Rigorous Biogenetic Network for a Group of Indole …alkaloids derived from secologanin and...
Transcript of Rigorous Biogenetic Network for a Group of Indole …alkaloids derived from secologanin and...
Molecules 2008, 13, 1875-1896; DOI: 10.3390/molecules13081875
molecules ISSN 1420-3049
www.mdpi.org/molecules
Review
Rigorous Biogenetic Network for a Group of Indole Alkaloids Derived from Strictosidine†
László F. Szabó
Department of Organic Chemistry, Semmelweis University, Hőgyes utca 7, H-1092 Budapest, Hungary; E-mail: [email protected]
† Chemotaxonomy of Indole Alkaloids, Part 5 (for Part 4, see [15]). This paper is dedicated to Prof. Heinz G. O. Becker on the occasion of his 85th birthday.
Received: 5 August 2008; in revised form: 24 August 2008 / Accepted: 26 August 2008 / Published: 27 August 2008
Abstract: Strictosidine, the precursor of more than 2,500 indole alkaloids, was isolated from four species of three plant families. By searching the Dictionary of Natural Products on DVD it was found that about 150 indole alkaloids were obtained from the same species (coalkaloids), which is a direct proof of their common origin. On the base of their three-dimensional structure, taxonomic properties and standard reaction mechanisms an extended network was established which involved the four fundamental skeletons, the three types of carbon framework in the secologanin subunit and all major groups of indole alkaloids derived from secologanin and tryptamine (except a few minor groups, in which only less then 10 alkaloids were known). The system was extended to the heterodimer indole alkaloids and the quinoindole alkaloids as well.
Keywords: Secologanin, coalkaloid, dimer alkaloid, reaction mechanism, computer searching, chemotaxonomy.
Introduction The monoterpenoid indole alkaloids form a uniform group of natural products. Several generations
of researchers have worked on their isolation, structure determination, chemical transformations and synthesis. Much effort has also gone into elucidating their biogenesis, and as a consequence, the main
OPEN ACCESS
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pathways of their formation are already known [1-4]. However, the applied methods consume much time, material and human energy. In addition, it is often dubious if the postulated in vitro or biomimetic reactions really take place in vivo [5]. There is a certain gap between the level of the biological micromolecules (alkaloids) and macromolecules (enzymes and genes), and it is difficult to follow the processes on the micromolecular level. Although a large amount of knowledge has been accumulated concerning the starting steps and the formation of some key compounds [6-8], many questions are still unanswered at the more remote points and in special groups.
Recently, specialized data bases and their electronic searching features have offered an alternative tool for chemotaxonomic studies. The fact that more than 2,500 indole alkaloids were isolated mainly from three plant families (Rubiaceae/Naucleaceae RUB, Loganiaceae/Strychnaceae LOG and Apocynaceae APO) and formed from two building blocks [secologanin (1) and tryptamine (2) or tryptophane] through a single precursor [strictosidine (3)] suggested a strong coherence in this collection of alkaloids. Compounds isolated from the same cells, species, genera and/or families in parallel and/or consecutive reactions may be guideposts in their genesis, and in cases where highly reactive or sensitive intermediates cannot be isolated in intact form from biological sources, they can be postulated according to standard organic reaction mechanisms. The rich collections of structural, physical, chemical and taxonomic data effectively contribute to such an approach. It seems, therefore, that the isolated compounds themselves could give a more realistic basis and complementary method for these studies.
Our previous work in the chemistry of secologanine and especially of strictosidine provided good starting points [9-10]. The internal consistance was further supported by the mechanism of chirality transfer at C-15 and C-3 in the type I class of indole alkaloids, and some stereoselectivity could be demonstrated even in the type II and III classes as well [11, 12]. Extended biogenetic networks could be established by studies in the large group of type I alkaloids [13] and in the small but highly specific group of Melodinus alkaloids [14]. In addition, a long evolutionary line was constructed for the formation of ellipticine from ajmalicine (corynanthean skeleton) and an analogous line postulated for olivacine from isodihydrocadambine (malindan skeleton) [15].
In this paper we look for those indole alkaloids which have a direct chemotaxonomic contact with strictosidine, the primary precursor of indole alkaloids. In this relation two main questions were to be answered:
1. Compounds isolated from the same species reveal their common origin. Which alkaloids could be isolated from those plant species which produce also strictosidine (3)? In other terms: which are the “coalkaloids” of this universal precursor of indole alkaloids?
2. The monomer components necessarily coexist in the same species, from which the dimer alkaloids were isolated. This fact likewise reveals chemotaxonomic connections among the individual alkaloids and species. Which types of monomer components are connected in the dimers?
As the reaction mechnisms were already discussed previously or will be so in the future, they are mentioned in this paper only briefly and schematically, however, the chemotaxonomic connections are analyzed in detail.
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Scheme 1. The Coupling Reaction.
1
2
34
56
7 8
9
10
11 OH3CO
O
H
O
O
H O
OHOH
OHHO
1
2
5 6
“trioxo aglikon”
16
NHN
H3CO
O
OH H HH
OH
17
2021
1 4
22
18
19
“primer aglikon”
NHN
OH3CO
O
OHH H HH
tryptamine
glc = β-D-glucopyranosylsecologanin ISS38
Strychnos nux vomica LOGLonicera xylosteum APO
1
910
11
12 1332
45
678
14
15
1617
1819
2021
22
NHN
OH3CO
O
OglcH H HH
3 3α-H, strictosidine CCF30
4 3β-H, vincoside CCK08 Vinca rosea APO
Anthocephalus cadamba RUB
Rhazya stricta APOCatharanthus roseus APOStrychnos mellodora LOG
αβ
NH2N
H
H
II. III.
3 2114
15
16 1718
1920
22
type I skeleton
3 2114
1819
22
151716 20
type II skeleton
21 314
1520
1819
171622
type III skeleton
Compounds Tested in the Coupling Reaction in the Presence of Strictosidine Synthase
only reactions involving secologanin, 8,10-dihydro secologanin and tryptamine w ere catalyzed by strictosidine synthaseand the product w ith 3S conf iguration w as formed exclusively
2-oxo-2,3-dihydro-tryptamine
secologanin~ tetraacetyl~ 8,10-dihydro~ tetraacetyl,
8,10-dihydro
1
7-hydoxy-N-methyl-bakankozin~ 8,10-dihydro
N(a)-methyl tryptamineN(b)-methyl tryptamineN(b)-benzyl tryptamine
tryptamine
2 23
N NH2
HO
7
810
ON
O
Ogkc
HH
Me
HO
The necessary structural, chemical and taxonomic data were taken from the database Dictionary of
Natural Products on DVD Version 16.2 (in the following DNP) [16], and completed occasionally with data from the Beilstein Crossfire and the Chemical Abstracts online data bases. In the structural formulas and throughout the text, the biogenetic numbering system shown in formula of strictosidine (3) was used [17]. The only exceptions are the building blocks 1 and 2, which are numbered as indicated in their own formulas. All isolated compounds in the schemes and in Table 1 were provided with Chapman and Hall (C&H) code numbers, which give access to the rich primary literature sources. The figures giving the numbers of alkaloids in the different taxons are approximative and in several cases only estimations, as they are changed by the continuous renewal of the database and depend on the selection principles used as well. The Biogenetic-type System of Indole Alkaloids
In this work the indole alkaloids natural products are considered, which are formed from
secologanine (1) and tryptamine (2) (or tryptophan). However, even within this field certain limitations had to be applied.
