Narciclasin

Fessner et al. have reported an elegant strategy for the stereospecific synthesis of novel pancratistatin analogs [42]. The pancratistatin alkaloid and its closely related natural congeners, including notably trans-dihydrolycoricidine and the anhydro and deoxy derivatives narciclasine and lycoricidine (Figure 4.2), have attracted considerable attention due to their biological activities [43]. 

Total synthesis of (-l-)-lycoricidine, (—)-lycoricidine and (-l-)-narciclasine via 6-exo cyclization of substituted vinyl radicals with oxime ethers has been reported . Thus, interaction of oxime ether 321 with thiophenol and then with Sml2 and TFA afforded (-l-)-lycoricidine 322 in good overall yield (equation 139). 

Phenanthridine and Related Alkaloids Narciclasine Related Alkaloids Dibenzo[c,e]azocine Alkaloids —Tetracyclic Alkaloids... 

Pancratistatln. The first total synthesis of ( )-pancratistatin (94) (Scheme 14), the structurally most complex of narciclasine alkaloids, was achieved by Danishefsky [27]. The requisite starting material, the substituted benzaldehyde 95 prepared from pyrogallol in six steps in 18% overall yield, was converted via the homoallylic alcohol 96 into the diene 97. Reaction of 97 with 2-nitrovinylsulphone yielded the cycloadduct 98, which on treatment with tributyltinhydride and 2,2 -azobisisobutyronitrile furnished the cyclohexadiene 99. Whilst the cyclisation of the silylether 99 or the derived phenol, under the influence of iodine, could not be accomplished, the more nucleophilic stannylether did participate in the desired ring closure and provided via the iminium salt, the iodolactone 100 on aqueous work-up. 

Other interesting approaches yet to culminate in successful chiral syntheses of narciclasine alkaloids are reported in the recent literature [32-40],... 

Whereas narciclasine (215) had been previously shown to be identical with lycoricidinol, the mutual identity of lycoricidine (214) and margetine has now also been established by a comparison of the H-NMR spectra of the derived triacetates (141). Although the names narciclasine and margetine have chronological priority, common usage appears to have, established narciclasine and lycoricidine as the preferred names. In agreement with a previous recommendation (141), and to avoid any further confusion in the literature, this nomenclature should be maintained. 

Narciclasine (215) is an antitumor agent which exerts an antimitotic effect during metaphase by immediately terminating protein synthesis in eukaryotic cells at the step of peptide bond formation (97,101,141,142), apparently by interaction with the ansiomycin area of the ribosomal peptidyl transferase center (142). The alkaloid has also been found to inhibit HeLa cell growth and to stabilize HeLa cell polysomes in vivo (97). Although DNA synthesis was retarded by narciclasine, RNA synthesis was practically unaffected (97,142). Sev-... 

Feeding experiments with specifically labeled 11-hydroxyvittatine have provided evidence of its intermediacy in the biosynthesis of narciclasine (215) (M3). 

A number of potentially useful chemical transformations of narciclasine (215) have been reported (141). For example, 215 may be converted to its monomethyl... 

The majority of the approaches that have been adopted for the synthesis of narciclasine (215), lycoricidine (214), and related alkaloids have involved the strategy of constructing the ring system in the order A — C —> B. There have also been examples of the A — BC and C —> A —> B type. 

An alternate entry to the narciclasine class of alkaloids has provided access to compounds related to isonarciclasine (263) (Scheme 24). In the event, the aryla-tion of p-benzoquinone with diazonium salts derived from the aryl amines 250 and 251 yielded the aryl-substituted benzoquinones 252 and 253, respectively (146). The selective hydroxylation of 252 and 253 with osmium tetraoxide provided the corresponding m-diols 254 and 255. Catalytic hydrogenation of 254 and 255 using Pd/C or Raney Ni and subsequent lactonization gave the triols 256 and 257 together with small amounts of the C-2 a-epimers 258 and 259. Aminolysis of 256 and 257 afforded the corresponding racemic tetrahydrophen-anthridones 260 and 261, whereas similar treatment of the a-epimers 258 and 259 led to the formation of ( )-isolycoricidine (262) and ( )-isonarciclasine (263), respectively. 

