Spirolactone-type diterpenoids

Before 1979, the only 6,7-secokauranes were of what we have called the enmein-type, but since then a number of spirolactone-type diterpenoids have been reported, the first being shikodonin (88). As shown in Table VIII, each group is classified into four types. NMR data for a representative of all eight types are also listed. 

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. 

Spirolactone-type diterpenoids having a 15-carbonyl group are generally unstable to alkali. For instance, trichorabdal B (93) on treatment with dilute alkali for a brief period undergoes rearrangement by way of a re ro-Claisen reaction which is followed by an aldol condensation as shown in Scheme 8 (79). If the reaction time is extended isolation of the product is difficult, because a number of other products are formed. 

The antitumor activity of spirolactone-type diterpenoids has also been studied. Shikodonin (88) had antitumor activity 64). Very recently in vivo antitumor activity has been reported for trichorabdals A-C (92-94) and related diterpenoids against Ehrlich ascites carcinoma in the mouse. The trichorabdals exhibited greater activity than oridonin and while the activity of their dihydro derivatives was greatly reduced, they were still active, in contrast to dihydroenmein and its analogs which are inactive. Hence, the trichorabdals may possess a second active site, presumably the spirolactone aldehyde part, and it was assumed that the enhanced activity of the trichorabdals is due to synergism between the two active sites 82, 142). 

The 6-hydroxy-7-hemiacetal structure which is common to oridonin-type and longikaurin C-type diterpenoids is oxidatively cleaved at the C-6, C-7 bond by periodate oxidation. If a hydroxyl is present at C-1, then relactonization occurs to give enmein-type diterpenes 36, 78). If no hydroxy group is present at C-1 (R = H or OAc in Scheme 3), then the oxidative cleavage gives spirolactone-type compounds [26, 36, 79, 80, see also III-5-(a)]. 

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