Diterpenoid alkaloid aconitine

The tubers of A. karakolicum collected from the Terskei Ala-Tan ranges of the Kirghiz S.S.R. yielded a new alkaloid (16) designated as aconifine (C34H47NO12 mp 195-196°). Along with this new alkaloid, the tubers of A. karakolicum also afforded the well-known Ci9-diterpenoid alkaloid aconitine (4) and the two known -diterpenoid alkaloids, songorine and napelline. 

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. ... 

Alkaloids of Aoonitum epiaaopale Levi.- Yang and coworkers S have reported a n.m.r. study of several diterpenoid alkaloids isolated from Aoonitum species used in traditional medicine in the Yunnan Province in China. The C n.m.r. chemical shifts for yun-aconitine (30), vilmorrianine A (42), karakoline (vilmorrianine B) (18), vilmorrianine C (43), vilmorrianine D (44), 3-acetylyunaco-nitine (45), and 3-acetylvilmorrianine A (46) and 3-acetylaconitine... 

Similarly it has been shown that the most potent norditerpenoid alkaloids acting as inhibitors of mammalian and insect cholinergic receptors have the C-l 8 anthranilic acid esterification, characteristic of the Delphinium norditerpenoid alkaloid methyllycaconitine (MLA), structurally-related to aconitine [40-42], MLA also had antifeedant effects against Spodoptera eridania with associated post-ingestive and toxic effects at doses within the effective antifeedant dose range of compound 30 [40], suggesting a similar antifeedant mode of action between MLA/aconitine and the C-20 diterpenoid alkaloids. 

These diterpenoid alkaloids may be divided into two broad groups those based on a hexacyclic Cjp-skeleton, and those based on a C20-skeleton. The Ci9-alkaloids are commonly called aconitines, and all possess either the aconitine, the lycoctonine, or the heteratisine skeleton. Usually in the literature, the Ci9-diterpenoid alkaloids are referred to as either aconitine-type or lycoctonine-type alkaloids without structural differentiation. Because this practice sometimes creates confusion, we have divided the Ci9-diterpenoid alkaloids into three categories, defined as follows ... 

In 1972, Jones and Benn (100, 101) made a significant contribution in the application of 13CNMR spectroscopy by demonstrating the use of 13C NMR studies in elucidating the structures of two new Ci9-diterpenoid alkaloids. The 13C NMR spectra of the several aconitine- and lycoctonine-... 

Heteratisine.—A detailed report on the chemical elucidation of the structure and stereochemistry of heteratisine (19) has appeared. This lactone diterpenoid alkaloid has been isolated along with its monobenzoyl ester from the roots of Aconitum heterophyllum Wall. Heteratisine has not been detected in any other plant. An earlier 2f-ray crystallographic analysis of the hydrobromide monohydrate of heteratisine indicated the identical structure. Heteratisine thus bears a closer structural relationship to the highly toxic and polyoxygenated alkaloids of the lycoctonine-aconitine type than to its companion bases atisine, atidine, and hetisine. 

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... 

Applications of N.M.R. Spectrometry to the C19 Diterpenoid Alkaloids 14-Acetylbrowniine.—A review of recent applications of carbon-13 n.m.r. spectrometry to the solution of some of the complex problems of C19 diterpenoid alkaloid chemistry has appeared. Using proton-decoupling techniques and additivity relationships, the carbon-13 chemical shifts for eighteen aconitine and lycoctonine-type alkaloids were assigned. Applications of these methods for the identification and structure elucidation of several new diterpenoid alkaloids were discussed. The new data presented in this work included the identification of... 

According to this classification, actinidine described in this chapter is classified as a monoterpenoid alkaloid, whereas nupharidine and aconitine are classified as sesquiterpenoid and diterpenoid alkaloids, respectively. Batrachotoxin A, which possesses a steroidal skeleton, is classified into steroidal alkaloid. Steroids are derived through the degradation of a triterpenoid skeleton (C30 unit) [2,4]. 

Table 28.2 Diterpenoid alkaloids (compound 1-2 ranaconitine-type Cig-diterpenoid alkaloids, 3-13 aconitine-type Cig-diterpenoid alkaloids, 14—24 lycoctonine-type Cig-diterpenoid alkaloids, 25 Cig-rearranged-type Cig-diterpenoid alkaloid, 26-27 atisine-type C2o-diterpenoid alkaloids, 28 hetidine-type C2o-diterpenoid alkaloid, 29-36 hetidine-type C2o-diterpenoid alkaloids, 37-41 denudatine-type C2o-diterpenoid alkaloids, 42-51 vakognavine-type C2o-diterpenoid alkaloids, 52 atisine-denudatine-type C2o-diterpenoid alkaloid)...

