The Alkaloids: Chemistry and Biology 72

604 Pages·2013·23.36 MB·English

by  Hans-Joachim Knölker (Eds.)

VOLUME SEVENTY TWO
T A
he lkAloids
CHEMISTRY AND BIOLOGY
Edited by
HANS-JOACHIM KNÖLKER
Department Chemie
Technische Universität Dresden
Dresden
Germany
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ISBN: 978-0-12-407774-4
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CONTRIBUTORS
Numbers in parentheses indicate the pages on which the author’s contributions begin.
Martín A. Iglesias-Arteaga (153)
Facultad de Química, Universidad Nacional Autónoma de México, México D.F., México
Jacek W. Morzycki (153)
Institute of Chemistry, University of Białystok, Hurtowa, Białystok, Poland
Johann Mulzer (1)
Institute of Organic Chemistry, University of V ienna, Währinger Straße 38, 1090 Vienna,
Austria
Uwe Rinner (1)
Institute of Organic Chemistry, University of V ienna, Währinger Straße 38, 1090 Vienna,
Austria
Peter Siengalewicz (1)
Institute of Organic Chemistry, University of V ienna, Währinger Straße 38, 1090 Vienna,
Austria
vii
PREFACE
Volume 72 of The Alkaloids contains two articles describing recent achieve-
ments in two important classes of alkaloids, Lycopodium Alkaloids ( chapter 1) and
Cephalostatins and Ritterazines (chapter 2).
The Lycopodium Alkaloids represent a classic group of natural products
and thus, they have been covered frequently in this series over the decades:
first, in volume 5 (published in 1955) and volume 7 (1960) in two articles
by the founding editor R.H.F. Manske, then in three articles by D.B.
MacLean in volume 10 (1968), volume 14 (1973), and volume 26 (1985).
W.A. Ayer and L.S. Trifonov summarized this group of alkaloids in volume
45 (1994) and the most recent coverage by J. Kobayashi and H. Morita
appeared in volume 61 published in the year 2005. The present chapter
Lycopodium Alkaloids – Synthetic Highlights and Recent Developments written
by Peter Siengalewicz, Johann Mulzer, and Uwe Rinner from the Univer-
sity of Vienna in Austria describes recent synthetic efforts since the previous
review in this series covering the literature till 2012. Moreover, with high
competence the authors demonstrate in their article the applications of
modern synthetic strategies to this classic group of alkaloids.
In the second chapter, Martín A. Iglesias-Arteaga from the National
Autonomous University of Mexico in Mexico City and Jacek W. Morzycki
from the University of Białystok in Poland summarize recent research in
the area of Cephalostatins and Ritterazines, structurally unique bissteroidal
pyrazine alkaloids which have been identified much more recently. The
cephalostatins were isolated first by Pettit and co-workers in 1988 and the
ritterazines have been described first by Fusetani and his group in 1994. In
this series, cephalostatins and ritterazines so far have been discussed only
briefly by Atta-ur-Rahman and M. I. Choudhary in volume 52 which was
published in 1999. The present article covers the literature till mid 2012 and
summarizes the isolation, synthetic approaches, structure–activity relation-
ships, and physical and spectroscopic data of cephalostatins and ritterazines.
