In the course of our screening for NADH-fumarate reductase (NFRD) inhibitors, nafuredin (1), which is potentially a selective antiparasitic agent, was isolated from the fermentation broth of a fungal strain, Aspergillus niger FT-0554. Nafuredin (1) inhibited NFRD of Ascaris suum with an IC_<50> value of 12 nM without cytotoxicity and exerted anthelmintic activity against Haemonchus contortus in in vivo trials with sheep. These useful biological activities of 1 attracted our attention and prompted us to undertake the total synthetic study. In the beginning, we elucidated the absolute configuration of 1 as (2R,3S,4S,5R,6E,8E,10R,12E,14E,16S)-3,4-epoxy-2-hydroxy-4,10,12,16-tetramethyl-6,8,12,14-octadecatetraeno-5-lactone by degradation and synthetic studies (Schemes 1, 2, 3, and Fig. 1). Next, we embarked on the total synthetic study and envisioned a convergent approach towards 1 via a stereoselective one-pot Julia olefination between the sulfone 17 and aldehyde 18 followed by appropriate functional group elaboration of the resulting 16 (Scheme 4). The sulfone 17 and aldehyde 18 were derived efficiently from D-glucose and (S)-(-)-2-methyl-1-butanol 15, respectively (Schemes 5 and 6). The one-pot Julia olefination between 17 and 18 could be effected to provide the desired (6E,8E,12E,14E)-alcohol 31 in 79% yield as a single isomer (Scheme 7). Finally, 31 was converted to nafuredin (1) via formation of epoxide and lactone. Synthetic nafuredin (1) was identical with natural (1) in all respects ([α]D, ^1H- and ^<13>C-NMR, IR, FAB-MS and inhibitory activity against NFRD). We have achieved the first total synthesis of nafuredin. Investigation of the structure-activity relationship and biological studies of 1 are currently in progress.
