Aconitine-Type Alkaloids

The original degradative work on oxonitine used in the chemical elucidation of the structure of aconitine 74) assumed an iV-acetyl group instead of an iV-formyl group but a later paper (82) has summarized this work and corrected the structures. 

Another reaction which indicated that the CD ring structure of aconitine is similar to that of delphinine was the oxidation of oxonine (CXXXVIII), the hydrolysis product of oxonitine (CXXXIII), with Sarett s reagent to obtain the rearranged diketone CXL. The latter is assumed to arise from a base-catalyzed acyloin rearrangement of the original oxidation product (CXXXIX) which was not isolated. 

Chemical evidence for the ketonic nature of pyroaconitine (CXLI), formed by p3Tolysis of aconitine, was demonstrated by subjecting it to Wolff-Kishner reduction (85). The product of this reaction contained no carbonyl absorption in its IR spectrum, showing that not only had the ketone been reduced but also that the benzoyloxy group had been saponified. Further, one of the methoxyl groups had been eliminated. The Wolff-Kishner product was thus assumed to possess structure CXLIII since it resisted catalytic hydrogenation. A later correlation involving 

A final demonstration that aconitine possessed the CD ring system as shown was the periodic acid cleavage of oxonine to the secoketoaldehyde 

The corresponding aromatization reaction sequence was then repeated with a-oxoisopyrodelphinine (CLIX) since the structure and substitution of the CD ring system of this compound was already known. Compound 

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Zenda, H., Thin-layer chromatography of aconitine-type alkaloids, Kagaku No Ryoiki Zokan, 64, 133, 1964. 

Research on diterpenoid alkaloids published during the past year has continued to expand the body of structural and synthetic information available on these complex plant bases. The structures of ten new alkaloids from Aconitum and Delphinium species, including seven new bisditerpenoid alkaloids, have been reported. Tlie most significant progress in methods of structure elucidation has been the very successful applications of n.m.r. to the study of complex diterpenoid alkaloids. The New Bruns wick group under Professor Karel Wiesner has continued its progress toward the syntheses of the Ci9-aconitine-type alkaloids. An historical account of the synthesis of talatisamine (1), the first synthesis of a hexacyclic aconite alkaloid, has been published. This work was reviewed in a previous Report. ... 

The detection of aconitine-type alkaloids has been performed at 254 nm, although the maximum UV absorption is at 235 nm. 

The most important difference between an aconitine-type and a lycoctonine-type skeleton is that the latter contains an oxygenated functional group at C-7 whereas the former does not. The presence or absence of a ditertiary a-glycol system—either as its free hydroxyl or in its methylenated form—is thus the determining factor in the classification, as well as much of the chemistry, of the lycoctonine- and aconitine-type alkaloids, respectively. Two further trends are to be noted. All of the known lycoctonine-type alkaloids have had a (8-methoxyl at C-6 while in all of the aconitine-type alkaloids which contain a C-6 methoxyl, it is in the a-configuration. Also, whereas many of the aconitine-type alkaloids possess a bridgehead hydroxyl at C-13, none of the lycoctonine-type alkaloids have yet been isolated with a substituent of any kind at this position. 

The placement of the remaining two methoxyls at C-18 and C-6, as well as the configuration of the latter, is based on the formation of certain derivatives of neoline with an internal ether between C-18 and C-6. The configuration of the C-14 hydroxyl has not yet been established, although by analogy with all of the other aconitine-type alkaloids it would be expected to be equatorial (a). A full publication of the neoline work was promised. 

Delphisine.—A new alkaloid, delphisine, C28H43NO8, m.p. 121—122 °C, has been isolated from the seeds of Delphinium staphisagria, by a combination of pH extractions and chromatographic techniques. Chemical and spectral studies indicated it to be a member of the aconitine-type alkaloids. 

Recently, Ichinohe and Yamaguchi have reported the isolation of a new aconitine-type alkaloid from the roots of A. sachalinense Fr. Schmidt (31). 

In 1952 Edwards and Marion (62) observed the apparent diene chromophore in the pyro compounds derived from the aconitine-type alkaloids with no hydroxyl group at the C-15 position. Wiesner and coworkers (63) reported an unexpected UV absorption (Amax 245 nm, emax 6300) for pyrodelphonine (32) and pyroneoline (33), which disappears upon acidification. To explain the unusual behavior of these pyro compounds, they postulated the participation of the lone-pair electrons of the nitrogen with the C-7-C-17 cr bond and the ir system of C-8-C-15 double bond in an excited state resembling structure 32A in pyrodelphonine and 33A in pyroneoline. Later, the same phenomenon, was also explained using valence bond language by Cookson and his co-workers... 

It is interesting to note that cammaconine is the first example of an aconitine-type alkaloid with a /3-hydroxyl group at the C-16 position instead of the usual / -methoxyl group. 

