Synthesis of lycopodium alkaloids

CHAPTER ONE

Lycopodium Alkaloids – Synthetic
Highlights and Recent
Developments
Peter Siengalewicz, Johann Mulzer, Uwe Rinner1
Institute of Organic Chemistry, University of   Vienna, Währinger Straße 38, 1090 Vienna, Austria
1Corresponding author: E-mail:

Contents
1. Introduction
2. G
 eneral Background
3. Isolation of Lycopodium Alkaloids and Their Biological Properties
3.1. L ycopodine Group
3.2. F awcettimine Group
3.3. L ycodine Group
3.4. M
 iscellaneous Alkaloids (Phlegmarine Group)
4. T otal Synthesis of Lycopodium Alkaloids – Historic Aspects
4.1. F irst Synthesis of the Lycopodine Skeleton: (±)-12-epi-Lycopodine
(Wiesner, 1967)
4.2. T he Quest for Lycopodine: Syntheses of Stork and Ayer, 1968
4.2.1. (±)-Lycopodine; Heathcock, 1978101

4.3. O
 ther Highlights in Lycopodium Synthesis
4.3.1. ( ±)-Fawcettimine; Heathcock, 1986107,108
4.3.2. (±)-Huperzine A; Kozikowski, 1993109–111
4.3.3. (−)-Magellanine, (+)-Magellaninone; Overman, 1993113

5. T otal Synthesis of Lycopodium Alkaloids – Recent Developments
5.1. L ycopodine Group
5.1.1. L ycopodine/Clavolonine/Deacetylfawcettiine/Acetylfawcettiine/
7-Hydroxylycopodine

5.2. F awcettimine Group
5.2.1. F awcettimine/Fawcettidine/Lycoposerramine B and C/
Phlegmariurine A/Lycoflexine/Huperzine Q
5.2.2. Sieboldine
5.2.3. Serratinine/8-Deoxyserratinine/Serratezomine A
5.2.4. Lycopladine A/Lycoposerramine R
5.2.5. Magellanine/Magellinanone/Paniculatine

5.3. L ycodine Group
5.3.1. L ycodine/Complanadine A
5.3.2. Huperzine A
5.3.3. Huperzine B
© 2013 Elsevier Inc.
The Alkaloids, Volume 72
ISSN 1099-4831, All rights reserved.

2
4
6
6
12
12
12
12
25

26
29

31
31
32
34

36
36
36

51
51
74
80
84
91

96
96
103
108

1


2

Uwe Rinner et al.

5.3.4. Fastigiatine

5.4. M
 iscellaneous Alkaloids (Phlegmarine Group)
5.4.1.
5.4.2.
5.4.3.
5.4.4.
5.4.5.

 ermizine C/Senepodine G
C
Cernuine/Cermizine D
Lycoposerramine V/Lycoposerramine W/Lycoposerramine X/Lycoposerramine Z
Lyconadin A/Lyconadin B
Luciduline/Nankakurine A/Nankakurine B

6. C
 onclusion
Acknowledgment
References

111

114
114
120
123
127

135

143
144
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. Lycopods 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:
“Similar to savin is the herb known as “selago.” Care is taken to gather it
without the use of iron, the right hand being passed for the purpose
through the left sleeve of the tunic, as though the gatherer were in the
act of committing a theft. The clothing too must be white, the feet bare
and washed clean, and a sacrifice of bread and wine must be made
before gathering it: it is carried also in a new napkin. The Druids of Gaul
have pretended that this plant should be carried about the person as
a preservative against accidents of all kinds, and that the smoke of it is
extremely good for all maladies of the eyes.”5

Hildegard of Bingen knew different recipes and formulas with clubmoss for the treatment of various medical conditions. Skin irritations
and acne were treated with a tea brewed from L. clavatum and couch


Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

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 kidney 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 diverging 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 covering 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 synthetic 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

Uwe Rinner et 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 investigation 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 isolate 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 elucidation 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


Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

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 lycopods 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 decarboxylation of the intermediary formed β-ketoester (6). Most likely, pelletierine 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

Uwe Rinner et al.

H

H
D
C
N

D
B

A

H

O

(–)-lycopodine (12)

HO

B

O

C
N A

(+)-fawcettimine (13)

C
N
H

A

H

D

N
H

B
A

N

(–)-lycodine (11)

C
D
N
H H

(–)-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 possible 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 lycopodine 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 biological properties; however, several compounds are structurally compelling. Thus, investigation of Lycopodium japonicum and H. serrata revealed
interesting N-oxides, whereas with the isolation of several lannotinidines (29–33) from L. annotinum, structurally novel ring systems were
discovered.


