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Current Organic Chemistry
ISSN: 1385-2728
Current Organic
Chemistry,
Volume 9, Number 15, October 2005
Contents
Recent Progress in Alkaloid Chemistry
Guest Editor: Hans-Joachim Knölker
Editorial Pp.1429
Alkaloid Biosynthesis in Rauvolfia–cDNA Cloning of Major Enzymes of the Ajmaline Pathway Pp.1431
Martin Ruppert, Xueyan Ma & Joachim Stöckigt
[Abstract] [Purchase
Article]
Chemistry of Indole Alkaloids Related to the Corynanthe-Type
from Uncaria, Nauclea and Mitragyna
Plants Pp.1445
Hiromitsu Takayama, Mariko Kitajima & Noriyuki Kogure
[Abstract] [Purchase
Article]
New Strategies for the Synthesis of Monoterpene Indole
Alkaloids Pp.1465
Hans-Jürg Borschberg
[Abstract] [Purchase
Article]
Novel Indole Chemistry in the Synthesis of Heterocycles Pp.1493
Gordon W. Gribble, Mark G. Saulnier, Erin T. Pelkey,
Tara L.S. Kishbaugh, Yanbing Liu, Jun Jiang, Hernando A. Trujillo,
Daniel J. Keavy, Deborah A. Davis, Sam C. Conway, Frank L.
Switzer, Sujata Roy, Richard A. Silva, Judy A. Obaza-Nutaitis,
Mukund P. Sibi, Nikolai V. Moskalev, Timothy C. Barden, Louis
Chang, Wendy M. Habeski (née Simon), Benjamin Pelcman,
William R. Sponholtz, III, Ryan W. Chau, Brett D. Allison,
Sarah D. Garaas, Michael S. Sinha, Meredeth A. McGowan, Matthew
R. Reese & Karen S. Harpp
[Abstract] [Purchase
Article]
Synthesis of Alkaloid Natural Products Using Solid-Supported
Reagents and Scavengers Pp.1521
I. R. Baxendale & S. V. Ley
[Abstract] [Purchase
Article]
Ring-Closing Metathesis as a Construct for the Synthesis
of Polycyclic Alkaloids Pp.1535
Jehrod B. Brenneman & Stephen F. Martin
[Abstract] [Purchase
Article]
Challenge Palau'amine: Current Standings Pp.1551
Delphine E. N. Jacquot & Thomas Lindel
[Abstract] [Purchase
Article]
Pyrroloiminoquinone Alkaloids: Discorhabdins and Makaluvamines Pp.1567
Yu Harayama & Yasuyuki Kita
[Abstract] [Purchase
Article]
Pyrroles and gem-Dihalocyclopropanes as Building
Blocks for Alkaloid Synthesis Pp.1589
Martin G. Banwell, Daniel A. S. Beck, Pauline C. Stanislawski,
Magne O. Sydnes & Rebecca M. Taylor
[Abstract] [Purchase
Article]
Novel Routes to Pyrroles, Indoles and Carbazoles –
Applications in Natural Product Synthesis Pp.1601
Sameer Agarwal, Simon Cämmerer, Salima Filali,
Wolfgang Fröhner, Jan Knöll, Micha P. Krahl, Kethiri
R. Reddy & Hans- Joachim Knölker
[Abstract] [Purchase
Article]
Abstracts
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Editorial
Alkaloid natural products have always been an invaluable
source for the development of novel pharmaceutical drugs.
Till today numerous new lead structures for medicinal chemistry
are being isolated from nature. Over the last century the
chemistry of alkaloids underwent a tremendous evolution. The
present thematic issue of Current Organic Chemistry entitled
Recent Progress in Alkaloid Chemistry emphasizes in ten personal
reviews past-decade achievements in this area. The state of
the art is demonstrated by articles from research teams in
Australia, Germany, Japan, United Kingdom, United States of
America and Switzerland whose research programs are devoted
to alkaloid natural products.
Stöckigt and his group from the University of Mainz
describe the biosynthetic pathway to the monoterpenoid indole
alkaloid ajmaline in the Indian medicinal plant Rauvolfia.
Most of the ten steps from the early precursors tryptamine
and secologanin to ajmaline have been established at the enzyme
level. The article provides a deep insight into the complicated
transformations and mechanisms involved in the biogenesis
of indole alkaloids in higher plants.
