The Alkaloids: Chemistry and Biology 71

298 Pages·2012·7.29 MB·English

by  Hans-Joachim Knölker (Eds.)

THE ALKALOIDS
Chemistry and Biology
71
VOLUME
Edited by
HANS-JOACHIM KNÖLKER
Department Chemie
Technische Universität Dresden
Dresden
Germany
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ISBN: 978-0-12-398282-7
ISSN: 1099-4831
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CONTRIBUTORS
Numbers in parentheses indicate the pages on which the author’s
contributions begin.
Gordon W. Gribble (1), Department of Chemistry, Dartmouth College,
Hanover, New Hampshire, USA
Karl-Heinz van Pée (167), Department Chemie und Lebensmittelchemie,
Technische Universität Dresden, Dresden, Germany
Walter Vetter (211), Institute of Food Chemistry, University of Hohenheim,
Stuttgart, Germany
vii
PREFACE
From time to time, we will publish thematic volumes within this series
in order to emphasize developments in very important areas of alkaloid
chemistry and biology from different perspectives presented by different
authors. The present volume of The Alkaloids is such a thematic volume
which is devoted to halogenated alkaloids and covers the subject in three
chapters.
In the first chapter, Gordon W. Gribble from Dartmouth College in
Hanover (New Hampshire, USA), one of the leading researchers in this
field, describes the Occurrence of Halogenated Alkaloids. About a quarter
of the more than 5000 halogenated natural compounds known today
are alkaloids which have been mostly isolated from marine organisms.
The present chapter represents the first comprehensive summary of this
rapidly growing class of compounds which appears in The Alkaloids. In a
highly systematic treatise the halogenated alkaloids are classified follow-
ing their different heterocyclic frameworks: pyrrolizidines, indolizidines,
pyrroles, indoles, carbazoles, indolocarbazoles, carbolines, quinolines,
and other nitrogen heterocycles. Moreover, the final section summarizes
the occurrence of halogenated tyrosines. Marine bromotyrosine deriva-
tives have been discussed previously in this series by Peng, Li, and
Hamann in volume 61 (published in 2005) covering the literature till 2003.
Thus, bromotyrosines are presented as an update considering the work
published since then.
The second chapter by Karl-Heinz van Pée from the Chemistry Depart-
ment of the Technische Universität Dresden (Germany) provides a deep
insight into the Biosynthesis of Halogenated Alkaloids. The first sections show
how and at which stage of the heterocyclic framework formation (pyrroles,
indoles, and indolocarbazoles) the halogen atoms are being introduced. In
a further section, it is demonstrated that introduction of new halogenase
genes into alkaloid producing bacterial strains leads to the formation of
new halogenated alkaloids due to pathway modification. The final section
takes a close look at the halogenating enzymes actually involved in the
biosynthesis of alkaloids and describes their mode of action supported by
protein crystal structure determination.
The third chapter by Walter Vetter from the Institute of Food Chemis-
try of the University of Hohenheim (Germany) shows the potential impact
these compounds may have on our daily life by describing Polyhalogenated
Alkaloids in Environmental and Food Samples. The classes of compounds
ix
x        Preface
under discussion are: polyhalogenated 2,2’-bipyrroles, polyhalogenated
1,2’-bipyrroles, polybrominated pyrroles, and brominated indoles. More-
over, the problems and the techniques for identification and quantification
of polyhalogenated alkaloids in the environment and in food samples are
discussed in detail. Further sections briefly summarize physicochemical
properties and biological activities of polyhalogenated alkaloids.
