Alkaloids: Chemical and Biological Perspectives (eBook)

4 TRICYCLIC ALKALOIDS

A remarkable range of structural classes of tricyclic alkaloids have been characterized from amphibian skin and it appears likely that further structural classes will be discovered. The alkaloids include the gephyrotoxins, which are structurally related to the decahydroquinolines, the unique cyclopenta[b]quinolizidines, which are unprecedented in Nature, the coccinellines and related tricyclics previously known from coccinellid beetles and the spiro-pyrrolizidines, including an alkaloid previously isolated from a millipede. In addition, the pyridylazabicycloheptane epibatidine (Section 6.1), the dipyridylpiperidine noranabasamine (Section 6.2) and the pseudophrynamines (Section 7.1) are tricyclic alkaloids, but are distinguished by the presence of aromatic rings.

4.1 Gephyrotoxins

One of the alkaloids isolated from extracts of 1100 skins from a particularly abundant population of the Colombian dendrobatid frog Dendrobates histrionicus was initially termed HTX-D, even though it was noted that the MS fragmentation was not that of a histrionicotoxin [107]. Histrionicotoxins were the most abundant alkaloids in that same extract. The name was later changed to gephyrotoxin when the structure was elucidated by X-ray analysis [108]. The name derives from the Greek gephyra meaning bridge and the structure does “bridge” several classes of frog skin alkaloids, since gephyrotoxin has a decahydroquinoline ring, an indolizidine ring and a enyne side-chain at that time known only from histrionicotoxins. The name is unfortunate in one regard since gephyrotoxin is relatively non-toxic. Structures of the gephyrotoxin 287C and dihydrogephyrotoxin 289B are shown in Figure 30.

The absolute configuration of gephyrotoxin present in skin extracts of Dendrobates histrionicus remains in doubt. The structure shown is that derived from X-ray analysis of a single crystal of the hydrobromide salt of gephyrotoxin isolated from skin extracts obtained in 1971 of an abundant population of D. histrionicus from the environs of the town Guaya-cana in southwestern Colombia [108]. An unambigous synthesis of this enantiomer in 1980 afforded a dextrorotatory [ α ]D25+50.0°) gephyrotoxin [298]. An optical rotation had not been obtained from the 1971 sample and the gephyrotoxin proved quite labile to oxidation. Thus, the gephyrotoxin from the first collection had decomposed by 1980, but an optical rotation on gephyrotoxin isolated from skin extracts obtained in 1974 from the same population of D. histrionicus was levorotatory ( α ]D25−51.5°). Thus, the gephyrotoxin from the 1974 collection appeared to be mainly the levorotatory enantiomer opposite in absolute configuration to the gephyrotoxin hydrobromide of the single crystal subjected to X-ray analysis and derived from skin extracts of a 1971 collection. A satisfactory explanation is not evident [see discussion in ref. 10]. An error in X-ray analysis, in the enantioselective synthesis or in the sign of the optical rotation appears unlikely. It may be that the major natural enantiomer is not that of the single crystal subjected to X-ray analysis. The X-ray structure for gephyrotoxin (287C) depicted in Figure 30 corresponds in absolute configuration at C-3a with the presumably biosynthetically analogous C-2 carbon in the histrionicotoxins (see Figure 11) that are always present in extracts containing gephyrotoxins. Gephyrotoxin (287C) and dihydrogephyrotoxin (289B) represent the only members of this class of alkaloids as yet detected.

The MS fragmentation of gephyrotoxins is dominated by α-cleavage resulting in loss of the CH2CH2OH substituent [107,108]. The vapor-phase FTIR spectrum of gephyrotoxin (287C) has been published [11]. The Bohlmann band near 2800 cm−1 is relatively weak as it is in the corresponding 5E,9Z-3,5-disubstituted indolizidines.

Brief summaries with references for physical (optical rotation) and spectral (UV, NMR) properties have been provided [10,11]. A detailed NMR analysis of gephyrotoxin is available [299]. The properties of the two gephyrotoxins are tabulated in the Appendix.

