Atisine synthesis

A similar sequence 109) has been used for an atisine synthesis starting with the dZ-acid CCCXIVb. Conversion to the acyl azide CCCXXIIb was effected by treatment with ethyl chloroformate and triethylamine followed by sodium azide. Conversion of the acyl azide CCCXXIIb to the lactam CCCXXIIIb was effected via intermediates CCCXXIIIb-CCCXXVb as in the previously described Garrya sequence. This sequence constitutes a simple high-yield construction of the basic tetracyclic atisine skeleton (109). 

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. 

Beams and Manders reported (177) the synthesis of the tricyclic dione 349 via two different synthetic routes. The Australian chemists utilized an approach analogous to one developed earlier by Masamune (178) during the synthesis of atisine and kaurene. They prepared tetrahydro-7-methoxy-2-naphthoic acid (350) from 7-methoxytetral-l-one by published procedures. 

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. 

The synthesis of the tetracyclic amide 437 has been reported by Meyer and co-workers (196) in work directed toward a general diterpenoid synthesis. The enantiomer of this amide has been prepared earlier by Tahara and colleagues (197) and converted to atisine, veatchine, and garryine. 

Musso has reported the synthesis of diasterane (tricyclo-[3.1.1.I2 4]octane) 15. For this first member of the series of asteranes, the decarboxylation of 16b -> 16c was best achieved via the photolysis of the Barton ester of 16a in the presence of BuSH, as shown in Scheme 5.14 Fukumoto has accomplished asymmetric total synthesis of atisine 17, where the bridged pentacyclic intermediate 18, a precursor for atisine, was synthesized via an intramolecular double Michael reaction starting with 19, Scheme 6.15 Barton protocol was favored during the late stages of the synthesis and the presence of various functionalities was easily accommodated. 

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 synthesis of the aromatic methyl ether (191) and the reduction of ring C has been studied." The backbone rearrangement of the synthetic intermediate (192) has been examined in the context of the synthesis of rearranged diterpenoids. The synthesis of the phenol (193), which is a degradation product of atisine, has been reported. 

C, Synthesis.—Atisine and Veatchine Types. Zalkow and co-workers developed syntheses of intermediates potentially transformable into atisine-type alkaloids, starting with podocarpic acid. The general approach is illustrated by a synthesis" of an ajaconine degradation product. Methyl O-methyl-7-keto-podocarpate (56) was reduced to the diol, which was converted by Birch reduction to dienone (57). The diene diol diacetate from this was converted to the 7,8-epoxide. Boron trifluoride converted this to the non-conjugated enone (58) which isomerised and... 

The challenge of effecting in the laboratory the rearrangement from an atisine to a lycoctonine skeleton is very relevant for both partial and total synthesis. Attempts to do this by solvolysis of derivatives with either configuration at C-15 of compounds derived from atisine had given products with the wrong skeleton (e.g. 133 134). However, Johnston and Overton have found that pyrolysis... 

Addition of hydrogen cyanide. As one step in a total synthesis of effect conjugate addition of hydrogen cyanide to the intermediate... 

Synthesis of an Atisine-type Intermediate.—Two synthetic routes to the tricyclic dione (50) were explored by Beames and Mander.30 Using an approach analogous to one developed by Masamune,31 they converted l,2,3,4-tetrahydro-7-hydroxy-2-naphthoic acid (51) into the bromide (52). The reaction of the latter with t-butoxide produced a 3 1 mixture of the dienone ethers (54) and (55). The use of deblocking and oxidation reactions furnished the diketone (50). Reduction of (50) with borohydride furnished a 2 3 mixture of the alcohols (56) and (57). 

Hydrocarbon CXXXIV has also been synthesized by a similar sequence of reactions from abietic acid via maleopimaric acid (CXLI) by Zalkow and Girotra 44, 45). These authors have also converted CXLII, an intermediate obtained en route to hydrocarbon CXXXIV, to CXLIII, which possesses the complete carbocyclic skeleton of atisine in its correct relative configuration. Bell and Ireland had reported previously the synthesis of racemic CXLIII 46). 

Masamune 104) has also converted compound CCCXII, obtained from veatchine azomethine acetate, by a multistep procedure to the monoester carboxylic acid CCLIII. Since the latter has already been converted to atisine by Pelletier and Parthasarathy 96) this work completes in a formal sense the synthesis of atisine also. 

A synthesis of garryine, veatchine, and atisine from (— )-abietic acid also has been described 111). 

The emphasis in C19 and C20 diterpenoid alkaloid research as evidenced by published accounts during the past year has shifted from synthesis to structure determination. Of particular interest are the reports of the isolation of two new C19 bases, acomonine and iliensine, having no C-1 oxygen function. The structures of delphisine and deoxydelcorine have been determined, and revisions of the structures earlier proposed for neoline, chasmanine, homochasmanine, and excelsine have appeared. The numbering systems for the lycoctonine, atisine, and veatchine skeletons are indicated in structures (A), (B), and (C), respectively. 

In 1974 Wiesner and his co-workers reported (96) the first formal total synthesis of talatisamine (68) starting from an atisine-type intermediate (242). A key step in this synthesis involved a rearrangement of the atisine skeleton to the aconitine-type skeleton, a reaction previously suggested... 

In 1973 Wiesner and his colleagues reported (161) a new synthetic route for the construction of the substituted C/D ring system of delphinine-type alkaloids. This process was based on a previous photochemical synthesis of the atisine skeleton (162). 

The Total Synthesis of Talatisamine.—The atisine-type intermediate (62) has been used in the synthesis of talatisamine (63).A key step in this synthetic route is the rearrangement of an atisine skeleton (structure B) to a lycoctonine skeleton (structure A). This type of rearrangement has been proposed in the biogenesis of alkaloids possessing the lycoctonine skeleton. Johnson and Overton S and Ayer and Deshpande have previously reported studies of this process. 

Several new synthetic approaches to the atisine and veatchine alkaloids have been reported, and a detailed account of the synthesis of an optically active relay intermediate in the synthesis of delphinine has appeared. 

Since garryine (84) and veatchine (63) had been previously synthesized from this lactam,and veatchine converted into atisine (36), this work completes another formal total synthesis of these alkaloids. 

The total synthesis of actinomycin G3, a phenoxazone derivative with peptide side chains as well as the total synthesis of atisine and other diterpene alkaloids have been published. 

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