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Scheme 2. System of Indole Alkaloids Derived from Secologanin.
N
N2
721
1716
22
19
20
18
3
14
15
21
3
1819
20
14
15
N
N
H16
1722
N
N
H
N
N
22
1716
314
15
21
7
2019
18
β2
N Nα2
321
22 1617 14
15
7
20
19
18
17
N
Nβ72
22 16
21
20
19 18
3
14
15
N
N
21
16 17
22
31415
18
19
2072
β
N Nα2
321
22 1617
14
15
7
20
1918
N N
N
N
H
2
321
1516
22 17
14
2019
18β 714
20
19
18
72
321
22 17
1615
β
N
N
H
910
1 4
N N
H
3
22
15
16 17
2
7
2019
18
21α
5
68
13
11
12
14
N N
H
vincosan
>1000 alkaloidsRUB, LOG, APO
including cyclovincosans
ibogan
84 alkaloidsAPO
isoibogan
5 alkaloidsLOG
plumeran
340 alkaloiidsAPO
eburnan
56 alkaloidsAPO
stemmadenine derivativeAPO
4 alkaloids
14 alkaloids
isoplumeranAPO
8 alkaloidsAPO
isoeburnan
aspidospermatan
28 alkaloidsAPO
I αI β S I β A
II α
II β
II III
III α
III β- HX
(RUB), LOG, APOstrychnan
530 alkaloids
type II skeleton
3 21
14
18
1922 151716 20
21 3
1415
20
181917
16
22
type III skeleton
II. III.
3 2114
15
16 1718
1920
22
type I skeleton
1517
N
N21
22 1614
2 2019 18
β7 3
APO7 alkaloids
secodine derivative
In the “quinoindole” alkaloids group (about 100 isolated natural products), the original indole
subunit is extended into a quinoline subunit during the biosynthesis. They are dispersed among all three plant families mentioned above, as well as in some additional ones. Their special groups are the camptothecan (in the Icacinaceae and Nyssaceae families), as well as the cinchonan and melodan alkaloids. In another group of alkaloids derived from secologanin, the heterocyclic base in the coupling reaction is a substituted phenylethyl amine and provides the isoquinoline ring system which was found in some 90 isolated natural products (“Ipecacuanha” alkaloids) mainly in the Rubiaceae and Alangiaceae families. The problem of the quinoindole alkaloids will be discussed briefly, and the group of the Ipecacuanha alkaloids temporarily disregarded.
Previously, the system of indole alkaloids was based mainly on formal, structural properties of the individual compounds [18, 19]. For our purposes, a chemically and biologically oriented system was constructed [11] which is shown in Scheme 2 with slight modifications. It is based on the following principles:
level 0: formation of strictosidine (3) from secologanin and tryptamine and removal of the glucosyl subunit (Scheme 1);
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level 1: cyclization of the secologanin subunit to N-1 or/and N-4 of the tryptamine subunit (Scheme 2 shows only cyclizations to N-4); level 2: in the secologanin subunit, transformation of the type I skeleton into the type II and type III ones (Scheme 1); level 3: attachment of C-3 or C-21 or neither of them to C-2 (α) or C-7 (β) position of the the indole ring; level 4: further cyclizations between the secologanin and the tryptamine subunits; level 5: further cyclizations inside the secologanin subunit; level 6: further transformations (e.g. rearrangements, ring extensions and ring contractions; fragmentation of the tryptamine side chain, formation of sesqui- and dimers, which are temporarily omitted).
The system is shown in Scheme 2 up to level 4. It has an internal consistancy and predictive power, hard in principles, but soft for accomodating any existing or new alkaloid. The Main Precursor Strictosidine
The precursor of most indole alkaloids is strictosidine (3), having S configuration at C-3 (Scheme
1). Its formation from secologanin and tryptamine is catalyzed by the enzyme strictosidine synthase. Both the chemo- and stereoselectivities of the enzyme are high in vitro (i.e. under cell-free conditions). It was demonstrated [20], that of the components shown in Scheme 1 only the 8,10-dihydro derivative of 1 (of course over 1 and 2) can participate in the coupling reaction, and no trace of vincoside (4) (with 3R configuration) was formed. In the absence of the enzyme the reaction is much slower, and neither chemically, nor stereochemically selective [9a]. The complete stereoselectivity is remarkable, because strictosidine synthase was isolated both from Catharanthus roseus [21] and Rauwolfia serpentina [22]. From the first species strictosidine (3) with 3S and vincoside (4) with 3R configuration were isolated, and from the second species ajmaline (GQZ67) with 3S and reserpine (CFD56) with 3R configuration. This raises the obvious question, what is the source of the 3R chirality in the species mentioned above? The answer is not known yet.
The S chirality of C-15 in both compounds comes from the C-5 center of secologanin. Most of the type I alkaloids having a bridged skeleton with participation of C-15 (e.g. the akuammidan, akuammilan, pleiocarpaman, strychnan and aspidospermatan alkaloids) have S configuration at C-3, which suggests that their precursor is strictosidine, and the formation of the bridge is possible only with the cis orientation of the hydrogens attached to C-3 and C-15 [11a]. However, in a limited number of alkaloids with fused skeleta, the configuration at C-3 is R. The cause of it is likewise unknown.
Strictosidine (like vincoside) belongs to the type I α alkaloids, i.e. it contains the secologanin subunit in its unrearranged form, and its C-3 is attached to the α-position of the indole ring (vincosan skeleton 7 in Scheme 3). The biosynthetic power of strictosidine is mainly revealed after deglucosylation. The primarily formed aglucone 5 cannot be isolated, as it undergoes many types of isomerizations (which are represented in the trioxo form 6 in Scheme 1) [23]. Subsequent cyclizations and further transformations provide a high number of type I α alkaloids, whose formation was discussed previously [13].
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Scheme 3. Primary Cyclizations of Vincosan.