Isolation Origin

Biol. Activity

Lycopodium annotinum

No activity against P388 and L1210
murine leukemia and KB human
epidermoid carcinoma cells

Lannotinidine I (15)47

Lycopodium annotinum

No activity against P388 and L1210
murine leukemia and KB human
epidermoid carcinoma cells

Lannotinidine C (16)48

Lycopodium annotinum

Enhanced NGF mRNA/β-actin in
1321N1 human astrocytoma cells

Lannotinidine D (17)48

Lycopodium annotinum

Enhanced NGF mRNA/β-actin in
1321N1 human astrocytoma cells

Lannotinidine H

(14)47

7

Continued

Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

Table 1.1  Newly isolated alkaloids of the lycopodine subgroup
Structure
Name


(18)49

8

Table 1.1  Newly isolated alkaloids of the lycopodine subgroup—cont’d
Structure
Name
Isolation Origin

Biol. Activity

N/A

Malycorin B (19)50

Lycopodium phlegmaria

N/A

Malycorin C (20)50

Lycopodium phlegmaria

N/A

(12β)-12-Hydroxyhuperzine
G (21)51

Huperzia serrata
Thunb.

N/A
Uwe Rinner et al.

Lycopodium obscurum

Obscurumine B


Huperzia serrata
Thunb.

N/A

Lycopladine E (23)52

Lycopodium complanatum

Enhanced mRNA expressions
for NGF in 1321N1 human
­astrocytoma cells

Miyoshianine C (24)53

Lycopodium japonicum
Thunb.

N/A

N-Oxidehuperzine E (25)54

Huperzia serrata
Thunb.

N/A

N-Oxidehuperzine F (26)54

Huperzia serrata
Thunb.

N/A

Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

(5β,6β,15α)15-Methyllycopodane5,6-diol (22)51

Continued
9


Biol. Activity

Lycopodium obscurum

N/A

Diphaladine A (28)55

Diphasiastrum complanatum

N/A

Lannotinidine J (29)47

Lycopodium annotinum

No activity against P388 and L1210
murine leukemia and KB human
epidermoid carcinoma cells

Lannotinidine A (30)48

Lycopodium annotinum

Enhanced NGF mRNA/β-actin in

1321N1 human astrocytoma cells

Lannotinidine E (31)48

Lycopodium annotinum
var. acrifolium

Enhanced NGF mRNA/β-actin in
1321N1 human astrocytoma cells

Uwe Rinner et al.

Obscurumine A (27)49

10

Table 1.1  Newly isolated alkaloids of the lycopodine subgroup—cont’d
Structure
Name
Isolation Origin


Lycopodium annotinum

Enhanced NGF mRNA/β-actin in
1321N1 human astrocytoma cells

Lannotinidine G (33)48

Lycopodium annotinum

N/A

Complanadine C (34)56

Lycopodium complanatum

Anitmicrobial activity against
Cryptococcus neoformans (Minimal
inhibitory concentration (MIC):
0.26 µg/mL) and Aspergillus niger
(MIC: 4.16 µg/mL)

Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

Lannotinidine F (32)48

11


12

Uwe Rinner et al.

3.2. Fawcettimine Group
A total of 20 alkaloids of the fawcettimine class have been isolated and characterized over the last few years, all of which are displayed in Table 1.2. Again,
the biological activity of these newly isolated natural products is unspectacular
or has not been assessed. Interestingly, although isolated quite recently, several
of the alkaloids shown in Table 1.2 have already been accessed by total synthesis.Thus, lycoposerramine B (36), isolated in 2005 by Takayama,57 was synthesized by Mukai in 2010.58 Lycopladine A (42) was successfully prepared by
Toste (2006),59 Martin (2010),60 and Hiroya (2011),61 whereas the synthesis

of lycoposerramine R (47) was recently reported by Sarpong (2010).62

3.3. Lycodine Group
All newly isolated members of the lycodine group, a total of 14 compounds,
are shown in Table 1.3. Remarkably, these alkaloids originated from two
Lycopodium species, namely L. complanatum and Lycopodium casuarinoides.The
substances depicted in Table 1.3 exhibit great structural variations. While
derivatives of huperzine are relatively simple natural products, complanadine B (57) and E (59) possess a challenging dimeric structure.
Of all compounds shown in Table 1.3, only lycopladine F (55) and G
(56) have been prepared and the total synthesis of these Lycopodium constituents is discussed by Sarpong along with the preparation of complanadine
A, a dimeric alkaloid related to 55 and 56.71

3.4. Miscellaneous Alkaloids (Phlegmarine Group)
An overview of newly discovered Lycopodium alkaloids of the miscellaneous
or phlegmarine group is presented in Table 1.4. The compounds out of this
list synthesized so far are lycoposerramine V (69), W (70), X (71), and Z
(73), all four of them prepared by Takayama,77,78 as well as lyconadin B (85),
which has been prepared by Smith in 2007.79 Nankakurine A (89) and B
(90) have also been successfully synthesized by different workgroups.80,81

