Studies directed toward the stereochemical structure determination of the naturally occurring glucosidase inhibitor, kotalanol: Synthesis and inhibitory activities against human maltase glucoamylase of seven-carbon, chain-extended homologues of salacinol
Studies directed toward the stereochemical structure determination of the naturally occurring glucosidase inhibitor, kotalanol: Synthesis and inhibitory activities against human maltase glucoamylase of seven-carbon, chain-extended homologues of salacinol
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DOI：
10.1021/jo800855n
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发表时间：
2008-08-15
影响因子：
3.6
通讯作者：
Pinto, B. Mario
中科院分区：
文献类型：
--
作者：
Nasi, Ravindranath;Patrick, Brian O.;Pinto, B. Mario
本文描述了天然糖苷酶抑制剂salacinol的类似物1，4-脱水-4-硫代-D-阿拉伯糖醇的新型七碳扩链锍盐的合成。这些化合物是根据salacinol的扩链类似物的结构活性数据设计的，目的是确定kotalanol（天然存在的salacinol的七碳扩链类似物）迄今未知的立体化学结构。通过PMB保护的1，4-脱水-4-硫代-D-阿拉伯糖醇在两个1，3-环状硫酸酯的最小位阻碳原子上的亲核进攻，合成了目标两性离子化合物。以D-葡萄糖为原料，经Wittig烯化和Sharpless不对称二羟基化反应合成了目标环状硫酸酯。通过使用两步序列对偶联产物进行脱保护，得到两种硫酸锍。我们的化合物之一的旋光数据表明与kotalanol报告的对应关系。然而，合成化合物的H-1和C-13 NMR光谱数据与kotalanol的数据的比较表明差异。从这个和发表的工作的集体数据被用来提出一个天然存在的化合物，kotalanol的初步结构。以前合成的类似物与最近分离的六碳链类似物，ponkoranol或reticulanol的物理数据的比较，也导致了这种结构的阐明。有趣的是，我们的两种化合物抑制重组人麦芽糖酶葡糖淀粉酶（NIGA），正如我们先前对低级同系物的结构活性研究所预期的，Ki值为0.13 +/-0.02和0.10 +/-0.02 μ M。
The synthesis of new seven-carbon, chain-extended sulfonium salts of 1,4-anhydro-4-thio-D-arabinitol, analogues of the naturally occurring glycosidase inhibitor salacinol, are described. These compounds were designed on the basis of the structure activity data of chain-extended analogues of salacinol, with the intention of determining the hitherto unknown stereochemical structure of kotalanol, the naturally occurring seven-carbon chain-extended analogue of salacinol. The target zwitterionic compounds were synthesized by means of nucleophilic attack of the PMB-protected 1,4-anhydro-4-thio-D-arabinitols at the least hindered carbon atom of two 1,3-cyclic sulfates differing in stereochemistry at only one stereogenic center. The desired cyclic sulfates were synthesized starting from D-glucose via Wittig olefination and Sharpless asymmetric dihydroxylation. Deprotection of the coupled products by using a two-step sequence afforded two sulfonium sulfates. Optical rotation data for one of our compounds indicated a correspondence with that reported for kotalanol. However, comparison of H-1 and C-13 NMR spectral data of the synthetic compounds with those of kotalanol indicated discrepancies. The collective data from this and published work were used to propose a tentative structure for the naturally occurring compound, kotalanol. Comparison of physical data of previously synthesized analogues with those for the recently isolated six-carbon chain analogue, ponkoranol or reticulanol, also led to elucidation of this structure. Interestingly, both our compounds inhibited recombinant human maltase glucoamylase (NIGA), as expected from our previous structure activity studies of lower homologues, with K-i values of 0.13 +/- 0.02 and 0.10 +/- 0.02 mu M.