Synthesis

Synthetic routes to racemic and dextrorotatory gephyrotoxin (287C), racemic dihydrogephyrotoxin (289B) and racemic perhydrogephyrotoxin were reviewed in detail in 1986 [10]. Minor amounts of the epimer at C-1 were produced in certain synthetic routes. Another stereoselective synthesis of racemic perhydrogephyrotoxin was reported in 1986 [300]. Further synthetic approaches to gephyrotoxins have appeared [301–303]. We are unaware of any more recent synthetic efforts.

Occurrence

The gephyrotoxins are known only from skin extracts of dendrobatid frogs of the neotropical genus Dendrobates. Within that genus, gephyrotoxins have been detected only rarely, primarily in skin extracts from various Colombian populations of Dendrobates histrionicus, where they are always accompanied by histrionicotoxins as the major alkaloids [1]. Gephyrotoxin 287C has now been detected in skin extracts from a population of the Panamanian D. auratus [6]. Nineteen-carbon histrionicotoxins were major alkaloids in the same skin extracts. A dietary source for gephyrotoxins is unknown. However, both gephyrotoxin and nineteen-carbon histrionicotoxins were detected in skin extracts of D. auratus raised on leaf-litter insects from Ancon Hill in Panama [6]. Gephyrotoxins, like 3,5-disubstituted pyrrolizidines, 3,5-disubstituted indolizidines, 4,6-disubstituted quinolizidines, 3,5-disubstituted azabicyclo[5.3.0]decanes, decahydroquinolines and histrionicotoxins, could be derived by cyclizations of a precursor with a linear carbon-chain. Except for the histrionicotoxins all such alkaloid classes have been detected in myrmicine ants. Thus, it appears likely that myrmicine ants will prove to be the dietary source for gephyrotoxins.

Activity

Gephyrotoxin is relatively nontoxic and exhibits only weak activity as a muscarinic antagonist and as a noncompetitive blocker of nicotinic receptor-channels [87,133, 155,157, 304, see ref. 10]. Gephyrotoxin appears somewhat selective as a noncompetitive blocker for ganglionic-type versus neuromuscular-type nicotinic receptor-channels [133 and unpublished results].

4.2 Cyclopenta[b]quinolizidines

A unique tricyclic alkaloid, 251F, was detected in skin extracts from two populations of the dendrobatid frog Minyobates bombetes found in a mountainous region west of Cali, Colombia [305]. The EI-MS of alkaloid 251F and congeners were interesting in yielding an odd mass fragment as the base peak. The amount of alkaloid 251F present in skin extracts obtained in 1983 from 100 frogs from a montane population of Minyobates bombetes at that time was deemed insufficient to warrant an isolation for NMR spectral analysis. Some seven years later, 340 μg of alkaloid 251F were isolated by chromatography and detailed MS and NMR spectral analysis led to the 3,7,10-trimethyl-2-hydroxymethylcyclopenta[b] quinolizidine structure shown in Figure 31 [306]. The absolute configuration is unknown. Tentative structures of nine congeners are also shown. A structure for a tenth congener, 253G, is not proposed (see Appendix). The EI-MS fragmentation of 251F is very complex with a base peak at m/z 111. Major fragmentation pathways are proposed in Scheme 12.

The vapor-phase FTIR spectrum of 251F has been reported [306]. It has a strong Bohlmann band at 2755 cm−1. The MS and NMR spectral properties of 251F and the O-acetyl derivative of 251F have been presented along with MS data of the nine congeners depicted in Figure 31 [306]. The properties of the cyclopenta[b]quinolizidines are tabulated in the Appendix.

Synthesis

The diastereoselective synthesis of 251F was recently reported [307]. The synthesis involved the enantiospecific preparation of a substituted cyclopentyl intermediate, followed by coupling to a substituted piperidine and finally a rhodium-mediated cyclization. The synthetic alkaloid was identical with natural 251F, based on GC-MS, GC-FTIR and NMR spectral analysis.

Occurrence

Cyclopentaquinolizidine 251F represents the parent member of a unique structural class of alkaloids unknown elsewhere in Nature. The structure and presence of isoprenoid units suggests that, unlike many alkaloids from...