NNH2
NH2
NH
O
NH
Br
HN
O
HN
Br
NH
O
HN N
HN
NH2Br
sceptrin
194193
oroidin
enzyme
?
O O
Me
H
MeH
Me
Me
H
H
H
Ph
O
O
Me
biyouyanagin A
197
Me
H
MeH
Me
Me
O O
O
O
Me
Ph
enzyme
?
196195
Scheme 47
The observation that in solution the vinyl ether 138 undergoes ready cyclisation
when exposed to ambient laboratory light also raises the possibility that elecanacin 36 is
81
actually an artifact, arising through photochemical cyclisation of 138 during isolation
and workup of the plant extract. However, we consider it unlikely that the vinyl ether
138 is in fact a natural product. The formation of elecanacin 36 under laboratory light is,
as in the preparative reactions, accompanied by isoelecanacin 151. In view of the close
chromatographic Rf values of these products, it seems unlikely that 151 would have
been missed during the isolation of elecanacin 36. Thus elecanacin 36 is more likely to
be a product of a diastereoselective enzyme-mediated reaction rather than an artifact
arising from photochemical transformation of vinyl ether 138. Further work is required
to establish this.
2.7 Concluding Remarks
The current study has established through synthesis the nature of the novel ring
skeleton and absolute configuration of elecanacin 36. The biosynthetic origin of 36
remains to be determined, but may well involve an enzyme-mediated [2 + 2]
cycloaddition.
82
Chapter 3
The Synthesis of
3-Hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-
5,10-dione
83
3.1 Introduction to 3-Hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione 37
Another plant species which has attracted interest as a source of bioactive
naphthoquinones is the common tropical American tree Crescentia cujete L.
(Bignoniaceae). Traditionally, Crescentia cujete has been an important source of folk
medicine across Central America, the Northern half of South America and the
Caribbean,142 with both extracts and pulp of the seeds, fruit, leaves and flowers being
used to treat a variety of ailments. These include colds and other respiratory
illnesses,143-145 hypertension146 and the haemorrhagic effect of venomous snake bites.147
Like many other plant species used in traditional medicine, Crescentia cujete has also
attracted increasing interest as a source of novel and biologically active compounds
which could provide possible lead structures in the development of new
pharmaceuticals.48, 148-150
During an investigation into potentially useful anticancer agents from the wood
of Crescentia cujete, Kingston and coworkers isolated a series of nine related furo[b]-
fused naphthoquinone derivatives,48, 148 which are shown in Figure 29. Although
naphthoquinones 198-201 were known previously, five of the compounds 202-205 and
37 were new. Of particular interest are the two tetracyclic naphthoquinones, which were
isolated as red pigments and assigned structures 3-hydroxymethylfuro[3,2-
b]naphtho[2,3-d]furan-5,10-dione 37 and 9-hydroxy-3-hydroxymethylfuro[3,2-
b]naphtho[2,3-d]furan-5,10-dione 205 on the basis of extensive spectroscopic
analysis.48 Both compounds were found to be cytotoxic and 37 exhibited selective
DNA-damaging activity in an assay involving a DNA repair-deficient strain of yeast,48
suggesting that 37 may be useful in the development of new antitumour drugs. Kingston
and coworkers have also noted that the planar structure of naphthoquinones 37 and 205
84
means that intercalation into DNA is likely to contribute to their mode of action for
DNA damage.151
O
O
O
O
OH
205
OH
O
O
O
O
OH
37
O Me
OH
O
O
O Me
OH
O
OOH
O
OH
Me
O
OMeO
MeOH
H
O Me
O
OMeO
MeOH
H
O Me
O
OMeO HH
O Me
O
O HH
O Me
O
OOH HH
198
201
204203202
199 200
Figure 29
As well as having potentially useful biological activity, naphthoquinones 37 and
205 are rather interesting in terms of their structure. The tetracyclic ring system,
composed of a naphthoquinone ring fused to a furo[3,2-b]furan moiety, appears to be
unique to these compounds and represents a new natural product skeleton. In addition,
85
the presence of the aromatic furofuran moiety makes the two naphthoquinones highly
unusual for naturally occurring compounds. There are a several examples of natural
products which incorporate a reduced furo[3,2-b]furan ring system (Figure 30),
including panacene 206, a marine metabolite isolated from the sea hare Aplysia
brasiana,152 rutagravine 207, a plant metabolite isolated from a tissue culture of Ruta
graveolens,153 as well as two related xanthones psorofebrin 208 and 5’-
hydroxyisopsorofebrin 209, which have been obtained from the roots of Psorospermin
febrifugum.154 However, naphthoquinones 37 and 205 appear to be the first natural
products containing a fully aromatic furo[3,2-b]furan ring.
N
O
Me
OH
O
OOH
Me
HHO
OEt
H
H
H
CBr
H
H
206 207
O O
OOH
O OMe
HH
OHMe
O O
OMeO
O OH
HH
OH
OH209208
Figure 30
Synthetic compounds incorporating a fully aromatic furo[3,2-b]furan ring are
also very uncommon. The parent heterocycle 210 has not been synthesised to date
(Figure 31), although it has been included in a number of computational studies on
86
fused heterocycles.155-158 Similarly, the benzo-fused and naphtho-fused compounds 211
and 212 have not been prepared.
O
O
O
O
O
O
210 212211
Figure 31
In fact, syntheses of any compounds incorporating the aromatic furo[3,2-b]furan ring
system are rare, with only two reports describing the preparation of several benzo-fused
derivatives appearing to date.
Tolmach and coworkers have synthesised benzofuro[3,2-b]benzofuran 216 from
“hydrosalicyloin” 213 according to the route in Scheme 48.159
O
O
O
O
O
OBr
OH
OH
OH OH
hvNBS, benzoyl peroxideCCl4, reflux
silicachromatography
H
H
HBr
H
213 214
215216
DCC35 ºC
Scheme 48
87
The fused furofuran framework was constructed in the first step by a simple dehydrative
cyclisation of 213 with dicyclohexylcarbodiimide (DCC). The resulting dihydro
compound 214 was then converted into the bromo derivative 215 via photohalogenation
with N-bromosuccinimide (NBS). Spontaneous dehydrobromination of 215 during this
procedure and subsequent chromatographic purification on silica finally delivered the
fully aromatic compound 216 in 32% yield.
Vaidya and Agasimundin have also achieved the synthesis of three related
benzofuro[3,2-b]furan derivatives, which share the general structure 223 (Scheme
49).160 Compounds 223a, 223b and 223c have been reported to arise from Dieckmann
condensation involving treatment of the appropriate benzofuran 217 with strong base,
followed by acidification. A positive ferric chloride colour test seems to indicate that
these compounds exist at least partially in the enol form. Whilst most β-hydroxyfurans
tend to exist largely as the more stable keto tautomer, there is evidence that the enol
form may be predominant for some compounds.161 For instance, IR and NMR
spectroscopy of 2-acetyl-3-hydroxyfuran 224 provides evidence for only the enol
tautomer (Scheme 49). In this case, it has been suggested that intra- and/or
intermolecular hydrogen bonding plays an important role in stabilizing the β-
hydroxyfuran form.161 Similar opportunities for stabilizing hydrogen bonding would be
expected for the benzofuro[3,2-b]furan derivatives 223a and 223b.
88
O
OCH2R
C O
OCHR
C
OC
CO
O
O
O
O
O
O
O
OEt
O
OEt OC
CHO
OEtO
R
O
H
R
O
RR
O
R
OH
Base
where a: R = CO2Et b: R = C(O)Me c: R = CN
217
222 221 220
219218
223
H3O+
O C
Me
O
O H
224
OEt
Scheme 49
To date, there have been no reported syntheses of the two naturally occurring
furofuranonaphthoquinones 37 and 205. The novel structure, along with the potentially
useful selective DNA-damaging activity, make 3-hydroxymethylfuro[3,2-
b]naphtho[2,3-d]furan-5,10-dione 37 a particularly attractive target. Thus, it was
decided to develop an approach to the synthesis of 37, which should allow the structure
of the unusual tetracyclic ring skeleton to be confirmed. The construction of the fused
aromatic furofuran moiety in the natural product would be an important step in this
89
synthesis and it was thought that this might be possible by employing a cycloaddition-
cycloreversion strategy.
3.2 A Synthetic Approach to 3-Hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-
5,10-dione 37
A possible approach to the natural product is shown in Scheme 50.
O
O
OMe
OMe
CO2R
225
O
O
O
O
OH
OMe
OMe
O CO2R
O
OH
OMe
OMe
O
37
O
O
OMe
OMe
CO2R
226227
228
R = alkyl
Scheme 50
90
Retrosynthetic analysis suggested that the furofuranonaphthalene 225 would serve as a
suitable precursor to the natural product 37. Considering the synthetic direction, the
target compound should then be available from 225 through a short sequence involving
reduction of the ester group and oxidative demethylation. It was envisaged that the
furofuranonaphthalene 225 would in turn be available from the epoxy-bridged
dihydrobenzene derivative 226 via a cycloreversion strategy. Thus, loss of the etheno
bridge from 226 through a retro-Diels-Alder reaction should in principle provide the
furofuranonaphthalene 225. A possible route to the required epoxy-bridged intermediate
226 could involve an intramolecular Diels-Alder reaction within the substituted
naphthalene 227. Furan may be considered to be an oxygen-bridged diene and many
furan derivatives are able to undergo cycloaddition with various dienophiles, including
suitable acetylenes.162-165 Acetylenic furans of general structure 229 have been used
successfully in intramolecular Diels-Alder reactions to generate epoxy-bridged
polycyclic ring systems (Scheme 51).163
O
O
229 230
Scheme 51
On this basis, it was thought that compound 226 should be accessible through an
intramolecular Diels-Alder addition of the acetylenic ether moiety to the furan diene
within 227 (Scheme 50). Although the use of furan precursors has been somewhat
limited by the tendency of some intramolecular Diels-Alder adducts to undergo
cycloreversion to the starting material,163 the reaction involving acetylenic dienophiles
can be accomplished under milder conditions if the terminal carbon of the acetylene is
91
substituted with an activating group.166 Thus, it was reasoned that the presence of the
ester group in the acetylene chain of 227 should facilitate the proposed intramolecular
cycloaddition (Scheme 50). The acetylenic ether 227 may in turn be available from the
naphthol 228.
Buttery, Moursounidis and Wege have used a similar cycloaddition-
cycloreversion approach to prepare a furo[3,4-b]furan derivative 237 in good yield
(Scheme 52).166
O
231
O
O
CO2Me
N
N CO2MeN
O
OCO2Me
O
OCO2Me
O
NN
N
Py
Py
237
233
234
232
NN N
N
Py
Py
Py
Py
O
O
MeO2C
toluenereflux
N2
NN
Py
Py
236
1
2
5
8
9
10
3
235
Scheme 52
92
The activated acetylenic furan 231 was converted into 237 via a one pot reaction
involving heating 231 at 110 ºC in the presence of 3,6-di(pyridin-2’-yl)-1,2,4,5-tetrazine
233. This reaction proceeds according to the series of transformations depicted in
Scheme 52. An initial intramolecular Diels-Alder reaction generates adduct 232, which
undergoes cycloaddition at the electron-rich C8-C9 double bond to the electron-
deficient tetrazine 233 (Scheme 52). Spontaneous loss of nitrogen from the resulting
intermediate 234, followed by cycloreversion of 235 then produces the furo[3,4-b]furan
derivative 237. Thus, it was thought that a similar reaction may be applicable to the
synthesis of the natural product 37.
3.3 Previous Work Towards the Synthesis of 3-Hydroxymethylfuro[3,2-
b]naphtho[2,3-d]furan-5,10-dione 37
In order to test the viability of the tandem Diels-Alder-retro-Diels-Alder
approach to the fused furo[3,2-b]furan moiety present in the natural product 37,
previous work within our group by Slamet and Wege has focused on preparing a model
compound furo[3,2-b]benzofuran-3-methanol 238 (Figure 32).167, 168
O
O
238
OH
Figure 32
The first stage in the route to 238 involved preparation of an appropriate
acetylenic ether for the intramolecular Diels-Alder reaction. This was eventually
93
accomplished by employing a widely used dehydrohalogenation approach to acetylenic
ethers,169, 170 which has enabled the synthesis of a large variety of acetylenic ether
derivatives.171 The general strategy involves initial preparation of a 1,2-dichlorovinyl
ether 240 by reaction of an alkoxide with trichloroethylene (Scheme 53). Subsequent
dehydrohalogenation of the ether 240 upon treatment with an alkyllithium then
generates an intermediate lithium acetylide 241, which can be functionalized in situ by
trapping with various electrophiles (E-X) to give 242.
ROH
RO
Cl H
Cl
LiRO
ERO
1. Base
2. Cl2C=CHCl
R'Li
E-X
242
241240239
Scheme 53
Applying this approach to 245, the lithium salt of 2-(2’-furyl)phenol 243 was treated
with trichloroethylene, which gave dichloroether 244 in 93% yield (Scheme 54).167
Sequential treatment of 244 with butyllithium and methyl chloroformate then afforded
the desired acetylenic ether 245 in moderate yield (39%).
94
OH
O O
O Cl
Cl H
244
O
O
CO2Me
1. LiOMe MeOH
2. Cl2C=CHCl DMF
1. n-BuLi, Et2O2. Cl-CO2Me
243
245
Scheme 54
With the required ether 245 in hand, efforts were directed towards construction
of the furofuran framework via the proposed cycloaddition-cycloreversion sequence.
Encouragingly, treatment of 245 with 3,6-di(pyridin-2’-yl)-1,2,4,5-tetrazine 233 in
refluxing toluene was successful, affording methyl furo[3,2-b]benzofuran-3-carboxylate
247 in 93% yield (Scheme 55). The structure of this compound was confirmed using 2D
NMR techniques. Finally, reduction of ester 247 with lithium aluminium hydride
provided the target compound 238 in 64% yield.
95
O
O
CO2Me
NN N
N
py
py
toluene, reflux
O
O
CO2Me
233
246
247
heatO
O
CO2Me
O
O
238
OH
LiAlH4Et2O
245
Scheme 55
The success of the tandem Diels-Alder-retro-Diels-Alder approach to the model
compound 238 showed that this strategy should be applicable to the synthesis of the
natural product 3-hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione 37.167 In
order to extend this approach to 37, Slamet made a number of attempts to prepare and
isolate the required intermediate acetylenic ether 249 (Scheme 56). Reaction of the
naphthoxide generated from naphthol 228 and lithium methoxide with trichloroethylene
proceeded smoothly and gave the 1,2-dichlorovinyl naphthyl ether 248 in 66% yield.
However, the subsequent dehydrochlorination step proved to be troublesome and failed
to provide 249. It is worth noting that a number of similar alkoxyacetylenic ester
derivatives are reported to be relatively unstable and prone to decomposition.172 In order
to avoid possible degradation of acetylenic ether 249 during purification, an attempt was
also made to prepare the advanced intermediate 251 by subjecting the crude reaction
96
product directly to the subsequent cycloaddition-cycloreversion sequence (Scheme
56).167
OMe
OMe
O
O
CO2MeO
O
OMe
OMe
CO2Me
OMe
OMe
O
O
CO2Me
heat
251
250 249
NN N
N
Py
Py
toluene, reflux
233
OMe
OMe
O
OH
228
OMe
OMe
O
O Cl
Cl H
248
1. LiOMe MeOH
2. Cl2C=CHCl DMF
1. n-BuLi, Et2O2. Cl-CO2Me
Scheme 56
Thus treatment of the presumed ether 249 with tetrazine 233 in reluxing toluene
afforded in 2% yield a product, which was formulated as the desired
furofuranonaphthalene 251 on the basis of NMR spectroscopy.167 However, re-
97
examination of the 1H NMR spectrum suggests that the correct structure for this
compound is actually 252 (Figure 33). In particular, the chemical shift of the furyl
proton singlet (7.39 ppm) is further upfield than would be expected for the target
furofuranonaphthalene 251 based on the value observed for the analogous proton (8.11
ppm) in the model ester 247167 (Figure 33). Moreover, the furyl proton shift of the
reaction product is more comparable to that observed for the H3 signal in furan 253
(7.57 ppm),173 providing further support for structure 252.
