Type Diterpene Alkaloids

There is a small group of diterpene alkaloids occurring in the mother liquors oiAconitum heterophyllum Wall., which are modeled on a modified lycoctonine-type skeleton and contain a lactone ring. Since the most prevalent of these compounds, heteratisine, is related in a simple fashion to the other members of the series, its chemistry will be considered in some detail. 

Heteratisine 145, 146) occurs in the weak-base fraction of A. heterophyllum to the extent of 0.03%. It may be an artifact obtained during isolation by hydrolysis of its benzoyl ester. The molecular formula 145, 146), C22H33NO5, has been confirmed by crystallographic studies 147). The usual chemical tests revealed the presence of the following functional groups two hydroxyls, one methoxyl, one A-ethyl, and a 

S-lactone (1739 cm i). These groups account for all the hetero atoms and leave a 6-ring 19-carbon skeleton. The high level of oxygenation and failure to yield phenanthrenes on dehydrogenation suggested that heteratisine consists of a modified lycoctonine-type skeleton. The structure (CCCXCV) shown for heteratisine has been deduced independently by X-ray analysis of heteratisine hydrobromide monohydrate 150) and by chemical and spectral studies 151,152). 

Other structural features clearly recognizable are a quaternary C—CH3 (t9.03, 3H singlet), H—C—OH (t5.5, IH multiplet), H—C—OCO (approx. t5.26, IH), and OH (t4.97, IH singlet) (151). One of the two hydroxyls is tertiary (resistant to acetylation and oxidation) and the other secondary. Heteratisine forms a basic monoacetate (CCCXCVI) and monobenzoate (CCCXCVII). The latter is identical with the naturally occurring benzoyl ester (145,146). The monoacetate with 

Analysis of the NMR spectra of heteratisine and its derivatives at lower field than the methoxyl resonance, in conjunction with biogenetic analogies, permits location of the lactone, the tertiary hydroxyl, and, with some reservations, the methoxyl group (151). The splitting of the H—C acetoxyl signal in heteratisine acetate (CCCXCVI) and oxoheteratisine acetate (CCCXCVIII) into a doublet of doublets is consistent with its location at C-6 and spin coupling to H(C-7) and H(C-5). 

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As represented in Fig. 166, ring closure to y-piperidonc may occur, starting both from precursors 442 and aminoketones 443 with the suitable aldehyde. The synthesis of aconitine-type diterpene alkaloids" takes place similarly (Fig. 167), the only difference being the presence in the reactive site of an allylic carbon atom (446) instead of the alkyl group in a position to the carbonyl. 

Hg. 167. Synthesis of aconitine-type diterpene alkaloids by intramolecular aminomethyla-tioii leading to a P-aminoalkene (bold lines) derivative. 

Liu YM, Sun L, Liu QH, Lu SR, Chen BQ. Dolabellane-type diterpene alkaloids from Nigella glanduhfera. Biochem Syst Ecol 2013 49 43-6. 

Even though much is already known about the toxicity of diterpene alkaloids that contribute to the toxicity of Consolida, Delphinium, and Aconitium species, no antiviral study has been so far reported on this type of alkaloids. Therefore, no SAR studies have been encountered by us on the antiviral or antimicrobial activities of these alkaloids. However, a quantitative SAR analysis performed on a number of diterpene alkaloids isolated from an Aconitum sp. indicated that biological activity of these alkaloids may be related to their toxicity rather than to a specific pharmacological action [40]. In a current study on 43 norditerpenoid alkaloids from Consolida, Delphinium, and Aconitum species against several tumor cell lines, lycoctonine and browniine were... 

Species in a relatively small number of herbivorous families dominate the list of plant feeders associated with alkaloid-rich foods. Lepidoptera (butterflies and moths) have catholic tastes when it comes to alkaloid-fortified plants, being represented by the families Nymphalidae (calystegine A-3, pyrrolizidine alkaloids lycopsamine type, harman), Arctiidae (senecionine type), Papilionidae (synephrine, isoquinolines), and Pterophoridae (monoterpene alkaloid rhexifoline).6 In addition, beetles (Chrysomelidae) sequester PAs (senecionine), grasshoppers (Acrididae) store senecionine, and aphids (Aphididae) sequester QAs (sparteine and diterpene alkaloids). 

The first Mexican substance searched for, found, and isolated based on old traditions, was the sesquiterpene hemandulcin from Lippia dulcis Trev. It was determined by a human taste panel to be more than 1000 times sweeter than sucrose. The structure of this sesquiterpene was determined and confirmed by chemical synthesis. It was nontoxic when administered orally to mice, and did not induce bacterial mutation.5 Further work has been carried out with some of the plants more frequently used (Table 12.3). The sesquiterpene alkaloids hippocrateine I, hippocrateine II, and emarginatine were identified in Hippocratea excelsa used in Mexican traditional medicine, and antimicrobial abietane type diterpenes were isolated from Salvia albocaerulea.6 7... 

Whilst gas chromatography has been used for the analysis of many of the lycoctonine-based alkaloids [52], the larger, less volatile, and more thermally labile MSAL compounds require analytical procedures such as TLC and HPLC for separation and detection. For example, both normal phase liquid chromatography [53] and reversed phase liquid chromatography [54] with UV detection have been used for separation, detection, and quantitation of alkaloids from Delphinium species associated with livestock poisonings in the western US and Canada. The introduction of API techniques has allowed the analysis of all types of diterpene alkaloids by direct MS methods and with MS methods coupled to liquid chromatography. 