Songorinediacetate (192), in which the C-l oxygen functionality is in a steric environment similar to that in the aconitine-type alkaloids, was also hydrolyzed partially to the C-l monoacetyl derivative (193) in 45 min. On the other hand, the anamolous facile hydrolysis of the C-l acetyl group in di- and tetraacetylkarakolidine (109 and 194) was explained by the steric influence of the C-10 hydroxyl group in these compounds. 

In 1969 Yunusov and his co-workers (143) reported on their mass spectral studies of aconitine- and lycoctonine-type alkaloids. On the basis of mass spectral analysis of isotalatizidine (61), condelphine (67), talatizamine (68), neoline (47), aconitine (4), aconine, lycoctonine (58), and some of their derivatives, they reported that the main ionization center in these alkaloids is the nitrogen atom. During the study of lycoctonine-type alkaloids, they observed that the base peak is usually derived by the loss of the C-l substituents as a radical. If a C-3 substituent was present, as in many of the aconitine-type alkaloids, the heteroring fragmented in a... 

This synthesis represents an outstanding achievement and provides a clarification of the structure of delphinine and related aconitine-type alkaloids. 

Johnston and Overton have reported (153,154) the conversion of the atisane skeleton to the aconitine skeleton, thus effecting the key step in the commonly accepted (152) route for the biogenesis of the aconitine-type alkaloids. 

Ayer and Despande (155) have reported the rearrangement of tosylate 313 into diene 319 by solvolysis or even by passage of a benzene solution through silica gel. This rearrangement serves as a model for the proposed (152) biosynthetic transformation of the atisine-type alkaloids to the aconitine-type alkaloids. 

The acid (337) prepared from (-)-abietic acid was reduced by lithium ethylamine-terf-amyl alcohol to compound 338. The methyl ester of 338 was hydroxylated and the resulting diol cleaved to give diketone 339. The latter was cyclized by treatment with acid to the a,/8-unsaturated ketone (340). Although rings A and can be easily substituted by appropriate reactions to derive the corresponding aconitine-type alkaloid, the major problem with this route is the introduction of the ring C substituents. 

Aconitine-type Alkaloids Syntheses Directed toward Delphinine.— The New Brunswick group have published in detail their work on the stereoselective total synthesis of optically active (62), an advanced relay compound in the synthesis... 

Aconitine-type Alkaloids Syntheses Directed toward Delphinine 246... 

Reactions of Some Aconitine-type Alkaloids.—Ichinohe et al have reported a study of some reactions of C,9 diterpenoid alkaloids. They attempted to correlate... 

The dried tubers of Aconitum plants (Ranunculaceae) are known as U-zu or Bu-shi in Japan, and are used in Kampo medicine (formerly regarded as a form of traditional Chinese medicine). The crude drug is known to contain very poisonous aconitine-type alkaloids (Section 14.4). On the other hand, the methanol extract of the tubers of Anhalonium carmi-chaeli showed hypertensive activity against rats by intravenous injection. The active component was identified as the phenylethylamine-type alkaloid... 

Respiratory center paralysis, stimulation after cardiac conduction failure, paralysis of the circulatory system, and perception efiects and paralysis of motor nerves are the demonstrated biological activities of the aconitine-type alkaloids in animal models. As for cardiotonic substances, other than higenamine, corynerine was also isolated and these alkaloids were described in Chapter 1 (phenylalanine- and tyrosine-derived alkaloids). 

The aconitine-type alkaloid (96) is most probably formed from the atisine skeleton through different modifications as indicated in Scheme 28.4. The intermediate 94 after a Wagner-Meerwein rearrangement process converts two fused six-membered rings into a (7 -i- 5)-membered bicyclic system in which C-17 exocyclic... 

The norditerpenoid alkaloids are complex, multi-cyclic Ciq diterpene alkaloids which are highly substituted with hydroxyl, methoxyl and ester groups. These alkaloids occur in members of the Ranunculaceae family (primarily in Aconitum spp. and Delphinium spp.) and many have been determined to be highly toxic to humans and animals. They occur as two skeletal structure types [36,37]. Three structural sub-types are associated with skeletal type 36, based upon C-7 substitution patterns and C-8, C15 unsaturation aconitine type (i.e. aconitine [38]) lycoctonine type (i.e. lycoctonine [36]) and pyrodelphinine type (i.e. pyrodelphinine [39]). Skeletal type 37 is designated the heteratisine type (i.e. heteratisine [37]) norditerpenoid alkaloids (Pelletier et al., 1984). Only a small number of pyrodelphinine and heteratisine type norditerpenoid alkaloids have been characterized and there is very limited toxicity data available for them (Benn and Jacyno, 1983). More than 300 aconitine and lycoctonine norditerpenoid alkaloids have been characterized (Pelletier et al., 1984, 1991). Aconitum spp. contain almost exclusively aconitine type alkaloids while Delphinium spp. contain primarily lycoctonine type with a few aconitine type alkaloids. 

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