OMe
OMe
O
O
H
252
CO2Me
O
O
CO2Me
247
H
O CO2Me
H
253
δH 7.39
δH 7.57
δH 8.11
Figure 33
This compound is derived from metallation of the furan ring of 248 during the
dehydrohalogenation step (Scheme 57). Reaction with methyl chloroformate at the
furan ring then generates intermediate 255. Finally, an intramolecular cycloaddition
between the acetylene moiety and furan ring within 255, followed by the usual
cycloreversion sequence upon treatment of the resultant adduct 256 with tetrazine 233
delivers the unexpected furofuranonaphthalene 252.
98
OMe
OMe
O
O
Li
O
O
OMe
OMe
OMe
OMe
O
O
heat
252
256
254
NN N
N
Py
Py
toluene, reflux
233
OMe
OMe
O
O Cl
Cl H
248
n-BuLi Et2O
Li
OMe
OMe
O
O
H
255
CO2MeCO2Me
CO2Me
1. Cl-CO2Me, Et2O2. H2O
Scheme 57
In view of the problems encountered with the dehydrohalogenation approach to
the required acetylenic ether 249, it was decided to begin the present project by
99
investigating an alternative approach to an appropriate acetylenic ether, which could be
used as a key intermediate in the proposed route to the natural product 37 (Scheme 50).
3.4 An Alternative Approach to an Intermediate Acetylenic Ether
A general method that has been employed for preparing acetylenic ethers
involves substitution of a halide with an alkoxide at an acetylenic carbon, which
proceeds by the addition-elimination mechanism shown in Scheme 58.171, 174 For
example, Tanaka and Miller have used this approach to prepare 1-ethoxy-2-
phenylacetylene 261 in 42% yield from sodium ethoxide and 1-chloro-2-
phenylacetylene 260.175
C CX R
RO
C CR
RO
XC CRO R
X
257 258 259
Cl Ph EtO PhNaOEt
DMSO
260 26142%
Scheme 58
Traditionally the synthesis of acetylenic ethers via the reactions of simple
haloacetylenes and alkoxides has been of limited utility because these reactions, like the
example above, tend to be rather low-yielding.171, 176 These low yields are usually
100
attributed to a number of competing reactions, including displacement of acetylide
RC≡C- by attack of the alkoxide anion on the halogen atom.176, 177 Nevertheless, it was
envisaged that the target acetylenic ether 263 might be available by a similar strategy
involving the base-catalysed reaction of naphthol 228 and an appropriate haloacetylene
262, as the presence of the ester functional group should activate the acetylene
sufficiently for effective nucleophilic addition (Scheme 59).
OMe
OMe
OH
O
1. Base
2. X CO2Et
OMe
OMe
O
O
CO2Et
263228
262
Scheme 59
Acetylenes substituted with electron-withdrawing groups, including carbonyl, nitrile
and imine groups, are very reactive towards nucleophilic addition because the resulting
carbanionic intermediates can be stabilized through resonance.178, 179 An efficient route
to ethylenic ethers which takes advantage of this reactivity involves conjugate addition
of an alkoxide to an activated acetylene 264, followed by protonation of the vinyl anion
intermediate 265.178, 179 The reaction pathway is outlined for the generic reaction in
Scheme 60, where the activating group in the acetylenic substrate is an ester.
101
102
C CH COR
RO
264
O
C C COR
265a
O
C C COR
O
H
RO
H
RO
C CHH
RO
CO2R
[H+ ]
265b
266
Scheme 60
For example, Ciganek has prepared the ethylenic ether 269 in high yield (92%) by a
base-catalysed addition of 2-hydroxy-3-methoxybenzaldehyde 267 to methyl propiolate
268 (Scheme 61).180
CHO
OHO NMe
HC CCO2Me
267 268
CHO
OCO2Me
269
MeCN
Scheme 61
On this basis, it was thought that the target acetylenic ether 263 should be available
according to the reaction pathway outlined in Scheme 62, beginning with a similar base-
catalysed conjugate addition of naphthol 228 to an activated haloacetylene 262. In this
case, however, elimination of the halide from intermediate 270 should regenerate the
acetylenic system.
C CX COEt C C COEt
O
X
ArOC CArO CO2Et
270 263
OAr
HB
O
where Ar =
OMe
OMe
O
228 262
Scheme 62
This approach to acetylenic ethers has received only limited attention, which is possibly
due to problems associated with the reactivity of the activated carbon-carbon triple bond
in the product. For instance, Vereshchagin and coworkers have reported that the
acetylenic ether 273, which arose from the base-catalysed reaction of phenol 271 and
the bromoacetylenic ketone 272, was too reactive to be isolated (Scheme 63).181 Instead,
273 underwent further nucleophilic addition with a second equivalent of phenol
affording the ethylenic ether 274 in high yield (94%).
103
K2CO3Me2CO
2
Br
OPhOH PhO
O
PhPhO
PhOO
Ph
Ph271
274273272
Scheme 63
Despite these results, it was felt that the reaction outlined in Scheme 62 was worth
examining, particularly since the pendant furan ring within 263 could potentially
intercept the reactive alkyne moiety.
3.5 Attempted Synthesis of Acetylenic Ether 263
The initial step in the synthesis of acetylenic ether 263 required preparation of
the precursor naphthol 228 and a suitable haloacetylene. The naphthol 228 has been
prepared previously within our group by the route shown in Scheme 64.167, 168 A
Hauser-Kraus annulation reaction182, 183 of cyanophthalide 275 and the Michael acceptor
2-(2-furyl)acrolein 277, followed by methylation of the resultant hydroxyquinone 281
gave the aldehyde 282 in 85% yield. Baeyer-Villiger oxidation of 282 with aqueous
hydrogen peroxide and diphenyl selenide and subsequent hydrolysis of the aryl formate
283 then provided the target naphthol 228. However, the Baeyer-Villiger step proved
difficult and the naphthol 228 could be prepared in only moderate yield (49%) at best.167
This suggested that a more efficient approach to 228 would be needed in order to
synthesise a sufficient quantity of starting material for the current work.
104
O
O
CNH
LDATHF
O
O
CN
H
O
O
O
O
CNO
H
OO
O
CHO
O
CN
O
O
CHO
O
CHO
OH
OH
O
CHO
OMe
OMe
O
OCHO
OMe
OMe
O
OH
OMe
OMe
O
H3O+
MeI, K2CO3Me2O
275
228
283 282
280 281
278
277276
279
H2O2diphenyl diselenideCH2Cl2
NaOHH2O/MeOH
Scheme 64
105
The naphthol 228 was prepared more conveniently following the sequence
outlined in Scheme 65.
CH2OLi
O
O
Br
Br
O
O
OCH2Ph
Br
OBu3Sn
O
O
OCH2Ph
O
OH
OH
O
OCH2Ph
OMe
OMe
O
OCH2Ph
OMe
OMe
O
OH
Pd(Ph3)4CuBrdioxane
Na2S2O4Bu4NBrCH2Cl2/H2O
H2, 10% Pd/CEtOAc
1. NaOH2. (MeO)2SO2
THF 0 ºC
284
287
286285
288289
228290
Scheme 65
The benzyl ether 290 was readily obtained according to the method of Slamet and
Wege,167, 168 beginning with the reaction of 2,3-dibromo-1,4-naphthoquinone 284 and
the lithium salt of benzyl alcohol 285, which gave the naphthoquinone 286. A Stille
106
coupling reaction of stannane 287184 and 286, in the presence of
tetrakis(triphenylphosphine)palladium(0) and copper (I) bromide, then provided the red
naphthoquinone 288 (86%), which was converted into the benzyl ether 290 via a one
pot reduction/methylation in 96% yield. The final step involved removal of the benzyl
protecting group. Since furans are susceptible to reduction by catalytic
hydrogenation,185, 186 it was envisaged that a milder method may be required to liberate
the naphthol. Nevertheless, careful hydrogenolysis of 290 with 10% Pd/C catalyst at
room temperature proceeded smoothly and returned the naphthol 228 as a pale yellow
oil in 91% yield (Scheme 64).
Ethyl 3-bromopropiolate 292 was chosen as the acetylenic substrate as it could
be readily obtained by bromination of commercially available ethyl propiolate 291 with
N-bromosucciniminde according to the general method of Leroy187 (Scheme 66).
H CO2Et
NBSAgNO3 Br CO2Et
291 292
Me2CO
Scheme 66
With the naphthol 228 and bromoacetylene 292 in hand, attention was turned to
the synthesis of the acetylenic ether 263 via the proposed base-catalysed addition-
elimination sequence. In an intial experiment, treatment of naphthol 228 in
tetrahydrofuran with butyllithium followed by ethyl 3-bromopropiolate 292 gave only a
complex mixture of products, most of which could not be identified, with no sign of the
target ether 263 (Scheme 67).
107
OMe
OMe
O
OH
OMe
O
O
MeO
CO2Et
BuLi THF
Br CO2Et
294
228
30%
OLi
OMe
OMe
O
293
292
OMe
OMe
O
O
CO2Et
Br CO2Et
292
263
Scheme 67
However, the product mixture did include a compound which was assigned structure
294 on the basis of NMR and mass spectral evidence. The mass spectrum showed a
molecular ion at m/z 366 corresponding to a molecular formula of C21H18O6. The
downfield region of the 1H NMR spectrum includes signals integrating for four
aromatic protons and three furyl protons (Figure 34). The upfield region of the spectrum
shows two methoxy signals at 3.75 and 3.48 ppm, along with a methylene quartet and
methyl triplet at 4.22 ppm and 1.28 ppm respectively, corresponding to the ethyl ester
moiety. The target acetylenic ether structure 263 could be ruled out on the basis of the
13C NMR spectrum which includes not only an ester carbonyl signal at 165.7 ppm but
108
also a second carbonyl signal at 190.7 ppm attributable to a keto group. The infrared
spectrum shows two carbonyl absorbances at 1713 and 1676 cm-1 and an alkynyl
absorption at 2237 cm-1, confirming the presence of the ketone and acetylenic ester
moieties.
Figure 34. 1H NMR spectrum of 294 (300 MHz, CDCl3).
This compound arises by carbon-alkylation of the naphthoxide 293, rather than
the desired oxygen-alkylation. Although this result was not expected, with hindsight the
isolation of ketone 294 is not surprising as the formation of C-alkylated products in
nucleophilic substitution reactions involving the β-naphthoxide system is well
established,188, 189 and can be explained by considering the ambident nucleophilic nature
of the β-naphthoxide intermediate 293 wherein the negative charge is shared by the
oxygen and α-carbon atoms (Figure 35).
109
O O
293b293a
OMe
OMe
O
OMe
OMe
O
Figure 35
Since a β-naphthoxide ion can attack an alkylating agent via either the oxygen or the α-
carbon atom, the formation of both O- and C-alkylation products is possible.188 In
practice, however, the resulting O/C-alkylation product ratio for ambident anions is
largely influenced by solvent effects.189, 190 Although it is unclear why none of the target
acetylenic ether 263 was isolated from the reaction in Scheme 67, the formation of the
C-alkylated product is consistent with the observations of Kornblum and coworkers
who similarly found that a significant amount of C-alkylation occurred when the related
sodium β-naphthoxide salt 295 was treated with benzyl bromide in aprotic non-
dissociating solvents including tetrahydrofuran (Scheme 68).188
ONa PhCH2BrO
CH2Ph OH
CH2Ph
295 297296
60% 36%
THF
Scheme 68
This tendency for C-alkylation of β-naphthoxide species in aprotic non-dissociative
solvents has been interpreted in terms of the strength of the electrostatic attraction
between the naphthoxide ion and counter-cation, which is particularly important in
these solvents due to their poor cation solvating ability.188, 189 In the case of the reaction
in Scheme 68, the hard sodium ion is likely to preferentially associate with the harder
110
oxygen centre in the β-naphthoxide ion rather than with the softer α-carbon centre, and
this strong interaction provides a barrier to O-alkylation.189 As the α-carbon is relatively
free to associate with the alkylating agent benzyl bromide, C-alkylation of the
naphthoxide ion is promoted. It would be expected that the stronger the electrostatic
attraction between the cation and naphthoxide oxygen atom, the greater the proportion
of C-alkylation product that should form. Thus smaller cations, such as Li+, which have
higher charge densities should increase the tendency for C-alkylation because they bind
tightly to the hard oxygen atom.188, 189 On reflection therefore, it is not surprising that
the ketone 294 arose from our reaction because the use of lithium β-naphthoxide 293 in
tetrahydrofuran would be expected to promote C-alkylation (Scheme 67). If the desired
O-alkylated product 263 was also formed in this reaction, it may well have been
consumed by side reactions.
On this basis, it was thought that the use of a bulkier cation might be beneficial
in encouraging the formation of the target ether 263 as the lower charge density on the
cation should weaken the naphthoxide oxygen-cation interaction in the intermediate 293
and therefore promote O-alkylation. Accordingly, a number of bases were investigated.
The reaction was attempted by gently heating a solution of naphthol 228 and ethyl 3-
bromopropiolate 292 and N-methyl morpholine in acetonitrile (Scheme 69).
OMe
OMe
OH
O
N OMe , MeCN
(or K2CO3, acetone)
Br CO2Et
228292
OMe
OMe
O CO2Et
OH
298
Scheme 69
111
Unfortunately, there was no sign of the desired ether 263, with the reaction returning
only starting material and a complex mixture of products. Although most of these
compounds could not be identified, the mixture did include a small amount of a highly
crystalline product (4%), which was assigned structure 298 on the basis of NMR and
mass spectral evidence. The mass spectrum includes a molecular ion at m/z 366, which
corresponds to a molecular formula of C21H18O6. Importantly, the downfield region of
the 1H NMR spectrum exhibits a singlet at 11.55 ppm, indicating the presence of an
intramolecularly H-bonded phenolic substituent, along with signals for six aromatic
protons, which resonate as three multiplets at 8.36-8.34, 8.3-8.22, 7.54-7.51 ppm, and a
doublet at 7.03 ppm (Figure 36). Further upfield are two singlets at 4.45 and 4.09 ppm,
which are attributable to the two methoxy groups. The ethyl ester methylene and methyl
protons occur as a quartet at 4.57 ppm and a triplet at 1.56 ppm respectively.
Figure 36. 1H NMR spectrum of 298 (500 MHz, CDCl3).
112
Similarly, repeating the reaction with potassium carbonate in acetone also afforded the
phenol 298, albeit in higher yield (28%), accompanied by a complex mixture of
products, none of which was the desired ether 263 (Scheme 69). A mechanistic rationale
for the formation of phenol 298 is outlined in Scheme 70, and indicates that both the
target acetylenic ether 263 and the advanced intermediate 299 are being produced as
reactive intermediates.
