Tricyclic Alkaloids

Further properties of gephyrotoxin are presented in Table VIII. The proton magnetic resonance spectrum of gephyrotoxin has been presented (58,143). Proton and carbon-13 assignments for gephyrotoxin have been reported (144). The vapor-phase FTIR spectrum of gephyrotoxin is shown in Fig. 16. 

The biological activity of gephyrotoxin has been examined in several systems (see review of Ref. 5). Gephyrotoxin is relatively nontoxic a subcutaneous dose of 80 fig in mice causes only a reduction in spontaneous activity (60). Gephyrotoxin has weak activity as a muscarinic antagonist 

Gephyrotoxins are unique in Nature to amphibians and, indeed, occur only in certain populations of the extremely variable Colombian poison frog, Dendrobates histrionicus (1). Gephyrotoxin might be derived by cyclization of a c/.r-decahydroquinoline having a trans orientation of the 

2- and 8a-substituents in the piperidine ring, such as found in decahydro-quinolines c -219A and cis-243A. 

m/z205(38),204(54), 190(100). OD. Hjderiva-tive. The tentative structure (Fig. 17) reported in Ref. 77 is under further study. 

Angustifoline, C14H22ON2 (mp 81° [ ]i —8.0°), has been isolated from Lupinus angustifolius L., L. polyphyllus L., and L. albus L. Its structure was elucidated almost simultaneously by three different groups (31-33). It forms an A-acetyl derivative, has a terminal double bond as indicated by IR-spectra and proved by oxidation to formaldehyde, and reduction of the lactam grouping with lithium aluminum hydride generates a tmws-quinolizidine system (trans bands in the IR-spectrum), and these facts lead to structure XXXVII for angustifoline. 

Its conversion to 13-epihydroxylupanine (XXXVIII) by reaction with formaldehyde (31, 33, 50) via the intermediate XXXIV (R = H, a 

Cytisine (VIII) was the starting point in a synthesis of angustifoline. Tetrahydrocytisine (XLI) was converted to the A -chloro derivative (XLII) with hypochlorite. The elimination of hydrogen chloride from the latter leads specifically to the Schiff hase (XLIII) which is stereospecifically alkylated with allyl magnesium chloride. The approach of the reagent from the under side of the molecule is sterically very improbable (52). 

Dehydroalbine (XLIV), C14H18ON2 (mp 50° [a] —103° perchlorate, mp 252°), was isolated from the seeds of L. albus (53). Its imonium salt has structure XLV. Vigorous hydrogenation converts it into XLVI which is epimeric at C-11 with dihydrodesoxyangustifoline. 

This alkaloid (XLVII), C15H22ON2 (mp 67.5° [a] , —559), is related to multiflorine and was isolated from L. albus (54, 55). Spectral comparison with multiflorine and V-methylangustifoline permitted structure XLVII to be assigned to it. 

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The stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

Since the discovery of tetraponerine-8 in 1987 by Braekman et al. [195] the tetraponerines, the defensive alkaloids of ants of the genus Tetraponera, have been the target of considerable synthetic efforts and have served to demonstrate the utility of various synthetic methodologies [114]. Recently a few further syntheses of these unusual tricyclic alkaloids have been reported. 

Aminocarbonylation has been combined with the Pauson-Khand reaction to construct fused tricyclic alkaloid skeletons (see 00154). The tandem aminocarbonylation/Pauson-Khand reaction of haloalkynes with a chiral allylic amine promoted by Co2(CO)8 gave angular triquinanes as exemplified in Scheme 25. Thus, the reaction of l-chloro-2-phenylethyne 175 with Co2(CO)8 at 0°C gave alkyne-dicobalt complex 176, which was converted to enoyl-dicobalt complex 177 upon warming to 25 °C. The reaction of enoyl-dicobalt complex 177 with cyclopente-nylmethyl(l-phenylethyl)amine 179 yielded Pauson-Khand reaction product, angular triquinane 180, via A -allylic aminocarbonylated alkyne-dicobalt complex 178 (Scheme 25). ... 

The Tasmanian ascidian Clavelina cylindrica has yielded two interconvertible tricyclic alkaloids, cylindricine A (178) and B (179), which are toxic to brine shrimp [140]. 

