Enmein derivatives

Details of the conversion of enmein into ( — )-kaurene have been described. The hemi-acetal (67), produced by an acyloin condensation of enmein derivatives,... 

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. 

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. 

The NMR spectra of enmein-type diterpenoids in which 6a-H is part of a hemiacetal contain only a singlet assignable to this proton because of its ca. 90° dihedral angle with 5-H [e.g. isodocarpin (64), carpalasionin (77) in Table VIII, and enmein (62), isodotricin (65) etc. in Table II]. In spirolactone-type diterpenoids having a hemiacetal function 6-H is a doublet [e. g. trichorabdal E (96) in Table VIII and trichorabdals F (97) and G (98) in Table II]. In the enmein-type diterpenoids of this group, C-6 is R except for rabdosin A (73), while the spirolactone-type diterpenoids occur as a mixture of 6R- and 6S-isomers 81). Shikodonin has been reported to have structure (88) on the basis of X-ray analyses of its 6-O-methyl and 6-0-ethyl derivatives, but our experimental results are inconsistent with this proposal, and thus the stereochemistries of C-5 and C-6 in (88) seem questionable. 

E. Fujita and coworkers were interested in conversion of a 6,7-secokaurane type diterpenoid such as enmein to e /-abietane (123), a hydrocarbon unknown at the time. Alcohol (119) [derived from enmein (62) as shown in Scheme 16] was cleaved with NaH to an aldehyde, a ring-D open derivative. The latter was converted into a lactone ester (120) which was subjected to the acyloin condensation to give isomeric products (121) and (122). Both compounds were deoxygenated in four steps to give a hydrocarbon (123). On the other hand, starting from (—)-abietic acid and/or dihydroabietic acid, hydrocarbon (118) was prepared by the route shown in Scheme 17. The products (123) and (118) were shown to be enantiomeric, hence they were f-abietane and abietane, respectively (705). 

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. 

This type of conversion is easily achieved by periodate oxidation of a 6,20-dihydroxy-7-oxokaurene derivative. The 6,7-secokaurene-type product from this reaction is either of the enmein-type or the spirolactone-type when the starting material has a hydroxy group at C-I, an enmein-type compound is produced when it has no hydroxy group at C-1, a spirolactone-type product is formed (see Scheme 26). 

The chemical conversion of oridonin (32) into isodocarpin (64) was achieved through the route shown in Scheme 27 112). Intermediate (142) was obtained from dihydroisodocarpin (143) by treatment with acidic methanol as (143) is derived in turn from enmein (62) (32), nodosin (66) 32, 35), and trichokaurin (56) 78), this means the chemical conversion of enmein, nodosin, and trichokaurin into isodocarpin. 

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. 

To discover whether 7-oxygenated c t-kaurene derivatives are potential precursors of enmein and oridonin, the 17-labeled 7-oxygenated kaurenes (200,201 a, 202, and 203) were prepared (127) and administered to growing plants. The results showed that 7-oxygenated kaurenes as well as 15-oxo-kaurene (195) are potential precursors of Rabdosia diterpenes (128). 

Kubota and coworkers reported high antibacterial activity for enmein (62), isodonal (71), nodosin (66), oridonin (32), and enmein-3-acetate (63) against Gram-positive bacteria (134) and showed that trichodonin (70), shikokianin (24), umbrosin A (1), and umbrosin B (2) inhibited the growth of Bacillus subtilis 134, 135). Shikokianidin (49) and the dihydro derivatives of the active diterpenoids were inactive, while their acetates retained the activity. It was therefore concluded that the a-methylene-cyclopentanone moiety was essential for antibacterial activity, the activity being attributed to a Michael-type addition of a sulfhydryl enzyme to this function (Scheme 40) 134). 

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

Fujita, T, I. Masuda, S. Takao, and E. Fujita Biosynthesis of Natural Products. Part 3. Syntheses of ent-[ l- C] Kaur-16-en-20-ol from Enmein and ent-[ 7- C] Kaur-16-ene Derivatives oxygenated at C-3 from e t-Kaur-16-ene-3p, 19-diol. J. Chem. Soc. Perkin Trans. I 1979, 915. 

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