Hans-Joachim Knölker
Technische Universität Dresden,
Dresden, Germany
1
CHAPTER
Occurrence of Halogenated
Alkaloids
Gordon W. Gribble*
Contents I. Introduction 1
II. Occurrence 2
A. Pyrrolizidine, Indolizidine, and Related Alkaloids 2
B. Pyrroles 6
C. Indoles 38
D. Carbazoles 87
E. Indolocarbazoles 88
F. Carbolines 89
G. Quinolines and Other Nitrogen Heterocycles 99
H. Tyrosines 111
III. Summary 141
References 142
I. INTRODUCTION
This review is an outgrowth of two previous comprehensive surveys by
the present author of all known naturally occurring organohalogen com-
pounds.1,2 Coverage in the present review is limited to halogenated alka-
loids. With the exception of halogenated tyrosines, which were expertly
covered by Peng et al. in this series in 2005,3 the present review attempts
full coverage of halogenated alkaloids. It should be noted that halogenated
amino acids and their derivatives and miscellaneous nitrogen-containing
metabolites that are generally considered not to be alkaloids (e.g., macro-
lides, tetracyclines, enediynes, malyngamides) are not treated in this review.
Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA.
*Corresponding author.
E-mail address: [email protected]
The Alkaloids, Volume 71 © 2012 Elsevier Inc.
ISSN 1099-4831, http://dx.doi.org/10.1016/B978-0-12-398282-7.00001-1 All rights reserved.
1
2 Gordon W. Gribble
II. OCCURRENCE
A. Pyrrolizidine, Indolizidine, and Related Alkaloids
A small group of chlorine-containing pyrrolizidine alkaloids seem to be
the first examples of halogenated alkaloids of any type to be identified
(Figure 1). Thus, jaconine (1) was isolated from Senecio jacobaea in 1937.4–9
Cl
Cl H HO R OH
OH
O O
HO
O O
O O O O
H H
N N
1 R = H (jaconine) 2
9 R = OH (18-hydroxyjaconine) (chlorodeoxysceleratine)
Cl Cl
AcO OH
O O
HO HO
O O
O O O O
O H
N N
+
Me O
3 (doronine) 4
(merenskine N-oxide)
Cl
HO Cl NHAc
HO Me
O O N
O O H N O N
O HO H O
N 6 (lolidine)
5 O OH
Cl
OH Cl
N
Cl HN
N O
N
NH
Cl
7 -OH (clazamycin A)
10
8 -OH (clazamycin B)
(oxypterine)
11
(5-chlorobohemamine C)
Figure 1 Chlorinated pyrrolizidine and related alkaloids 1–11.
Occurrence of Halogenated Alkaloids 3
This plant, “tansy ragwort,” is highly toxic to cattle and other livestock, as
are other Senecio sp. plants.10,11 Other members of these pyrrolizidine and
related chlorohydrins are chlorodeoxysceleratine (2) (Senecio sceleratus),12
doronine (3) (Doronicum macrophyllum),13 merenskine N-oxide (4) (Senecio
latifolius),14 alkaloid 5 (Cryptantha clevelandii and C. leiocarpa),15 lolidine
(6) (Lolium cuneatum),16 and clazamycins A (7) and B (8) (Streptomyces
sp.).17,18 A new addition to this group is 18-hydroxyjaconine (9) (Senecio
selloi).19 Jaconine was also isolated from Senecio alpinus,20 and doronine
was found in S. clevelandii21 and S. abrotanifolius.22 The most implausible
structure 10 was put forth for oxypterine (Lotononis oxytera),23 which, if
correct, is a “ring-opened” pyrrolizidine. “Antibiotic 354” from cultures
of Streptomyces pumiceus subsp. doliceus seems to be identical with claza-
mycin B (8).24 A marine cultured Streptomyces sp. has furnished the chlo-
rohydrin 5-chlorobohemamine C (11), which was demonstrated not to be
an isolation artifact.25
Several organochlorine plant alkaloids of the hasubanan type are known,
characterized by the prototypes acutumine (12), acutumidine (13), and acu-
tuminine (14), which were initially isolated from Sinomenium acutum and
Menispermum dauricum26–30 and later from M. canadense31 (Figure 2). The cor-
responding epimers, dauricumine (15) and dauricumidine (16), were found
in M. dauricum.32 Clolimalongine (17) is present in Limacia oblonga,33 and
2-O-demethylacutumine (18) was isolated from Sinomenium acutum.34 The
OMe OMe
R2 OH
Cl Cl
O
O
N R1 NR
O OMe O OMe
OMe OMe
12 R = Me, R = OH (acutumine)
1 2
13 R = H, R = OH (acutumidine) 15 R = Me (dauricumine)
1 2
14 R = Me, R = H (acutuminine) 16 R = H (dauricumidine)
1 2
OH NEt
2
OH
OH
Cl
MeO Cl Cl
O
O
O
NH NMe NMe
O OMe O OMe O OMe
OMe OMe OMe
17 (clolimalongine) 18 (2-O-demethylacutumine) 19 (hypserpanine A)
Figure 2 Chlorinated hasubanan type alkaloids 12–19.
