5,10b-Ethanophenanthridines

The alkaloid (+)-epimaritidine (389), which constitutes a missing link in the C-3 epimeric pairs of 5,10b-ethanophenanthridine alkaloids of the vittatine-... 

In 1966 (Vol. XI, p. 352) over thirty alkaloids possessing the 5,10b-ethanophenanthridine nucleus were reported. The absolute configuration relied, first, on the interconversions of those alkaloids which permitted correlation with tazettine (240) whose absolute stereochemistry seemed firmly established through degradation to (+ )-(i )-2-methoxyadipic acid and, second, on empirical reasonings based on the application of Mill s rule. 

Subsequently, the application of a quadrant rule developed for compounds bearing an asymmetric center adjacent to the aromatic chromophore by means of considerations of the CD and ORD spectra of products of established absolute configuration to the alkaloids of the 5,10b-ethanophenanthridine series led to conclusions on their absolute stereochemistry at variance with those mentioned above 42). 

At this point the synthesis of the pretazettine nucleus with the inverted (cis) B-D ring fusion seemed possible starting from 11-epi-haemanthidine (262). Indeed, 262 easily undergoes rearrangement to N-demethyl-6a-epipretazettine (263) which cannot be converted back to the 5,10b-ethanophenanthridine form. Since 6a-epipretazettine... 

Several biogenetic-type syntheses of 5,10b-ethanophenanthridine derivatives have been realized. The model compound 273 (R2 = OMe) in a two-phase oxidation in CHC13/1 N FeCl3 (1 1) yielded 12% of the dienone 271 which, under basic conditions, gave the product 272 (56). 

The crinine-type skeleton has been obtained starting from the cyclohexanone derivative 300 which, with NH3, gave the cyclic enamine 301, hydrogenated (Pd/C) in turn to the m-octahydroindole derivative 302. The conversion of 302 into the tetracyclic 5,10b-ethanophenanthridine 303 proceeds by standard methods (67). 

In the biosynthesis of haemanthamine (318) hydroxylation at the methylene at position 11, to the nitrogen atom, takes place late in the sequence once the 5,10b-ethanophenanthridine skeleton had been constructed from O-methylnorbelladine (102). The stereochemical course of the hydroxylation process has been studied independently by two groups. 

Galanthamine-type alkaloids derived from a dibenzofuran ring Crinine-type alkaloids derived from 5,10b-ethanophenanthridine Montanine-type alkaloids derived from 5, 11b-... 

Supplementary stereochemical studies relating tazettine to the alkaloids of the family derived from 5,10b-ethanophenanthridine are... 

The fourteen alkaloids discussed in this section constitute a remarkable series of structurally and stereochemically interrelated substances. Superficially, all the alkaloids contain the same basic ring system, 5,10b-ethanophenanthridine (145), but alkaloids are elaborated from both enantiomorphs of this basic nucleus. Further variations are produced by differences in aromatic substitution and the functional groups attached to rings C.and D. It has been possible to interrelate all the alkaloids of this section through a combination of simple oxidation, reduction, and dehydration reactions coupled with four rather specific degradative techniques. These reactions are (1) aromatic demethoxylation by sodium and amyl alcohol (82), (2) replacement of OH by H via the action of lithium aluminum hydride on an intermediate chloro compound (146), (3) acid hydrolysis of ally lie methyl ethers to alcohols (147, 148), and (4) 0-methylation of hydroxylic alkaloids with... 

CCIII (R = NO) exists in equilibrium with its open chain form (CCII, R = NO) as evidenced by the slow formation of a conjugated 2,4-dinitrophenylhydrazone. Like haemanthidine, the N-nitroso derivative of haemanthidine underwent alkaline oxidation-reduction to form N-nitrosonortazettine (CCV). Thus, the oxidation-reduction reactions of Cg and Cn in haemanthidine require neither a basic nitrogen nor the 5,10b-ethanophenanthridine ring system. The rearrangement is almost certainly intramolecular and may proceed by hydride transfer either through CCII or CCIII. 

The alkaloids derived from 5,10b-ethanophenanthridine (crinine and haemanthamine types), 2-benzopyrano[3,4c]indole (tazettine type), phenanthridine (narciclasine type) and 5,11b-methanomorphanthridine (montanine type) originate from a para-para oxidative phenolic coupling (Fig. 9). 

H) was assigned and confirmed by correlation with powelline (5 R — R = H), a known alkaloid. Several interesting reactions of the new alkaloids were also reported." In contrast to other 5,10b-ethanophenanthridine... 

Maritidine is of significance because it is the first alkaloid with the 5,10b-ethanophenanthridine nucleus to contain dimethoxy rather than methylenedioxy substituents at C-8—C-9. 

The crinine alkaloids, which can embody either enantiomeric form of the 2,3, 4,4a-tetrahydro-l//-6//-5,10b-ethanophenanthridine framework, represent an important sub-class within the Amaryllidaceae alkaloid family [53]. Many members of this subclass display interesting biological properties including immuno-stimulatory, cytotoxic and anti-malarial activities. As a consequence, they have been the subject of numerous synthetic studies [53]. 

Hydrogen chloride [2]Benzopyrano[3,4-c]indoles from 5,10b-ethanophenanthridines... 

Haemanthidine, one of the more complex Amaryllidaceae alkaloids characterized by the crinine skeleton bears a C-6 hydroxyl substitution unique among the 5,10b-ethanophenanthridine group. For a review of Amaryllidacea alkaloids, see W. C. Wildman, The Alkaloids, 6, 290 (1960). 

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