OMe
OMe
OH
O
OMe
OMe
O
O
CO2Et
O
O
O
OH
CO2Et
OMe
OMe
OMe
OMe
CO2Et
O
OMe
OMe
CO2Et
OH
H
OMe
OMe
O CO2Et
OH
N OMe, MeCN
(or K2CO3, acetone)
Br CO2Et
H+
H+
228
298301
300 299
263
292
Scheme 70
113
The initial base-catalysed reaction of naphthol 228 and activated bromoacetylene 292
proceeds as expected to give the ether 263, which is evidently too reactive to be isolated
and is converted into the required Diels-Alder adduct 299 via an intramolecular
cycloaddition between the acetylenic ether moiety and furan ring within 263. Finally,
acid-catalysed opening of the epoxy bridge within adduct 299, possibly during
hydrolytic workup, effects aromatisation, generating the phenol 298.
3.6 Synthesis of Key Intermediate Ethyl 5,10-Dimethoxyfuro[3,2-b]naphtho[2,3-
d]furan-3-carboxylate 304
Despite the generation of the unexpected phenol 298 according to the reaction
pathway outlined in Scheme 70, the formation of the two required intermediates 263
and 299 was rather encouraging as it seemed that the synthesis of the key
furofuranonaphthalene 304 might be achieveable if adduct 299 could be trapped with
3,6-di(pyridin-2’-yl)-1,2,4,5-tetrazine 233 (Scheme 71). Subsequent loss of nitrogen
from the resultant intermediate 302, followed by cycloreversion of 303 should then
generate furofuranonaphthalene 304. Towards this end, a stirred suspension of naphthol
228, ethyl 3-bromopropiolate 292 and potassium carbonate in acetone was heated gently
until the starting material had been consumed (TLC analysis) (Scheme 71). Without
hydrolytic workup, the reaction mixture was filtered, diluted with toluene, and most of
the acetone was removed by distillation. Then, the solution of the presumed adduct 299
was subjected to the action of tetrazine 233 in refluxing toluene. Gratifyingly, this
afforded the target furofuranonaphthalene 304, albeit only in low yield (11%).
114
OMe
OMe
OH
O
OMe
OMe
O
O
CO2Et
O
O
OMe
OMe
CO2Et
K2CO3, acetone
Br CO2Et
NN N
N
py
py
toluene, reflux
OMe
OMe
O
O
CO2Et
O
OMe
OMe
CO2Et
O
N Npy
N Npy
O
OMe
OMe
CO2Et
O
N Npypy
N2
228
303
302
233
299
292
263
304
N
N
py
py
236
heat
Scheme 71
The structure of the furofuranonaphthalene 304 follows from its NMR and mass
spectral properties. The mass spectrum exhibits a molecular ion at m/z 340, which
supports the molecular formula C19H16O6. The 1H NMR spectrum is very simple (Figure
115
37). The high field region includes two singlets at 4.39 and 4.30 ppm, corresponding to
the two methoxy group protons, as well as a methylene quartet at 4.45 ppm and a
methyl triplet at 1.45 ppm due to the ethyl ester moiety. The aromatic region integrates
for five protons: the four aryl protons, which resonate as three multiplets at 8.33-8.31,
8.28-8.16 and 7.54-7.47 ppm, and the furyl α-hydrogen, which resonates as a singlet at
8.10 ppm. The furyl α-carbon occurs at 150.6 ppm in the 13C NMR spectrum.
Figure 37. 1H NMR spectrum of 304 (500 MHz, CDCl3).
A comparison of the α-furyl chemical shifts of 304, the related model compound 247
prepared previously within our group167, 168 and the natural product 3748 is shown in
Figure 38.
116
O
O
O
O
O
O
OH
OMe
OMe
CO2EtO
O
CO2Et
304 247
δC 150.8, δΗ 8.18
δC 150.6, δΗ 8.10 δC 150.8, δΗ 8.11
O δC 142.5, δΗ 7.43
30537
Figure 38
The similarity between these shift values provided support for the presence of the
furofuran moiety in the target furofuranonaphthalene 304. It is interesting to note that
the α-furyl chemical shifts for 304, 247 and 37 are considerably downfield of the
analogous carbon and proton signals in furan191 itself (Figure 38). This is likely to be
due to the electron-withdrawing effect of the ester groups in 304 and 247 and the
carbonyl group in 37, which effectively deshields the α-furyl position (Figure 39).
117
O
O
OMe
OMe
C
304a
O
O
O
O
OH
37a
O
OEt
O
O
OMe
OMe
C
O
OEt
304b
O
O
O
O
OH
37b
Figure 39
Although the overall yield of the reaction sequence outlined in Scheme 71 was
disappointing, the successful synthesis of the key intermediate 304 was encouraging as
it validated this approach to the novel furo[3,2-b]naphtho[2,3-d]furan ring system. In an
attempt to improve this yield, a number of different reaction conditions were examined
(Scheme 72). Cesium carbonate has received much attention for its effective use in the
O-alkylation of phenols,192, 193 with the product ethers often returned in yields higher
than those achieved with potassium carbonate.192 In an attempt to improve the
efficiency of the initial ether formation step, and thus the overall yield of the sequence
outlined in Scheme 71, potassium carbonate was replaced with cesium carbonate.
However, this returned the desired furofuranonaphthalene 304 in only 4% yield
(Scheme 72a).
118
OMe
OMe
OH
O
OMe
OMe
O
O
CO2Et
O
O
OMe
OMe
CO2Et
i) Cs2CO3, acetone, RTor ii) KOMe, MeOH, 0 ºC to RTBr CO2Et
NN N
N
py
py
toluene, reflux
OMe
OMe
O
O
CO2Et
228
233
299
292
263
304
heat
a)
OMe
OMe
OH
O Br CO2Et
228
292
b)NN N
N
py
py
toluene, reflux
233complex mixture
Scheme 72
Alternatively, performing the initial step of the sequence with potassium methoxide in
methanol was also unsuccessful and afforded only a trace of the target compound
(Scheme 72a). As it seemed possible that the equilibrium concentration of adduct 299 is
very low, it was thought that it may be beneficial to include 3,6-di(pyridin-2’-yl)-
1,2,4,5-tetrazine 233 in the reaction mixture during the intramolecular cycloaddition
step because trapping adduct 299 immediately upon its formation could help to drive the
overall cycloaddition-cycloreversion sequence to completion. In this case, the tetrazine
119
233 could also act as as the base for the initial base-catalysed conjugate addition-
elimination step to form the acetylenic ether 263. Unfortunately, when a mixture of
naphthol 228, bromoacetylene 292 and tetrazine 233 in toluene were heated under
reflux, the reaction returned only a complex mixture with no recognizable products
(Scheme 72b).
Although the yield of furofuranonaphthalene 304 could not be increased, it
seems possible that with further experimentation conditions may be found for
improving the efficiency of the sequence. In particular, the use of an aprotic dipolar
solvent, such as N,N-dimethylformamide, which is known to promote O-alkylation of β-
naphthoxide,188, 189 may be beneficial for encouraging the synthesis of the initial ether
intermediate 263. The strong cation-solvating ability of these solvents should result in
effective dissociation of the naphthoxide salt, thereby increasing the nucleophilicity of
the naphthoxide oxygen and promoting attack of the bromoacetylene 292. Similarly, the
use of another effective dissociating agent, such as a crown ether,189 may also be worth
investigating. However, time constraints prevented further experimentation at this stage.
Instead, attention was briefly turned to the route employed by Slamet and
Wege167, 168 for preparing the model furo[3,2-b]benzofuran 247, which involved
synthesis of the precursor acetylenic ether 245 via dehydrohalogenation of a 1,2-
dichloroether, as discussed in Section 3.3 (p. 93). Although an attempt at extending this
approach to one possible furofuranonaphthalene intermediate 251 had been
unsuccessful, it was thought that the sequence might be more successfully applied to the
present target 304, particularly in light of the knowledge that the two intermediates 263
and 299 require careful experimental manipulation due to their high instability.
120
The required 1,2-dichlorovinyl l ether 248 was prepared from naphthol 228 by
adapting the method of Slamet and Wege167, 168 described in Section 3.3. Naphthol 228
was treated with n-butyllithium in tetrahydrofuran at 0 ºC and the resulting lithium salt
was treated with trichloroethylene in dimethylformamide to give 248 in 85% (Scheme
73).
OMe
OMe
O
O Cl
Cl H1. n-BuLi, THF, 0 ºC
2. trichloroethylene, DMF, RT
248
OMe
OMe
O
OH
228
Scheme 73
Attention was then turned to the synthesis of the target furofuranonaphthalene 304
(Scheme 74). In an effort to prepare the acetylenic ether 263, a solution of 1,2-
dichlorovinyl ether 248 in tetrahydrofuran at –78 ºC was treated with t-butyllithium.
When TLC analysis indicated that all the starting material had been consumed, ethyl
chloroformate was added to the resulting precipitate and the mixture was allowed to
warm to room temperature over 1 h. Then, without hydrolytic workup, the crude
reaction product was subjected to the action of 3,6-di(pyridin-2’-yl)-1,2,4,5-tetrazine
233 in refluxing toluene.
121
OMe
OMe
O
O Cl
Cl H
1. t-BuLi, THF, -78 ºC2. Cl-CO2Et, THF, -78 ºC to RT
248
OMe
OMe
O
O
CO2Et
O
O
OMe
OMe
CO2Et
OMe
OMe
O
O
CO2Et
heat
304299
268
NN N
N
Py
Py
toluene, reflux
233
Scheme 74
However, the sequence was not successful and afforded an unexpected product, which
can be formulated as one of two possible structures 306 and 307 on the basis of NMR
and mass spectral evidence (Scheme 75). Structure 306 arises from lithiation at both the
ethylenic ether and α-position of the furan moiety in 248, followed by reaction with
ethyl chloroformate. The second possible structure 307 is the product of an
intramolecular Diels-Alder addition between the pendant ethylenic ether and the furan
diene within structure 306.
122
O
O
OMe
OMe
CO2EtCl
Cl
CO2Et
OMe
OMe
O
O
CO2Et
Cl
Cl
CO2Et
OMe
OMe
O
O Cl
Cl H
1. t-BuLi, THF, -78 ºC2. Cl-CO2Et, THF, -78 ºC to RT
248 306
307
heat
Scheme 75
The high resolution mass spectrum exhibits a molecular ion at m/z 508.0692,
corresponding to the molecular formula C24H22Cl2O8. The 1H NMR spectrum includes
signals for four aromatic protons, which occur as two multiplets at 8.23-8.11 and 7.65-
7.57 ppm (Figure 40). The high field region exhibits two methoxy singlets at 4.00 and
3.89 ppm, as well as resonances consistent with two ethyl ester groups, with two sets of
methylene quartets at 4.39 and 4.31 ppm and two methyl triplets at 1.39 and 1.36 ppm.
The spectrum also includes two doublets, resonating at 7.33 and 6.94 ppm with J = 3.6
Hz, which can be assigned to either the furyl protons in 306 or the vinylic protons in
adduct 307.
123
Figure 40. 1H NMR spectrum of compound assigned to either structure 306 or 307 (300
MHz, CDCl3).
However, it seems more likely that the product has structure 306 rather than 307 as the
magnitude of the coupling constant is characteristic of the H3-H4 coupling constants
typically observed for furans.194 For example, this J value compares well with 3.3 Hz
reported for the H3 and H4 protons in a similar system 308195 and is significantly
smaller than the coupling constant (J = 5.2 Hz) reported for the vinylic protons in a
representative 7-oxanorbornene derivative 309196 (Figure 41).
OCO2Et
308
HH
J 3.3 Hz
O
CO2CH3H3CO2C
H H
CH3H
J 5.2 Hz
309
Figure 41
124
Signals at 162.1 and 158.7 ppm in the 13C NMR spectrum are consistent with two
carbonyl groups and confirmed the presence of the ethyl ester moieties.
In view of the synthesis of the undesired dichloro compound, any further
attempts to improve the yield of the furofuranonaphthalene intermediate 304 were
deferred at this stage. A small quantity of 304 was available from the reaction sequence
described in Scheme 71. This was used to investigate the remaining steps in the
proposed route of the natural product, which is the subject of the next section.
3.7 Final Steps in the Synthesis of 3-Hydroxymethylfuro[3,2-b]naphtho[2,3-
d]furan-5,10-dione 37
Initially, it was envisaged that the target naphthoquinone 37 would be accessible
by a short sequence involving reduction of the ester group in furofuranonaphthalene
304, followed by oxidative demethylation of the resultant alcohol 310 (Scheme 76).
O
O
OMe
OMe
CO2EtO
O
OMe
OMe
OH
O
O
O
O
OH
LiAlH4THF, 0 ºC
CANMeCN/H2O0 ºC
304 310
37
Scheme 76
125
Treatment of 304 with lithium aluminium hydride in tetrahydrofuran, followed by
aqueous workup gave an orange residue, which was kept in the freezer overnight. The
1H NMR spectrum of the crude reaction product provided evidence for the structure of
alcohol 310 with a singlet at 4.83 ppm, attributable to the methylene protons of the
hydroxymethyl moiety, as well the disappearance of the ethyl ester group methylene
and methyl signals, which resonated in the high field region of the 1H NMR spectrum of
the precursor furofuranonaphthalene 304. However, attempted oxidative demethylation
of alcohol 310 with ceric ammonium nitrate in aqueous acetonitrile197 was not
successful and resulted in a complex mixture of products (by 1H NMR), with no trace of
the target naphthoquinone 37. Although the reason for this is unclear, it is possible that
the electron-rich furofuran moiety of 310 may have undergone oxidative degradation.
Fortunately a modified route to naphthoquinone 37, which avoids intermediate
alcohol 310, proved to be successful (Scheme 77).
O
O
O
O
CO2EtO
O
OMe
OMe
CO2Et
O
O
OH
OH
OH
O
O
O
O
OH
CANMeCN/H2O0 ºC
LiAlH4THF, 0 ºC
304 311
31237
ON(SO3K)2
Scheme 77
126
The furofuranonaphthalene 304 was first converted into the bright yellow quinone 311
by oxidative demethylation with ceric ammonium nitrate (Scheme 77). Here the
presence of the electron-withdrawing ester group presumably stabilizes the furofuran
system. Subsequent treatment with lithium aluminium hydride, followed by aqueous
workup effected reduction. The intermediate hydroxyquinone 312 was then isolated and
immediately subjected to oxidation with Fremy’s salt; this delivered the target 3-
hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione 37 as a red solid in 49% yield
over two steps.
Although the natural product is reported to melt at 217-218 ˚C,48 the synthetic
material was observed to sublime and undergo a phase change from ca 204 ˚C onwards
and then melt at 240-241 ˚C. The 1H NMR spectrum of the synthetic material compares
well with that reported for the natural product (Figures 43a and Table 2).48 However, the
furyl proton signal at 8.16 ppm is better resolved and resonates as a triplet due to long
range coupling to the methylene group protons (Figure 44), rather than a broad singlet
as reported for the natural material. The methylene protons occur as a doublet of
doublets at 4.58 ppm and are further coupled to the adjacent hydroxyl proton, which
itself resonates as a triplet at 5.49 ppm. The four aromatic protons occur as two
multiplets with a non-first order spin pattern in the same region as in the reported
spectrum (Figure 44). A computer simulation of these signals is shown in Figure 45 and
allowed the chemical shifts and coupling constants shown in Table 2 to be extracted.
The signals in the 13C NMR spectrum are also consistent with the values reported for
the natural product, except for the position of the methylene carbon signal of the
hydroxymethyl substituent, which resonates at 52.3 ppm compared to 54.5 ppm
reported48 for the natural material (Figure 43b and Table 2). The chemical shift of the
methylene peak remained at 52.3 ppm during a series of dilution experiments, which
127
ruled out the possibility that the position of this signal is concentration dependent.
