Lycorine structure

A considerable amount of evidence has now been amassed supporting formula IXa for lycorine. Structure XXIV is not acceptable since dihydrolycorinone (VII), obtained by mild permanganate oxidation of diacetyldihydrolycorine followed by hydrolysis, shows lactam carbonyl absorption at 6.13 n, in good agreement with 6.10 /a found for oxyhydra-stinine (100). The lactam derived from XXIV would be expected to show absorption near 6.0 jj, (cf. 2-methylphthalimidine, 6.97 fi). Formulas IX and Villa can be eliminated since the dissociation constants of lycorine (pK, 6.4) and dihydrolycorine (pK 8.4) indicate that the double bond in lycorine is not a,/3 to the nitrogen atom (100). 

Evidente A, Cicala MR, Randazzo G, Riccio R, Calabrese G, Liso R, et al. Lycorine structure—Activity relationships. Phytochemistry 1983 22 2193-6. 

The first asymmetric total synthesis of (+)-lycorine is outlined in Scheme 15. While our earlier applications of the Birch reduction-alkylation of chiral benzamide 5 were focused on target structures with a quaternary stereocenter derived from C(l) of the starting benzoic acid derivative, the synthesis of 64 demonstrates that the method also is applicable to the construction of chiral six-membered rings containing only tertiary and trigonal carbon atoms. s... 

Oxidation of the alkaloid lycorine (359) gives a red, hygroscopic solid which readily forms salts with mineral acids. This product, which has been assigned the betaine structure 358, has also been obtained from Ungernia minor and named ungeremine. . zss TV-methyl derivative (357 R = Me, R R = OCH2O) has also been described. ... 

Extracts of Amaryllidaceae alkaloids have long been used in traditional medicine for the treatment of a variety of illnesses. As early as the fourth century B.C., Hippocrates had reputedly advised the use of preparations of Amaryllidaceae plants to control uterine tumours [157]. More recently, a systematic bioassay of these alkaloids of different structural types has revealed a diversity of interesting biological properties. Thus, (+)-pretazettine (369) [158,159], and ungeremine (182) [160] show anti-leukemic activity. Cytotoxicity was observed for (-)-lycorine (245) [161], (-)-pseudolycorine (574) [162], 6-a-hydroxycrinamine (575) [163],... 

Lycorine (1) and derivatives thereof have been the subject of a number of spectroscopic studies (42,90-92), and the proton and carbon resonances of lycorine and the a-dihydro derivative 18 have been completely assigned (90). The crystal and molecular structure of lycorine (93) and lycorine hydrobromide (94) have been established by X-ray analysis, and the structure of lycorine-chlorohydrin, which had originally been formulated as the cw-chlorohydrin 19, has been corrected and determined to be the rra/ts-chlorohydrin 20 (95). 

The discovery of lycorine-1-O-p-D-glucoside (4) and the related alkaloid pseudolycorine-1 -0- (i-D-glucoside (10) in Pancratium biflorum represented the first report of the natural occurrence of glucosyloxy alkaloids in the family Amaryllidaceae (73). The structures of 4 and 10 were deduced from H NMR and mass spectroscopy coupled with the observation that hydrolysis of the glycosides with emulsin afforded lycorine (1) and pseudolycorine (9), respectively, together with D-glucose. 

The synthesis of the tetracyclic intermediate 49 was therefore studied in the hope that it might further cyclize to the desired lycorine skeleton. Birch reduction of o,p-dimethoxyphenethylamine led to the amine 50 which was converted into 51, giving rise in turn upon hydrolysis to 49. Its structure rests on physical data. Ordinary methods for nitro group reduction seemed to also destroy the 289-nm chromophore, but hydrogen transfer (a-phellandrene and Pd/C) gave a product which analyzed for the product of nitro reduction to amine in 49, the mass spectrometric data also being in agreement. The product was, however, not affected by diazotization, and, on the basis of spectral data, was... 