N N
H
α
1821 19
16
4 17
20
22
1αN N
H22 17
20
18419
21
16
1N N
H
α
16
21 1918
N N
H
4 22
17
20
N N
H
10
7 5
N N
H
H H
18
19
20
21
161722
α
15
NN
H
αβ
20
12
3
45
678
910
11
1213
1415
1617
1819
21
22
NN
O
OglcH HH
H3CO2C
OH
H
1819
2021
2216
17
N N
CO2Me
OHC
H
H H
18
1920
21
16
17
2222
1617
20
1918
NN
OO
MeO
H
H
H
H21
22
16
17
N N
OH
H H
Oglc
O
212019
18
RUB, LOG, APO
vallesiachotaman24 alkaloids
RUB, LOG, APO
malindan38 alkaloids
RUB, LOG, APO
corynanthean~1000 alkaloids
The Primary Skeletons (Cyclovincosans)
Representatives of the Primary Skeletons
RUB, LOG, APO44 alkaloidsvincosaman
7
8 9 11
12 13 14 15
vallesiachotamine CCH53Rhazya stricta APO
Vallesia dichotoma APO
isodihydrocadambine GPX51Anthocephalus cadamba RUB
geissoschizine CDP34Rhazya stricta APO
Tabernamontana tetrastachya APO
strictosamide GPX64Rhazya stricta APO
Nauclea latifolia APO
RUB, LOG, APO53 alkaloids
vincosan, I α alkaloid
Strictosidine was isolated from four plant species (in this paper they are called “strictogenic
species”) ranked into three plant families (Anthocephalus cadamba, Rubiaceae, Strychnos mellodora, Loganiaceae, Catharanthus roseus (=Vinca rosea; the two names are considered as synonyms, and in this paper mainly the first name is used) and Rhazya stricta, Apocynaceae). The next step in the further molecular evolution of strictosidine is the primary cyclization between the nucleophilic N-4 center and one of the four electrophilic centers (C-17, C-19, C-21 and C-22) of the secologanin subunit, which gives the vallesiachotaman, malindan, corynanthean and vincosaman skeletons 8-11, respectively (primary “azacyclizations”). These “cyclovincosan” skeletons and their probable first representatives (12, 13, 14, and 15) are shown in Scheme 3. During the biosynthesis, some structural elements (mainly C-17 or C-22) may be lost (“truncated” alkaloids). Analogous cyclizations also take place with participation of N-1, and gives nearly 100 alkaloids, however, they will not be discussed in this paper.
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Coalkaloids of Strictosidine in Type I α Class Fortunately, coalkaloids resulting from all four types of azacyclizations were found in the
strictogenic species, as is shown in Schemes 3 and 4, as well as in Table 1. Azacyclization to C-22 corresponds to a simple (often spontaneous) lactamization. The group of the vincosaman alkaloids, 11, is rather homogenous, and contains nearly 50 alkaloids, among others strictosamide (15) from the strictogenic Strychnos mellodora (Loganiaceae), and its C-3 epimer vincosamide from Adina rubescens (Rubiaceae), found as glucosides.
Scheme 4. Further Representatives of the Malindan and Vallesiachotaman Skeletons.
N N
H
HH
HO18
21 19
16
17
20
NN
N
HH 20 21
1819
N N
O
H H
H
MeO2C Oglc
O
2021
19
18N N
O
H H
H
MeO2C Oglc
OHH
2021
19
18
vallesiachotaman
anthirine natural form CGV97 Rhazya stricta APO
malindan
normalindine LCQ52Strychnos johnsonii LOG
16 17 18 19
isomalindan
dihydrocadambine GPX71Anthocephalus cadamba RUB
Nauclea latifolia RUBNauclea diderrichii RUB
isomalindan
cadambine CFJ83Anthocephalus cadamba RUB
Nauclea latifolia RUB
Azacyclization to C-19 (Scheme 4) results in the formation of the malindan skeleton 9. It can take place likewise on the glycosidic level, after activation of C-19 of the vinyl group, e.g. by epoxidation. This activation is known in secologanin chemistry [24], and is suggested in the present case by the hydroxy group at C-18 of isodihydrocadambine (13). The corresponding glycoside was isolated from the strictogenic Anthocephalus cadamba, Rubiaceae. The six-membered ring D of the fused cyclic system might be extended into a seven-membered azepin ring (20(19→18)-abeo-) (isomalindan skeleton), which was supported by isolation of dihydrocadambine (16) and cadambine (17) from the same species (Scheme 4). The (iso)malindan skeleton appears in more than 40 alkaloids (e.g. normalindine, 18), partially also on higher levels and even at the end of the molecular evolution, in the derivatives of olivacine (66) (Scheme 12).
Table 1. Coalkaloids of Strictosidine (parent name, number of derivatives, C&H number, type of skeleton).
Anthocephalus cadamba (RUB) (8 alkaloids) Rhazya stricta (APO) (50 alkaloids) Cadambine, CFJ 83, isomalindan Akuammicine deriv. GNP98, strychnan Cadamine, 2 derivs. HFP34, GZM28, malindan Akuammidine CGS53, akuammidan Dihydrocadambine, 2 derivs. GPX71, GPX73, isomalindan Akuammiline deriv. CGS78, akuammilan Isodihydrocadambine, 2 derivs. GPX51, GPX53, malindan Anthirine deriv. CGV97, anthiran Strictosidine, CCF30, vincosan Aspidospermidine 2 derivs. NSG56, NGX40, plumeran Bharhingine GRD15, strychnan Catharanthus roseus (= Vinca Rosea) (APO) (49 alkaloids) Burnamine deriv. CGP15, akuammilan
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Table 1. Cont. Ajmalicine deriv. BFV84 (VR), GNX93, corynanthean Decarboxymethoxytetrahydrosecodine deriv NQD29
secodan Ajmalicine hydroxyindolenine deriv. GNX49, corynanthean Dihydrocorynantheol deriv. GNZ33, corynanthean Akuammicine deriv. CGS34, strychnan Dihydroeburnamenine LCR84, eburnan Akuammiline deriv. LTT85, akuammilan Eburenine 2 derivs. GZP25, LNJ42, plumeran Alioline, OSQ04, ibogan Geissoschizine CDP34, corynanthean Alstonine 2 derivs. GNX52 (VR), CCC44, corynanthean Isorhazicine BQR50, secoajmalan Apparicine (S)-form, CGW23, vallesaman Isositsirikine 4 derivs. LCS06, CCW87, NBV19, NBV18,
corynanthean Bannucine CQG04, plumeran Lanceomigine deriv. CHL97, akuammilan Catharanthine CFM58 ibogan (VR) Leuconolam NNZ31, plumeran Fluorocarpamine indoxyl deriv. GRG17 pleiocarpaman Nor-C-fluorocurarine deriv. HHZ45, strychnan Isositsirikine 3 derivs. CCW78 (VR), CCW86, CCW87, corynanthean
Quebrachamine deriv. CFB72, plumeran
Lochneridine BQS00 (VR) strychnan Rhazidigenine hydroxyindolenine 2 derivs. CFF52, CFF54, plumeran
Perivine 2 derivs. CGN81 (VR), CGN86 (VR), vobasan Rhazimine 2 (quinoline) derivs. CFK02, CFK05, FYL18, akuammilan
Preakuammicine CGQ70 (VR), strychnan Rhazinaline 2 derivs. CDR88, NXF68, akuammilan Rosicine CFK07, plumeran/isoplumeran Rhazinilam 2 derivs. GPF00, FNO12, plumeran Sarpagin deriv BCC19 (VR) akuammidan Rhazizine LDC76, strychnan Sitsirikine 2 derivs. HJQ31 (VR), BCF50 (VR), corynanthean
Secodine 2 derivs. CHM24, BFV95, secodan
Strictamine deriv. CFF61, akuammilan Stemmadenine CCD41, strychnan/aspidospermatan Strictosidine CCF30 (+VR), vincosan Strictamine 3 derivs. HHT53, CDR79, BFY65, akuammilanStrictosidine 2 derivs. CCK08 (VR), CCK10 (VR) Strictanine BQS42, plumeran Tabersonine 2 derivs. GQZ42, HJQ42 (VR), plumeran Stricticine GRD24, GRG17, plumeran Talpinine deriv. GQW95, akuammidan Strictine GRD25, pleiocarpaman Tombozine deriv. GRC35 (+VR), akuammidan Strictosamide GPX64, vincosaman Venalstonine deriv. CCH72, plumeran Strictosidine CCF30, vincosan Vincadifformine deriv. CCJ46 (VR), plumeran Vallesiachotamine 3 derivs. CCH54, CCH55, LXQ87,
anthiran Vincarodine GNK80, eburnan Vincadifformine 3 derivs. HBN54, LHX61, CCJ49,
plumeran Vincoline CCK01 (VR), plumeran Vincamajine deriv. LJB72, akuammidan Vindolidine 5 derivs. KLJ88 (+VR), JHQ68, JRJ50 GQZ38 GQZ39, plumeran
Vindolinine 4 derivs. BQX53 (+VR), MVY20, BQX56, BQX57, plumeran
Strychnos mellodora (LOG) (5 alkaloids)
Voalutein indoxyl deriv. CFK06, ibogan Lyaloside 2 derivs. GVY09, GVY10, vincosan (VR) indicates alkaloids isolated (also) from Vinca rosea Strictosidine CCF30, vincosan Strictosidine 2 derivs. LHX56, MTN39, vincosan
After deglucosylation, the other two previously masked electrophilic centers will be free, and the
azacyclizations involving C-17 and C-21, respectively, can take place. Azacyclization to C-17
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provides the vallesiachotaman skeleton 8, with nearly 25 compounds, in the majority of which C-22 is lost during the biosynthesis (i.e. .in the anthirine derivatives). Both vallesiachotamine (12) and anthirine (19), the characteristic alkaloids of this group, were isolated from the strictogenic Catharanthus roseus (Apocynaceae). If C-17 (in vallesiachotaman) or C-22 (in vincosaman) was removed during the biogenetic process, the two “truncated” skeletons 8 and 11 became formally (but not biogenetically) indentical.