Hans-Joachim Knölker
Technische Universität Dresden, Dresden, Germany
ix
CHAPTER ONE
Lycopodium Alkaloids – Synthetic
Highlights and Recent
Developments
Peter Siengalewicz, Johann Mulzer, Uwe Rinner1
Institute of Organic Chemistry, University of V ienna, Währinger Straße 38, 1090 Vienna, Austria
1Corresponding author: E-mail: [email protected]
Contents
1. I ntroduction 2
2. G eneralBackground 4
3. I solationofLycopodiumAlkaloidsandTheirBiologicalProperties 6
3.1. L ycopodineGroup 6
3.2. F awcettimineGroup 12
3.3. L ycodineGroup 12
3.4. M iscellaneousAlkaloids(PhlegmarineGroup) 12
4. T otalSynthesisofLycopodiumAlkaloids–HistoricAspects 12
4.1. F irstSynthesisoftheLycopodineSkeleton:(±)-12-epi-Lycopodine
(Wiesner,1967) 25
4.2. T heQuestforLycopodine:SynthesesofStorkandAyer,1968 26
4.2.1. (±)-Lycopodine; Heathcock, 1978101 29
4.3. O therHighlightsinLycopodiumSynthesis 31
4.3.1. (±)-Fawcettimine; Heathcock, 1986107,108 31
4.3.2. (±)-Huperzine A; Kozikowski, 1993109–111 32
4.3.3. (−)-Magellanine, (+)-Magellaninone; Overman, 1993113 34
5. T otalSynthesisofLycopodiumAlkaloids–RecentDevelopments 36
5.1. L ycopodineGroup 36
5.1.1. Lycopodine/Clavolonine/Deacetylfawcettiine/Acetylfawcettiine/
7-Hydroxylycopodine 36
5.2. F awcettimineGroup 51
5.2.1. Fawcettimine/Fawcettidine/Lycoposerramine B and C/
Phlegmariurine A/Lycoflexine/Huperzine Q 51
5.2.2. Sieboldine 74
5.2.3. Serratinine/8-Deoxyserratinine/Serratezomine A 80
5.2.4. Lycopladine A/Lycoposerramine R 84
5.2.5. Magellanine/Magellinanone/Paniculatine 91
5.3. L ycodineGroup 96
5.3.1. Lycodine/Complanadine A 96
5.3.2. Huperzine A 103
5.3.3. Huperzine B 108
The Alkaloids, Volume 72 © 2013 Elsevier Inc.
ISSN 1099-4831, http://dx.doi.org/10.1016/B978-0-12-407774-4.00001-7 All rights reserved. 1
2 UweRinneret al.
5.3.4. Fastigiatine 111
5.4. M iscellaneousAlkaloids(PhlegmarineGroup) 114
5.4.1. Cermizine C/Senepodine G 114
5.4.2. Cernuine/Cermizine D 120
5.4.3. Lycoposerramine V/Lycoposerramine W/Lycoposerramine X/Lycoposerramine Z 123
5.4.4. Lyconadin A/Lyconadin B 127
5.4.5. Luciduline/Nankakurine A/Nankakurine B 135
6. C onclusion 143
Acknowledgment 144
References 144
1. INTRODUCTION
The genus Lycopodium comprises nearly 1000 different species,
endemic to temperate and tropical climates, and particularly occurring in
coniferous forests, mountainous areas, and marshlands. Members of this
genus are characterized as flowerless, terrestrial or epiphytic plants with
small needle-like or scale-like leaves, covering stem and branches. Lyco-
pods are fern-like club-mosses, which reproduce either via gametes in an
underground sexual phase, or in an alternating life cycle via spores. These
fascinating organisms have been identified as remnants of prehistoric ferns,
with early fossils dating back as far as 300 million years (late Silurian to early
Devonian period).1–4
In view of the wide distribution of club-mosses, it is no wonder that
various species of this genus have been utilized in traditional folk medicine.
Pliny the Elder reported on a celtic harvesting ritual of selago, most likely
the ancient name of Lycopodium clavatum5:
“Similartosavinistheherbknownas“selago.”Careistakentogatherit
withouttheuseofiron,therighthandbeingpassedforthepurpose
throughtheleftsleeveofthetunic,asthoughthegathererwereinthe
actofcommittingatheft.Theclothingtoomustbewhite,thefeetbare
andwashedclean,andasacrificeofbreadandwinemustbemade
beforegatheringit:itiscarriedalsoinanewnapkin.TheDruidsofGaul
havepretendedthatthisplantshouldbecarriedaboutthepersonas
apreservativeagainstaccidentsofallkinds,andthatthesmokeofitis
extremelygoodforallmaladiesoftheeyes.”5
Hildegard of Bingen knew different recipes and formulas with club-
moss for the treatment of various medical conditions. Skin irritations
and acne were treated with a tea brewed from L. clavatum and couch
LycopodiumAlkaloids–SyntheticHighlightsandRecentDevelopments 3
grass (Agropyron repens L.). A tea from club-moss (L. clavatum), greater
burnet-saxifrage (Pimpinella major), common tormentil (Potentilla erecta),
wormwood (Artemisia absinthium), and dandelion (Taraxacum officinale)
was employed to medicate inflammation of the liver. Other mixtures
for the treatment of nosebleed, irritation of the intestinal tract, and kid-
ney disorders, just to name a few, have been used similarly for hundreds
of years.