The azabicyclononane system is a common structural feature in diterpene alkaloids, and the nitrene insertion route to the ring system has been studied in detail in model decalins as well as in steroids (Scheme 11). Thus irradiation of the rrans-acyl azide (21) gave, in addition to isocyanate (30-33%), a mixture of Ae 7- and 8-lactams (22) and (23). The y-lactam (22) predominated, dthough the overall yield was poor. > The corresponding c/s-azide (24), however, gave the 8-lactam (25) as Ae major product, again in low yield. One elegant application of this type of intramolecular nitrene insertion reaction... 

This type of spectroscopy is used very extensively in the diterpene alkaloid field, and is as important as X-ray diffraction analysis as a method of structure investigation. 

Synthesis of a Veatchine-type Intermediate.—A recent synthesis32 of gibberellin-A15 involves an intermediate of interest for the synthesis of diterpene alkaloids. Enmein (58) had previously been converted to the alcohol (59).33 Oxidation of this alcohol afforded an aldehyde which was converted to its oxime. Removal of the blocking group afforded (60). The nitrone (61), prepared by treatment of (60) with bromonium azide, was photolysed to (62). The resemblance of this intermediate to several alkaloids of the veatchine-type is obvious. Minor variations of this scheme may prove to be of synthetic interest. 

The structures of the more complicated diterpene alkaloids may be subdivided into two general types of skeletons which are closely related. 

To further asses such hypothesis we carried out a comparative study on the antifeedant and insecticidal effects of the ryanodol/isoryanodol-type diterpenes from P. indica (non-alkaloidal type ryanoids 1-9) [9, 10, 11] and ryanodine-type (alkaloidal type) ryanoids (ryanodine/spiganthine ryanoids 10-18), isolated from Spigelia anthelmia (Loganiaceae) [15, 16]. We studied their effects on the feeding behavior, survivorship and performance (biomass gain and food ingestion) of S. littoralis larvae and L. decemlineata (Colorado potato beetle, CPB) adults [17]. 

Structural and synthetic studies of the diterpene alkaloids of the Aconitum, Delphinium, and Garrya species continue to provide more insight into the chemistry of these complex bases. In recent years Japanese workers have isolated a series of isoprenoid alkaloids from plants of Daphniphyllum macropodum Miquel. Structural work on four new alkaloids representing three new structural types has been reported during this year. 

Mass Spectral Studies of the C g-Diterpene Alkaloids. Yunusov and co-workers have published further studies on the mass spectra of diterpene alkaloids possessing the lycoctonine-type skeleton. ... 

Alkaloids can be divided into different t q3es according their pure chemical structures pointing first at the alkaloid base, a basic chemical nucleus. The following are basic types of alkaloids acridones, aromatics, carbo-lines, ephedras, ergots, imidazoles, indoles, bisindoles, indolizidines, manza-mines, oxindoles, quinolines, quinozolines. quinolizidines, phenylisoquinolines, phenylethylamines, piperidines, purines, pyrolidines, pyrrolizidines, pyrro-loindoles, pyrydines, sesquiterpenes, simple tetrahydroisoquinolines, stereoids, tropanes, terpenoids, diterpenes, and triterpenes. 

Tashkhodzhaev B, Saidkhodzhaeva SA, Bessonova lA, Antipin MYu. Arcutin— a new type of diterpene alkaloids. Chem Nat Comp 2000 36(l) 79-83. 

A modified type of e f-kaurene system is found in the diterpene alkaloids of the Garryaceae and the Ranunculaceae see Diterpene Alkaloids in Chapter 36). 

The genus Taxus (Taxaceae) is noted for the presence of diterpenes and diterpene alkaloids such as taxine see Chapters 22 and 36). There is a complete dichotomy in the types of alkaloids present in the two groups. These data do not support union of the two families. 

Two main structural types of diterpene alkaloids are found in these genera. One group includes a series of comparatively simple and relatively nontoxic amino alcohols and esters modeled on a C20 skeleton. These alkaloids are not extensively oxygenated and contain, at most, one methoxyl... 

Correlations within a stereochemically homogeneous series of compounds, such as monosaccharides and steroids, which are well documented elsewhere in the literature are considered in outline only. Series of compounds which are essentially dimeric or polymeric types built up from chiral monomeric units are not covered in detail, since their configurations follow readily from those of the monomeric unit. Examples of such polymeric-type compounds are di-, oligo- and polysaccharides bis (benzylisoquinoline) and other dimeric alkaloids biflavonoids and polypeptides. Series of natural products having essentially the same carbon skeleton but known in a variety of stereochemical types due to epimerism at one or more chiral centres are frequently covered by general notes rather than by large numbers of examples. This treatment is given, for example, to the labdane-type diterpenes and the yohimbane-type alkaloids. 

Similar types of diterpene alkaloids have been found in Garryaceae plants. Garryine and veatchine were isolated from the bark of Garrya veatchiU a tree distributed in the area from the southwestern United States to Mexico and Guatemala (162). 

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. 

Fig. 5 Molecular structures of tyrosinase-active diterpene (8-10) and napelline (11, 12) type alkaloids [49]...

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