The Ci9-diterpenoid alkaloids are the largest class of naturally occurring diterpenoid alkaloids with more than 700 compounds so far isolated and characterized from around 315 species of plants mainly from the generz. Aconitum and Delphinium. This class of alkaloids is divided into six types aconitine type (B-1), lycoctonine type (B-2), pyro type (B-3), lactone type (B-4), l, l-seco type (B-5), and rearranged type (B-6) (Fig. 28.2). The order of types from B-1 to B-6 is based upon the higher to lower number of alkaloids obtained so far. In between 2009 and Feb. 2012, only aconitine, lycoctonine, and rearranged-type Cig-diterpenoid alkaloids have been isolated and are discussed herein. 

The aconitine-type Cig-diterpenoid alkaloids, namely, macrorhynine (28) and ouvrardianine A (29), with a rare C-19 imino unit, were isolated from A. macrorhynchum and A. ouvrardianum, respectively. The group at C-19 in both compounds 28 and 29 was determined on the basis of its ID and 2D NMR and other spectroscopic data analysis [31, 35]. 

Liangshantine (30) features an a,)S-unsaturated carbonyl group at ring A [36], A novel aconitine-type Cig-diterpenoid alkaloid named aconitorientaline (31) was isolated from the roots of A. orientale [37]. This compound contains an epoxy group... 

The characteristic feature of this type of Cig-diterpenoid alkaloids is the presence of an oxygenated functionality at C-7. Like that of aconitine type, these alkaloids are also subdivided into amines, imines, amides, and iV,0-mixed acetals based upon the substitution pattern of the nitrogen. A total of 11 lycoctonine-type Ci9-diterpenoid alkaloids (32-42) have been obtained between 2009 and Feb. 2012. Compoxmds 32-35 possess a benzoyl ester moiety at C-18 with a variety of amide groups in the ortho position. Anthriscifoldine A (36) [30] and delphidenine (37) [39] are identical compounds reported by different research groups almost at the same time from D. anthriscifolium and D. densiflorum, respectively. 

Scheme 28.4 Possible biosynthetic pathways of aconitine-type (94) and lycoctonine-type (97) Ci9-diterpenoid alkaloids...

Baillie LC, Batsanov A et al (1998) Synthesis of the A/E/F sections of conacraiitine, napelline and related diterpenoid alkaloids of the aconitine group. J Chem Soc Pericin Trans l(20) 3471-3478... 

The most toxic alkaloids of aconite, such as aconitine, mesaconitine, hypaconitine, etc., are known to possess arrhythmogenic effect. Aconitine itself has long been used to induce arrhythmia in experimental models [38, 39]. Aconitine and its structural analogues induce ventricular ectopics, ventricular tachycardia, torsades de pointes, and ventricular fibrillation in a dose-dependent manner. Aconitine has a positive inotropic effect on the heart. It has hypotensive and bradycardic actions [40]. Another group of diterpenoid alkaloids possessing C18 and C19 skeleton, such as lappaconitine, A -deacetyllappac(Miitine, heteratisine, and 6-benzoylheteratisine, are... 

Table 48.6 The structural differences of aconitine-like diester diterpenoid alkaloids...

The second group of diterpenoid alkaloids comprises moderately toxic Cig-alkaloids having a benzoyl moiety on the C-6, C-4, or C-14 positions, and without an acetyl moiety on the C-8 position. The representatives of alkaloids with a C-6 or a C-4 benzoyl moiety are 6-benzoylheteratisine, lappaconitine, and ranaconitine. Even if the LD50 values of lappaconitine and 6-benzoylheteratisine found in the literature are not identical [32, 33, 35], these compounds remain about 20-50 times less toxic than diester alkaloids. However, they are more toxic than the de-esterified derivatives of aconitine-like alkaloids having a benzoyl group at C-14, such as benzoylaconine, benzoylmesaconine, and benzoylhypaconine, which indicates the importance of the position of the benzoyl moiety for toxicity. 

Some useful reviews of diterpenoid chemistry have appeared. During the year the n.m.r. resonances of a number of groups of diterpenoids have been assigned. These include the labdanes, podocarpanes, kauranoids, beyeranes, gibberellins, and aconitine alkaloids.In addition n.m.r. has played a major role in the elucidation of the structure of many new diterpenoids during the year and this is discussed in the relevant sections. 

Though no detailed reports on the biosynthesis of aconitine alkaloids are reported, it seems that these alkaloids may initially have a similar biosynthetic pathway to that of taxol (Section 14.5) and possess the diterpenoid skeleton as the basic skeleton. However, unlike the case of taxol, a nitrogen atom is incorporated into the parent nucleus. The biogenesis for the incorporation of four C5 units into the aconitine system is shown in the Figure [8]. 

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