4. T
 OTAL SYNTHESIS OF LYCOPODIUM
ALKALOIDS – HISTORIC ASPECTS

The following section highlights milestone achievements in the area of
total synthesis of Lycopodium alkaloids. Although these synthetic contributions
have been previously summarized, a detailed discussion of some syntheses seems


Lycoposerramine A

(35)63

Biol. Activity

Lycopodium serratum Thunb. No effect on the inhibition of
­acetylcholinesterase from bovine
extracts at the concentration of
200 µmol/L

Lycoposerramine B (36)57

Lycopodium serratum Thunb. N/A

Lycoposerramine T (37)64

Lycopodium serratum Thunb. N/A

Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

Table 1.2  Newly isolated alkaloids of the fawcettimine subgroup
Structure
Name
Isolation Origin

N-Methyllycoposerramine T (38)64 Lycopodium serratum Thunb. N/A

13

Continued

Biol. Activity

14

Table 1.2  Newly isolated alkaloids of the fawcettimine subgroup—cont’d
Structure
Name
Isolation Origin

N-Formyllycoposerramine T (39)64 Lycopodium serratum Thunb. N/A

Palhinine cernua

No inhibition of ­acetylcholinesterase
(IC50 > 200 µM), and
­butyrylcholinesterase; no activity
against myelogenous leukemia K562
cells

Lannotinidine B (41)48

Lycopodium annotinum

Enhanced NGF mRNA/β-actin in
1321N1 human astrocytoma cells

Lycopladine A (42)66

Lycopodium complanatum

IC50 = 7 µg/mL against murine
­lymphoma L1210 cells

Lycopladine B (43)67

Lycopodium complanatum

No activity

Uwe Rinner et al.

Palhinine (40)65


Lycopodium complanatum

No activity against murine lymphoma
L1210 cells and human epidermoid
carcinoma KB cells (IC50 > 10 µg/mL)

Lycopladine D (45)67

Lycopodium complanatum

No activity against murine lymphoma
L1210 cells and human epidermoid
carcinoma KB cells (IC50 > 10 µg/mL)

Lycotetrastine A (46)68

Huperzia tetrasticha

Acetylcholinesterase (AchE) with
IC50 = 85 µM

Lycoposerramine R (47)64

Lycopodium serratum Thunb. N/A

Malycorin A (48)50

Lycopodium phlegmaria

N/A

11α-Hydroxyfawcettidine (49)69

Lycopodium serratum

No inhibition of acetylcholinesterase

15

Continued

Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

Lycopladine C (44)67

Biol. Activity

Lycopodium serratum

AChE (IC50 27.9 µm)

8α,11α-Dihydroxyfawcettidine
(51)69

Lycopodium serratum

N/A

2β-Hydroxylycothunine (52)69

Lycopodium serratum

N/A

8α-Hydroxylycothunine (53)69

Lycopodium serratum

No inhibition of acetylcholinesterase

Lycovatine A (54)70

Lycopodium clavatum var.

robustum

Antimicrobial activity against Cryptococcus neoformans (MIC: 0.52 µg/mL) and
Aspergillus niger (MIC: 2.05 µg/mL)

Uwe Rinner et al.

2α,11α-Dihydroxyfawcettidine
(50)69

16

Table 1.2  Newly isolated alkaloids of the fawcettimine subgroup—cont’d
Structure
Name
Isolation Origin


Isolation Origin

Biol. Activity

(55)72

Lycopodium complanatum

N/A

Lycopladine G (56)72

Lycopodium complanatum

N/A

Complanadine B (57)49

Lycopodium complanatum

Enhanced NGF mRNA in 1321N1
human astrocytoma cells

Complanadine D (58)56

Lycopodium complanatum

Enhanced mRNA expression for NGF,
cytotoxic activity against L1210 cells
(IC50: 7 µg/mL), antimicrobial activity against Cryptococcus neoformans
(MIC: 0.52 µg/mL) and Aspergillus
niger (MIC: 2.05 µg/mL)

Lycopladine F

17

Continued

Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

Table 1.3  Newly isolated alkaloids of the lycodine subgroup

Structure
Name


Biol. Activity

Lycopodium complanatum

Enhanced NGF mRNA in 1321N1
human astrocytoma cells (2.8 fold)

Lycoparin A (60)74

Lycopodium casuarinoides

No inhibition of acetylcholinesterase

Lycoparin B (61)74

Lycopodium casuarinoides

No inhibition of acetylcholinesterase

Lycoparin C (62)74

Lycopodium casuarinoides

AChE with IC50 = 25 µM

Carinatumin A (63)75

Lycopodium carinatum

AChE with IC50 = 4.6 µM

Uwe Rinner et al.