Interestingly, this shift is identical to the value reported by the same authors48 for the
analogous methylene carbon in the related co-metabolite 205 (Figure 42). Since the
phenolic OH group of 205 is unlikely to have an electronic effect on the CH2OH group,
we believe that the shift of 54.5 ppm reported for naturally occurring 37 may be in error.
O
O
O
O
OHδC 52.3
205
HO
Figure 42
Given the similarities between the spectra of the synthetic material and natural
product, we conclude that the structure 37 has been confirmed by total synthesis.
3.8 Concluding Remarks
The current study has confirmed the novel ring system of 3-
hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione 37 through total synthesis
and represents a new approach to a compound incorporating the unusual fully aromatic
furo[3,2-b]furan ring. However, only a small amount of the target compound 37 was
obtained due to a number of low yielding steps in the preparation of the key
intermediate furofuranonaphthalene 304. It is clear that this route requires further work
if a sufficient quantity of 37 is to be synthesised for any further investigations into the
natural product’s potentially useful biological activity. Preliminary experiments carried
out during this study suggest that the yield of intermediate 304 is at least partly
128
dependent upon the reaction conditions employed in the synthesis of the precursor
acetylenic ether 263. Thus, it seems possible that with further experimentation,
especially in regard to variation of the solvent and base, conditions may be found for
improving the efficiency of the sequence. In particular, the use of an effective
dissociating agent, such as an aprotic dipolar solvent, which is known to promote O-
alkylation may be beneficial for encouraging the synthesis of the initial ether
intermediate 263 and would be worth examining (Scheme 78).
OMe
OMe
OH
O
OMe
OMe
O
O
CO2Et
O
O
OMe
OMe
CO2Et
Br CO2Et
NN N
N
py
py
toluene, reflux
OMe
OMe
O
O
CO2Et
228
233
299
292263
304
heat
base,aprotic dipolar solvent(eg DMF)
Scheme 78
129
Figure 43a. 1H NMR spectrum of 37 (500 MHz, d6-DMSO).
Figure 43b. 13C NMR spectrum of 37 (125.75 MHz, d6-DMSO).
130
Figure 44. Expansions of the low field region in the 1H NMR spectrum of 37 showing
the aromatic H6-H9 and furyl H2 proton signals.
Figure 45. Computer simulation of the 1H NMR signals for the aromatic H6-H9 protons
in 37 obtained using using the programme gNMR version 4.0 (Cherwell Scientific
Publishing Limited).
131
132
Chapter 4
Experimental
133
4.1 General Details
4.1.1 Solvents and Reagents
All solvents were distilled prior to use. Anhydrous solvents were prepared by
refluxing with the reagents shown in Table 3, followed by distillation under an
atmosphere of nitrogen or argon. Ether refers to diethyl ether and light petroleum refers
to the hydrocarbon fraction which distills from 65-70 °C.
Table 3. Drying agents for solvents
Solvent
Drying Agent
acetone
acetonitrile
dichloromethane
dimethylformamide
dioxane
dimethyl sulfoxide
ether
hexane
methanol
2-propanol
tetrahydrofuran
toluene
potassium carbonate
phosphorus pentoxide
calcium hydride
4Å molecular sieves
sodium benzophenone ketyl
calcium hydride
sodium benzophenone ketyl
calcium hydride
3Å molecular sieves
calcium hydride
potassium benzophenone ketyl
calcium hydride
Most liquid reagents were distilled prior to use. A number of liquid reagents,
which were used in reactions carried out under anhydrous conditions, were dried by
134
refluxing with the reagents listed in Table 4, followed by distillation under an
atmosphere of nitrogen or argon.
Table 4. Drying agents for liquid reagents
Liquid Reagent Drying Agent
benzyl alcohol
ethyl chloroformate
propylene oxide
trichloroethylene
triethylamine
potassium carbonate, then 4Å molecular
sieves
potassium carbonate
potassium carbonate
potassium carbonate
calcium hydride
Fremy’s salt was prepared according to the method described by Goodgame,198
then stored in a desiccator over calcium oxide and ammonium carbonate.
4.1.2 Reactions and Chromatography
Reaction temperatures refer to bath temperatures. Kugelrohr distillation
temperatures refer to the oven temperature. Unless otherwise stated, all organic extracts
were dried over anhydrous magnesium sulfate. Solvents were evaporated using a rotary
evaporator with minimal heating.
Ozonolyses were performed with a Welsbach model T-408 ozonator. Irradiation
of reaction solutions was carried out through Pyrex in an Oliphant photochemical
chamber reactor equipped with Sylvania F 815/BLB tubes emitting at 350 nm.
135
Analytical thin layer chromatography (TLC) was carried out using Merk silica
gel 60 F254 aluminium-backed plates that were visualised under UV light (254 nm) and
by spraying the plates with a 6% ceric sulfate in 2 M sulfuric acid solution, followed by
heating (> 200 ºC). Silica gel filtrations were carried out under water aspirator vacuum
using either Fluka Kieselgel 60 or Merk silica gel 60 as adsorbent on a sintered glass
funnel. Radial chromatography was carried out using a Chromatotron model 7924T
(Harrison Research, Palo Alto, California) using plates coated with Kieselgel 60 PF254
gipshaltig (Merk Art. 7749). For both techniques, increasing proportions of ethyl acetate
in light petroleum were used as eluent and fractions were monitored by TLC.
4.1.3 Characterisation
Melting points were determined on a Kofler hot stage apparatus and are
uncorrected. Microanalyses were performed by MHW Laboratories, Phoenix, Arizona.
Optical rotations were measured with a Perkin Elmer 141 polarimeter in a microcell (1
ml, 10 cm path length).
Nuclear Magnetic Resonance (NMR) spectra were recorded with Varian Gemini
(200 MHz, 1H), Brucker ARX300 (300 MHz, 1H; 75.5 MHz, 13C), Brucker AV500 (500
MHz, 1H, 125.7 MHz, 13C) spectrometers. Chemical shifts are expressed in ppm relative
to CHCl3 (1H, 7.26 ppm), CDCl3 (13C, 77.0 ppm), D3CSOCD2H (1H, 2.49 ppm) or
D3CSOCD3 (13C, 39.5 ppm) as appropriate; J values are given in Hertz (Hz). Routine
assignments of 13C signals were made with the assistance of DEPT 135 and DEPT 90
experiments and full assignments of the 1H and 13 C signals of (±)-isoelecanacin 151
were derived from HMBC, HSQC and NOESY experiments performed using the
Brucker AV500 spectrometer.
136
Mass spectra were recorded in the EI mode using a VG Autospec instrument,
except where specified. Only molecular ion peaks and peaks with intensities registering
15% (relative to base peak) and greater are reported. Infrared spectra were measured
using a Perkin Elmer Spectrum One FT-IR spectrometer with absorption recorded in
terms of frequency (vmax) in cm-1. Electronic spectra were recorded using a Milton Roy
Array 3000 Spectrophotometer and are reported in terms of wavelength (λ) in nm.
High Performance Liquid Chromatography (HPLC) was performed using a
Chiracel OD column (Daicel Chemical Industries) fitted to an ICI 1110 pump interfaced
with a Hewlett Packard Series 1050 instrument using UV detection at 254 nm. The
solvent was 2-propanol-hexane 1 : 5 with a flow rate of 0.5 mL min-1.
137
4.2 Experimental for Chapter 2
5-Methoxy-1-(2-propenyloxy)naphthalene 42
The procedure was adapted from that described by Eisenhuth and Schmid.59 5-
Methoxy-1-naphthol 41 (3.51 g, 20.2 mmol), allyl bromide (2.8 ml, 3.88 g, 32.1 mmol)
and potassium carbonate (4.28 g, 31.0 mmol) in acetone (90 ml) were refluxed for 3 h
under nitrogen. The reaction mixture was allowed to cool to room temperature, left to
stand overnight and then poured into water (450 ml) and extracted with ether (3 x 60
ml). The combined organic extracts were washed successively with 10% sodium
hydroxide solution (50 ml), water (50 ml) and brine (50 ml), then dried and evaporated
to give 5-methoxy-1-(2-propenyloxy)naphthalene 42 as a yellow crystalline solid (4.17
g, 97%), mp 96-98 °C (lit.,59 98 °C). δ H (200 MHz, CDCl3) 7.91 (1H, d, J 8.5, ArH),
7.85 (1H, d, J 8.5, ArH), 7.43-7.32 (2H, m, 2 x ArH), 6.86 (2H, d, J 7.7, 2 x ArH), 6.19
(1H, ddt, J 17.3, 10.5 and 5.1, CH, vinylic), 5.53 (1H, dtd, J 17.3, 1.5 and 1.5, CH,
vinylic), 5.34 (1H, dtd, J 10.5, 1.5 and 1.5, CH, vinylic), 4.72 (2H, ddd, J 5.1, 1.5 and
1.5, CH2), 4.00 (3H, s, OCH3).
5-Methoxy-2-(2-propenyl)naphthalen-1-yl acetate 147
A stirred solution of 5-methoxy-1-(2-propenyloxy)naphthalene 42 (4.17 g, 19.5 mmol)
in acetic anhydride (31.0 ml, 33.5 g, 328 mmol) and N,N-diethylaniline (100 ml, 93.3 g,
625 mmol) was heated at 165-170 °C (bath) for 6 h under argon, then allowed to cool to
room temperature and left to stir for 24 h. The solution was diluted with water (250 ml)
and extracted with ether (3 x 60 ml). The combined ether extracts were washed with 2
M hydrochloric acid solution (3 x 100 ml), followed by saturated sodium carbonate
solution (80 ml) and brine (80 ml), dried and evaporated to give 5-methoxy-2-(2-
propenyl)naphthalen-1-yl acetate 147 as a yellow-brown oil (4.74 g, 95%), which was
138
pure by 1H NMR. δH (200 MHz, CDCl3) 8.11 (1H, d, J 8.8, ArH), 7.46-7.29 (3H, m,
ArH), 6.80 (1H, d, J 7.4, ArH), 6.06-5.82 (1H, m, CH, vinylic), 5.18-5.04 (2H, m, 2 x
CH, vinylic), 3.97 (3H, s, OCH3), 3.43 (2H, ddd, J 6.6, 1.5 and 1.5, CH2), 2.45 (3H, s,
CH3).
5-Methoxy-2-(2-propenyl)naphthalene-1,4-dione 44
The procedure was adapted from that of Eisenhuth and Schmid.59 5-Methoxy-1-
naphthol 41 (4.21 g, 24.2 mmol), allyl bromide (3.4 ml, 4.6 g, 38 mmol) and potassium
carbonate (5.14 g, 37.2 mmol) in acetone (110 ml) were refluxed for 3 h under nitrogen.
The reaction mixture was allowed to cool, then poured into water and extracted with
ether (3 x 60 ml). The extracts were washed with 10% aqueous sodium hydroxide
solution (40 ml) followed by brine, dried and evaporated to give 5-methoxy-1-(2-
propenyloxy)naphthalene 42 as a pale brown solid (4.89 g, 94%), which was pure by 1H
NMR. δ H (200 MHz, CDCl3) 7.91 (1H, d, J 8.5, ArH), 7.85 (1H, d, J 8.5, ArH), 7.43-
7.32 (2H, m, 2 x ArH), 6.86 (2H, d, J 7.7, 2 x ArH), 6.19 (1H, ddt, J 17.3, 10.5, 5.1,
CH, vinylic), 5.53 (1H, dtd, J 17.3, 1.5, 1.5, CH, vinylic), 5.34 (1H, dtd, J 10.5, 1.5, 1.5,
CH, vinylic), 4.72 (2H, ddd, J 5.1, 1.5, 1.5, CH2), 4.00 (3H, s, OCH3). The foregoing
ether 42 (4.89 mg, 22.9 mmol) was heated at 160-185 °C (oil bath) for 2 h 15 min under
argon, affording almost pure 5-methoxy-2-(2-propenyl)naphthalen-1-ol 43 as a pale
brown waxy solid (4.62 g). δ H (200 MHz, CDCl3) 7.80 (1H, d, J 8.5, ArH), 7.73 (1H,
d, J 8.5, ArH), 7.38 (1H, dd, J 8.5, 7.7, ArH, 7.21 (1H, d, J 8.5, ArH), 6.81 (1H, d, J
7.7, ArH), 6.18-5.99 (1H, m, CH, vinylic), 5.50 (1H, s, br, OH), 5.30-5.20 (2H, m, 2 x
CH, vinylic), 3.99 (3H, s, OCH3), 3.58 (2H, ddd, J 6.2, 1.6, 1.6, CH2). A solution of the
phenol 43 (1.49 g, 6.96 mmol) in ether (30 ml) was added to a separating funnel
containing Fremy’s salt (5.23 g, 19.5 mmol) dissolved in an aqueous borax buffer
solution (0.025 M sodium tetraborate, 148 ml; 0.1 M sodium hydroxide, 72 ml). The
139
resulting mixture was shaken until TLC indicated that all the starting material had been
consumed (ca 1.5 h). Argon was bubbled through the solution to evaporate most of the
ether, during which time a yellow-brown precipitate separated. The solid was collected
and dried over phosphorus pentoxide to give 5-methoxy-2-(2-propenyl)naphthalene-1,4-
dione 44 (1.44 g, 91%), which was pure by 1H NMR and used in the next reaction
without further purification. A sample recrystallised from dichloromethane-light
petroleum as yellow needles, mp 95-96 °C (lit.,59 96-97 °C) δ H (200 MHz, CDCl3)
7.76-7.57 (2H, m, ArH), 7.26 (1H, d, J 7.7, ArH), 6.68 (1H, s, 3-CH, vinylic), 5.96-5.76
(1H, m, CH, vinylic), 5.22-5.12 (2H, m, 2 x CH, vinylic), 3.98 (3H, s, OCH3), 3.58
(2H, ddd, J 6.8, 1.9 and 1.3, CH2).
5-Methoxy-2-(2-formylmethyl)naphthalen-1-yl acetate 150
Ozone was bubbled through a solution of 5-methoxy-2-(2-propenyl)naphthalen-1-yl
acetate 147 (3.87 g, 15.1 mmol) in dichloromethane/methanol (4:1, 180 ml) at –78 °C
until TLC indicated that all the starting material had been consumed (45 min). The
solution did not turn blue. Oxygen, followed by nitrogen was bubbled through the
solution in order to displace the ozone. The cold solution was added dropwise to a
stirred suspension of thiourea (1.41 g, 18.5 mmol) and sodium bicarbonate (826 mg,
9.84 mmol) in dichloromethane (50 ml) at ice bath temperature and stirred for 1.5 h
under nitrogen. The resulting reaction mixture was diluted with water (350 ml) and the
organic layer was separated. The aqueous layer was extracted with dichloromethane (2
x 40 ml) and the combined organic extracts were washed with brine, dried and
evaporated to give the aldehyde 150 as a yellow oil (4.03 g), which was refrigerated
overnight. δH (200 MHz, CDCl3) 9.69 (1H, t, J 2.4, CHO), 8.20 (1H, d, J 8.8, ArH),
7.48-7.30 (3H, m, ArH), 6.85 (1H, d, J 7.5, ArH), 4.00 (3H, s, OCH3), 3.70 (2H, d, J
140
2.4, CH2), 2.46 (3H, s, CH3). Due to its instability, the aldehyde was used directly in the
next reaction without purification or further characterisation.