In the next chapter Takayama and coworkers from Chiba University
describe their phytochemical as well as synthetic studies
on monoterpenoid indole alkaloids related to the Corynanthe-type
from plants of the genus Uncaria, Nauclea and Mitragyna. The
review points out how biogenetic considerations can lead to
imaginative syntheses and in this respect nicely complements
the preceding one by the Stöckigt group.
Additional new strategies for the synthesis of monoterpenoid
indole alkaloids are described in the contribution of Borschberg
from the ETH Zürich. His research group developed very
elegant stereoselective synthetic routes to structurally highly
complex indole alkaloids of the Aristotelia, Yohimbane, Corynanthe
and Iboga class.
The following articles focus more on synthetic methodologies.
Gribble gives a nice overview on novel synthetic methods for
functionalization of the indole nucleus developed by his group
at Dartmouth College in Hanover (New Hampshire). Lithiation
reactions of indoles, nucleophilic additions to nitroindoles
and Diels-Alder cycloadditions using indole or pyrrole ortho-quinodimethane
analogues represent efficient strategies to important building
blocks useful for alkaloid synthesis.
Ley describes the synthesis of alkaloid natural products
using solid-supported reagents and scavengers. His group in
Cambridge (England) provided significant contributions to
this field. One of the advantages of solid-supported reactions
is the simple separation of products from reagents, thus providing
environmentally cleaner and more efficient reactions. The
presented applications include: tetrahydrobenzylisoquinoline
alkaloids, Amaryllidaceae alkaloids, nicotine and epibatidine.
The synthesis of polycyclic alkaloids by using ring closing
metathesis is reviewed by Martin from the University of Texas
in Austin. Applications of the Grubbs and Schrock carbene
complexes as metathesis catalysts open up the way to highly
efficient total syntheses of a broad range of bridged azabicyclic
and bridged macrocyclic alkaloids including manzamine A, nakadomarin
A and roseophilin. Very impressive is the functional group
tolerance of this method.
Lindel from the University of Munich reports the current
standings in the race to the first total synthesis of the
marine natural product palau'amine. This pyrrole-imidazole
alkaloid constitutes a major challenge for organic synthesis.
Oroidin, another natural product isolated from a marine sponge,
represents the biogenetic key precursor for palau'amine and
is involved in biomimetic approaches. Furthermore, completed
total syntheses of the structurally related alkaloids dibromophakellstatin
and agelastatin A are discussed.
Kita and his group at Osaka University devised efficient
synthetic routes to the discorhabdins and makaluvamines which
represent antitumor active pyrroloiminoquinone alkaloids isolated
from marine sources. The high pharmacological potential of
this class of natural products is reflected by the strong
interest in these compounds. Kita’s article summarizes
different synthetic approaches and biological activities of
the pyrroloiminoquinone derivatives.
In the following account Banwell and coworkers from the Australian
National University in Canberra describe the utility of pyrroles
and gem-dihalocyclopropanes as building blocks for the synthesis
of alkaloids. Applications of the former include for example
the lamellarins, the longamides, aspidospermidine and showdomycin.
The latter are used for approaches to seco-analogues of phenanthroquinolizidine
alkaloids, Amaryllidaceae alkaloids, crinine-type alkaloids,
erythrina alkaloids and hapalindole.
Finally, a review from our own laboratories in Dresden describes
the development of novel routes to pyrroles, indoles and carbazoles.
The common feature of the different synthetic methods is a
key cyclization reaction which is either mediated or catalyzed
by a transition metal (silver, iron or palladium). Applications
of these methods to total synthesis include fused indolizidine
alkaloids, Yohimbane alkaloids, Amaryllidaceae alkaloids and
structurally diverse carbazole alkaloids.
I am grateful to all the authors and coauthors of this thematic
issue for their contributions and efforts. It is desired that
many young researchers and students may use this issue as
a fruitful and stimulating source of recent developments in
alkaloid chemistry.
Hans-Joachim Knölker
Institut für Organische Chemie,
Technische Universität Dresden,
Germany
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Alkaloid Biosynthesis in Rauvolfia–cDNA Cloning of Major Enzymes of the Ajmaline Pathway
Martin Ruppert, Xueyan Ma & Joachim Stöckigt
All the major reactions taking part in the biosynthesis
of ajmaline in cell suspension cultures of the Indian medicinal
plant Rauvolfia have now been established at the
enzyme level. Of the well investigated 10 steps six of the
involved enzymes have been functionally cloned. These are
strictosidine synthase (STR), strictosidine glucosidase (SG),
polyneuridine aldehyde esterase (PNAE), vinorine synthase
(VS), cytochrome P450 reductase (CPR) and acetylajmalan acetylesterase
(AAE). Because the cDNAs of these enzymes are now known their
detailed molecular analysis became attainable for the first
time. Some of these enzymes such as STR, SG or VS could be
produced in E. coli at a preparative scale resulting
in mg amounts of pure enzymes. They also have been crystallized
and their preliminary X-ray analyses were published recently.
