(؊)-Methyl 7b b-hydroxykaurenoate (3) and its 4-demethyl acetate (؊)-4 were both synthesized via methods that contained radical cyclization and intramolecular Diels-Alder reactions as key steps. Both compounds displayed potent neuroprotective activity against N-methyl-D-aspartate toxicity in cultured cortical neurons.Key words kaurene diterpenoid; neuroprotective activity; chiral synthesis; radical cyclization It has been suggested by a number of previous studies [1][2][3][4] that excess activation of glutamate receptors causes severe and irreversible damage to the mammalian central nervous system (CNS). Akaike and coworkers have recently reported the isolation of atisane diterpenes, serofendic acids A (1) and B (2) (Fig. 1), from fetal calf serum and described their potent protective activity in cortical neurons against both nitric oxide donor and glutamate cytotoxicity. 5) These observations prompted us to examine the possible neuroprotective activity of our synthetic compounds that have a variety of bridged skeletons. Here we report that kaurene derivatives act as potential neuroprotective agents.Among the many compounds that we tested, racemates of 7b-hydroxykaurenoate (3) 6) and its demethyl acetate 4 6) display potent activity for lactate dehydrogenase (LDH) 7) induced by N-methyl D-aspartate (NMDA) in cortical cell cultures (Fig. 2). The activity was comparable to that of memantine, which received US FDA approval for the treatment of moderate to severe Alzheimer's disease.To elucidate further the mechanisms of their biological activity, the corresponding optically active compounds were then synthesized. For the purposes of preparing chiral compounds that have the same absolute configuration as serofendic acids, a suitable chiral precursor was sought. The half ester 5, which can be readily synthesized in large quantities with high optical purity from the corresponding diester using porcine liver esterase (PLE), 8) was eventually selected. Compound 5, which has an optical purity of 95% ee, was then treated with isobutene in the presence of concentrated sulfuric acid, followed by reaction with sodium hydroxide in methanol (Chart 1). This generated the t-butyl ester 6 in 67% overall yield. A subsequent Grignard reaction and treatment with diluted sulfuric acid produced the lactone 7 in an overall yield of 45%. Optically active (Ϫ)-7 was transformed into the kaurene-type diterpene 3 utilizing the same procedure previously described for the racemate synthesis.6) The optical purity of product 7 was determined at a later stage.Introduction of a propargyl group into lactone 7 produced 8 in 92% yield and this product was then subjected to radical cyclization. The desired tricyclic compound 9 was successfully obtained in 93% yield following treatment with silica gel. Reduction of the lactone 9 with lithium aluminum hydride generated the diol product 10 in 97% yield, which was then converted into the corresponding (R)-methoxy(trifluoromethyl)phenylacetate 11, the 1 H-NMR spectrum of which indicated an optical purity ...

Terpenes U 0200Synthesis of Optically Active Methyl 7β-Hydroxykaurenoate with Potent Neuroprotective Activity. -Two 7β-hydroxykaurenoates (X) possessing potent neuroprotective activity are prepared by a multistep procedure involving the radical cyclization of acetylenic compound (II) and intramolecular Diels-Alder reaction of epimeric acetates (IV) as key steps. -(TOYOTA, M.; MATSUURA, K.; YOKOTA, M.; KIMURA, M.; YONAGA, M.; SUGIMOTO, H.; IHARA*, M.; Chem.