1-(1-Hydroxy-5-methoxynaphthalen-2-yl)propan-2-ol 149
A solution of methyl iodide (6.2 ml, 14.1 g, 99.7 mmol) in anhydrous tetrahydrofuran
(35 ml) was added dropwise to magnesium turnings (2.28 g, 93.8 mmol) at room
temperature under argon. The mixture was stirred and diluted by the dropwise addition
of anhydrous tetrahydrofuran (70 ml). Upon completion of the reaction, the Grignard
reagent was cooled in an ice bath and a solution of crude 5-methoxy-2-(2-
formylmethyl)naphthalen-1-yl acetate 150 (4.03 g, 15.6 mmol) in anhydrous
tetrahydrofuran (100 ml) was added dropwise. Then the resulting mixture was allowed
to warm to room temperature and stirring was continued for a further 2 h. The reaction
mixture was carefully quenched with water (300 ml), acidified with concentrated
hydrochloric acid, and extracted with ethyl acetate (3 x 70 ml). The combined organic
extracts were washed with water (70 ml) followed by brine (70 ml), dried and
evaporated to give 1-(1-hydroxy-5-methoxynaphthalen-2-yl)propan-2-ol 149 as an
orange oil (3.55 g), which was used directly in the next reaction. A small sample was
subjected to radial chromatography. Elution with 10% ethyl acetate-light petroleum
gave a clear oil, which solidified upon refrigeration and recrystallised from
dichloromethane-light petroleum as white plates, mp 83-84 °C (Found: C, 72.4; H, 7.0.
C14H16O3 requires C, 72.4; H, 6.9%). (Found M+•, 232.1103. C14H16O3 requires
232.1099). Mass Spectrum m/z: 232 (M, 25%), 214 (100), 212 (28), 199 (47), 187 (18),
186 (29), 171 (28), 169 (21), 128 (21), 115 (43). δ H (300 MHz, CDCl3) 7.88 (1H, dt, J
8.5 and 0.8, ArH), 7.74 (1 H, dd, J 8.5 and 0.6, ArH), 7.37 (1 H, dd, J 8.5 and 7.7, ArH),
7.12 (1H, d, J 8.5, ArH), 6.80 (1H, d, J 7.7, ArH), 4.36-4.27 (1H, m, CH), 3.99 (3H, s,
OCH3) 3.01 (1H, dd, J 14.7 and 2.5, CH of methylene), 2.90 (1H, dd, J 14.7 and 7.1,
141
CH of methylene), 1.27 (3H, d, J 6.2, CH3). δ C (75.5 MHz, CDCl3) 155.1 (C), 150.9
(C), 129.0 (CH), 126.8 (C), 126.0 (C), 125.0 (CH), 118.9 (C), 114.6 (CH), 113.5 (CH),
103.8 (CH), 70.9 (CH), 55.5 (OCH3), 40.5 (CH2), 23.2 (CH3).
2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-dione 46
A solution of 1-(1-hydroxy-5-methoxynaphthalen-2-yl)propan-2-ol 149 (3.48 g, 15.0
mmol) in ethyl acetate (80 ml) was added to a separating funnel containing Fremy’s salt
(8.25 g, 30.8 mmol) dissolved in an aqueous borax buffer solution (0.025 M sodium
tetraborate, 250 ml; 0.1 M sodium hydroxide, 121 ml). The resulting mixture was
shaken until TLC indicated that the starting material had been consumed (ca 40 min).
The mixture was diluted with brine (50 ml) and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate (4 x 60 ml). The combined organic
extracts were washed with brine (80 ml), dried and evaporated to give a yellow oil,
which was subjected to silica gel filtration. Elution with 30% ethyl acetate-light
petroleum gave 2-(2-hydroxypropyl)-5-methoxynaphthalene-1,4-dione 46 as a yellow
oil (1.54 g, 41% over 3 steps) which solidified upon refrigeration. A small sample
recrystallised from ethyl acetate-light petroleum as fine yellow needles, mp 95-96 °C
(lit.,59 96-97 °C). (Found M+•, 246.0894. C14H14O4 requires 246.0892). Mass Spectrum
m/z: 246 (M, 23%), 230 (27), 204 (73), 203 (54), 202 (100), 187 (15), 175 (17), 174
(32), 173 (38), 159 (25), 144 (15), 131 (23), 115 (34). δ H (300 MHz, CDCl3) 7.75 (1H,
dd, J 7.7 and 1.2, ArH), 7.66 (1H, dd, J 8.4 and 7.7, ArH), 7.29 (1 H, dd, J 8.4 and 1.1,
ArH), 6.78 (1H, t, J 1.0, CH, vinylic), 4.15-4.03 (1H, m, CH), 4.00 (3H, s, OCH3) 2.74
(1H, ddd, J 13.8, 4.1 and 1.0, CH of methylene), 2.59 (1H, ddd, J 13.8, 8.0 and 1.0, CH
of methylene), 1.29 (3H, d, J 6.2, CH3). δ C (75.5 MHz, CDCl3) 186.1 (C=O), 184.3
(C=O), 159.4 (C), 145.6 (C), 139.2 (CH), 134.7 (CH), 134.3 (C), 119.8 (C), 119.5 (CH),
142
117.8 (CH), 66.7 (CH), 56.4 (OCH3), 39.1 (CH2), 23.7 (CH3). λmax (CH2Cl2) (log ε) 247
(4.14), 268 (3.22), 354 (4.06), 396 (3.54). vmax(CH2Cl2) /cm-1 1658 (C=O).
5-Methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-dione 138
A solution of 2-(2-hydroxypropyl)-5-methoxynaphthalene-1,4-dione 46 (1.43 g, 5.80
mmol) and mercuric acetate (351 mg, 1.10 mmol) in ethyl vinyl ether (35 ml, 26.4 g,
366 mmol) and dichloromethane (10 ml) in a foil-covered flask was refluxed for 6 h
under argon. The solution was kept at room temperature for 2 days, then poured into
water and extracted with dichloromethane (3 x 40 ml). The combined organic extracts
were washed with brine, dried and evaporated to give a yellow residue, which was
subjected to silica gel filtration. Elution with 15% ethyl acetate-light petroleum gave 5-
methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-dione 138 (903 mg, 57%) as a yellow
oil. (Found M+•, 272.1054. C16H16O4 requires 272.1049). Mass Spectrum m/z: 273
(M+1, 17%), 272 (M, 97), 243 (16), 230 (34), 229 (100), 228 (36), 227 (18), 215 (15),
213 (31), 211 (19), 205 (19), 202 (27), 201 (19), 188 (27), 187 (36). δ H (300 MHz,
CDCl3) 7.74 (1H, dd, J 7.7 and 1.2, ArH), 7.66 (1H, dd, J 8.3 and 7.7, ArH), 7.28 (1 H,
dd, J 8.3 and 1.2, ArH), 6.75 (1H, t, J 1.1, CH, vinylic), 6.27 (1H, dd, J 6.7 and 14.2,
CH, vinylic), 4.30 (1H, dd, J 14.2 and 1.7, CH, vinylic), 4.26-4.15 (1H, m, CH), 4.00-
3.99 (1H, dd, J 6.7, 1.7, CH, vinylic), 3.99 (3H, s, OCH3) 2.79 (1H, ddd, J 13.9, 7.4 and
1.1, CH of methylene), 2.67 (1H, ddd, J 13.9, 5.3 and 1.1, CH of methylene), 1.27 (3H,
d, J 6.2, CH3). δ C (75.5 MHz, CDCl3) 185.4 (C=O), 184.3 (C=O), 159.4 (C), 150.3
(CH), 144.7 (C), 139.3 (CH), 134.7 (CH), 134.2 (C), 119.4 (CH), 117.7 (CH), 88.8
(CH2), 77.2 (C), 73.2 (CH), 56.4 (OCH3), 36.1 (CH2), 20.0 (CH3). λmax (CH2Cl2) (log ε)
230 (4.10), 238 (4.15), 262 (4.06), 333 (3.22), 249 (3.24), 393 (3.46).vmax (CH2Cl2)/cm-1
1658 (C=O).
143
(±)-Elecanacin 36 and (±)-isoelecanacin 151
A deoxygenated solution of 5-methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-dione 138
(122 mg, 0.45 mmol) in anhydrous dichloromethane (50 ml) was irradiated at 350 nm
through Pyrex for 65 min, when TLC indicated that all the starting material had been
consumed. The solvent was evaporated and the yellow residue was subjected to careful
radial chromatography. Elution with 20% ethyl acetate-light petroleum gave (±)-
isoelecanacin 151 (46 mg, 38%) as a yellow oil, which solidified upon refrigeration and
recrystallised from dichloromethane-light petroleum as white needles, mp 114-115 °C.
(Found M+•, 272.1048. C16H16O4 requires 272.1049). Mass Spectrum m/z: 273 (M+1,
16%), 272 (M, 100), 270 (22), 244 (22), 243 (87), 242 (20), 241 (16), 229 (41), 228
(20), 227 (30), 217 (19), 211 (19), 201 (15), 189 (19), 187 (22), 153 (65), 136 (57), 135
(17), 128 (16), 115 (27), 108 (19), 107 (71), 106 (55), 105 (39), 104 (17), 90 (19), 89
(96). The 13C and 1H NMR spectral data are given in Table 1 (p. 60). vmax (CH2Cl2)/cm-1
1683 (C=O). Analysis on the Chiracel OD column showed two peaks in a ratio of 48 :
52 at retention times 19.2 and 22.6 min. Further elution with 30% ethyl acetate-light
petroleum gave (±)-elecanacin 36 (31 mg, 25%) as a yellow oil, which could not be
induced to crystallise (lit.,47 mp 198 °C for optically active material). (Found M+•,
272.1050. C16H16O4 requires 272.1049). Mass Spectrum m/z: 273 (M+1, 17%), 272 (M,
100), 244 (22), 243 (88), 229 (30), 228 (19), 227 (21), 217 (15), 215 (15), 211 (15), 202
(16), 201 (15), 189 (17), 187 (17), 135 (18), 128 (16), 115 (23). The 13C and 1H NMR
spectral data are shown in Table 1 and are identical with those of natural elecanacin.
vmax (CH2Cl2)/ cm-1 1684 (C=O). Analysis on the Chiracel OD column showed two
peaks in the ratio of 52 : 48 at retention times 26.5 and 39.2 min.
When the irradiation was repeated and the reaction was interrupted at low
conversion of reactant, elecanacin 36 and isoelecanacin 151 were found to be present in
144
the same ratio as at complete conversion (TLC and NMR analysis). Irradiation of pure
samples of elecanacin 36 and isoelecanacin 151 in dichloromethane led to no change.
Conversion of the vinyl ether 138 into elecanacin 36 and isoelecanacin 151 also
was observed when a solution of 138 in dichloromethane was kept in ambient
laboratory light.
2-(2,3-Epoxypropyl)-5-methoxynaphthalen-1-yl acetate 155
a) A cold solution of an excess of dimethyldioxirane in acetone (60 ml), prepared
according to the procedure described by Murray and Singh,123 was added to a solution
of 5-methoxy-2-(2-propenyl)naphthalen-1-yl acetate 147 (1.16 g, 453 mmol) in acetone
(10 ml) and left to stir for 16 h at room temperature. The solution was diluted with
water (350 ml) and extracted with ethyl acetate (3 x 70 ml). The extracts were washed
with brine, dried and evaporated to give a brown oil, which was subjected to silica gel
filtration. Elution with 5% ethyl acetate-light petroleum returned unreacted starting
material as a yellow oil (89 mg). Further elution with 10% ethyl acetate-light petroleum
gave a yellow oil, which was subjected to radial chromatography. Elution with 5% ethyl
acetate-light petroleum gave the epoxide 155 as a colourless oil (279 mg, 23%). (Found
M+•, 272.1042. C16H16O4 requires 272.1049). Mass spectrum (FAB) m/z: 273 (M + 1,
74%), 272 (M, 100), 231 (32), 230 (88), 213 (64), 212 (32), 187 (35). δH (300 MHz,
CDCl3) 8.15 (1H, d, J 8.7, ArH), 7.44-7.39 (2H, m, ArH), 7.30 (1H, d, J 8.5, ArH), 6.82
(1H, d, J 7.1, ArH), 3.99 (3H, s, OCH3), 3.22-3.18 (1H, m, CH, X of ABX), 3.01 (1H,
dd, J 14.6 and 5.5, CH of methylene), 2.88-2.79 (2H, m, 2 x CH of methylene), 2.59
(1H, m, CH of methylene), 2.49 (3H, s, CH3). δC (75.5 MHz, CDCl3) 169.3 (C=O),
155.6 (C), 144.3 (C), 128.1 (C), 127.0 (CH), 126.8 (CH), 126.4 (C), 125.9 (C), 120.5
(CH), 113.2 (CH), 104.1 (CH), 55.6 (OCH3), 51.4 (CH), 47.0 (CH2), 33.5 (CH2), 20.7
(CH3).
145
b) m-Chloroperoxybenzoic acid (70%, 1.91 g, 7.75 mmol) and 2,6-di-t-butyl-4-
methylphenol (20 mg, 0.09 mmol) were added to a stirred solution of 5-methoxy-2-(2-
propenyl)naphthalen-1-yl acetate 147 (902 mg, 3.52 mmol) in dichloromethane (65 ml)
and the solution was refluxed gently for 1.5 h. The solution was allowed to cool to room
temperature and left to stand overnight, during which time a white precipitate separated.
The mixture was cooled in an ice bath and filtered. The filtrate was washed successively
with 10% sodium bisulfite solution (25 ml), 10% sodium bicarbonate solution (2 x 40
ml) and brine (60 ml), then dried and evaporated to give an orange residue, which was
subjected to radial chromatography. Elution with 10% ethyl acetate-light petroleum
returned unreacted starting material (56 mg). Further elution afforded a fraction, which
was concentrated under reduced pressure to give a yellow oil (114 mg).1H NMR
analysis revealed that the oil contained impure epoxide 155. Further attempts to purify
this fraction by radial chromatography were unsuccessful and the epoxide could not be
isolated.
1-Benzyloxy-5-methoxy-2-(2-propenyl)naphthalene 166
Benzyl bromide (6.13 g, 35.8 mmol) was added to a mechanically stirred suspension of
5-methoxy-2-(2-propenyl)naphthalen-1-ol 43 (6.40 g, 29.9 mmol) and potassium
carbonate (6.52 g, 47.2 mmol) in acetone (200 ml) and the mixture was refluxed for 3 h
under argon. The mixture was diluted with water (400 ml) and extracted with ether (3 x
60 ml). The combined organic extracts were washed with 10% sodium hydroxide
solution (60 ml), followed by brine (70 ml), dried and evaporated to give a yellow oil
(9.70 g). Kugelrohr distillation under a vacuum gave 1-benzyloxy-5-methoxy-2-(2-
propenyl)naphthalene 166 (7.63 g, 84%) as a pale yellow oil, which solidified upon
refrigeration. A sample recrystallised from light petroleum as white plates, mp 46-47
°C. (Found M+•, 304.1455. C21H20O2 requires 304.1463). Mass spectrum m/z: 304 (M,
146
60%), 214 (18), 213 (100), 198 (20), 153 (20), 115 (18), 91 (90), 77 (23). δH (300 MHz,
CDCl3) 8.03 (1H, d, J 8.7, ArH), 7.73 (1H, d, J 8.5, ArH), 7.59-7.56 (2H, m, ArH),
7.48-7.32 (5H, m, ArH), 6.82 (1H, d, J 7.3, ArH), 6.10-5.96 (1H, m, CH, vinylic), 5.14-
5.06 (2H, m, 2 x CH, vinylic), 5.02 (2H, s, OCH2), 4.01 (3H, s, OCH3), 3.61 (2H, ddd, J
5.0, 1.4 and 1.4, CH2). δC (75.5 MHz, CDCl3) 155.8 (C), 151.8 (C), 137.5 (C), 137.2
(CH), 129.4 (C), 129.1 (C), 128.6 (CH), 128.0 (CH), 127.7 (CH), 127.5 (CH), 126.0
(CH), 125.9 (C), 118.2 (CH), 115.9 (CH2), 114.4 (CH), 103.6 (CH), 76.2 (CH2), 55.5
(OCH3), 34.0 (CH2).
