The Diterpene Alkaloids

The Diterpene Alkaloids.— The crystal structures of several complex diterpene alkaloids have been reported. Denudatine, when first reported, was assigned 

Miyaconitine (121) and miyaconitinone are the major alkaloids of Aconitum miyabei The oxygenation pattern suggests a possible mode of formation 

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This C2Q pyrophosphate (122), thought to provide the carbon framework of the diterpene alkaloids such as veatchine (123), atisine (124),... 

Dr. Ken ichi Takeda, then Director of Shionogi Research Laboratories, Na-gata extended his research efforts to include the first total synthesis of the diterpene alkaloid group including atisine, garryine, and veatchine as well as the gibberellins all in their racemic form. 

Oxonine 1, a derivative of the diterpene alkaloid aconitine, undergoes smooth oxidation when treated with exactly one equivalent of periodic acid. The product thus obtained, which shows no aldehyde or ketone absorption in the ir spectrum, is converted into 2 when heated in dilute aqueous base with air passing through the solution. 

Fig. 3 Chemical structures of the diterpene alkaloids with antimicrobial activity...

Table 3 Antiviral activity and cytotoxicity of the diterpene alkaloids...

Briefly, our report was the first on antiviral, antibacterial, and antifungal activities of lycoctonine, 18-O-methyllycoctonine, delcosine, 14-acetyl-delcosine, and 14-acetylbrowniine. Furthermore, our data also suggest that all of the diterpene alkaloids are worthy of being evaluated for their antimicrobial and antiviral activities for future-promising results. 

Diterpene (C20) and norditerpene (C19) alkaloids are typically found in species of the Aconitum, Delphinium, and Consolida genera [43-46]. The toxic effects of the Delphinium and Aconitum species can be attributed to their norditerpene alkaloid content. Thus, many of the examples presented in this chapter have been taken from the analysis of norditerpene alkaloids however, similar experiments would be applicable for any of the diterpene alkaloids (Figure 13.19). 

Because of the difficulties associated with the Delphinium classification, the diterpene alkaloid content was assessed as an aid to determining the chemical taxonomic diversity of the toxic larkspur species [59]. Plant samples were collected from 18 different locations in five western states in the US. The crude methanolic extracts were analyzed for diterpene alkaloids using FI-ESI-MS. The data from the individual ESI mass spectra were statistically analyzed using canonical discriminant analysis and analysis of variance. In brief, the sample (100 mg) was extracted by mechanical shaking at room temperature with methanol (5mL) for 16h. Reserpine (500 p.g) was added as an internal reference standard and the sample mixed for 5 min and then centrifuged. An aliquot (30 jxL) of the supernatant was then diluted with of 1 1 methanol/1 % acetic acid (1.0 mL) and an aliquot (20 jjlL)... 

The use of acylnitrene cyclizations in the synthesis of diteipene alkaloids goes back to the early 1960s, and although much of the early work has been reviewed," selected examples are included here. The acyl azide (19), readily prepared from podocaipic acid, was irradiated to give the 8-lactam (20 20%), which has the azabicyclononane ring system of the diterpene alkaloids such as atisine. ... 

A useful review of the diterpene alkaloids has appeared.Partition chromatography of the Erythrophleum alkaloids from the bark of Erythrophleum guineense has led to the isolation of 8-dehydrocassaic acid. This may arise by the dehydration of a 6a-hydroxy-alkaloid (6a-hydroxycassaine), since erythro-phleguine (6a-hydroxycassamine) gives 8-dehydrocassamic acid on hydrolysis. 

Cyclohexadienones formed from phenols have figured as synthetic intermediates in the synthesis of kauranoid diterpenes. The preparation of a similar tricyclic intermediate (140), suitable for conversion into the diterpene alkaloids, has been described. 

The diterpene alkaloids of the Anopterus species, of which anopterine (R-tigloyl) is a major constituent, are... 

The ABCD ring system of the diterpene alkaloid atisine was constructed by T. Kametani et al using an intramolecular Diels-Alder cycloaddition reaction as the key step. The dienophile was obtained by the traditional Hofmann degradation of the corresponding dimethylamino precursor. The diene was prepared by the kinetic enolization of the cyclohexenone system with LDA. 

There has been an inescapable trend in natural product chemistry during the last decade. Because of advances and refinements in physicochemical techniques and their application to organic chemistry it has become possible to arrive at the structure of a compound with minimal investigation of its chemistry (in some cases with no chemical studies whatsoever). In no area of organic chemistry is this trend more noticeable than amongst the diterpene alkaloids. Many new bases have been isolated, often in very small amounts. This has precluded much in the way of chemical study, but... 

A modern computer-controlled diffractometer allows a structural problem to be solved in a matter of days (and in some cases hours). The technique is ideally suited to complicated structures, and has been used quite extensively in the diterpene alkaloid group. The so-called "direct method" (using a single crystal of the free base) has been applied, for example to the C2o-alkaloid veatchine (1) (Pelletier, Mody, and W. H. DeCamp, J. Amer. chem. Soc., 1978, 100,... 

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. 

The synthesis of the fragment (176) of the diterpene alkaloids, has been described. ... 

This c20 pyrophosphate (122), C20H36O7P2, is thought to provide the carbon framework of the diterpene alkaloids such as veatchine (123), atisine (124), and aconitine (125) (Fig. 5). It is not known at what stage the nitrogen is incorporated into the framework established by the skeleton. The potential for terpene rearrangements and the observation that the alkaloids are frequendy found esterified, often by acetic or benzoic acid, as well as free, has led to permutations and combinations producing over 100 such compounds. 

A totally different synthesis of the diterpene alkaloids has been reported by Masamune (102-104). The carboxylic acid CCXCII was converted via the bromo ketone CCXCIII to the tetrahydropyranyl ethers CCXCIV. Hydrogenolysis of the latter gave the corresponding phenols CCXCV. Base treatment of CCXCV effected cyclization of only one isomer to furnish a dienone ether (CCXCVI). Catalytic hydrogenation of the benzoate (CCXCVII) gave the tetrahydro cis-fused derivative... 

The chemistry of the diterpene alkaloids was last reviewed in a detailed manner in 1960, with coverage of the literature through the early part of... 

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. 

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