Scheme 5. Further Cyclic Systems Derived from the Corynanthean Skeleton.
2.
2.
5
3
7
1819
2021
N N
MeO2CO
H
H15
1617
22
αβ
N
NH
HMeO2C OH
2 16
3
7
1722
N N
Me02CH O
H
OH
H
H3
217
2015
1617
NN
MeO2C
H
H
4
2114
2019
O
18
3
15
1
16
NN
MeO2C
HH
OH22
16 4
6
2
17
15
5
NN
MeO2C CHO
H
72
3
15
16
22 17
4
N N
MeO2CO
H
HH H
3
7
1819
2021
N N
MeO2CO
H
HH H
3
7
1819
2021
N
OMeO2C
H
H
H7
N
O
H
3
N
OMeO2C
H
H
H2
7N
O
H
3
20
21 2223
24b
24d
25
2624c
akuammidine CGS53Rhazya stricta APO
Vinca rosea APOakuammidan
strychnan deriv. I β
preakuammicine CGQ70Vinca rosea APO
N N
HO
HO
MeO2C
3
14
1516
17
22
20
akuammilanRhazya stricta APORhazinaline CRD88
GNX49
corynanthean
ajmalicine hydroxyindolenine
Catharanthus roseus APO
abeoN1(16→17) pleiocarpaman
apogeissoschizine2,7-dihydro, 2α,7α-dihydroxy MTM06
Strychnos gossweileri APO
25a
24
GNX79
corynanthean
ajmalicine, 19,20-diepimer
Rauwolfia nitida APOUncaria elliptica RUB
rauniticine oxindole AGQX05
Uncaria elliptica RUBoxindole deriv. I βpseudoindoxyl deriv.
Uncaria elliptica RUB
rauniticine pseudoindoxylGRG13
pleiocarpamanRhazya stricta APO
strictine GRD25
corynanthean
ajmalicine BFV84 Vinca rosea APO
alstonine GNX52Vinca rosea APO
Strychnos gossweileri LOGRauwolfia nitida APO
corynanthean
1.
2.
2.
3.
3.
1. primary coalkaloid2. secondary coalkaloid
3. tertiary coalkaloid
N N
H
H H
OH
910
1 43
15
1617
2
7
2019
18
21
5
68
13
11
12
14
N
NH
HO
O
Me4
1
5
6
78
910
11
1213
2 3
14 1518
1920
21
16
17
N
N
H H17
12
3
45
71415
16
18
19
20
21
8
910
11
12 13
11
N N
O
HO
1 23 4
56
78
910
12 13
1415
1617
22
1819
20
21
27 28 29 30
dihydrocorynantheol (-)-formGNZ33
Rhazya stricta APOAspidosperma marcgravianum APO
corynanthean I α
dihydroquinidine
Aspidosperma marcgravianum APORemijia pedunculata APO
cinchonan I α
CFC07Catharanthus roseus APOErvatamia heyneana APO
apparicine (S)-form
vallesaman I β
CGW23
Camptotheca acuminata APOErvatamia heyneana APO
camptothecin (S)-form
camptothecan I α
CFK59
Molecules 2008, 13
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N-4 azacyclization to C-21 gives the corynanthean skeleton 10, which was found in nearly a thousand compounds, and provides the largest subclass of indole alkaloids. One of its first representatives is geissoschizine (14). Some additional characteristic structures are shown in Scheme 5. There are two main sources of the great variability of the corynanthean alkaloids: “secondary” cyclizations and oxidations.
The central element of the additional cyclizations is C-16 and mainly directed to C-5, C-7 or N-1. In the first case the akuammidan (including also the ajmalan skeleton), in the second the akuammilan, and in the third the pleicarpaman skeletons are formed. They are represented in Scheme 5 by akuammidine (21), rhazinaline (22) and strictine (23), respectively; all were isolated from the strictogenic Rhazya stricta and are primary coalkaloids of strictosidine. A typical compound in this evolutionary line is ajmalicine (20), isolated from the likewise strictogenic Vinca rosea. From this species several other ajmalicine derivatives were obtained. One of them is alstonine (24), a stereoisomer of ajmalicine (20), in which, however, ring C is aromatized. Fortunately, 24 was also isolated from Rauwolfia nitida and Strychnos gossweileri, and according to this fact, it may be a biogenetic link in the pathway towards the oxidized derivatives of the corynanthean skeleton.
From Strychnos gossweileri a dihydroxy derivative 24a of the unnatural apogeissoschizine could be obtained, which is a secondary coalkaloid of strictosidine. Its skeleton may be considered a 1(16→17)-abeo-derivative of the pleiocarpaman skeleton in 23. In Rauwolfia nitida a further ajmalicine stereoisomer 24b, likewise a secondary coalkaloid, was found, which was isolated from Uncaria elliptica as well. This last species, which belongs already to the Rubiaceae family, also provided the two main representatives of the pseudoindoxyl and the oxindole alkaloids, rauniticine pseudoindoxyl (24c) and rauniticine oxindole A (24d), respectively, both of which are tertiary coalkaloids. As it is shown, there are grades in the coalkaloid relation depending on the number of species concerning the parent and the derived compounds in each case. when the name “coalkaloid” is used without qualification (secondary, etc.), they are considered as primary coalkaloids, i. e. isolated from one common species.