It is only a matter of time that their molecular structure
and the mechanisms of the catalyzed reactions will be elucidated.
Of the soluble enzymes vomilenine reductase and 1.2-dihydrovomilenine
reductase remain to be heterologously expressed. Appropriate
cDNA clones have recently been isolated. What membrane bound
enzymes of this pathway is concerned cloning could not be
achieved up to now. Our future strategy is to purify these
enzymes first and to use the “reverse genetic”
approach as we did for the soluble enzymes. The sarpagine
bridge enzyme (SBE), vinorine hydroxylase (VH) and norajmaline
N-methyltransferase (NAMT) are the only enzymes which remain
as the major candidates for expression studies in order to
express heterologously the complete ajmaline biosynthetic
pathway.
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Chemistry of Indole Alkaloids Related to the Corynanthe-Type
from Uncaria, Nauclea and Mitragyna Plants
Hiromitsu Takayama, Mariko Kitajima & Noriyuki Kogure
A number of monoterpenoid indole and oxindole alkaloids
have been isolated from botanical sources, and many of them
have been found to possess significant pharmacological activities
and are utilized as key lead compounds in new drug development.
In this review, the recent results of our phytochemical and
synthetic studies of indole alkaloids having the Corynanthe-type
related skeleton from genera Uncaria, Nauclea, and
Mitragyna, which are classified under tribe Cinchoneae,
family Rubiaceae, are described.
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New Strategies for the Synthesis of Monoterpene Indole
Alkaloids
Hans-Jürg Borschberg
The synthetic efforts of the author’s research team
in several areas within the monoterpene indole alkaloid family
are summarized. Most of the work was accomplished in the field
of the Aristotelia alkaloids, where some 25 natural
products were synthesized for the first time. Systematic investigations
on the oxidative rearrangement of indoles to oxindoles and
pseudoindoxyl derivatives led to control over the chemoselectivity
and stereoselectivity of this process, which served for enantioselective
preparations of the simple alkaloids horsfiline and elacomine.
In addition, recent developments in a novel approach to Iboga
alkaloids containing a hydroxyl group at C(19) are presented.
The key steps involved a self-immolating 1,4-chirality transfer
in an Ireland-Claisen rearrangement and an intramolecular
nitrone-olefin [2+3]-cycloaddition to give the aliphatic isoquinuclidine
core of the target molecules. The first synthesis of (19R)-hydroxyibogamine
was completed by grafting a 3-ethylindole unit onto the aliphatic
nitrogen, followed by closing the 7-membered ring.
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Novel Indole Chemistry in the Synthesis of Heterocycles
Gordon W. Gribble, Mark G. Saulnier, Erin T. Pelkey,
Tara L.S. Kishbaugh, Yanbing Liu, Jun Jiang, Hernando A. Trujillo,
Daniel J. Keavy, Deborah A. Davis, Sam C. Conway, Frank L.
Switzer, Sujata Roy, Richard A. Silva, Judy A. Obaza-Nutaitis,
Mukund P. Sibi, Nikolai V. Moskalev, Timothy C. Barden, Louis
Chang, Wendy M. Habeski (née Simon), Benjamin Pelcman,
William R. Sponholtz, III, Ryan W. Chau, Brett D. Allison,
Sarah D. Garaas, Michael S. Sinha, Meredeth A. McGowan, Matthew
R. Reese & Karen S. Harpp
Indoles that are substituted at the 2- or 3-position with
electron-withdrawing groups (nitro, phenylsulfonyl) undergo
nucleophilic addition, 1,3-dipolar cycloaddition, and Diels-Alder
reactions to give a variety of indoles, pyrroloindoles, and
carbazoles. New methods for the synthesis of furo[3,4-b]indoles
and the novel ring system furo[3,4-b]pyrrole are described
for the first time. Diels-Alder reactions of furo[3,4-b]pyrroles
afford indoles after dehydration of the primary cycloadducts.
