Veratrum alkaloids, structure

Many of the alkaloids from Veratrum, Zygadenus and related genera are based on the cevane structure 1. The chemistry of the Veratrum alkaloids has been reviewed from time to time both in this treatise (1-3) and elsewhere (4-6). The most recent of these articles was published in 1973, and many new compounds have been discovered since then. Recent years have seen the announcement of many X-ray crystal structure determinations on these stereochemically complex alkaloids. A total synthesis has been reported for only one of the natural products, namely, verticine (7). The work that lead to this notable achievement has been reviewed (8). The pharmacology of both the alkaloids (9-12) and their synthetic derivatives (13) has been reviewed, although not since 1977. This chapter takes a different approach from previous reviews. The chemical reactions used for structure determination and modification are first summarized, but the main part of the chapter is a series of tables which include all the known cevane derivatives, both old and new. This is intended as a reference source for future workers in the field. The literature has been covered to the end of Volume 113 of Chemical Abstracts (1990). 

The application of traditional chemical methods to structure determination in Veratrum alkaloids is next illustrated by reference to selected examples. Some recent structural work, not previously reviewed, is included at the end of this section. 

Figure 26 shows the formula, conformation, and absolute configuration of veratridine (52). The structure and conformation of the C27-steroidal base is very similar to that determined for zygacine (C32H49N08) another Veratrum alkaloid (53). Variations in the pharmacological effects of Veratrum alkaloids appear to be dependent on the substituents attached to the essentially rigid molecular framework. The numerous intramolecular hydrogen bonds that enhance the molecular rigidity are indicated in Fig. 26. The positions of all the hydrogen atoms have been located for the veratridine molecule and the intramolecular donors and acceptors are identified as...

Neumcke B (1990) Diversity of sodium channels in adult and cultured cells, in oocytes and in lipid bilayers. Rev Physiol Biochem Pharmacol 115 1-49 Noda M (1993) Structure and function of sodium channels. Aim NY Acad Sci 707 20-37 Noda M, Shimizu S, Tanabe T, Takai T, Kayano T, Ikeda T, Takahashi H, Nakayama H, Kanaoka Y, Minamino N, Kangawa K, Matsuo H, Raftery MA, Hirose T, Inayama LS, Hayashida H, Miyata T, Numa S (1984) Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312 121-127 Ohta M, Narahashi T, Keeler RF (1973) Effects of veratrum alkaloids on membrane potential and conductance of squid and crayfish giant axons. J Pharmacol Exp Ther 184 143-154... 

II. Structures and Chemical and Physicochemical Properties of Veratrum Alkaloids... 

Reactions and Structure. The determination of the structures of those Veratrum alkaloids that have a large number of oxygen atoms offers considerable difficulty. Of these cevine has been the most thoroughly investigated, but it has not been possible to propose a satisfactory structure for it. 

Jervlne a jeveratrum type of Veratrum alkaloid with a C-nor-D-homo structure. M, 425.62, m.p. 238 °C, [a]o -147°. J. is the main alkaloid of white and green hellebore (Veratrum album and V. viride). 

Rubijervina 12a-hydroxysolanidine solanid-5-ene-3p,12a-diol, a Veratrum alkaloid of the jervera-trum type. M, 413.65, m. p. 242"C, [ajp -h 19 (ethanol). It occurs in hellebore (Veratrum album, V. nigrum and V. viride) and differs structurally from solanidine (see a-Solanine) by the presence of a 12a-hydroxyl group. Rubisco see Ribulose huphosphate carboxylase. 

Veratramine a Veratrum alkaloid (see) of the jer-veratrum type, with C-nor-D-homo structure, M, (anhydrous) 409, m.p. (monohydrate) 209.5-210.5 °C [o][3 (anhydrous) -70° (methanol), found in hellebores Veratrum album, V. eschscholtzii, V. viride). V. viride also contains veratrosine, a glycoalkaoid in which the 3-p-hydroxyl group of veratramine is linked glycosidically to o-glucose. 

The stereochemical structure of the Veratrum alkaloid veratrobasine (XXIV) was obtained by X-ray studies and this result required that the C-17 configuration in jervine be revised after it was demonstrated that veratrobasine and Jervine-llp-ol were one and the same. This also established the absolute configuration for jervine, 11-deoxojervine, veratra-... 

Reviews on various aspects of the chemistry of the Veratrum alkaloids have been written by Fieser and Fieser (i), Boit (2), Kupchan (5), and Narayanan (4). In addition, the occurrence of alkaloids in plants of the Veratreae, the classical botanical taxonomy of the Veratreae, and the implications of alkaloid occurrence and structure to the taxonomy of the Veratreae have been reviewed by Kupchan et al. (5). Relationships between structure and hypotensive activity of Veratrum alkaloids and their semisynthetic derivatives have recently been reviewed by Kupchan and Flacke (6). 

Keeler RF, Binns W. Teratogenic compounds of Veratrum californicum (Durand). V. Comparison of cyclopian effects of steroidal alkaloids from the plant and structurally related compounds from other sources. Teratology. 1968 1(1) 5-10. 

Since the establishment of the structure of conessine (1), and the discovery of numerous steroidal amines, the theoretical and economic interest of the steroidal amines and alkaloids has stimulated very active chemical research on the plants of the Apocynaceae and Buxaceae families. The main points in this work are set out in two monographs. The present account is confined to the results obtained since 1966 and deals only with the Apocynaceae and Buxaceae families. The Solanaceae and Veratrum groups are not included. 

The structure of two novel esters of germine containing an aromatic acid was elucidated as follows (57). Both alkaloids isolated from Veratrum album subsp. lobelianum were cleaved by alkaline hydrolysis to germine (82) and isogermine (83), respectively. One mole equivalent of veratric acid was isolated from the acidic portion after saponification of 84. In addition, compound 85 afforded one mole of acetic acid (53). 

Veralinine, a minor alkaloid from Veratrum album subsp. lobelianum, also has the rearranged 22,26-epiminocholestane skeleton (74). From chemical and spectroscopic evidence this Veratrum base is regarded as (22S,25S)-22,26-epimino-17/3-methyl-18-Jior-cholesta-5,12-dien-3 iS-ol (118). This structure was confirmed by correlation with veralkamine. The ketone 115 prepared from veralkamine was treated with ethanedi-thiol. Desulfurization of the resultant thioketal 119 with Raney nickel yielded the C-16 deoxo compound 120, which is identical with (22S,25S)-22,26-acetyl-epimino-17 3-methyl-18-7ior-5a,13a-cholestan-3j8-ol, also prepared from veralinine (118) via catalytic hydrogenation... 

The material of this review is discussed in Solanum and Veratrum sections in accordance with precedent/ although the division of material between these sections is sometimes arbitrary. Related steroidal alkaloids isolated from other genera are discussed in that section which seems most appropriate on structural grounds. 

The alkaloid constituents of Veratrum lobelianum have been the subject of continuing close scrutiny.Veralosidinine and veralodisine have recently been isolated from this plant and have been assigned the structures (18) and (19), respectively. 

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