The antimitotic activity of several Amaryllidaceae metabolites has been emphasized (79a, 79b), although, in the case of narciclasine (376), the considerable degree of toxicity seemed to prevent its clinical use. 

The following Narcissus plants contain the lactams narciclasine and lyeoricidine, Narcissus pseudonarcissus L., King Alfred, Flower Carpet, Rembrandt, Mount Hood, President Lebrun, Golden Harvest. 

Narciclasine has been detected along with traces of lycoricidine in Qalanthus nivalis L. 

Nearly equal amounts of narciclasine and lycoricidine have been detected in Lycoris radiata Herb. (78). 

Kuhn methylation of narciclasine led to the pentamethyl derivative 350 as well as a smaller amount of the aromatized product 357 whereas, upon acid treatment, narciclasine was transformed into a phenan-thridone which is identical with narciprimine. Structure 355 was assigned to narciprimine rather than the isomeric 356, equally acceptable on the basis of the three adjacent protons of the NMR spectrum, but because of its derivation from narciclasine which had assigned a structure bearing the three hydroxy group at positions 1, 2, and 3. 

From the mother liquors of narciclasine another lactam has been isolated in trace amount. On the basis of chemical and spectroscopic evidence the new compound, named margetine, was indicated as 7-deoxynarciclasine 77. 

Independently, lycoricidine and lycoricidinol, two lactams which presented physical and chemical properties identical with those of margetine and narciclasine, respectively, were isolated from Lycoris radiata. A different interpretation of the physical and chemical data... 

Several syntheses of phenanthridone derivatives related to the aromatization products of narciclasine and lycoricidine and apparently designed to further support the structural revision have been completed. In a photochemical synthesis starting from 368 the compound 360 was obtained yielding on debenzylation narciprimine (356), whereas from 369 in an analogous way arolycoricidine (361) was prepared. Also, starting from the amide 370 through photocyclization to 362 via 363 a compound identical with natural permethylisonarciprimine (357) was obtained (81). 

However, the problem of the stereochemistry and of the absolute configuration of narciclasine has been solved through X-ray analysis and biosynthetic investigations. Thus, the biological derivation of narciclasine from vittatine 284 and the X-ray data obtained on a single crystal of narciclasine tetraacetate pointed to the stereostructure 376 for the antimitotic lactam (87, 88). 

Subsequently, Mondon and Krohn revised their structure 375 to the correct 376 by chemical means. The acetonide 377 was obtained from 376 and oxidized to an ,/3-unsaturated ketone which was reduced back (NaBH4) to a mixture of the epimeric alcohols 377 and 378. NMR data permitted full assignment for the relative stereochemistry at positions 3, 4, and 4a of 377. The full stereochemical problem was however solved through the attainment, during catalytic hydrogenation of narciclasine, of the unsaturated product 351. Indeed, comparison of the NMR spectra of 352 with those of the model compounds 353 and 354 of known stereochemistry permitted the choice of stereostructure 376 for narciclasine (89). 

More recently, a detailed paper discussed the synthetic problems presented by the syntheses of the substituted phenanthridones of the narciprimine-isonarciprimine series along with the synthesis of per-methylisonarciprimine 357 (79). The potential pharmacological interest of narciclasine and other Amaryllidaceae metabolites has been suggested (79a, 79b). 

The antimitotic lactam narciclasine (376) is widely distributed in Amaryllidaceae plants. It seems, however, nonassociated apparently with any particular alkaloid, the only chemotaxonomic peculiarity being its absence in plants usually containing alkaloids possessing the ( - )-crinane skeleton (101). 

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