2-(1-Benzyloxy-5-methoxynaphthalen-2-yl)ethanal 167
Ozone was bubbled through a solution of 1-benzyloxy-5-methoxy-2-(2-
propenyl)naphthalene 166 (2.31 g, 7.60 mmol) in dichloromethane/methanol (4 : 1, 180
ml) at –78 °C, until TLC indicated that the starting material had been consumed (ca 20
min). The solution did not turn blue. Oxygen, followed by argon was bubbled through
the solution in order to displace the ozone. The cold solution was added dropwise to a
stirred suspension of thiourea (687 mg, 9.02 mmol) and sodium bicarbonate (457 mg,
5.44 mmol) in dichloromethane (60 ml) at ice bath temperature and the resulting
mixture was stirred for 1.5 h under argon. The reaction mixture was then diluted with
water (300 ml), the organic layer was separated and the aqueous layer was extracted
with dichloromethane (2 x 60 ml). The combined organic extracts were washed with
brine (80 ml), dried and evaporated to give a yellow oil, which was subjected to silica
gel filtration. Elution with 5% ethyl acetate-light petroleum gave the aldehyde 167 as a
faint yellow oil (1.51 g, 65%). (Found M+•, 306.1251. C20H18O3 requires 306.1256).
Mass spectrum m/z: 306 (M, 24%), 288 (54), 215 (43), 198 (26), 187 (54), 155 (25), 149
(29), 127 (19), 115 (22), 91 (100), 84 (20), 83 (17), 77 (18), 71 (20), 69 (21), 57 (36). δH
(300 MHz, CDCl3) 9.70 (1H, t, J 2.2, CHO), 8.09 (1H, dd, J 8.6 and 0.4, ArH), 7.73
147
(1H, d, J 8.5, ArH), 7.50-7.36 (6H, m, ArH), 7.26 (1H, d, J 8.6, ArH), 6.86 (1H, d, J
7.3, ArH), 5.02 (2H, s, OCH2), 4.02 (3H, s, OCH3), 3.78 (2H, d, J 2.2, CH2). δC (75.5
MHz, CDCl3) 199.7 (C=O), 155.9 (C), 152.9 (C), 136.8 (C), 129.2 (C), 128.6 (CH),
128.3 (CH), 128.0 (CH), 127.4 (CH), 126.8 (C), 126.5 (CH), 122.1 (C), 118.9 (CH),
114.3 (CH), 104.2 (CH), 76.2 (CH2), 55.6 (OCH3), 45.3 (CH2).
1-Benzyloxy-2-(2,3-epoxypropyl)-5-methoxynaphthalene 156
Trimethylsulfoxonium iodide (999 mg, 4.54 mmol) was added portionwise over 20 min
to sodium hydride (60% oil dispersion, 186 mg, 4.65 mmol) in anhydrous dimethyl
sulfoxide (4 ml) under argon and the resulting suspension was stirred for 30 min. 2-(1-
Benzyloxy-5-methoxynaphthalen-2-yl)ethanal 167 (526 mg, 1.72 mmol) in anhydrous
dimethyl sulfoxide (4 ml) was added dropwise and the resulting mixture was stirred at
room temperature for 1 h 45 min. The mixture was quenched with ice, diluted with
water (80 ml) and extracted with ether (4 x 40 ml). The combined organic extracts were
washed with brine (50 ml), dried and evaporated to give a yellow oil, which was
subjected to silica gel filtration. Elution with 5% ethyl acetate-light petroleum afforded
the epoxide 156 as a colourless oil (383 mg, 69%). (Found M+•, 320.1422. C21H20O3
requires 320.1412). Mass spectrum m/z: 321 (M+1, 20%), (M, 89), 230 (23), 229 (28),
201 (15), 199 (57), 187 (22), 186 (24), 171 (37), 155 (20), 128 (20), 127 (22), 115 (23),
91 (100), 77 (24), 69 (17), 57 (23). δH (300 MHz, CDCl3) 8.04 (1H, d, J 8.9, ArH), 7.72
(1H, d, J 8.5, ArH), 7.57-7.39 (7H, m, ArH), 6.83 (1H, d, J 7.3, ArH), 5.05 (2H, s,
OCH2), 4.01 (3H, s, OCH3), 3.24-3.18 (1H, m, CH, X of ABX), 3.10 (1H, dd, J 14.3
and 5.3, CH of methylene), 3.00 (1H, dd, J 14.3 and 5.4, CH of methylene), 2.85 (1H,
m, CH of methylene), 2.60 (1H, m, CH of methylene). δC (75.5 MHz, CDCl3) 155.8 (C),
152.3 (C), 137.4 (C), 129.3 (C), 128.6 (CH), 128.1 (CH), 127.7 (CH), 127.4 (CH),
148
126.7 (C), 126.3 (C), 126.2 (CH), 118.5 (CH), 114.3 (CH), 103.8 (CH), 76.3 (CH2),
55.6 (OCH3), 52.1 (CH), 47.1 (CH2), 32.9 (CH2).
2-(2,3-Epoxypropyl)-5-methoxynaphthalene-1,4-dione 168
m-Chloroperoxybenzoic acid (70 %, 278 mg, 1.13 mmol) was added to a stirred
solution of 5-methoxy-2-(2-propenyl)naphthalen-1,4-dione 44 (212 mg, 0.93 mmol) in
dichloromethane (10 ml) at ice bath temperature under argon. After 3 h, the mixture was
allowed to warm to room temperature and left to stir for a further 21 h. The mixture was
diluted with dichloromethane (50 ml) and washed with 2.5% sodium bisulfite solution
(20 ml), followed by saturated sodium bicarbonate solution (2 x 25 ml) and brine (30
ml), dried and evaporated to give a yellow-orange solid (257 mg), which was subjected
to radial chromatography. Elution with 40% ethyl acetate-light petroleum returned
unreacted starting material (21 mg). Further elution with 70% ethyl acetate-light
petroleum gave the epoxide 168 as an orange crystalline solid (152 mg, 67%, 74%
based on recovered starting material). A sample recrystallised from ethyl acetate-light
petroleum as orange plates, mp 159-160 °C. (Found: C, 68.9; H, 5.0. C14H12O4 requires
C, 68.85; H, 4.95%). (Found M+•, 244.0731. C14H12O4 requires 244.0736). Mass
spectrum m/z: 246 (M + 2, 35%), 245 (M + 1, 16), 244 (M, 100), 228 (15), 227 (23),
216 (27), 215 (42), 214 (32), 213 (32), 202 (73), 201 (52), 200 (31), 199 (24), 198 (43),
197 (29), 187 (30), 186 (117), 185 (56), 184 (20), 183 (31), 174 (15), 173 (45), 171
(23), 169 (24), 168 (24), 159 (21), 157 (48), 156 (26), 155 (25), 145 (22), 144 (21), 143
(21), 141 (22), 133 (16), 131 (20), 129 (42), 128 (90), 127 (39), 116 (25), 115 (77), 105
(23), 104 (39), 102 (20), 91 (18), 89 (16), 77 (29), 76 (71), 75 (21), 64 (15), 63 (26). δH
(300 MHz, CDCl3) 7.75 (1H, dd, J 7.6 and 1.1, ArH), 7.67 (1H, dd, J 8.3 and 7.6, ArH),
7.30 (1H, dd, J 8.3 and 1.1, ArH), 6.84 (1H, t, J 1.2, 3-CH, vinylic), 4.00 (3H, s, OCH3),
3.22-3.16 (1H, m, CH, X of ABX), 2.91-2.82 (2H, m, CH of methylene and CH of
149
oxirane methylene), 2.66-2.57 (2H, m, CH of methylene and CH of oxirane methylene).
δC (75.5 MHz, CDCl3) 185.1 (C=O), 184.1 (C=O), 159.5 (C), 144.4 (C), 138.5 (CH),
134.8 (CH), 134.2 (C), 119.8 (C), 119.4 (CH), 117.9 (CH), 56.5 (OCH3), 50 (CH), 47
(CH2), 32.2 (CH2). vmax (solution, CH2Cl2) 1660 cm-1 (C=O).
Attempted resolution of epoxides 155, 156 and 168
Attempted hydrolytic kinetic resolution of the epoxides 155, 156 and 168 with
Jacobsen’s catalyst under standard conditions116, 118 in each case returned starting
material exhibiting no significant optical rotation.
5-Methoxy-1-methoxymethoxynaphthalene 173
This was prepared as described128 and obtained in 86% yield as colourless needles, mp
74-75 °C (lit.,128 75-76 °C). δH (200 MHz, CDCl3) 7.91 (2H, m, ArH), 7.45-7.35 (2H,
m, ArH), 7.14 (1H, d, J 7.6, ArH), 6.86 (1H, d, J 7.6, ArH), 5.40 (3H, s, CH2), 4.01 (3H,
s, OCH3), 3.56 (3H, s, CH3).
(R)-propylene oxide 158
The procedure described by Jacobsen and coworkers was followed.116, 118 The
precatalyst, (R,R)-N,N’-bis(3,5-di-tert-butylsalicalidene)-1,2-
cyclohexanediaminocobalt(II) (604 mg, 1.00 mmol) and glacial acetic acid (123 mg,
2.05 mmol) in toluene (5 ml) were stirred for 2 h at room temperature while exposed to
the atmosphere. The solvent was evaporated under reduced pressure leaving the crude
(R,R)-(salen)Co(III)(OAc) catalyst 160 as a dark brown residue. Anhydrous propylene
oxide (35 ml, 29.0 g, 499 mmol) was added and the resulting solution was cooled in an
ice-water bath. Water (4.90 ml, 272 mmol) was added slowly to the stirring solution,
ensuring the temperature stayed between 15-20 °C. After the addition was complete (ca
150
0.5 h), the solution was allowed to warm to room temperature and left to stir for 18 h.
Distillation gave (R)-propylene oxide 158 bp 35 °C (12.0 g, 41%), [α]D20 + 14.0 (neat)
(lit.,199 [α]D31
+ 13.8 (neat)), followed by 1,2-propanediol bp 46 °C (0.7 mm Hg) (16.9
g, 45%). The remaining residue was diluted with methanol and the red precatalyst (563
mg) was recovered by filtration.
(2R)-1-(5-Methoxy-1-methoxymethoxynaphthalen-2-yl)propan-2-ol 176
n-Butyllithium in hexane (1.6 M, 5.4 ml, 8.6 mmol) was added dropwise to a stirred
solution of 5-methoxy-1-methoxymethoxynaphthalene 173 (1.43 g, 6.56 mmol) in
anhydrous tetrahydrofuran (30 ml) cooled in an ice-water bath under argon. After 2 h
the mixture was treated with hexamethylphosphoramide (3.54 ml, 20.3 mmol), followed
by the immediate dropwise addition of (R)-propylene oxide 158 (491 mg, 8.45 mmol) in
anhydrous tetrahydrofuran (2 ml). The resulting yellow solution was allowed to warm to
room temperature and left to stir for 17 h. The solution was diluted with saturated
ammonium chloride (70 ml) and extracted with ether (3 x 50 ml). The combined organic
extracts were washed with water (40 ml), followed by brine (50 ml), dried and
evaporated to give a yellow oil (2.18 g), which was subjected to silica gel filtration.
Elution with 1% ethyl acetate-light petroleum returned unreacted starting material as a
white crystalline solid (293 mg). Further elution with 10% ethyl acetate-light petroleum
gave (2R)-1-(1-methoxy-5-methoxymethoxynaphthalen-2-yl)propan-2-ol 177 (66 mg)
as a colourless oil, which became a white crystalline solid upon refrigeration and
recrystallised from dichloromethane-light petroleum as white plates, mp 74-75 °C.
[α]D21
- 26.9 (c 0.015 in CH2Cl2). (Found M+•, 276.1366. C16H20O4 requires 276.1362).
Mass spectrum m/z: 276 (M, 41%), 258 (36), 226 (18), 214 (56), 212 (19), 201 (15), 200
(40), 199 (34), 198 (17), 187 (23), 185 (24), 171 (23), 169 (15), 157 (17), 155 (24), 153
(20), 149 (37), 141 (18), 139 (16), 129 (18), 128 (31), 127 (23), 121 (15), 115 (37), 109
151
(17), 107 (20), 105 (17), 98 (16), 97 (24), 96 (16), 95 (29), 93 (18), 91 (19), 86 (49), 85
(20), 84 (78), 83 (38), 82 (23), 81 (45), 79 (19), 78 (40), 77 (33), 71 (36), 70 (33), 69
(100), 68 (24), 67 (34), 63 (62), 61 (15), 60 (32), 57 (67), 56 (34). δH (300 MHz,
CDCl3) 8.03 (1H, dd, J 8.6 and 0.4, ArH), 7.73 (1H, dt, J 8.4 and 0.8, ArH), 7.44 (1H
dd, J 8.4 and 7.7, ArH), 7.33 (1H, d, J 8.6, ArH), 7.09 (1H, dd, J 7.7 and 0.8, ArH), 5.39
(2H, s, OCH2O), 4.16 (1H, m, CH), 3.94 (3H, s, OCH3), 3.54 (3H, s, OCH3), 2.96 (2H,
d, J 6.2, CH2), 2.29 (1H, s, br, OH), 1.28 (3H, d, J 6.2, CH3). δC (75.5 MHz, CDCl3)
153.8 (CO), 153.2 (CO), 129.2 (C), 128.2 (CH), 127.5 (C), 126.5 (C), 126.1 (CH),
118.3 (CH), 115.4 (CH), 107.7 (CH), 94.6 (OCH2O), 68.6 (CH), 61.8 (OCH3), 56.2
(OCH3), 39.9 (CH2), 23.2 (CH3). Further elution with 10% ethyl acetate-light petroleum
gave a fraction containing a 15 : 85 mixture of (2R)-1-(1-methoxy-5-
methoxymethoxynaphthalen-2-yl)propan-2-ol 177 and the title alcohol (2R)-1-(5-
methoxy-1-methoxymethoxynaphthalen-2-yl)propan-2-ol 176 as a pale yellow oil (1.13
g), which was used directly in the next reaction. The crude oil obtained from a second
reaction was subjected to careful radial chromatography. Elution with 5% ethyl acetate-
light petroleum allowed the isolation of a small analytical sample of (2R)-1-(5-methoxy-
1-methoxymethoxynaphthalen-2-yl)propan-2-ol 176 as a colourless oil. [α]D21
+ 8.7 (c
0.078 in CH2Cl2). (Found M+•, 276.1359. C16H20O4 requires 276.1362). Mass spectrum
m/z: 276 (M, 21%), 244 (24), 215 (30), 214 (100), 199 (41), 187 (49), 115 (20). δH (300
MHz, CDCl3) 8.03 (1H, d, J 8.6, ArH), 7.59 (1H, d, J 8.6, ArH), 7.41 (1H, dd, J 8.6, 7.6
ArH), 7.33 (1H, d, J 8.6, ArH), 6.81 (1H, d, J 7.6, ArH), 5.18 (1H, d, J 5.9, CH), 5.16
(1H, d, J 5.9, CH), 4.23 (1H, m, CH), 3.99 (3H, s, OCH3), 3.70 (3H, s, OCH3), 3.10-
2.94 (2H, m, CH2), 2.32 (1H, d, J 4.6, OH), 1.30 (3H, d, J 6.2, CH3). δC (75.5 MHz,
CDCl3) 155.7 (C), 151.6 (C), 129.4 (C), 128.3 (C), 127.7 (C), 126.3 (CH), 126.1 (CH),
118.8 (CH), 114.2 (CH), 103.8 (CH), 100.3 (CH2), 68.6 (CH), 57.6 (OCH3), 55.6
(OCH3), 40.1 (CH2), 23.6 (CH3).
