Enmein synthesis

In the course of the total synthesis of enmein, Fujita and co-workers (7) have discovered that the intramolecular cyclization of the enolate 23 of the corresponding tetracyclic keto-aldehyde at room temperature gave only ketol 24. However, when the same reaction is conducted at 60°C, thermodynamically controlled conditions prevail, and the epimeric product 25 is obtained. Inspection of molecular models indicates that the kinetically controlled product 24 is again the result of an anti peri planar arrangement of the enolate and the aldehyde double-bonds. Also, as in the previous examples, the isomer 25 comes from a synclinal arrangement of the reacting functional groups. 

Enmein was converted to 20-hydroxykaur-6-en-15a-pyranylether (382), which was oxidized with chromium trioxide in pyridine to afford the aldehyde 383. The latter was converted with hydroxylamine to the oxime 384. The nitrone 385 was prepared by treatment of 384 with bromine azide. Photolysis of 385 gave the desired compound 381 in 46% yield. This intermediate possesses several useful functionalities (e.g., carbinolamine ether linkage), which may be of interest for synthesis of C20-diterpenoid alkaloids after minor changes in this scheme. 

The partial synthesis from epicandicandiol of some C- and H-labelled kaurene derivatives has been described.These have possible application in the study of the biosynthesis of the Isodon diterpenoids. The syntheses of [17- C]kaur-16-en-20-ol from enmein and of 3-oxygenated derivatives of [17- C]kaur-16-ene from ent-3jS,19-dihydroxy-kaur-16-ene have also been described. The synthesis of radioactive aphidicolin has also been reported. It has been shown ° that ent-kaur-15-ene is formed by the dwarf mutant (ds) of maize in place of ent-kaur-16-ene. 

During a total synthesis of the diterpenoid enmein, the tricyclic alcohols (47) and (48) were converted into a range of c-ring ketones (Scheme 5). The degree of reduction and the ease with which it occurs, relative to (23), make it apparent that intramolecular protonation is involved here also. ... 

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. 

In 1961, two experiments which provided the basis for deducing the skeleton of enmein were carried out by Kanatomo (75, 16). In the first he obtained l-ethyl-4(3,3-dimethylcyclohexyl)-benzene (II) whose structure was proved by synthesis (75). In the second he isolated retene (III) by selenium dehydrogenation of the material obtained by LiAlH4 reduction of enmein (16). Thus enmein was proved to be a diterpene and a phyllocladene (IV) skeleton was proposed for it (16). Kubota and coworkers (77) deduced the presence of a hemiacetal ring (V) and partial structure (VI), with the lactone function part of a six-membered ring, on the basis of chemical evidence and spectral data of various derivatives, and advanced four formulas including (VII) as possible structures for enmein. 

In 1966, when the structure of enmein (62) was elucidated, the total synthesis of natural gibberellins had not yet been reported. Hence, Okamoto and co workers attempted the chemical transformation of enmein into a gibberellane derivative (106) and reported the formation of such compound by a benzilic acid rearrangement-like reaction of keto hemi-acetal (128), an oxidation product of acyloin (110). This is shown in Scheme 20. 

The foregoing chemical conversions of enmein into gibberellins A15 and A37 correspond to a formal total synthesis of the latter compounds, because the total synthesis of enmein has been accomplished. A more direct total synthesis was also carried out. Compound (137) was synthesized from 5-methoxy-2-tetralone and converted into (138) as shown in Scheme 25. 

Meerwein-Ponndorf reduction of the ketone obtained by deprotection of compound (191) gave the desired 3P-axial hydroxy product. Selective reduction of the y-lactone ring of this substance was achieved by LiAlH4 in THF at — 30°C to give hemiacetal (192). Subsequent acetalization at C-6, acetylation at C-3, bromination at allylic C-17, and epoxidation converted (192) to (193), which on treatment with zinc dust in ethanol at reflux gave the A -allylic 15 3-ol. Oxidation of the latter, deacetylation, and hydrolysis produced the desired enmein (62). Thus, a relay total synthesis of enmein was achieved (see Scheme 38). 

Shudo, K., M. Natsume, and T. Okamoto Synthesis of Gibbane Derivatives from Enmein. Chem. Pharm. Bull. (Japan) 14, 311 (1966). 

Shibuya, M., and E. Fujita Terpenoids. Part XXX. Chemical Conversion of Enmein into an Important Relay Compound for its Total Synthesis. J. Chem. Soc. Perkin Trans. I 1974, 178. 

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