Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)–C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)–C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third- generation syntheses, designed with the goal of accessing one gram of (+)-spongistatin 1 (1), maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis-Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mgs of the EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.

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Previously, we reported that when the cytotoxic effects of 4Ј-O-alkylaloenin derivatives (from methyl to hexadecyl) derived from aloenin (1) are compared, the longer the alkyl chain of the 4Ј-O-alkylaloenin derivatives, the greater is the enhancement in the cytotoxic effects on human colorectal (HCT 116) and human hepatoma (Hep G2) cancer cell lines.1) Furthermore, we reported that pseudodiosgenone derivatives having various amino groups, thiocyano (SCN), and selenocyano (SeCN) groups at the 26 position derived from diosgenin (2) exhibited the potent cytotoxic activities against the same cancer cell lines, 2) while compounds 1 and 2 have not been known to exhibit cytotoxic activity yet. In our preliminary investigation, these compounds also showed no marked cytotoxicity in less than 500 mM of the IC 50 valuethe concentration at which 50% of the cells are inhibited from growing. However, from the both above-mentioned reports, it is evident that a compound that possessed an alkyl chain with an appropriate length or that introduced appropriate substituents such as amino, thiocyano, and selecocyano groups in the molecule seemed to exhibit potent cytotoxic activity.In the present study, we investigate the preparation of 1,8-di-O-alkylaloe-emodins and 15-amino-, 15-thiocyano-, and 15-selenocyanochrysophanol derivatives from aloe-emodin (3) which has been known to have several pharmacological activities such as cytotoxic activity, [3][4][5] antifungal activity, 6) antibacterial activity, 7) and so on, and further we evaluate the cytotoxic effects of the synthetic derivatives on HCT 116 and Hep G2 cancer cell lines. Results and DiscussionAloe-emodin 3 is an anthraquinone derivative isolated from many Chinese herbal medicines such as Aloe arborensces MILL. var. natalensis BERGER (Liliaceae), 8,9) Rheum palumatum L. (Poligonaceae), 10,11) Cassia tora L. (Leguminosae), 12) and so on. This anthraquinone derivative has two phenolic hydroxyl groups at the 1 and 8 positions and one aliphatic hydroxyl group at the 15 position. In this study, the alkylations of the phenolic hydroxyl groups and the substitution reactions with various amino groups and thiocyano and selenocyano groups at the 15 position of 3 were performed to compare their cytotoxic activities. First, several alkyl derivatives were prepared from 3. The methylation of 3 with dimethylsulfate in the presence of K 2 CO 3 was done according to the method reported by Ross and Mitali. 13) to give 1,8-di-O-methylaloe-emodin 4 in a 61.6% yield. Other alkylations were performed according to the method of MacTough et al. 14) Compound 3 was reacted with propyl iodide, hexyl bromide, dodecyl iodide, and octadecyl iodide in the presence of K 2 CO 3 to give 1, Sciences, Josai International University; 1 Gumyo, Togane, Chiba 283-8555, Japan: and c Faculty of Pharmaceutical Sciences, Himeji Dokkyo University; 7-2-1 Kami Ohno, Himeji, Hyogo 670-8524, Japan. Received November 9, 2007; accepted February 6, 2008 1,8-Di-O-alkylaloe-emodin derivatives (namely, methyl-, propyl-, ...

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