Regioselective functionalization of one of the multiple hydroxy groups is a fundamental challenge in current organic synthesis. Synthesis of complex glycoconjugates has usually been achieved by multi-step protection/deprotection procedures, which results in long synthetic steps and low atom economy. Recently, we have developed a perfectly regioselective acylation of D-glucose derivative 2 with organocatalyst 1 (Scheme 1). We report here total synthesis and functionalization of natural glycosides via organocatalytic regioselective acylation. Toward the total synthesis of natural glycosides, we investigated functional group tolerance in the regioselective acylation catalyzed by 1. Introduction of functionalized acyl groups such as a-amino acyl, cinnamoyl, and galloyl groups to monosaccharide 2 and disaccharides 11-13 has been achieved in high regioselectivity (rs). (Figure 2, 4-10 and Table 2) These results indicate that this protocol for regioselective acylation is applicable to the introduction of functionalized acyl groups to a variety of saccharides with a glucopyranose terminus. Regioselective functionalization of lanatoside C (14) was then investigated. Compound 14 is a naturally occurring cardiac glycoside which has been used for the treatment of atrial fibrillation and supraventricular tachycardia. (Figure 3) As expected, acylation of 14 took place at C(4''')-OH in high regioselectivity in the presence of catalyst 1. On the other hand, the acyl group was introduced to C(3''')-OH selectively in DMAP catalyzed acylation. (Scheme 2, A) Because the biological activities of some glycosides have been known to depend on the acyl groups by their position and functionality, the direct regioselective introduction of various acyl groups seems to be a unique and useful method for exploring bioactive materials. Regioselective total syntheses of multifidoside A (15) and B (16) have been achieved. Compounds 15 and 16, 4-0-p-coumaroylglycosides isolated from pteris multifida in China, showed cytotoxicity against the HepG2 tumor cell line with IC_<50> < 10μM. (Figure 4) We have accomplished the first total syntheses of 15 and 16 via two types of organocatalytic reactions. The first key reaction is an intramolecular asymmetric aldol reaction of 19, which was synthesized from commercially available 20 by nine steps. (Scheme 3) After thorough screening of known and unknown catalysts, we found that catalyst 24 has reactivity sufficient to give indanone 25 in high stereoselectivity. The second key reaction is organocatalytic regioselective acylation of 26 and 28. As expected, acylation took place at C(4)-OH in high regioselectivity (up to 86% rs). Finally deprotection of the products gave 15 and 16. (Scheme 4 and 5) Further optimization of regio- and enantioselectivity of the key reactions is currently underway.