Lycopods were highly valued herbal remedies in several early cultures all
over the world. Native American tribes employed L. clavatum in wound care.
Thus, the standard treatment for injuries and lesions was the application of
spores in the open wound. Members of the Blackfoot tribe used Lycopodium
complanatum for the treatment of pulmonary disease, while Iroquois believed
in the ability of the plant to induce pregnancy.6
Today, Lycopodium plants and extracts are not commonly employed as
herbal remedies as the side effects often exceed the benefits. However,
species of the genus Lycopodium have much to offer to different scientific
areas; biologists are fascinated by the fact that lycopods are ancient relicts
dating back to the carboniferous period and grant insight to prehistoric
times.1–4 The isolation of biologically and structurally complex alkaloids
exerts a fascination on phytochemists and rises the question how such
simple plants are able to synthesize such complex and structurally diverg-
ing metabolites. Several medicinally active Lycopodium constituents, the
most notable being huperzine, raise interest among the pharmaceutically
interested community while last, but not the least, synthetic chemists are
intrigued by the challenging structural features of the various alkaloids
isolated from lycopods.
The fascinating area of Lycopodium alkaloids has been summarized on
several occasions,7–10,276 and so far, a total of seven review articles cov-
ering isolation, physiological properties, as well as synthetic approaches
have been published within this series.11–17 This contribution serves as
an update of this area since the last overview article in The Alkaloids by
Kobayashi and Morita in 200517 and covers the literature until December
2011, with the exemption of two syntheses of fawcettimine, which have
been reported in 2012. Key intermediates and key steps are depicted in
blue color for clarity.
The main section of this article is devoted to the discussion of recent syn-
thetic efforts with a brief excursion to early highlights of alkaloid synthesis.
One chapter of this review article summarizes recently isolated L ycopodium
alkaloids along with the reported biological data.
4 UweRinneret al.
2. GENERAL BACKGROUND
The chemical interest in constituents of Lycopodium species started
with the isolation of lycopodine from L. complanatum by Bödeker in 1881.18
Later, Orechoff reported a high alkaloid content in Lycopodium annotinum L.19
The same observation was attested by Muszynski who extended the investi-
gation to three additional Lycopodium species and furthermore reported the
toxic effect of the newly isolated natural compounds on frogs.20
A few years after these findings (1938), Achmatowicz and Uzieblo
investigated constituents of the species L. clavatum and were able to iso-
late lycopodine along with clavatine and clavatoxine.21 A broader study of
Lycopodium species was published by Marion and Manske who were able to
isolate a large number of new alkaloids from various species.22–29
Interest in the isolation, characterization, and biological evaluation of
structurally intriguing alkaloids of the Lycopodium family, as well as eluci-
dation of the biosynthetic pathway, persisted and even increased over the
next decades with Canadian scientists originating from the laboratory of
W. A. Ayer, one of the pioneers of Lycopodium research. Several milestone
achievements are well worth mentioning: In 1967, Wiesner reported the
preparation of 12-epi-lycopodine and was credited with the first synthesis
of the tetracyclic skeleton of this important natural product.30 The seminal
publication preceded the synthesis of lycopodine by only one year as 1968,
Stork31 and Ayer32 completed their routes to lycopodine. All three synthetic
achievements are discussed in a later section of this review article. Many
other syntheses of Lycopodium alkaloids, published since Wiesner’s important
contribution, may well be considered as synthetic and intellectual highlights
and have been discussed in several review articles.
During the 1980s, much effort was devoted to the isolation of new
metabolites, and this effort resulted in the identification of numerous
structurally fascinating natural products. Among the newly characterized
Lycopodium constituents, several ones expressed potent biological properties.