Finally, ajmalicine hydroxyindolenine (25), a fourth variant of the oxidized I α alkaloids was isolated from the tissue culture of strictogenic Catharanthus roseus. Its main importance is shown in its formula: according to the electron stream indicated by curved arrows in the formula of 25, C-3 can be shifted from C-2 (indole α-position) to C-7 (indole β-position) and simultaneously (or subsequently) C-16 attached to C-2, i.e. a type I α alkaloid could be transformed into a type I β alkaloid. After a potential reduction of the formyl group, the first representative of the strychnan alkaloids, preakuammicine (26) would be formed similarly in Catharanthus roseus. It is clear that already the type I oxindole alkaloids should be considered as type I β compounds because C-3 is attached to C-7 (β-position of the indole ring) in them. It is also known that the oxindole, pseudoindoxyl and hydroxyindolenine derivatives were found in the type II and type III alkaloids as well. The oxidative processes shown above were carried out also under in vitro conditions [25-27]. The chemical mechanisms of the cyclizations and the formation of the oxidative derivatives were discussed previously [13a]. In addition, the last line of Scheme 5 shows that this analysis could even be extended to the two important subgroups of the “quinoindole alkaloids”. Both dihydrocorynantheol (-)-form 27 and apparicine (S)-form 29 were isolated from strictogenic species (primary coalkaloids from Rhazya stricta and Catharanthus roseus, respectively). The first, 27, was obtained also from
Molecules 2008, 13
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Aspidosperma marcgravianum which provided also dihydroquinidine (28, cinchonan skeleton), the other, 29, was found also in Ervatamia heyneana, together with camptothecine (S)-form (30, camptothecan skeleton), consequently both 28 and 30 are secondary coalkaloids of strictosidine.
Of course, the coexistance of these alkaloids (in Scheme 5 and elsewhere) in the given species does not mean that they are formed immediately one from other, but more probably from some common precursors which, however, were not found in natural sources, perhaps because of their high reactivity. As a final conclusion, it should be remarked, that of the four primary azacyclizations only the malindan and the corynanthean skeletons may be transformed into the type I β structure. Coalkaloids of Strictosidine in Type I β Class
The three main subclasses of the type I β alkaloids are the type I oxindoles (e. g. 24d, Scheme 5),
the strychnan (I β S) (34) and the aspidospermatan (I β A) (35) alkaloids (Scheme 6). The strychnan group 34 is rather uniform and its alkaloids (together with the type I oxindole alkaloids) number nearly 400. Several coalkaloids of strictosidine were found among them. The small group (less than 30 compounds) of the aspidospermatan alkaloids 35 is likewise uniform, but has no coalkaloid of strictosidine 3 and only indirect chemotaxonomic connections to it. Therefore it is of high importance that the formation of the aspidospermatan alkaloids (I β A) is biogenetically strongly related to that of the strychnan alkaloids (I β S), as is shown in the formulas and family tree of Scheme 6.
Scheme 6. Chemotaxonomic Interrelations between Strychnan and Aspidospermatan Alkaloids.
Family tree of the main representatives of the strychnan and aspidospermatan alkaloids
preakuammicine precondylocarpine
akuammicine condylocarpine
Catharanthus roseus Rhazya stricta
Strychnos angolensis
Vallesia dichotoma
Diplorhynchus condylocarpon
stemmadenine
vallesiachotamine
strictosidine
26 31 32 33
34 3536 37
18
56
16
14
321
15
19 20
N
N
HH
MeO2C OH
H
H
stemmedenine-A+stemmedenine-S+
+ H+
- H+-H+,+H+
-H+,+H+ + H+- H+
14
1
456
8
910
11
12 13 20
19
18
N
N
H
H72
3
21
17
16
15β
(22)
N
N
H
H2
3
21
1516
17
14
201918
β 7
(22)
21
7
OH
N
NH
HMeO2C
+ H2O
16
56
213
18
19
20
14
15
N
N
HH
MeO2C
H
OH
H
3
7
OH
N
NH
HMeO2C
N
NH
HH
CO2Me
N
NH
HH
CO2Mecondylocarpine CFR40
Diplorhynchus condylocarpon Strychnos angolensis
preakuammicine CGQ70Vinca rosea
precondylocarpine CHJ55Vallesia dichotoma
4 alkaloidshypothetic monoseco derivatives
akuammicine CGS34Catharanthus roseusStrychnos angolensis
530 alkaloids LOG, APOstrychnan (I β S)
28 alkaloids APOaspidospermatan (I β A)
Molecules 2008, 13
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In the formula of preakuammicine (26) curved arrows show the electron stream in the N-4→N-1 direction, which is increased by protonation. The result may be the cleavage of the C-3–C-7 bond and the formation of the charged monoseco structure stemmadenine-S+ (31), which can be tautomerized by deprotonation–reprotonation to give stemmadenine-A+ (32). In these intermediates the tryptamine and secologanin subunits can be turned around one another along the C-5–C-6 bond and around C-16, consequently in a further proton-catalyzed step, the C-7 center can be reclosed either to the original C-3 in 31 or to the alternative C-21 center in 32, as the centers are in analogous positions. In this latter case, after deprotonation, precondylocarpine 33 (aspidospermatan skeleton) can be formed. Preakuammicine (26) and precondylocarpine (33) are structural isomers formed by simple rotation and without any change of chirality at C-15. Although the charged stemmadenine-S+ (31) and stemmadenine-A+ (32) are hypothetic monoseco intermediates, some of their reduced derivatives (e. g. stemmadenine, 38) were found in the strictogenic Rhazya stricta (and other species as well).
There is a tight chemotaxonomic connection between these structural and stereoisomers. Preakuammicine (26) from Catharanthus roseus is a primary coalkaloid of strictosidine, unlike precondylocarpin (33), which could be isolated only from the non-strictogenic Vallesia dichotoma. However, from this species vallesiachotamine was likewise isolated which could be obtained from Rhazya stricta as well. The chemotaxonomic relation is further supported in the case of the analogous pair akuammicine (36, strychnan) and condylocarpine (37, aspidospermatan), which are in the same structural and stereoisomeric relation as their precursors 26 and 33, and both were isolated from Strychnos angolensis. Akuammicine (36) was directly obtained also from the strictogenic Catharanthus roseus. On the other line the contact is indirect: condylocarpine (37) was isolated from Diplorhynchus condylocarpon producing also stemmadenine (38), which was isolated from Rhazya stricta (and from several other species as well). In the family tree it can easily be recognized that preakuammicine and akuammicine are primary, and precondylocarpine and condylocarpin secondary coalkaloids of strictosidine; in addition, preakuammicine and akuammicine, as well as akuammicine and condylocarpine, are primary, while precondylocarpine and condylocarpine are tertiary coalkaloids of each other.
