The Atisine Alkaloids

At the time of the 1960 review (6) the structures for atisine and iso-atisine were considered to be XXX and XXXI, respectively. However, aside from the suggestive nature of certain dehydrogenation data, all the chemical evidence for atisine could be accommodated as well by structure XXXII, in which the positions of the allylic hydroxyl and exocyclic methylene groups are reversed. 

Definitive evidence on this point has been provided by Dvomik and Edwards (17), who have shown that hydration of the C2o-azomethine alcohol XXXIII derived from atisine (18, 19) gave the diol XXXIV, which on reduction, acetylation, selective hydrolysis, and oxidation gave a 7,8-secomethylketo acid (XXXV). Treatment of the latter with tri-fluoroacetyl peroxide followed by hydrolysis and dichromate oxidation gave the bis norketo acid XXXVI (1712, 1602 cm i). Dibromination of 

XXXVI followed by dehydrohalogenation gave a crystalline phenol 

XXXVII (828, 1586, 1638 cm i, A, ax 282 mp. shifting to 300 mp. in alkali), and a keto y-lactone (1796, 1734, 1639 cm i). Formation of the latter, involving displacement of bromine a. to the keto group by carb-oxylate anion demonstrates a 1,4-relationship of the ketone and carboxyl groups in XXXVI. Thus these results, when taken with Jacobs dehydrogenation evidence for substitution at C-12 (20, 21), show clearly that a bicyclo[2.2.2]octane system is present in atisine and that the terminal 

Additional evidence on this point is provided by the following sequence of reactions (22, 23). Isomerization of isoatisine (XXXI) with ethanolic hydrochloric acid gave a mixture of epimeric methyl ketones (XXXVIII, 1712 cm i). That skeletal rearrangement had not occurred during the isomerization was shown by borohydride reduction of XXXVIII to give 

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The lactam (Formula 470) has been converted to Formula 471 which proved to be the enantiomer of a degradation product of atisine (209). This clarifies the stereochemistry of the atisine alkaloids, the garrya alkaloids, and related diterpenes (209). 

This type of alkaloids has a hexacycUc core with an additional bond at C-20-C-14. They are more complex than the atisine alkaloids. One new hetidine-type C2o-diterpenoid alkaloid named anthriscifolmine I (46) was reported between 2009 and Feb. 2012 from D. anthriscifolium [44]. 

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

A. heterophyllum, in which atisine was the chief alkaloid, after standing four years, yielded 8 grams of isoatisine, due to isomerisation with heter-atisine. O 4 gm., and atisine hydrochloride, 0-35 gm. ... 

The C2o-diterpene alkaloids have long served as classic targets within the field of natural product synthesis [14], Total syntheses of four C2o-diterpene alkaloids have thus far been reported atisine [15], veatchine [16], garryine [17], and napelline [18]. In spite of this progress, synthetic efforts toward the hetisine alkaloids have been relatively sparse. Prior to our work in the area, these efforts include one total synthesis and five synthetic studies. 

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. 

Staphisagnine (193) and staphisagrine (194) were also isolated (150) in extremely small amounts from the mother liquors accumulated during the isolation of delphinine from the seeds of D. staphisagria. These alkaloids are unusual in containing an oxazolidine ring of the atisine and veat-chine type in addition to many of the uncommon features of the staphisine skeleton. 

The 13C-NMR spectra of these compounds were analyzed to identify and distinguish skeletal features of the atisine and veatchine-type alkaloids for use in the structure elucidation of new C20-diterpenoid alkaloids. 

Beams, Halleday, and Mander (179) reported the preparation of the BCD ring system intermediates of the atisine- and veatchine-type alkaloids by intramolecular carbenoid addition reactions. 

To establish the generality of this procedure, the Australian chemists synthesized (179) the enedione 376 from 375 as shown in Scheme 2. Compound 376 contains the BCD ring system of the atisine-type alkaloids. 

The acid-catalyzed rearrangement of 377 and 379 afforded 378 and 380, respectively, in good yields. The tricyclic ketone 380 contains all appropriate functionality for the synthesis of the atisine-type alkaloids, ajaconine and atidine. 

Alkaloids of Aconitum falconeri Falaconitine and Mithaconitine. In addition to the previously known veratroylpseudaconine (5), pseudaconitine (6) and indaconi-tine (7), two new C19 diterpenoid alkaloids, falaconitine and mithaconitine, have been isolated from the roots of Aconitum falconeri Stapf.13,14 Singh and coworkers15 had reported a preliminary study of the two alkaloids, bishatisine and bishaconitine , isolated from this species. However, in the recent work,13,14 no bishatisine or any atisine-type alkaloid was identified, and the data reported for bishaconitine were consistent with a mixture of falaconitine and several closely related bases. The identities of (5), (6), and (7) were determined primarily by H and 13C n.m.r. techniques and confirmed by comparison with authentic samples.14... 

The use of acylnitiene 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 podocarpic acid, was irradiated to give the 8-lactam (20 20%), which has the azabicyclononane ring system of the diteipene alkaloids such as atisine. ... 

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. 

The numbering system for the alkaloids used in this chapter is based upon the standard skeletons atisane, kaurane, and aconane and corresponds with the proposal suggested by J. W. Rowe and endorsed by O. E. Edwards, K. Wiesner, and the author. Thus the atisine, veatchine, and lycoctonine systems are numbered as in (1), (2), and (3), respectively.1... 

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. 

Alkaloids of the atisine and hypognavine types yield phenanthrenes on dehydro-... 

V. The Ternary Iminium Salts of the Atisine and Garrya Alkaloids. 166... 

The atisine and Garrya (35,36) alkaloids have been interrelated by converting both atisine (XXX) and veatchine, by a parallel sequence of degradations, to the same A-acetyl ester (XCV) (35, 36). The respective azomethine acetates (LXXXVII, LXXXVIII) derived from atisine (12,16-bond) and veatchine (13,16-bond) were converted to the A-acetyl derivatives (LXXXIX, XC) by reduction, acetylation, and saponification. Oxidation of LXXXIX and CX with permanganate/periodate under controlled conditions gave the respective carboxylic acids (XCIa,... 

With the absolute configuration of the atisine and Garrya alkaloids established, it is interesting to note that these compounds join the ranks of terpenes with antipodal stereochemistry of the A/B ring fusion as compared with that of the steroids, e.g., andrographolide, atisirene, cafestol. 

Early in their studies on the structure of atisine, Jacobs and Craig observed that brief treatment with warm alkali was sufficient to iso-merize atisine to another base named isoatisine 48). Subsequent work has shown that the related alkaloids veatchine 49), garryfoline 50), and... 

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