Synthesis of Diterpene Alkaloids

There has been such great activity in this area within the past few years that only the most significant developments will be summarized. 

Methylation of CCLVII proceeded smoothly with methyl iodide and sodium hydride in dimethyl sulfoxide to give a mixture of epimeric 

A synthesis of dLgarryine and dZ-veatchine has also been reported by Nagata et al. (99, 100). The dimesyl derivative CCLXXVI was refluxed 

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 

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. 

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Although the functionalization of unactivated C—H bonds by intramolecular nitrene insertion has been aj Iied to the synthesis of diterpene alkaloids and in the modification of steroids as described below, it has also been used to good effect in simpler systems. For example, 1-adamantyl azidoformate, readily prepared from 1-adamantanol, gives the oxazolidinone (17) on irradiation in cyclohexane by in-... 

Fascinating rearrangements of aziridines have been applied to the synthesis of diterpene alkaloids by Wiesner and co-workers (Scheme 40). For example, the ester 217, prepared from cyclopentadiene carboxylate (215) and the benzyne precursor 216 by a Diels-Alder reaction, was converted to the aziridine 218 by treatment with benzenesulfonyl azide in 83% yield. When the aziridine 218 was heated with water for 24 h, the hydroxy ester 219 was obtained in 97% yield subsequent oxidation with the Jones reagent afforded the ketone 220. This rearrangement is analogous to that of the benzenesulfonylaziridine of norbomene. ... 

Further synthetic studies of diterpene alkaloids with the aziridine rearrangement as a key reaction have been reported and led to the synthesis of diterpene alkaloids chasmanine (234) and 13-deoxydelphonine (235). 

In investigating the synthesis of diterpene alkaloids, Wiesner et al.1 1 have used the combination of sodium chlorate with a catalytic amount of osmium tetroxide, for example ... 

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 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. ... 

An approach to the polycyclic diterpenes, including veatchine, was initiated by Meyer. 2,2-Dimethylcyclohexanone was converted to the cyano-enone (110). This was elaborated into the cyano-phenol (111) which has potential for the synthesis of the alkaloids. 

Several other interesting approaches to the C2o-diterpene alkaloids have been reported 46, 113-138)—some involving total synthesis and others partial synthesis from natural products. Very brief surveys of diterpene alkaloid chemistry have also been published (139-141). 

The seventh volume in this series is in preparation and is planned for publication in about one year, covering the synthesis of diterpenes, diterpene alkaloids, macrocycles, and anthracyclinones. 

Many spectral data for terpene-derived alkaloids have been reviewed (Pelletier and Mody, 1979, 1981). Both the and C-NMR spectra for several diterpene alkaloids have been discussed (Crabb, 1982). The results of feeding studies leading to the synthesis of several alkaloids of this group have been tabulated (Leete, 1983). 

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. 

The benzyne route to 1-cyanobenzocyclobutenes has been employed for the synthesis of a myriad of complex natural products. The cyano group in (74) was used to attach the dienophile as well as for building die imino bridge of (75), an important precursor for some diterpene alkaloids (Scheme 15).110... 

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. 

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. 

Kametani, T., Honda, T Fukumoto, K., Toyota, M., lhara, M. Synthetic approach to diterpene alkaloids - a simple and novel synthesis of the A,B,C and D ring part from 1-benzyl-1,2,3,4-tetrahydroisoquinoline. Heterocycles 1981, 16, 1673-1676. 

Unsymmetrical alkenes can be prepared by mixed intermolecular reactions if one of the components, commonly acetone, is used in excess (equation 83). As the isopropyl group is a common subunit of many terpenes this method provides a valuable route for its introduction. Pattenden and Robertson used such a reaction followed by a Grob-type fragmentation in their preparation of the daucenone (42) from the readily enolized ketone (43). The bicycle (42) was used as an intermediate for the synthesis of the diterpene ( )-isoamijiol (44 equation 84). Mixed couplings are not restricted to acetone, and almost any carbonyl may be used. For example, Paquette et al. employed the aldehyde (45) in a synthesis of ( )-a-vetispirene (46 equation 85). More complex mixed couplings are also possible. For example, the aldehydes (47) and (48) are coupled efficiently to the stilbene (49), which in turn is converted to phenan-threne alkaloids such as atherosperminine and thalictuberine (equation 86). ... 

A total synthesis of the C19 alkaloid chasmanine (7) has been described it represents a landmark in diterpene alkaloid chemistry (K. Wiesner and co-workers, Canad. J. Chem., 1975, 2140 1976, 54, 1039 1977, 1091 Heterocycles, 1977,... 

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

Diterpene Alkaloid Synthesis from a Diterpene Acid Intermediate. Mori, Saeki, and Matsui have converted an intermediate (78) in their synthesis of kaur-16-en-19-oic acid (79) into the tetracyclic lactam (83). This lactam was an intermediate in Wiesner s total syntheses of garryine and veatchine. ... 

A New Approach to the Synthesis of Ring E of the Diterpene Alkaloids. An intramolecular carbenoid insertion as a means of introducing the C-20 functionality has been employed by Ghatak and Chakrabarty in work related to their general diterpenoid syntheses. 

Syntheses Directed toward Ajaconine and Atidine. The conversion of podocarpic acid (92) into a key intermediate (93) in the synthesis of the enantiomers of the diterpene alkaloids ajaconine (94) and atidine (50) has been reported by 2 1kow and co-workers. The pentacyclic unsaturated keto-lactam (93) was prepared... 

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