Abstract
Squalamine was isolated from the stomach of the dogfish shark Squala Acanthias by Zasloff and coworkers in 1993 and was demonstrated to have a potent antiangiogenic activity. Zasloffs group discovered that squalamine inhibited endothelial cell function and effected the growth of solid tumors. Since extensive clinical test is under way, establishment of practical synthetic method has been urged. Although the route reported by kinney's group is the most practical so far, it includes somewhat laborious steps such as a cleavage and reconstruction of the side chain and a stoichiometric asymmetric reduction of C-24 carbonyl group. In order to improve these drawbacks, we tried to start our synthetic route from desmosterol. Desmosterol has been considered to be very expensive and hard to prepare in short steps. However, Fujimoto and coworkers of Yoshikawa Seiyu Co. Ltd. discovered that 10-25% of desmosterol was included in a filtrate of recrystallization of cholesterol which was made from lanoline alcohol. The alcohol was obtained in a saponification of wool-grease which is a washing waste of wool imported from Australia. The crude mixture including desmosterol was acetylated and then asymmetrically dihydroxylated by using AD-mix-β. The compound (2) was isolated by flash column chromatography. We were offered the compound 2 from the company and started the synthesis to get the target compound (12) which is a critical precursor to squalamine via 9 steps. We also succeeded in obtaining squalamine in high yield by a modified procedures of Kinney's method via 11 steps. Compound 2 was selectively benzoylated at 24(R)-OH to give compound (3). Compound (4) was obtained by chlorination at C25-OH and then dehydrochlorination at C-25 and C-26 of compound 3. After selective hydrogenation of the terminal olefin of compound 4, allylic air oxidation at C7 of compound (5) reported by Kinney gave compound (6). Hydrogenation of compound 6 provided the desired product (8) together with compound (7) in which the carbonyl group was also hydrogenated. Compound 7, however, was transformed quantitatively to compound 8 by PCC oxidation. Hydrolysis of 3-OAc of compound 8, stereoselective reduction of C7 carbonyl group of compound (9) with K-selectride, regioselective oxidation of C3-OH of compound (10) with silver carbonate and saponification of C24(R)-O-Bz at high temperature in ethylene glycol afforded the target compound 12. In order to get squalamine in good yield, we carried out the following steps according to Kinney's method. It was demonstrated, however, that their procedures of the final step gave lower yield than 10%. Detailed examination of the reaction conditions disclosed that employing sodium cyanoborohydride instead of sodium borohydride for reduction of spermidino imine at C3 from compound (13) provided squalamine in good yield (60%). Therefore, the target precursor, compound 12 for formal total synthesis and squalamine were obtained in 11.3% total yield and in 5.2% total yield, respectively.