Prenyl-quinolones and Related Tricyclic Alkaloids.—The l-methyI-3-prenyl-2-quinolone (6 R1 = H, R2 = OMe), already known as a synthetic compound, has been isolated from the roots of Glycosmis mauritiana it is converted into a mixture of the dihydropyrano-quinolones (8 R1 = H, R2 = OMe) and (9 R1 = H, R2 = OMe) by formic acid (Scheme 2).4 A new l-methyl-3-prenyl-2-quinolone, 7V-methylpreskimmianine (6 R1 = R2 = OMe), was obtained from the stem bark of Vepris louisii-, its structure was established by spectroscopy and by its preparation from preskimmianine (7) (Scheme 2).11 A second new alkaloid of Vepris louisii, named veprisine, was shown by spectroscopic studies and by its synthesis from A-methylpreskimmianine to be the pyrano-quinolone (10) (Scheme 2).11 Five furoquinoline alkaloids were found in the wood of Esenbeckia flava (see Table 1) and a non-crystalline bisprenyl compound (11) was also isolated from this source the new alkaloid, which was first obtained as a synthetic compound,17 is readily converted into the dihydropyrano-4-quinolone (9 R1 = R2 = H) (Scheme 2).1... 

Another highlight of the period under review is the report of the total synthesis of the tricyclic alkaloid fawcettimine (22) (Scheme 2).9 Lewis-acid-catalysed Diels-Alder addition of butadiene to 2-allyl-5-methylcyclohex-2-enone provided the ds-octalone (23), which was modified as indicated to give the dialdehyde (24). After considerable experimentation, conditions were defined which led to regioselective ring-closure in the desired direction. The unsaturated aldehyde was treated directly with the Wadsworth-Emmons reagent to provide... 

Since the first publication, amine-catalyzed Diels-Alder reactions of a,/ -unsaturated aldehydes have been investigated in much detail [15, 26-33]. Catalyst immobilization studies on solid support [26, 27], as well as in ionic liquids [29], have shown advantages for amine recycling, while partially maintaining good levels of asymmetric induction [34]. The use of this reaction in total synthesis has allowed the rapid preparation of (+)-hapalindole Q, a tricyclic alkaloid natural product containing four contiguous stereocenters (Scheme 3.2) [28]. 

Fig. 17. Structures of a coccinelline and a related tricyclic alkaloid from amphibians. The absolute configuration of 193C is unknown. The structure of205B is tentative (77) and under investigation.

Precoccinelline (193C) and related tricyclic alkaloids have been detected only rarely in dendrobatid frogs and bufonid toads. Precoccinelline is a minor alkaloid in one Central American population of Dendrobates aura-tus 31), but it was a major alkaloid in an introduced population of D. 

Three novel tricyclic alkaloids (222, 236, and 252A) were isolated from skin extracts of a Panamanian population of the poison frog Dendrobates pumilio. Amidine structures were proposed for these alkaloids in 1987 based on mass spectral and nuclear magnetic resonance spectral analyses (77). However, recent gas chromatographic-FTIR spectra showed that these three alkaloids could not be amidines, since they had no absorption around 1630 cm where amidines show an intense absorption. A reexamination of the nuclear magnetic resonance spectral data and acquisition of new data led to revised structures 153). The simplest member (222) is a spiropentanopyrrolizidine oxime, whereas 236 is the corresponding... 

Thiazolidines. formation, 168-169 Tricyclic alkaloids, 242-251 coccinellines, 245, 246-247 cyclopenta[b]quinolizidines. 247-249 gephyrotoxins, 242-245 pynolizidine oximes, 249-251 Trypargine, 262-263... 

Porantherilidine (415), the only bicyclic member of a group of quinolizidine alkaloids from the Australian shrub Poranthera corymbosa, was described in the previous chapter on simple indolizidine and quinolizidine alkaloids in Volume 28 of this series (/). The related tricyclic alkaloid porantheiidine (416) is included here as an obvious carbinolamine derivative of the simple bicyclic system. 

Mono-, di-, and tricyclic alkaloids from ladybird beetles... 

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