Efficient syntheses of both 2- and 3-nitroindoles from indole
are reported, and the first generation and successful electrophilic
trapping of a 2,3-dilithioindole has been achieved.
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Synthesis of Alkaloid Natural Products Using Solid-Supported
Reagents and Scavengers
I. R. Baxendale & S. V. Ley
Supported reagents and scavengers have become key tools
for the synthesis of biologically important molecular entities.
The complexity of the target molecules attainable and the
synthetic flexibility afforded by these systems now rivals
any solution phase approach whilst offering the added advantage
of rapid purification and work-up. This short review highlights
the application of these immobilized reagents to the preparation
of alkaloid natural products.
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Ring-Closing Metathesis as a Construct for the Synthesis
of Polycyclic Alkaloids
Jehrod B. Brenneman & Stephen F. Martin
Molybdenum and ruthenium alkylidene-catalyzed ring-closing
metathesis (RCM) reactions have emerged as key constructs
for the facile assembly of the polycyclic frameworks of a
variety of natural products. Advances in catalyst development,
particularly of highly reactive ruthenium species, have enabled
facile ene-ene and eneyne bond metatheses to create both carbocyclic
and heterocyclic systems, sometimes possessing remarkable
functional and structural complexity in a single operation.
The operational simplicity, ease of handling, and generally
high turnover numbers of the ruthenium-catalysts have brought
RCM reactions to the forefront of practical carbon-carbon
bond forming transformations. Some recent applications of
RCM to the synthesis of alkaloid natural products are reviewed.
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Challenge Palau'amine: Current Standings
Delphine E. N. Jacquot & Thomas Lindel
The marine natural product (–)-palau'amine from the
sponge Stylotella aurantium represents one of the
toughest challenges to total synthesis. It possesses a strained
hexacyclic skeleton which leads current methods of organic
synthesis to their limit. Recently, several research groups
have undertaken independent approaches, focussing on possibly
biomimetic approaches involving the underlying biogenetic
key metabolite oroidin. Oroidin is the parent compound of
the pyrrole-imidazole alkaloids. In this review, recent developments
in the field since 2003 are discussed, outlining progress
on the dimerization of 4(5)-alkenylimidazoles, total syntheses
of non-cyclized pyrrole-imidazole alkaloids, of dibromophakellstatin,
agelastatin, and an update on hymenialdisine. Although palau'amine
has not yet been synthesized, there are original approaches
to the system which have afforded biologically active, smaller
pyrrole-imidazole alkaloids such as dibromophakellstatin and
agelastatin A.
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Pyrroloiminoquinone Alkaloids: Discorhabdins and Makaluvamines
Yu Harayama & Yasuyuki Kita
The pyrroloiminoquinone alkaloid family consisting of discorhabdins
and makaluvamines exhibits antitumor activities derived from
their unique highly-fused structures. The total synthesis
of them and the key reactions used in the total synthesis
of these compounds are described.
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Pyrroles and gem-Dihalocyclopropanes as Building
Blocks for Alkaloid Synthesis
Martin G. Banwell, Daniel A. S. Beck, Pauline C. Stanislawski,
Magne O. Sydnes & Rebecca M. Taylor
Pyrroles and gem-dihalocyclopropanes are both readily
accessible classes of compound. They have considerable potential
as building blocks in the construction of alkaloid frameworks.
This review details work, carried out within the authors'
laboratories, directed towards such ends and with a particular
emphasis on the engagement of the title moieties in intramolecular
processes. An emerging area involving efforts to exploit the
complementary electronic characteristics of pyrroles and gem-dihalogenocyclopropanes
in the synthesis of alkaloids is also discussed.
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Novel Routes to Pyrroles, Indoles and Carbazoles –
Applications in Natural Product Synthesis
Sameer Agarwal, Simon Cämmerer, Salima Filali,
Wolfgang Fröhner, Jan Knöll, Micha P. Krahl, Kethiri
R. Reddy & Hans- Joachim Knölker
Using organometallic chemistry several novel methods for
the efficient construction of pyrroles, indoles, and carbazoles
have been developed. The key reactions are transition metal-mediated
or -catalyzed oxidative cyclizations and cycloadditions. In
the present article we summarize some recent applications
of these methods to short and convergent total syntheses of
naturally occurring biologically active alkaloids including
fused indolizidines, yohimbanes, Amaryllidaceae alkaloids,
and carbazoles. |