4 Gordon W. Gribble
diethylamino analog of dauricumine, hypserpanine A (19) was characterized
in the Chinese medicinal herb Hypserpa nitida Miers. (Menispermaceae).35
The saturated 1H-pyrrolo[2,1-j]quinoline ring system is present
in cylindricine A (20), in equilibrium with cylindricine B (21), both of
which are found in the Tasmanian ascidian Clavelina cylindrical36 (Figure
3). These novel alkaloids are in equilibrium via an aziridinium ion in a
well-known process.37 These biologically active halichlorine (22), from
the black marine sponge Halichondria okadai,38,39 and pinnaic acid (23) and
tauropinnaic acid (23), from the bivalve Pinna muricata,40 have received
intense synthetic interest and led to both confirmation and revision of the
original structures.41,42 A new member of the halichlorine family is pinna-
rine (25) from Halichondria okadi.43 The Chinese medicinal plant Hyperzia
serrata contains 2-chlorohyperzine E (26).44
A culture of Aspergillus fischeri var. thermomutatus produces CJ-12662
(27) and UK-88051 (28)45 (Figure 4). The Ecuadorian poison frog Epipe-
dobates anthonyi ( = Epipedobates tricolor = Dendrobates tricolor) contains
O O
H
N N
Cl
Cl
20 (cylindricine A) 21 (cylindricine B)
H
R
O N O HN
O
Cl
Cl
OH HO OH
22 (halichlorine) 23 R = OH (pinnaic acid)
24 R = NHCH CH SO H (tauropinnaic acid)
2 2 3
O HN O
O
N OH
Cl OH Cl
25 (pinnarine) 26 (2-chlorohyperzine E)
Figure 3 Chlorinated pyridoquinoline and related alkaloids 20–26.
Occurrence of Halogenated Alkaloids 5
the remarkably active epibatidine (29)46,47 along with phantasmidine
(30) and N-methylepibatidine (31).48 The story of epibatidine has been
reviewed.49–52
The first chromone to be discovered in a marine invertebrate is tubas-
traine (32), which is found in the stony coral Tubastraea microantha53
(Figure 5). This organism is able to thwart attack by the destructive
Crown-of-Thorns sea star, perhaps because of tubastraine. The soil fungus
O O
HO H H H
HO HO
O O
NH NH
AcO
Cl N O Cl N O
Me Me
27 (CJ-12662) 28 (UK-88051)
R N Cl O N Cl
N
H
HN
H
29 R = H (epibatidine)
31 R = Me (N-methylepibatidine) 30 (phantasmidine)
Figure 4 Chlorinated alkaloids 27–31.
OH O
O
O O
O
Br Br
O
N
Me
32 (tubastraine)
OMe
OH O Cl
Cl O OMe
MeO Y OH
O
X N
H
MeO N OH N O
O
H
33 X = H, Y = Cl (WF-16775 A1) OH
34 X = Y = Cl (WF-16775 A )
2 36 (trichodermamide B)
35 X = Cl, Y = H (NBR123477 A)
Figure 5 Halogenated alkaloids 32–36.