Structure Proof and Synthesis of Kotalanol and De-O-sulfonated Kotalanol, Glycosidase Inhibitors Isolated from an Herbal Remedy for the Treatment of Type-2 Diabetes
Structure Proof and Synthesis of Kotalanol and De-O-sulfonated Kotalanol, Glycosidase Inhibitors Isolated from an Herbal Remedy for the Treatment of Type-2 Diabetes
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DOI：
10.1021/ja900867q
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发表时间：
2009-04-22
影响因子：
15
通讯作者：
Pinto, B. Mario
中科院分区：
文献类型：
--
作者：
Jayakanthan, Kumarasamy;Mohan, Sankar;Pinto, B. Mario
科塔拉醇和去-O-磺化科塔拉醇是五层龙水提取物中最具活性的成分，五层龙在印度、斯里兰卡和泰国传统上用于治疗糖尿病。我们在此通过合成并将它们的物理数据与相应天然化合物的数据进行比较，报道了这两种化合物的确切立体化学结构。候选结构基于我们最近关于类似物合成的报告以及低级同系物的构效关系研究。最初的合成策略依赖于对甲氧基苄基（PMB）保护的4 - 硫代 - D - 阿拉伯糖醇在两种不同的、选择性保护的1,3 - 环状硫酸盐中受阻最小的碳原子上的选择性亲核进攻，以得到硫酸锍盐。保护基团包括一个以七元环形式存在的亚甲基缩醛和苄基醚。加成物脱保护产生硫酸锍离子，但也导致去 - O - 磺化。通过将两种加成物的物理数据与报道的去 - O - 磺化天然科塔拉醇的数据进行比较，推断出科塔拉醇难以捉摸的结构。确定该化合物的侧链是另一种天然存在的庚糖醇，即C - 5位带有磺酰氧基的D - 波斯糖醇（D - 甘油 - D - 半乳糖 - 庚糖醇）。然后通过将PMB保护的4 - 硫代 - D - 阿拉伯糖醇与由天然存在的D - 波斯糖醇合成的环状硫酸盐偶联，实现了科塔拉醇本身的合成。这项工作明确确定了两种天然产物的结构，即科塔拉醇和去 - O - 磺化科塔拉醇。
Kotalanol and de-O-sulfonated-kotalanol are the most active principles in the aqueous extracts of Salacia reticulata which are traditionally used in India, Sri Lanka, and Thailand for the treatment of diabetes. We report here the exact stereochemical structures of these two compounds by synthesis and comparison of their physical data to those of the corresponding natural compounds. The candidate structures were based on our recent report on the synthesis of analogues and also the structure-activity relationship studies of lower homologues. The initial synthetic strategy relied on the selective nucleophilic attack of p-methoxybenzyl (PMB)-protected 4-thio-D-arabinitol at the least hindered carbon atom of two different, selectively protected 1,3-cyclic sulfates to afford the sulfonium sulfates. The protecting groups consisted of a methylene acetal, in the form of a seven-membered ring, and benzyl ethers. Deprotection of the adducts yielded the sulfonium ions but also resulted in de-O-sulfonation. Comparison of the physical data of the two adducts to those reported for de-O-sulfonated natural kotalanol yielded the elusive structure of kotalanol by inference. The side chain of this compound was determined to be another naturally occurring heptitol, D-perseitol (D-glycero-D-galacto-heptitol) with a sulfonyloxy group at the C-5 position. The synthesis of kotalanol itself was then achieved by coupling PMB-protected 4-thio-D-arabinitol with a cyclic sulfate that was synthesized from the naturally occurring D-perseitol. The work establishes unambiguously the structures of two natural products, namely, kotalanol and de-O-sulfonated kotalanol.