Tautomeric stemmadenine-S+ (31) and stemmadenine-A+ (32) may be starting points in the formation of those indole alkaloids in which the ethylene side chain of the tryptamine subunit is partially or completely absent (vallesaman, ulean, ellipticen and olivacen skeletons). In these groups until now only a single coalkaloid, apparicine (29, Scheme 5) was found, however, by detailed analysis some indirect chemotaxonomic relations could be demonstrated. Moreover, of the azacyclized skeletons 8–11 only the malindan and the corynanthean skeletons 9 and 11 can undergo this degradation, as is proved by isolation of both olivacine (66) and ellipticine (65), respectively (Scheme 12). But details of this work are already beyond the limits of the present paper [13b].
The Central Role of Stemmadenine and Secodine Derivatives
Now, the molecular evolution of the indole alkaloids is arrived at an important phase which is
shown in Schemes 7 and 8. In the charged tautomeric structures 31 and 32 shown in Scheme 7, ocurrence of a further fragmentation (shown again by curved arrows) is possible, which probably requires activation at C-17 either by enzyme or by acetylation. The possible fragmentation would
Molecules 2008, 13
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involve the cleavage of bond C-15–C-16 (“strategic bond”) by which the bisseco tautomeric and charged structures secodine-S+ (39) and secodine-A+ (40) could be formed. This bond can really be cleaved under mild abiotic conditions by proton or base catalysis in simple vincoside derivatives [9b] or even in secologanin derivatives as well [28]. In the charged structures 39 and 40 extended conjugated systems are present, from which neutral tautomeric secodine-S (41) and secodine-A (42) can be formed. Though all these structures are again hypothetic intermediates, some alkaloids stabilized by hydrogenation were isolated from natural sources [e.g. 16,17-dihydrosecodine (43) from Rhazya stricta].
Scheme 7. Central Role of Stemmadenine and Secodine Derivatives.
17
18
56
16
14
321
15
19 20
N
N
H MeO2C OHH22
17
16
56
213
18
19
20
14
15
N
N
HH
MeO2C OH
H
stemmedenine-A+stemmedenine-S+
-H+,+H+
-H+,+H+
4 alkaloidshypothetic monoseco derivatives
31 32
22
2021
1716
22
1918
3
1415
N
N
OHMeO
-H+,+H+
-H+,+H+ 42 41
2021
1716
22
19
18
31415
N
N
MeO OH
-H+,+H+
-H+,+H+39
2021
1716
22
19
18
3
1415
N
N
MeO OH
H
40
2021
1716
22
1918
3
1415
N
N
OHMeO
HN
N
HH
MeO2C OH
16
56
213
18
19
20
14
15
1722
N
N
MeO2CH
20
21
171622 19
18
3
14
15
456
7
21
- H- H
secodine-A+secodine-S+
- H2O - H2O
stemmadenine CCD41Rhazya stricta APO
Diplorhynchus condylocarpon APOsecodine, 16,17-dihydro CHM 24
Rhazya stricta
-H+,+H+
-H+,+H+
7 alkaloidshypothetic bisseco derivatives
secodine-S secodine-A
38 43
Scheme 8. Formation of Type II and Type III Alkaloids.
2021
1514
3
1617
N
N
OH
OMe
1
4
N
N
MeO2CH22
16
1415
220
β7
17
314
1520
21
1617
N
N
OH
OMe
22
16
20
21
3
14
157
17N
N
OH
OMe
H
22
16
2021
3
14
157
17N
N
OH
OMe
H
2222
C-14→C-17C-16→C-21
C-20→C-17C-16→C-3
1
4
17
N
N
MeO2C
H
β7
222
1620
3
14
15
+ H+, - H+ + H+, - H+ + H+, - H+ + H+, - H+
ibogan (II)84 alkaloids APO
isoibogan (III)5 alkaloids LOG
secodine-A secodine-S'
C-20→C-17C-7→C-21
C-14→C-17C-7→C-3
1
4
N
N
CO2MeH
21
1617
22
14
152072
β1
4
N
N
CO2MeH 22
17
16
314
15
7
20
β2
secodine-S secodine-A'plumeran (III β)
340 alkaloids APO
21
41
42
42'
41'
44 45
4647
14 alkaloids APOisoplumeran (II β)
isoeburnan (II α)8 alkaloids APO
eburnan (III α)56 alkaloids APO
-H+,+H+
-H+,+H+
-H+,+H+
-H+,+H+
Molecules 2008, 13
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In the structures of neutral conformer pairs secodine-S 41=41’ and secodine-A 42=42’ (Scheme 8) strongly polarized conjugated double bond systems are preformed, which may formally undergo four types of Diels–Alder reactions, as indicated by curved arrows in Scheme 8. In these cyclizations the isoplumeran (type II β), plumeran (type III β), isoibogan (type III) and ibogan (type II) skeletons 44-47can be formed. The details of these possible transformations were previously analyzed [11b]. Here it should be noted only that in some alkaloids of the new, rearranged type II and type III skeletons the double bonds (indicated by black lines) are conserved or formed just in the positions which are required by the hypothetical Diels–Alder reactions. It should also be mentioned that in the synthetic work by G. Kalaus, C. Szántay et al. for preparation of pandoline-like molecules, detailed quantum chemical calculations supported the two-step character of an analogous transformation [29].
In alkaloids having the isoplumeran (II β) or plumeran (III β) skeletons 44 and 45, C-7 (β position in the indole ring) has a covalent bond to C-3 or C-21, respectively. This bond can be shifted to the α- position of the indole ring (arrows in the formulas) and give in several steps the eburnan (III α) and isoeburnan (II α) alkaloids (see in Scheme 2), respectively. This would be the last phase in the molecular evolution of the indole alkaloids. Finally, it should be emphasized that the transition from the type I to the type II/III class of indole alkaloids is possible only in the evolution line of the corynanthean skeleton. Coalkaloids of Strictosidine in Type II and Type III Classes
In alkaloids which are formed after rearrangement of the original (type I) carbon skeleton of
secologanin subunit into the type II and type III ones, the number of coalkaloids is strongly reduced, however several of them were found. The isolation of natural products from their biological sources rarely means a fully systematic work; many different and accidental motivations influence which species of which families were investigated and which compounds obtained from them. Therefore the number of isolated compounds is very different.
The plumeran group with its nearly 400 individual compounds represents the third largest group of indole alkaloids, the isoibogan and isoeburnan groups are the smallest ones with 5 and 8 natural products, respectively. In these latter two groups, as well as in the isoplumeran group no coalkaloids of strictosidine were found. Some representatives of really existing coalkaloids having a rearranged secologanin subunit are shown in Scheme 9.
The ibogan group shows an interesting phenomenon: in the secologanin subunit of catharanthine (48) all chirality centers have configurations opposite to those found in rosamine (49) (and other ibogan alkaloids), however, both were isolated from strictogenic species. The aspidospermidan subgroup of the plumeran alkaloids has several monomer alkaloids isolated from strictogenic species (e.g. 50, 52 and 53), and in addition dimeric alkaloids of vinblastine (57, Scheme 11) as well.
Interestingly, both enantiomers of vincadifformine (50) were isolated from plants: the (+)-form from the strictogenic Rhazya stricta, the (-) form from the closely related Vinca minor. From the same species the eburnan alkaloid vincamine (51) was also obtained.
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Scheme 9. Some Coalkaloids with Rearranged Secologanin Subunits.