Structures 98-112 (the stereochemistry at position 7 of compounds 99, 102, 104, 105, 109, and 112 was unsettled) were reported in Volume XI, p. 334, for the alkaloids possessing the [2]benzopyrano[3,4-gr]indole nucleus. Since that time experimental support for the in vivo derivation of this class of compounds from the lycorine-type alkaloids by benzylic oxidation and cleavage of the C-7—N bond has been presented (18, 19) thus strengthening the stereochemical relationships between the two groups of natural products. 

An inversion mechanism had been previously observed in the hydroxylation of caranine (2) to lycorine by Wildman and Heimer. They observed 7% incorporation of [2/ -3H] caranine into lycorine in Zephyranthes Candida Herb., the 3H being retained at C-2 of 1 as shown by the conversion into the inactive 385. The stereospecifically labeled precursor was obtained through LiAl3H4 reduction of lycorine-1,2-a-epoxide prepared from lycorine via its cis-chlorohydrin and chromatography on Florisil. The structure of the a-epoxide rests on physical and chemical grounds, whereas the stereochemistry of the... 

The group of activated olefins, which has so far probably received most attention in radical cyclizations, are enamides. Syntheses of various natural products, especially alkaloids, have been successfully completed using this strategy. Cyclizations onto enamides of the 6-endo type led to erysotrine [76] and lycorine alkaloids [77-79]. The skeleton of hydroapoerysopines [80] was successfully constructed by a 1-endo cyclization. Two new examples of radical tandem reactions, which commence with a 1-endo type cyclization, have appeared in recent literature. Construction of the cephalotaxine core structure 29 was achieved from enamide 30 in only one step (Scheme 11) [81]. 

In connection with biosynthetic studies, compound (41) or (42) has been prepared, starting with OO-diacetyl-lycorine (37) (Scheme 6).13 Treatment of (37) with cyanogen bromide gave the cyanamide (38) in 80% yield this was not isolated but was directly oxidized to the aldehyde (39). Acetalization followed by reduction with lithium aluminium hydride gave the unstable amine (40), which upon hydrolysis gave a compound which, on the basis of its conversion into lycorine (37 OH in place of OAc) may be formulated as (41). This assignment is in doubt, since spectral evidence favours structure (42). 

An investigation of the alkaloid content of Crinum augustum resulted in the isolation of lycorine (8), buphanisine (1 R1 = R2 = H, R3 = Me), and crinamine (2) and the identification of six new alkaloids.1 Augustine, one of the latter group, was shown by a thorough study of its H n.m.r., 13C n.m.r., and mass spectra to be an epoxide with relative structure (3).2 Four of the new alkaloids were separated into two pairs of compounds and were shown by n.m.r. and mass spectroscopy to be... 

The phenanthridine alkaloid lycorine (narcissine, galanthidine) (MD—Phe G5N C6) has a widespread occurrence and inhibits protein synthesis. Like lycorine, the structurally similar alkaloids dihydrolycorinine, haemanthamine, narciclasine, pretazettine and pseudolycorine also inhibit protein synthesis at the level of peptide bond formation. Galanthamine (lycorimine) (Phe C6N C40 C6 ), from daffodil bulbs but also of widespread occurrence, is both a nACh-R allosteric modulator and an inhibitor of AChE. Galanthamine is clinically employed in the treatment of Alzheimer s disease (dementia linked to deficiency in acetylcholine-mediated signalling in the central nervous system). 

The latter also yields the known alkaloids lycorine, tazettine, vittatine, and hippacine in addition to three new bases, hippadine (CieHioNOs), hippagine (CJ6H17NO4), and hippafine. The structure of carinine (3), a new alkaloid from H. punecium, has been... 

CHj=CHCH=CHOCOCH, + CHjCOCHj Dieb-AUer reactions. Hill el al. used the reagent in one step of a synthesis of the parent structure of lycorine. 

The flower stem fluid of Crinum latifolium 31) has been examined, from which numerous Amaryllidaceae alkaloids have been isolated. Among them, two lycorine-type alkaloids, 2-epi-lycorine (4) and 2-epi-pancrassidine (7), are included, structures of which were determined by spectroscopy. 