Complanadine E (59)73

18

Table 1.3  Newly isolated alkaloids of the lycodine subgroup—cont’d
Structure
Name
Isolation Origin


Lycopodium carinatum

AChE with IC50 = 7.0 µM

Huperzinine N-oxide
(65)76

Lycopodium casuarinoides

N/A

8,15-Dihydrohuperzine
(66)73

Lycopodium complanatum

N/A

Lyconadin D (67)73

Lycopodium complanatum

No enhanced NGF mRNA in 1321N1
human astrocytoma cells

Lyconadin E (68)73

Lycopodium complanatum

No enhanced NGF mRNA in 1321N1
human astrocytoma cells

Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

Carinatumin B (64)75

19


Biol. Activity

Lycoposerramine V (69)77

Lycopodium serratum

N/A

Lycoposerramine W (70)77

Lycopodium serratum

N/A

Lycoposerramine X (71)82

Lycopodium serratum

N/A

Lycoposerramine Y (72)82

Lycopodium serratum

N/A

Lycoposerramine Z (73)82

Lycopodium serratum

N/A

Uwe Rinner et al.

Isolation Origin

20

Table 1.4  Newly isolated alkaloids of the phlegmarine subgroup
Structure
Name


Lycopodium carinatum

No inhibition of acetylcholinesterase (IC50 > 100 µM)

Huperzine J (75)82,83

Huperzia serrata, Lycopodium
serratum

N/A

Huperzine K (76)82,83

Huperzia serrata, Lycopodium
serratum

N/A

Huperzine M (77)84

Huperzia serrata

N/A

Huperzine N (78)84

Huperzia serrata

N/A

Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

Carinatumin C (74)75

21

Continued


Biol. Activity

Serratezomine D (79)85

Lycopodium serratum var.
­serratum

AChE with IC50 = 0.6 mM

Serratezomine E (80)85

Lycopodium serratum var.

­serratum

N/A

Lycochinine A (81)86

Lycopodium chinense

No activity against human blood
premyelocytic leukemia

Lycochinine B (82)86

Lycopodium chinense

No activity against human blood
premyelocytic leukemia

22

Table 1.4  Newly isolated alkaloids of the phlegmarine subgroup—cont’d
Structure
Name
Isolation Origin

Uwe Rinner et al.


Lycopodium chinense

Cytotoxicity against human
blood premyelotic leukemia
(HL-60, 46% inhibition at
100 µM)

Lycopladine H (84)87

Lycopodium complanatum

Lyconadin B (85)67

Lycopodium complanatum

No activity against L1210
murine leukemia and KB
human epidermoid carcinoma
cells (IC50 > 50 µg/mL)
Enhanced NGF mRNA in
1321N1 human astrocytoma
cells

Lyconadin C (86)88

Lycopodium complanatum

N/A

Lyconadin F (87)88

Lycopodium complanatum

N/A

Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

Lycochinine C (83)86

Continued
23


(88)89

Biol. Activity

AChE with IC50 = 90.3 µM
and anti-HIV-1 activity with
EC50 = 85 µg/mL

Nankakurine A (89)90,91

Lycopodium hamiltonii

Induced secretion of neurotropic
factors (1321N1 cells) and
promote neuronal differentiation of PC-12 cells

Nankakurine B (90)91

Lycopodium hamiltonii

N/A

Lycoperine A (91)92

Lycopodium hamiltonii

AChE with IC50 = 60.9 µM

Cryptadine A (92)93

Lycopodium cryptomerinum

AChE with IC50 = 106.3 µM

Cryptadine B (93)93

Lycopodium cryptomerinum

AChE with IC50 = 18.5 µM

Uwe Rinner et al.

Lycopodium japonicum

Lycojapodine A

24

Table 1.4  Newly isolated alkaloids of the phlegmarine subgroup—cont’d

Structure
Name
Isolation Origin


Lycopodium Alkaloids – Synthetic Highlights and Recent Developments

25

Scheme 1.2  Wiesner’s synthesis of (±)-12-epi-lycopodine [(±)-104]. (For color version of
this figure, the reader is referred to the online version of this book.)

appropriate in order to illustrate the development in this area and to appreciate
the scientific value and impact of these early accomplishments.The study of early
synthetic contributions appears even more striking when considering the limited
repertoire of synthetic procedures available to chemists only few decades ago.

4.1. F
 irst Synthesis of the Lycopodine Skeleton:
(±)-12-epi-Lycopodine (Wiesner, 1967)
In 1967, Wiesner reported the synthesis of 12-epi-lycopodine (104).30
With this seminal publication, the Wiesner group achieved the first synthesis of the lycopodine ring system. The epimer of the natural product
was first described by Ayer,94 who obtained the unnatural alkaloid together
with lycopodine (12) upon catalytic hydrogenation of anhydrolycodoline.
Wiesner’s synthesis of 12-epi-lycopodine is outlined in Scheme 1.2.