N
N
H
HO
O
5
20
21
191817
16
22β
3
N
N
H
CO2MeH
3
2021
1918
22
16
17
β
N
N
H
7
21
2019
1817
16
3
N
N
CO2MeH
H
O1415
N N
HO
MeO2C
H
162120
1918
17
N
N
H
CO2MeH
21
4
721
16
20
17
N
N
CO2MeH
HO
73 21
16
N
N
CO2MeH H
216
21
37
48 4950
51
52 53 54 55
β
β α
ibogan
catharanthine CFM28Vinca rosea APO
HJQ42
aspidospermidan
tabersonine; 14,15α-epoxide
Vinca rosea APOAmsonia tabernaemontana APO
ibogan
rosamine CFK06Catharanthus roseus APO
aspidospermidan
quebrachamine CFB72Rhazya stricta APO
Aspidospermaquebracho-blanco APO
vincadif formine, (-)-form HHM43
aspidospermidan
Vinca minor APOvincadif formine, (+)-form HBN54
Rhazya stricta APO
aspidofractinan
venalstonine CCH72Catharanthus roseus APO
Alstonia venenata APOMelodinus australis APO
eburnanVinca minor APO
vincamine (+)-form BCL77
kopsan
5,22-dioxokopsane GRG22Alstonia venenata APO
The transformation of vincadifformine into vincamine is indicated by curved arrows in formula 50
and was carried out in several steps even under abiotic conditions [30]. In the tabersonine derivative 52 the position of the epoxide oxygen shows the place of the previous double bond, which remained after the hypothetic Diels–Alder cyclization. In the aspidofractinan subgroup the sole alkaloid is venalstonine (54), which was obtained from the strictogenic Catharanthus roseus. However, it is a key structure isolated also from Alstonia venenata and Melodinus australis. The first species produces also 5,22-dioxokopsan (55), the second one condylocarpine (37), both of which are secondary coalkaloids of strictosidine, and show further chemotaxonomic connections to two other special groups of alkaloids, i.e. 55 to the kopsan subgroup of the plumeran group, 37 to the aspidospermatan group. The seco alkaloid quebrachamine (53) isolated from Rhazya stricta is likewise an important key compound in the biogenesis of the type III alkaloids. In the eburnan group only two alkaloids were isolated from strictogenic species, one of them is dihydroeburnamenine (62, Scheme 12) (from Rhazya stricta) which is probably the last coalkaloid in this molecular evolution.
From these data it may be concluded that most of the characteristic groups of indole alkaloids have primary (direct) and/or secondary/tertiary (indirect) coalkaloids of strictosidine, and they form an extended biogenetic network. However, at certain points there are holes on this net. In the isoibogan and isoeburnan groups no coalkaloids of strictosidine were found, a fact whch can easily be interpreted by the low number of known isolated compounds in them. In the isoplumeran and aspidospermatan groups the absence of coalkaloids can hardly be attributed to any low statistical probability. However, this lack of coalkaloids is compensated by the high number of dimeric alkaloids having an intact or seco isoplumeran subunit (see below) and by a strong chemotaxonomic relation between the aspidospermatan and the strychnan groups.
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At this point the importance of the two strictogenic species of the Apocynaceae family should be emphasized. As seen in Table 1, only a small number of coalkaloids were isolated from Anthocephalus cadamba of Rubiaceae and Strychnos mellodora of Loganiaceae having the malindan and vincosaman skeletons, respectively. However, in the Apocynaceae family from Catharanthus roseus (=Vinca rosea) 30 monomers and 20 homo- or heterodimers, from Rhazya stricta 50 monomers, 8 homodimers, as well as some stemmadenine and secodine derivatives of key importance were isolated. Most of them have the corynanthean, and only a few the vallesiachotaman skeleton. These two species together provide about 130 primary coalkaloids, of which only two are common in the two species!
Scheme 10. Types of Heterodimer Indole Alkaloids.
type IIItype α
eburnan
13 heterodimers1 homodimer56 monomers
α2
3N N21
22 1617
1415
7
20
19 18
N
N
21
16 17
22
31415
18
19
2072
β
type IIItype β
plumeran 340 monomers43 homodimers60 heterodimers
N
N21
22 1614
15
2 2019 18
β7 3
17
type II
ibogan84 monomers3 homodimers
73 heterodimers
14
1
456
8
910
11
12 13 20
19
18
N
N
H
72
321
22 17
1615
β
type Itype β S
530 monomers15 homodimers24 heterodimers
strychnan
N
N
H
2
321
1516
22 17
14
2019
18β 7
type Itype β A
aspidospermatan28 monomers
no dimers
N
N
22
1716
314
15
21
7
2019
18
β2
type IItype β
isoplumeran14 monomers
no homodimers41 heterodimers
α2
3N N21
22 1617 14
15
7
20
19
18
type IItype α
isoeburnan8 monomers
no dimers
17
N
Nβ72
22 16
21
20
19
18
3
14
15
type III
isoibogan5 monomers
no dimers
N
N
HH3CO O
H2
721
1716
22
19
20
18
3
14
15
seco intermediates7 monomers
9 homodimers
24
69
8
4
36
11
910
1
43
22
15
16 17
2
7
2019
18
21α
5
68
13
11
12
14
N N
H
type Itype α
>1000 alkaloids73 homodimers
100 heterodimers
vincosan
The Significance of Dimer Alkaloids in the Biogenesis of Indole Alkaloids In the class of the indole alkaloids nearly 300 dimer compounds are known, which are formed from
two monomer units (each monomer unit contains a tryptamine and a secologanin subunit). In the
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minority of these dimers the two monomers or at least their basic skeletons are identical (“homodimers”). From chemotaxonomic point of view the dimers having two different basic skeletons (“heterodimers”) are much more important because they indicate that in the species from which they were isolated the different monomers coexist, i. e. their origin is common: they were formed directly one from the other or indirectly from common precursors. Therefore their biogenetic relatedness is evident.
It is not the aim of this paper to analyze the mechanism of the formation of these dimers and investigate the types of the molecular connection between the monomer units (this study is in progress). The types of the heterodimers and the numbers of the subunit monomers are shown in Scheme 10. The connection may concern either the tryptamine or the secologanin subunit, or both of them. In the group of the seco intermediates (stemmadenine, secodine and secamine derivatives in the center of Scheme 10) no heterodimers were found. The phenomen, perhaps, depends on the chemical character of their ring systems. Likewise no dimers having either an isoibogan or an isoeburnan monomer are known, as even the number of the known free monomers is low.
Some examples of existing heterodimers are shown in Scheme 11. In geissospermine (60) and tenuicausine (59) the monomer components belong to the same type of skeleton (both type I or type III, respectively), but their attachment to the indole ring is different (α and β). 60 suggests an α→β bond shift, 59 a backward β→α shift between the two monomers.
Scheme 11. Selected Examples of Heterodimer Indole Alkaloids.