A new lycorine-type alkaloid named fortucine has been found in the leaves of Narcissus variety Fortune and its structure reported as 27 (87). From the bulbs of Crinum kirkii, two new alkaloids, kirkine (27) and 8-0-demethylvasconine (56), have been isolated and their structures established by physical and spectroscopic methods (29). In this study, the structure of kirkine was determined to be the same structure as that proposed for fortucine (87). Therefore, confirmation by direct comparison of each alkaloid remains to be conducted. 

C-Aromatic lycorine-type alkaloids have been discovered in the plants of the Amaryllidaceae family. Two new 2-oxo-pyrrolophenanthridinium alkaloids, zefbetaine (59) and zeflabetaine (60), together with several known Amaryllidaceae alkaloids, have been isolated from fresh mature seeds of Zephranthes flava by gradient solvent extraction, chromatography, and deri-vatization (108). Their structures were characterized by comprehensive spectroscopic methods, chemical transformations, and synthesis. They are listed in Fig. 9. 

Hamayne (153), 3-O-acetylhamayne (154), crinamine (156), ambelline (161), and a new alkaloid named Josephine (144), together with the lycorine-type alkaloid stembergine (16), were isolated from the bulbs of Brunsvigia josephirute (//). The mass spectrum of 144 showed the molecular peak at m/z 331, and prominent fragments at m/z 289, 242, and 202 that are characteristic of a 1,2-disubstituted crinane alkaloid (140). Its spectroscopic ( H and NMR) evidence established the structure as 144. A new alka-... 

The total synthesis of dihydrolycorine (38), the sole hydrogenation product of lycorine (6 R1 + R2 = CH2, R3 = R4 = H) and an alkaloid in its own right, has been reported.27 Scheme 3 shows how treatment of the Diels-Alder adduct (33) with methanol gave a mixture of two half-esters which were directly subjected to Friedel-Crafts cyclization to give the indanone ester (34) and a rearrangement product. Attempted Schmidt ring expansion on (34) failed, but a prior reduction-oxidation sequence followed by treatment with sodium azide and hydrolysis produced the desired lactam (35) and an isomeric compound whose structure remains undetermined. Lactam (35) was readily converted into a chain-extended... 

In the AmaryUidaceae the alkaloids seem to be confined to the subfamily Amaryllidoidae. Though the structural types are not uniform they seem to be confined to these monocotyledons with one remarkable exception, namely, the phenolic cocculine present in the Caucasian variety of CocctdMS laurifoUus DC. (Menispermaceae). This base, which appears to be absent from the East Asiatic varieties of the same species, apparently has the same ring skeleton as has lycorine, which is remotely related to the isoquinolines so common in the Dicotyledonae (193),... 

Culminating a series of investigations which was reviewed in Chapter 11, lycorine was assigned formula IX by Kondo and Katsura (96a). At that time, the reviewers pointed out that the available experimental data did not rule out structures Villa and IXa. Other investigators, from biogenetic and mechanistic considerations, have suggested formulas XXIV (97), XXV (98), and XXVI (99) for the alkaloid. 

This interpretation of the Hofmann degradation has been strengthened by the conversion of anhydrolycorinium chloride (XL) via XXXIX to ( )-anhydrolycorine methiodide (XXXIVc). Anhydrolycorinium chloride, originally called isolycorine hydrochloride by Kondo and Tomimura (107), is formed by the action of either phosphorus oxychloride or pentachloride on lycorine (108). The assigned structures have been verified by synthesis. Pschorr cyclization of l-(2-amino-4,6-methylenedioxybenzoyl)-indoline (XXXVII) gave the lactam... 

Dehydration of lycorine at 175—185° for 8—24 hours at 4x 10 mm. over alumina affords anhydrolycorine. Consistent with its dihydrophenanthridine structure, anhydro-lycorine is easily oxidized to XXXVm oven during the determination of its melting... 

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