152
(2R)-1-(1-Hydroxy-5-methoxy-2-naphthalenyl)propan-2-ol 152
A 15 : 85 mixture of (2R)-1-(1-methoxy-5-methoxymethoxynaphthalen-2-yl)propan-2-
ol 177 and (2R)-1-(5-methoxy-1-methoxymethoxynaphthalen-2-yl)propan-2-ol 176
(1.13 g) in anhydrous 2-propanol (20 ml) was treated with carbon tetrabromide (141
mg, 0.425 mmol) and refluxed for 1.5 h under argon. The solution was concentrated
under reduced pressure and the resulting yellow oil was subjected to silica gel filtration.
Elution with 5% ethyl acetate-light petroleum gave (2R)-1-(1-hydroxy-5-methoxy-2-
naphthalenyl)propan-2-ol 152 as a white crystalline solid (696 mg, 73%), which
recrystallised from ethyl acetate-light petroleum as white plates, mp 85-86 °C. [α]D21
- 6.7 (c 0.009 in CH2Cl2). The NMR spectral properties of this material were identical
with those of the (2R,S) compound 149 prepared previously.
Treatment of a sample of the (2R,S)-alcohol 149 with the chiral shift reagent
europium tris[3-heptafluoropropylhydroxymethylene)-(+)-camphorate] (7.5 mol%)
separated the H8 proton doublet signal into two doublets in the 1H NMR spectrum. The
enantiomeric excess within the (2R)-alcohol 152 was estimated to be greater than 90%
by examination of the H8 signal in the 1H NMR spectrum of a sample of 152 which had
been treated with 7.5 mol% of the chiral shift reagent.
(2R)-2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-dione 178
A solution of (2R)-1-(1-hydroxy-5-methoxy-2-naphthalenyl)propan-2-ol 152 (696 mg,
3.00 mmol) in ether (15 ml) was added to a separating funnel containing Fremy’s salt
(1.718 g, 6.11 mmol) dissolved in an aqueous borax buffer solution (0.025 M sodium
tetraborate, 84 ml; 0.1 M sodium hydroxide, 41 ml). The resulting mixture was shaken
until TLC indicated that the starting material had been consumed (ca 30 min). The
mixture was extracted with chloroform (4 x 50 ml) and the combined organic extracts
were washed with brine (60 ml), dried and evaporated to give (2R)-2-(2-
153
hydroxypropyl)-5-methoxynaphthalene-1,4-dione 178 as a yellow crystalline solid (717
mg, 97%), which was pure by 1H NMR. A sample recrystallised from ethyl acetate-light
petroleum as bright yellow needles, mp 116-117 °C. [α]D20 – 25.3 (c 0.015 in CH2Cl2).
The NMR spectral properties of this material were identical with those of the (2R,S)
compound 46 prepared previously.
(2R)-5-Methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-dione 179
A solution of (2R)-2-(2-hydroxypropyl)-5-methoxynaphthalene-1,4-dione 178 (692 mg,
2.81 mmol) and mercuric acetate (212 mg, 0.66 mmol) in ethyl vinyl ether (17 ml, 12.8
g, 178 mmol) and dichloromethane (4.5 ml) in a foil-covered flask was heated under
reflux for 5.5 h under argon. The solution was left to stand at room temperature
overnight and was then diluted with dichloromethane (40 ml) and washed with water
(80 ml). The organic layer was separated and the aqueous layer was extracted with
dichloromethane (3 x 40 ml). The combined organic extracts were washed with brine
(50 ml), dried and evaporated to give a yellow oil, which was subjected to silica gel
filtration. Elution with 15% ethyl acetate-light petroleum gave the vinyl ether 179 as a
yellow oil (393 mg, 51%, 81% based on recovered starting material). [α]D21 - 15.6 (c
0.010 in CH2Cl2). The NMR spectral properties of this material were identical with
those of the (2R,S) compound 138 prepared previously. Further elution with 40% ethyl
acetate-light petroleum returned unreacted starting material as a yellow crystalline solid
(255 mg).
154
(-)-Elecanacin 36 and (+)-isoelecanacin 151 A deoxygenated solution of (2R)-5-methoxy-2-(2-vinyloxypropyl)naphthalene-1,4-
dione 179 (131 mg, 0.482 mmol) in anhydrous dichloromethane (50 ml) was irradiated
at 350 nm through Pyrex for 65 min, when TLC indicated that all the starting material
had been consumed. The solvent was evaporated and the yellow residue was subjected
to careful radial chromatography. Elution with 20% ethyl acetate-light petroleum gave
(+)-isoelecanacin 151 (53 mg, 40%) as a yellow crystalline solid, which recrystallised
from dichloromethane-light petroleum as pale yellow plates, mp 138-139 °C. [α]D21 +
110.4 (c 0.010 in CH2Cl2). Analysis on the Chiracel OD column showed two peaks in
the ratio of 1 : 99 at retention times 20.1 and 23.4 min, giving an ee of 98% for this
material. The NMR spectral properties of this sample were identical with those of the
(2R,S) compound prepared previously. Further elution with 30% ethyl acetate-light
petroleum gave (-)-elecanacin 36 as a pale yellow crystalline solid (31 mg, 24%), which
recrystallised from dichloromethane-light petroleum as faint yellow plates, mp 167-168
°C (lit.,47 198 °C for material of low ee). [α]D21
– 145.2 (c 0.004 in CHCl3) (lit.,47 + 20.7
in CHCl3). Analysis on the Chiracel OD column showed a single peak at retention time
26.1 min. Under these conditions <0.5% of the other enantiomer (expected retention
time 39.2 min) could have been detected. The ee of this sample was thus >99%. The
NMR spectral properties of this material were identical with those of (2R,S) compound
prepared previously.
155
4.3 Experimental for Chapter 3
2,3-Dibromonaphthalene-1,4-dione 284
A stirred suspension of 1,4-naphthoquinone (12.8 g, 81.0 mmol), sodium acetate (65.0
g, 793 mmol) and bromine (12.8 ml, 39.8 g, 249 mmol) in acetic acid (320 ml) was
heated at 110 °C (bath) for 2 h under nitrogen, then allowed to cool room temperature
and left to stir for a further 16 h. The reaction mixture was poured into water (1 L) and a
yellow precipitate separated. The solid was collected, washed with water and dried over
phosphorus pentoxide to give 2,3-dibromonaphthalene-1,4-dione 284 (17.0 g), mp 218-
220 °C (lit.,200 216-218 °C), which was used directly in the next reaction without
purification.
2-Benzyloxy-3-bromonaphthalene-1,4-dione 286
The procedure described by Slamet was followed.167 n-Butyllithium in hexane (1.6 M,
35 ml, 56 mmol) was added dropwise to a stirred solution of benzyl alcohol (7.41 g,
68.6 mmol) in anhydrous tetrahydrofuran (180 ml) cooled in an ice bath under argon.
After 20 min the solution was treated with 2,3-dibromonaphthalene-1,4-dione 284 (16.4
g, 52.0 mmol) in anhydrous tetrahydrofuran (50 ml) and the resulting mixture was
stirred for a further 1.5 h. The reaction mixture was quenched with a little ice, then
diluted with water (500 ml) and extracted with ethyl acetate (3 x 100 ml). The combined
organic extracts were washed with water (100 ml), followed by brine (100 ml), dried
and evaporated to give a yellow residue, which was subjected to silica gel filtration.
Elution with 5-30% ethyl acetate-light petroleum gave an oily yellow solid, which
recrystallised from dichloromethane-light petroleum to give 2-benzyloxy-3-
bromonaphthalene-1,4-dione 286 as yellow needles (8.92 g, 50%), mp 103-104 °C
(lit.,167 103-104 °C).
156
2-Benzyloxy-3-(2-furyl)naphthalene-1,4-dione 288
The procedure described by Slamet was followed.167 A mixture of 2-benzyloxy-3-
bromonaphthalene-1,4-dione 286 (4.38 g, 12.8 mmol), 2-(tri-n-butylstannyl)furan184
(5.61 g, 15.7 mmol), palladium tetrakis(triphenylphosphine) (546 mg, 0.473 mmol) and
copper (I) bromide (531 mg, 3.70 mmol) in dioxane (60 ml) was heated at reflux for 30
min under argon. Then the reaction mixture was diluted with water (500 ml) and
extracted with ethyl acetate (3 x 60 ml). The combined organic extracts were washed
with water (60 ml), followed by brine (50 ml), dried and evaporated to give a red-brown
residue, which crystallised from dichloromethane-light petroleum to give 2-benzyloxy-
3-(2-furyl)naphthalene-1,4-dione 288 as dark red plates (2.92 g), mp 141 °C (lit.,167
139-140 °C). The mother liquor was concentrated under reduced pressure, adsorbed
onto silica and subjected to silica gel filtration. Elution with 2.5-5% ethyl acetate-light
petroleum gave a further portion of the title naphthoquinone 288 as a bright red solid
(0.825 g, total combined yield 89%). The 1H NMR spectrum was identical with that
described by Slamet.167
2-Benzyloxy-3-(2-furyl)-1,4-dimethoxynaphthalene 290
The procedure described by Slamet was followed.167 A mixture of 2-benzyloxy-3-(2-
furyl)naphthalene-1,4-dione 288 (1.71 g, 5.18 mmol), tetrabutylammonium bromide
(109 mg, 0.295 mmol) and sodium dithionite (2.87 g, 16.5 mmol) in dichloromethane
(45 ml) and water (45 ml) was stirred vigorously under argon. After 30 min the reaction
mixture was treated sequentially with a solution of sodium hydroxide (2.31 g, 57.8
mmol) in water (7 ml) and dimethyl sulfate (3.5 ml, 4.7 g, 37 mmol) and the resulting
solution was left to stir for 17 h. The organic layer was separated and the aqueous layer
was extracted with dichloromethane (2 x 40 ml). The combined organic extracts were
washed with water (40 ml), followed by brine (40 ml), dried and evaporated to give a
157
light brown oil, which was subjected to silica gel filtration. Elution with 2.5% ethyl
acetate-light petroleum gave 2-benzyloxy-3-(2-furyl)-1,4-dimethoxynaphthalene 290
(1.80 g, 96%) as a pale yellow oil. The 1H NMR spectrum was identical with that
described by Slamet.167
3-(2-Furyl)-1,4-dimethoxynaphthalen-2-ol 228
A solution of 2-benzyloxy-3-(2-furyl)-1,4-dimethoxynaphthalene 290 (1.86 g, 5.17
mmol) in ethyl acetate (50 ml) was hydrogenated in the presence of 10% palladium on
carbon (280 mg) until TLC indicated that most of the starting material had been
consumed (ca 3.5 h). The reaction mixture was filtered through a plug of Celite and the
filtrate was evaporated to give a yellow oil, which was subjected to silica gel filtration.
Elution with 3% ethyl acetate-light petroleum returned unreacted starting material (157
mg) as a pale yellow oil. Further elution with 7.5% ethyl acetate afforded 3-(2-furyl)-
1,4-dimethoxynaphthalen-2-ol 228 (1.27 g, 91%) as a yellow oil. δH (200 MHz, CDCl3)
8.11 (1H, d, J 8.4, ArH), 7.99 (1H, d, J 8.4, ArH), 7.65 (1H, d, J 1.8, furyl H) 7.56-7.32
(2H, m, ArH), 7.04 (1H, d, J 3.3, furyl H), 6.64 (1H, dd, J 3.3, 1.8, furyl H), 4.00 (3H, s,
OCH3), 3.78 (3H, s, OCH3). The 1H NMR spectrum of this material was identical to that
recorded for the title compound prepared previously by another method.167
Attempted synthesis of ethyl 3-[3-(2-furyl)-1,4-dimethoxynaphthalen-2-yloxy]propynoate 263 a) n-Butyllithium in hexane (1.6 M, 0.65 ml, 1.0 mmol) was added dropwise to a
stirred solution of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol 228 (261 mg, 0.967 mmol)
in anhydrous tetrahydrofuran (8 ml) cooled in an ice bath under argon. After 5 min the
solution was treated with ethyl 3-bromopropiolate187 (184 mg, 1.04 mmol) in anhydrous
tetrahydrofuran (1 ml), then the ice bath was removed and the reaction mixture was left
to stir at room temperature for a further 22 h. The mixture was diluted with water (80
158
ml) and extracted with dichloromethane (3 x 40 ml). The combined organic extracts
were washed with brine (30 ml), dried and evaporated to give a brown oil, which was
subjected to radial chromatography. Elution with 10% ethyl acetate-light petroleum
returned unreacted starting material (36 mg). Further elution with 20% ethyl acetate-
light petroleum gave ethyl 3-[3-(2-furyl)-1,4-dimethoxy-2-oxo-1,2-dihydronaphthalen-
1-yl]propynoate 294 as a yellow oil (105 mg, 30%, 34% based on recovered starting
material). (Found M+•, 366.1104. C21H18O6 requires 366.1103). Mass spectrum m/z: 366
(M, 51%), 337 (29), 336 (46), 335 (100), 321 (23), 308 (16), 307 (69), 306 (34), 305
(16), 293 (45), 291 (17), 279 (22), 277 (26), 265 (24), 264 (18), 263 (38), 247 (19), 236
(19), 235 (48), 234 (15), 221 (15), 220 (40), 165 (17), 164 (20), 163 (35), 152 (19), 151
(21). δH (300 MHz, CDCl3) 7.90-7.87 (1H, m, ArH), 7.80-7.77 (1H, m, ArH), 7.56-7.45
(3H, m, 2 x ArH, 1 x furyl H), 6.64 (1H, dd, J 3.3, 0.7, furyl H), 6.52 (1H, dd, J 3.3, 1.8,
furyl H), 4.22 (2H, q, J 7.1, CH2), 3.75 (3H, s, OCH3), 3.48 (3H, s, OCH3), 1.28 (3H, t,
J 7.1, CH3). δC (75.5 MHz, CDCl3) 190.7 (C=O), 165.7 (C=O), 152.8 (C), 144.5 (C),
142.6 (CH), 135.4 (C), 131.1 (CH), 129.7 (CH), 128.8 (C), 128.2 (CH), 125.5 (CH),
113.5 (CH), 111.5 (CH), 107.4 (C), 82.3 (C), 79.3 (C), 76.0 (C), 62.3 (CH2), 60.5
(OCH3), 54.5 (OCH3), 13.9 (CH3). vmax (CH2Cl2)/cm-1 1713 (C=O), 1676 (C=O), 2237
(C≡C).
b) A suspension of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol 228 (137 mg, 0.507
mmol), ethyl 3-bromopropiolate187 (93 mg, 0.52 mmol) and potassium carbonate (175
mg,1.27 mmol) in acetone (2.5 ml) was stirred at room temperature for 2.5 h under
argon. TLC analysis indicated that starting material still remained so the reaction
mixture was heated at 40 °C (bath) for 3 h, then allowed to cool to room temperature
and left to stir for a further 16 h. The mixture was diluted with water (40 ml) and
extracted with dichloromethane (3 x 20 ml). The combined organic extracts were
159
washed with brine (20 ml), dried and evaporated to give a brown oil, which was
subjected to radial chromatography. Elution with 2.5% ethyl acetate-light petroleum
gave ethyl 3-hydroxy-6,11-dimethoxybenzo[b]naphtho[2,3-d]furan-2-carboxylate 298
as a white crystalline solid (52 mg, 28%), which recrystallised from dichloromethane-
light petroleum as pale yellow prisms, mp 154-155 °C. (Found M+•, 366.1099. C21H18O6
requires 366.1103). Mass spectrum m/z: 366 (M, 41%), 351(19), 320 (18), 306 (19), 305
(100), 290 (26). δH (500 MHz, CDCl3) 11.55 (1H, s, OH), 8.36-8.34 (1H, m, ArH),
8.23-8.22 (2H, m, ArH), 7.54-7.51 (2H, m, ArH), 7.03 (1H, d, J 8.5, ArH), 4.57 (2H, q,
J 7.2, OCH2), 4.45 (3H, s, OCH3), 4.09 (3H, s, OCH3), 1.56 (3H, t, J 7.2, CH3). δC
(125.75 MHz, CDCl3) 169.7 (C=O), 162.8 (C), 156.2 (C), 143.9 (C), 142.8 (C), 134.9
(C), 129.3 (CH), 126.1 (C), 125.2 (C), 125.1 (CH), 124.7 (CH), 122.4 (CH), 121.4
(CH), 117.2 (C), 115.2 (C), 113.1 (CH), 99.6 (C), 62.0 (OCH2), 61.6 (OCH3), 60.6
(OCH3), 14.2 (CH3). vmax (CH2Cl2)/cm-1 1670 (C=O).
c) A solution of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol 228 (167 mg, 0.618
mmol), ethyl 3-bromopropiolate187 (275 mg, 1.55 mmol) and N-methylmorpholine (30
mg, 0.30 mmol) in anhydrous acetonitrile (2 ml) was stirred at room temperature for 20
h under argon. TLC analysis indicated that starting material was still present so the
reaction mixture was heated at 55-60 ºC (bath) for 4 h, then allowed to cool to room
temperature and left to stir overnight. The mixture was concentrated under reduced
pressure to give a yellow oil, which was subjected to radial chromatography. Elution
with 1% ethyl acetate-light petroleum afforded ethyl 3-hydroxy-6,11-
dimethoxybenzo[b]naphtho[2,3-d]furan-2-carboxylate 298 (8 mg, 4%, 5% based on
recovered starting material) as a white crystalline solid. Further elution with 10% ethyl
acetate-light petroleum returned unreacted starting material (45 mg).
