Total Synthesis of Enmein

Dehydration of the optically active relay (178) derived from enmein (62) gave a 1 2 mixture of 5,6-ene and 6,7-ene. Separation could be achieved by means of the ethylene acetal (187), whose ozonolysis product was subjected to successive Jones oxidation, methylation, Wittig reaction, and treatment with dilute hydrochloric acid to afford the 3-on-16-ol derivative (188). Bromination of (188) followed by dehydrobromination and subsequent dehydration afforded (189). The purified compound (189), after conversion into the acetal, was hydrolyzed to carboxylic acid (190), which was transformed into the desired lactone (191) by treatment with boron trifluoride etherate. The reaction produced a single product uncontaminated by the C-1 epimer, because of easy formation of a favored transition state which satisfied the stereoelectronic requirements. 

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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. 

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). 

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. ... 

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. 

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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