Linderol A (4), which has the potent inhibitory activity on melanin biosynthesis of cultured B-16 melanoma cells, was isolated from the fresh bark of Lindera umbellata (Lauraceae) (Fig. 2). The first total synthesis of (±)-linderol A (4) was achieved via 20 steps in 7.64% overall yield from 4,6-dimethoxysalicylaldehyde (5). 4,6-Dimethoxysalicylaldehyde (5) was converted to the coumarin (6) by Knoevenagel reaction. The coumarin derivative (6), which had an electron-withdrawing group at the 3-position, was treated with dimethylsulfoxonium methylide (2.2 eq) to afford the tricyclic 2-substituted cyclopenta[b]benzofuran-3-ol derivative (7) (Fig. 1). The benzofuran (7) was converted to the α,β-unsaturated ketoester (11), which was treated with isopropylmagnesium bromide in the presence of CuI and BF_3-etherate to afford stereoselectively the desired enolester 8 as a single product (Scheme 2, Table 1). Decarboxylation of 8 and one-carbon enlargement of the cyclopentanone ring gave the enol ester (13). Decarboxylation of 13 via 4 steps followed by Wittig olefination of the obtained ketone (15) afforded the exo-olefin (16) (Scheme 3). After the stereoselective cis-1,2-dihydroxylation with MC OsO_4, Friedel-Crafts reaction of the corresponding cyclic carbonate (21) was carried out by treatment with acetic anhydride/Sc(OTf)_3 to give regioselectively the 4-acetyl compound (22). Selective demethylation of 22 with BBr_3 afforded the phenol (23), and then alkaline hydrolysis of the cyclic carbonate function in 23 gave the diol (24). The ditosylate 25 was reduced by NaBH_3CN to convert the-CH_2OTs portion at the 6-position to the α-methyl group. Finally, treatment of 26 with benzaldehyde in the presence of tert-BuOK followed by alkaline hydrolysis gave crystalline (±)-4 (Scheme 6).