57 58
59 60 61
N
N
MeO2CH
HO
ibogan IIplumeran III β
N
N
H
CO2Me
O
H
β
eburnan III αplumeran III β
αN NH
H
β
N
NHMeO
H CO2Me
akuammidan I αisoplumeran III β
N
N
HH
β
akuammidan I α
NN
Me2OCH
Me
H
α
Tabernaemontana elegans APOHOP56
capuvosidine
strychnan I βcorynanthean I α
NN
MeO2C
H
H
H
H
α
N
N
H
O
β
vinblastineBCL63
Catharanthus roseus APO
β
β
isoplumeran II βplumeran III β
N
NOH
MeO2CH
H
N
NMeO
Me
H
HOAc
HO CO2Me
geissospermine
Geissospermum vellosii APOCDP43LDH28
Melodinus tenuicaudatus APO
tenuicausine tetrastachyneGRB68
Tabernaemontana tetrastachya APO
56
demethyltabernamine
Tabernaemontana dichotoma APOGPM42
N
N
HH
NN
HH
MeO2C H
H
α
akuammidan I α
ibogan II(perivine CGN81)
(ibogamine CCR72)
Molecules 2008, 13
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In tetrastachyne (61) and vinblastine (57) (with several derivatives) the monomers have two differently rearranged skeletons. It proves that type II and type III skeletons coexist in the cells, and should be formed at least in the same species. Several derivatives of vinblastine (57) emphasize the importance of this connection. Moreover, it was mentioned that no isoplumeran monomer is known as coalkaloid of strictosidine, however, in the 57 and its derivatives some isoplumeran subunits (in seco form) became important coalkaloids because most of the dimers of type 57 were isolated from the strictogenic Catharanthus roseus (=Vinca rosea). In 56 and 58 one of the monomers has a (differently) rearranged skeleton (type II or type III), and the other monomer has the original secologanin skeleton. These facts suggest that the monomers having an intact skeleton and any of the rearranged ones are produced of the same species. In 58 one of the components is again an isoplumeran monomer (now in its intact form) and by this fact its significance is further increased. Finally, in demethyltabernamine (56) the two monomers are perivine (akuammidan- and mainly vobasan-type) and ibogamine (ibogan-type). The dimer and both monomers were isolated from several Tabernaemontana species and in addition perivine from the strictogenic Vinca rosea as well. This latter fact is very important because it represents the chemotaxonomic link between strictosidine and the tabernamine-type dimers (about 70 alkaloids!). Outlook
The first line of Scheme 12 shows once more the precursor strictosidine 1, the central intermediate stemmadenine (38) and dihydroeburnamenine (62) as one of the final products of this long molecular evolution.
Scheme 12. Some Special Structures.
NHN
OH3CO
O
OglcH H HH
1
910
11
12 1332
45
678
14
15
1617
1819
2021
22
3 38 62
63 64
N
N
HMeO2C
HO
H
N
N
H O
O
OH21
31415
2019
18
17
16
N NO
O16 17
2120
1918
3
1415
20N
N
R'
H
R
12 3
4
1415
7
1617
N NH
3
141516
17 2021
1819
N
N
R'
H
R
20
12 3
4
1415
7
1617
vincosan, type I skeleton
strictosidine CCF30
Anthocephalus cadamba RUB
Rhazya stricta APOCatharanthus roseus APOStrychnos mellodora LOG
65 ellipticen (R = H, R' = Me = C-18)
66 olivacen (R = Me = C-18, R'=H)Aspidosperma subincanum APO
ellipticine HGP59
type I skeleton
olivacine CDW84Aspidosperma olivaceum APO
eburnan, type III skeleton
eburnamenine16,17-dihydro LCR84Rhazya stricta APO
stemmadenine CCD41
type I skeleton
Rhazya stricta APOstrychnan/aspidospermatan
plumeran / type III sleletonLeuconotis eugenifolia APO
Rhazya stricta APOleuconolam GDP93
plumeran / type III skeletonLeuconotis eugenifolia APO
leuconoxine MTM42
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In the second line the unusual leuconolam (63) and leuconoxine (64) as well as the ellipticine–olivacine pair 65 and 66 are placed which look to be, at least in appearence, very different to strictosidine or even stemmadenine, nevertheless they could find their appropriate position in the system. Compound 63 was isolated from the strictogenic Rhazya stricta and in addition from Leuconotis eugenifolia, in which 64 was also found as a secondary coalkaloid of strictosidine.
In Scheme 13 the case of the ellipticine–olivacine pair illustrates well the potential of the electronic searching in the special data bases [14]. Both compounds 65 and 66 are type I class alkaloids and structural isomers as the position of C-18 is different in the common ringsystem. They were isolated from closely related Aspidosperma species (Apocynaceae). It could be demonstrated, that their evolutionary lines branched at the very beginning, on the primary azacyclization level.
The evolution of ellipticine (65) started from ajmalicine (20) (coryanthean skeleton with nearly thousand alkaloids) isolated from the strictogenic Catharanthus roseus (Apocynaceae) and the main steps of its evolutionary line could be followed stepwise [14]. In the other case only the first and last compounds were found as natural products. The evolution of olivacine (66) started from isodihydrocadambine (13) (malindan skeleton with 40 alkaloids) isolated from the likewise strictogenic Anthocephalus cadamba (Rubiaceae) but its formation could not be followed stepwise because of the low number of isolated alkaloids having the malindan skeleton. However, it may be stated with high probability that the molecular evolution of olivacine passed steps analogous to those of ellipticine.
Scheme 13. A Special Case.
NN
OH3CO
O
OglcH H HH
OH3
4
15
1617
1819
2021
NN
OH3CO
O
H HH
H E18
4
19
17
15
3 21
16
Anthocephalus cadamba RUBCatharanthus roseus APO
3S strictosidine CCF30
malindan
isodihydrocadambine GPX51Anthocephalus cadamba RUB
corynanthean
ajmalicine BFV84Vinca rosea APO Aspidosperma subincanum APO
ellipticine HGP59
olivacine CDW84Aspidosperma olivaceum APO
NN
OH3CO
O
H HH
H E18
4
19
17
15
321
16
66
65
13
20
3
NHN
OH3CO
O
OglcH HH
H
1
910
11
12 1332
45
678
14 15
1617
1819
2021
22
12
3
4
1514
2120
1918
1617
78
910
11
12 13N
N
H
12
3
4
1514
2120
1918
1617
78
910
11
12 13N
N
H
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Summary In this paper chemotaxonomic investigations were carried out on 133 monomer and 25 dimer
coalkaloids, as well as on 152 dimers of strictosidine. The results are summerized in Table 2. It can be seen, that the isolated compounds form a biogenetic network. Coalkaloids and/or heterodimers were found in all three basic types I, II and III, and nearly all important taxonomic units of indole and quinoindole alkaloids (except such groups in which only a few alkaloids are known). Of course, the search for further indirect (secondary/tertiary) coalkaloids could and should be continued, in order to make the molecular network more dense. The results underline also the importance of the computer searching in the specialized large databases.
Table 2. Summary of Chemotaxonomic Relationships between Indole Alkaloids.
isoibogan IIIplumeran III βeburnan III α
not foundnot found
foundfound
type III
36 4
11
8
vincosan I αstrychnan I β S
aspidospermatan I β Aibogan II
isoplumeran II βisoeburnan II α
coalkaloid
foundfound
foundnot found
indirect
heterodimer skeleton
type I
type II
69
24
Acknowledgements
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