160
Ethyl 5,10-dimethoxyfuro[3,2-b]naphtho[2,3-d]furan-3-carboxylate 304
a) A stirred suspension of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol 228 (193 mg,
0.715 mmol), ethyl 3-bromopropiolate187 (201 mg, 1.14 mmol) and potassium carbonate
(250 mg, 1.80 mmol) in acetone (5 ml) was heated at 40 °C (bath) under argon until
TLC indicated that the starting material had been consumed (ca 3.5 h). The reaction
mixture was filtered through a plug of Celite and washed through with a little acetone.
The filtrate was diluted with toluene (5 ml) and most of the acetone was removed by
distillation. Then the solution was treated with 3,6-di(pyridin-2’-yl)-1,2,4,5-tetrazine
(169 mg, 0.716 mmol) and heated at reflux for 5.5 h under argon. The resulting dark
brown mixture was adsorbed onto silica and subjected to silica gel filtration. Elution
with 1% ethyl acetate-light petroleum gave a number of fractions containing the impure
title compound, which were combined and further subjected to radial chromatography.
Elution with 2.5-5% ethyl acetate-light petroleum gave ethyl 5,10-dimethoxyfuro[3,2-
b]naphtho[2,3-d]furan-3-carboxylate 304 as a pale pink crystalline solid (27 mg, 11%),
which recrystallised from dichloromethane-light petroleum as faint pink needles, mp
199-200 °C. (Found M+•, 340.0936. C19H16O6 requires 340.0947). Mass spectrum m/z:
341 (M + 1, 21%), 340 (M, 87), 326 (31), 325 (100), 297 (65). δH (500 MHz, CDCl3)
8.33-8.31 (1H, m, ArH), 8.28-8.26 (1H, m, ArH), 8.10 (1H, s, furyl H), 7.54-7.47 (2H,
m, ArH), 4.45 (2H, q, J 7.1, CH2), 4.39 (3H, s, OCH3), 4.30 (3H, s, OCH3), 1.45 (3H, t,
J 7.1, CH3). δC (125.75 MHz, CDCl3) 161.3 (C=O), 150.6 (CH, furyl), 148.7 (C), 146.2
(C), 142.3 (C), 141.5 (C), 134.4 (C), 125.6 (CH), 125.3 (C), 124.5 (CH), 123.1 (C),
122.3 (CH), 121.7 (CH), 110.4 (C), 106.0 (C), 61.6 (OCH3), 61.2 (CH2), 59.9 (OCH3),
14.3 (CH3). vmax (CH2Cl2)/cm-1 1724 (C=O).
161
b) A suspension of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol 228 (163 mg, 0.604
mmol), ethyl 3-bromopropiolate187 (190 mg, 1.07 mmol) and cesium carbonate (492
mg, 1.51 mmol) in acetone (4 ml) was stirred at room temperature under argon until
TLC indicated that the starting material had been consumed (ca 45 min). The reaction
mixture was filtered through a plug of Celite and washed through with a little acetone.
The filtrate was diluted with toluene (5 ml) and most of the acetone was removed by
distillation. Then the solution was treated with 3,6-di(pyridin-2’-yl)-1,2,4,5-tetrazine
(152 mg, 0.644 mmol) and heated at reflux for 4 h under argon. The reaction mixture
was filtered through a plug of silica and washed through with 20% ethyl acetate-light
petroleum. The filtrate was evaporated and the resulting residue was subjected to radial
chromatography. Elution with 5% ethyl acetate-light petroleum gave ethyl 5,10-
dimethoxyfuro[3,2-b]naphtho[2,3-d]furan-3-carboxylate 304 as a faint pink solid (8 mg,
4%).
c) Potassium methoxide in anhydrous methanol (0.51 M, 1.8 ml, 0.92 mmol) was
added dropwise to a stirred solution of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol 228
(232 mg, 0.859 mmol) in anhydrous methanol (1 ml) cooled in an ice bath under argon.
After the addition was completed, the ice bath was removed and the reaction mixture
was stirred for 30 min. The mixture was evaporated, then diluted with acetone (2 ml)
and treated with ethyl 3-bromopropiolate187 (230 mg, 1.30 mmol) and potassium
carbonate (301 mg, 2.18 mmol). The resulting suspension was stirred vigorously for 1 h
at room temperature under argon, then filtered through a plug of Celite and washed
through with a little acetone. Toluene (5 ml) was added to the mixture and most of the
acetone was removed by distillation. The mixture was treated with 3,6-di(pyridin-2’-yl)-
1,2,4,5-tetrazine (201 mg, 0.852 mmol) and heated under reflux for 3 h 20 min. The
resulting brown mixture was adsorbed onto silica and subjected to silica gel filtration.
162
Elution with 20% ethyl actetate-light petroleum gave a fraction which was further
subjected to radial chromatography. Elution with 2.5% ethyl actetate-light petroleum
afforded the title compound 304 (3 mg, 1%) as a white solid.
(E)-1,2-Dichloroethenyl 3-(2-furyl)-1,4-dimethoxynaphthalen-2-yl ether 248
The procedure was adapted from that described by Slamet.167 n-Butyllithium in hexane
(1.35 M, 1.2 ml, 1.6 mmol) was added dropwise to a stirred solution of 3-(2-furyl)-1,4-
dimethoxynaphthalen-2-ol 228 (393 mg, 1.46 mmol) in anhydrous tetrahydrofuran (7
ml) cooled in an ice bath under argon. After 10 min the mixture was concentrated under
reduced pressure and the resulting yellow residue was dissolved in dimethylformamide
(10 ml). The reaction mixture was then treated with trichloroethylene (1.74 g, 13.2
mmol) and left to stir overnight under argon. The mixture was diluted with water and
extracted with 50% ether-light petroleum (4 x 50 ml). The combined organic extracts
were washed successively with dilute sodium hydroxide solution and water, dried and
evaporated to give a brown oil, which was subjected to silica gel filtration. Elution with
2% ethyl acetate-light petroleum afforded (E)-1,2-dichloroethenyl 3-(2-furyl)-1,4-
dimethoxynaphthalen-2-yl ether 248 (454 mg, 85%) as a colourless oil. δH (200 MHz,
CDCl3) 8.26-8.09 (2H, m, ArH), 7.63 (1H, dd, J 1.8, 0.8, CH, furyl), 7.61-7.50 (2H, m,
ArH), 6.82 (1H, d, J 0.8, CH, furyl), 6.59 (1H, dd, J 3.4, 1.8, CH, furyl), 5.56 (1H, s,
CH, vinylic), 4.03 (3H, s, CH3), 3.75 (3H, s, CH3). This 1H NMR spectrum is identical
to that described by Slamet.167
163
Attempted synthesis of ethyl 5,10-dimethoxyfuro[3,2-b]naphtho[2,3-d]furan-3-
carboxylate 304 from (E)-1,2-dichloroethenyl 3-(2-furyl)-1,4-
dimethoxynaphthalen-2-yl ether 248
tert-Butyllithium in hexane (0.80 M, 3.85 ml, 3.1 mmol) was added dropwise over 10
min to a stirred solution of (E)-1,2-dichloroethenyl 3-(2-furyl)-1,4-
dimethoxynaphthalen-2-yl ether 248 (391 mg, 1.07 mmol) in anhydrous tetrahydrofuran
(35 ml) at –78 °C under argon. After 35 min ethyl chloroformate (0.70 ml, 794 mg, 7.3
mmol) was added, then the cold bath was removed and the resulting mixture was left to
stir for 50 min. The reaction mixture was diluted with anhydrous toluene (15 ml),
treated with 3,6-di(pyridin-2’-yl)-1,2,4,5-tetrazine (219 mg, 0.928 mmol) and most of
the tetrahydrofuran was removed by distillation. The resulting mixture was heated at
reflux for 5 h under argon, then filtered through a plug of Celite and washed through
with dichloromethane. The filtrate was concentrated under reduced pressure and
subjected to radial chromatography. Elution with 20% ethyl acetate-light petroleum
afforded a yellow solid (257 mg, 47%), which recrystallised from dichloromethane-light
petroleum as colourless rods, mp 131-132 °C. This compound was formulated as either
306 or 307. (Found M+•, 508.0692. C24H22Cl2O8 requires 508.0692). Mass spectrum
m/z: 511 (19%), 510 (68), 509 (27), 508 (M, 100), 475 (29), 474 (32), 473 (77), 472
(38), 457 (21), 429 (15), 427 (34), 409 (17), 357 (18), 353 (37), 327 (18), 325 (21), 313
(20), 281 (16). δH (300 MHz, CDCl3) 8.23-8.11 (2H, m, ArH), 7.65-7.57 (2H, m, ArH),
7.33 (1H, d, J 3.6, CH), 6.94 (1H, d, J 3.6, CH), 4.39 (2H, q, J 7.1, CH2), 4.31 (2H, q, J
7.1, CH2), 4.00 (3H, s, CH3), 3.89 (3H, s, CH3), 1.39 (3H, t, J 7.1, CH3), 1.36 (3H, t, J
7.1, CH3). δC (75.5 MHz, CDCl3) 162.1 (C=O), 158.7 (C=O), 151.7 (C), 149.3 (C),
148.6 (C), 144.7 (C), 144.4 (C), 138.9 (C), 128.8 (C), 128.1 (CH), 127.5 (C), 127.0
(CH), 123.3 (CH), 122.3 (CH), 119.1 (CH), 115. 1 (C), 114. 2 (CH), 103.6 (C), 62.6
164
(OCH3), 62.5 (OCH3), 62.2 (CH2), 61.0 (CH2), 14.3 (CH3), 14.1 (CH3). vmax
(CH2Cl2)/cm-1 1716 (C=O).
Ethyl 5,10-dioxofuro[3,2-b]naphtho[2,3-d]furan-3-carboxylate 311
A solution of ceric ammonium nitrate (149 mg, 0.272 mmol) in water (2 ml) was added
dropwise to a stirred suspension of ethyl 5,10-dimethoxyfuro[3,2-b]naphtho[2,3-
d]furan-3-carboxylate 304 (31 mg, 0.091 mmol) in acetonitrile (2 ml) cooled in an ice
bath under argon. The mixture was stirred vigorously for 10 min, then diluted with
water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic
extracts were washed with brine, dried and evaporated to give a bright yellow solid,
which was subjected to radial chromatography. Elution with 20-50% ethyl actetate-light
petroleum gave the ethyl 5,10-dioxofuro[3,2-b]naphtho[2,3-d]furan-3-carboxylate 311
(14 mg, 50%), which recrystallised from dichloromethane-light petroleum as fine
yellow needles, mp 219-220 °C. (Found M+•, 310.0478. C17H10O6 requires 310.0477).
Mass spectrum m/z: 311 (M + 1, 20%), 310 (M, 100), 282 (33), 265 (33), 238 (20). δH
(300 MHz, CDCl3) 8.33 (1H, s, CH, furyl), 8.27-8.20 (2H, m, ArH), 7.84-7.75 (2H, m,
ArH), 4.44 (2H, q, J 7.1, CH2), 1.43 (3H, t, J 7.1, CH3). δC (75.5 MHz, CDCl3) 178.9
(C=O), 173.5 (C=O), 160.0 (C=O), 156.0 (CH, furyl), 154.3 (C), 149.1 (C), 142.6 (C),
134.3 (CH), 133.9 (CH), 132.2 (C), 132.1 (C), 127.1 (CH), 126.0 (CH), 118.2 (C),
110.5 (C), 61.6 (CH2), 14.2 (CH3). vmax (CH2Cl2)/cm-1 1729 (C=O), 1674 (C=O).
3-Hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione 37
A solution of ethyl 5,10-dioxofuro[3,2-b]naphtho[2,3-d]furan-3-carboxylate 311 (12
mg, 0.039 mmol) in anhydrous tetrahydrofuran (1.5 ml) was added to a suspension of
lithium aluminium hydride (62 mg, 1.6 mmol) in anhydrous tetrahydrofuran (1.5 ml) at
165
0 ºC under argon and the resulting mixture was stirred until TLC indicated that the
starting material had been consumed (ca 20 min). The reaction mixture was quenched
with a little ethyl acetate and ice, then diluted with water (5 ml) and extracted with
chloroform (1 x 3 ml), followed by ethyl acetate (4 x 3 ml). The combined organic
extracts were washed with brine and concentrated under reduced pressure. To the
resulting brown residue was added Fremy’s salt (40 mg, 0.15 mmol), ether (3 ml) and
an aqueous borax buffer solution (0.025 M sodium tetraborate, 2.7 ml; 0.1 M sodium
hydroxide, 1.3 ml) and the resulting mixture was shaken vigorously for 20 min. The
organic layer was separated and the aqueous layer was extracted with chloroform (4 x 3
ml). The combined organic extracts were washed with brine, dried and evaporated to
give a red residue, which was subjected to radial chromatography. Elution with 50-70%
ethyl acetate-light petroleum afforded 3-hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-
5,10-dione 37 as a red solid (5 mg, 49%), mp 204 ºC onwards (sublimed and underwent
crystal phase change), 240-241 °C (melted).(lit.,48 217-218 °C). (Found M+•, 268.0368.
C15H8O5 requires 268.0372). Mass spectrum m/z: 269 (M + 1, 22%), 268 (M, 100), 252
(17). The 1H and 13C NMR spectral data are given in Table 2 (p. 132). vmax (KBr)/cm-1
3485 (OH), 1672 (C=O), 1651 (C=O).
166
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