For instance, huperzine A, isolated from Huperzia serrata in 1986,33,34 showed
potent acetylcholinesterase inhibition activity35,36 and as the compound
increased the efficiency for learning and memory in animals, it is discussed
as promising drug candidate for the treatment of Alzheimer’s disease and
myasthenia gravis.37
Only limited information on the biosynthetic pathway of Lycopodium
alkaloids is available as of until recently, cultivation of club-mosses was
impossible. Thus, Spenser and coworkers performed feeding experiments
LycopodiumAlkaloids–SyntheticHighlightsandRecentDevelopments 5
Scheme 1.1 Proposed biosynthetic pathway in the synthesis of Lycopodium alkaloids.
(For color version of this figure, the reader is referred to the online version of this book.)
with 13C- and 14C-labeled substrates and alkaloid precursors with lyco-
pods in their natural habitat and analyzed the alkaloids with respect to
their isotope content. Although no enzymes taking part in the biosynthetic
pathway have been identified with certainty, these studies are extremely
important indications for future investigations.38–43
The proposed biosynthetic pathway is outlined in Scheme 1.1 in
abbreviated form. The route starts with the formation of cadaverine (2)
via decarboxylation of lysine (1). Next, Δ1-piperideine (4) is generated via
5-aminopentanal (3), probably by action of the enzyme diamine oxidase.44
Subsequently, the imine is coupled to acetonedicarboxylic acid (5), or the
corresponding CoA derivative, and converted to pelletierine (7) after decar-
boxylation of the intermediary formed β-ketoester (6). Most likely, pel-
letierine then reacts with (6) and phlegmarine (8), a general intermediate
in the biosynthesis of all Lycopodium alkaloids, is generated. Cyclization of
phlegmarine to the tetracyclic lycodane skeleton (9) sets the stage for the
formation of all structurally diverging alkaloids.
As the main focus of this review article rests on the chemical synthesis
of Lycopodium alkaloids, further discussion of the biosynthesis is omitted.
Detailed information on proposed pathways have been previously reviewed
by Ayer,7,16 MacLean,15 Blumenkopf,45 Hemscheidt,46 and Gang.10
Ayer and Trifonov divided all known Lycopodium alkaloids into four
classes with a prominent alkaloid as lead substance, namely lycopodine (12),
6 UweRinneret al.
H A
H H
D D B O D NH
C B C B
N A H O HO NC A NH A N NC D
H H
(–)-lycopodine (12) (+)-fawcettimine (13) (–)-lycodine (11) (–)-phlegmarine (7)
Figure 1.1 Parent compounds of the four classes of Lycopodium alkaloids as defined by
Ayer and Trifonov. (For color version of this figure, the reader is referred to the online
version of this book.)
fawcettimine (13), lycodine (11), and phlegmarine (7) (outlined in Fig. 1.1).16
While some authors prefer a different system with a larger number of pos-
sible subgroups, the original system as introduced by Ayer is maintained
throughout this article. Noteworthy, the classification and group allocation
of some newly isolated Lycopodium alkaloids is often challenging and not
unambiguous as many products can be interconverted via simple skeletal
rearrangements.
3. ISOLATION OF LYCOPODIUM ALKALOIDS
AND THEIR BIOLOGICAL PROPERTIES
Even after years of intense research, the isolation, characterization,
and biological evaluation of Lycopodium alkaloids remain a fascinating and
prolific research area. Since the last major review article in this field, several
compounds have been isolated and investigated. The following section is
devoted to the discussion of newly isolated natural products and a total of
80 Lycopodium alkaloids are listed, subdivided into the four distinct classes as
described in the previous section.
3.1. Lycopodine Group
An overview of all newly isolated Lycopodium alkaloids of the lycopo-
dine class is provided in Table 1.1. All results depicted in the table were
obtained by Kobayashi and a number of Chinese researchers. None of
the structures outlined in Table 1.1 displayed highly promising biologi-
cal properties; however, several compounds are structurally compel-
ling. Thus, investigation of Lycopodium japonicum and H. serrata revealed
interesting N-oxides, whereas with the isolation of several lannotini-
dines (29–33) from L. annotinum, structurally novel ring systems were
discovered.