Synthesis of 5-epi-[6-2H2]valiolone and stereospecifically monodeuterated 5-epi-valiolones:: Exploring the steric course of 5-epi-valiolone dehydratase in validamycin A biosynthesis

被引:19
作者
Mahmud, T [1 ]
Xu, J [1 ]
Choi, YU [1 ]
机构
[1] Univ Washington, Dept Chem, Seattle, WA 98195 USA
关键词
D O I
10.1021/jo0101003
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
In validamycin A biosynthesis, as well as that of acarbose, the valienamine and validamine moieties are ultimately derived from a C-7 sugar, sedoheptulose 7-phosphate, which is cyclized to 2-epi-5-epi-valiolone by a cyclase that operates via a dehydroquinate (DHQ) synthase-like mechanism. 2-epi-5-epi-Valiolone is first epimerized at C-2 to give 5-epi-valiolone and then dehydrated between C-5 and C-6 to yield valienone. To probe the dehydration mechanism of 5-epi-valiolone to valienone, stereospecifically 6 alpha- and 6 beta -monodeuterated 5-epi-valiolones were synthesized. The key step in the synthesis was desulfurization of the tetrabenzyl-6,6-bis(methylthio)-5-epi-valiolone and introduction of the deuterium utilizing Zn, NiCl2, ND4Cl/D2O, and THF. Extensive studies using various combinations of protio- and deuteroreagents and solvents probed the mechanism of the reductive desulfurization, which is crucial for the preparation of stereospecifically monodeuterated 5-epi-valiolones. Incorporation experiments with the labeled precursors in the validamycin A producer strain, Streptomyces hygroscopicus var. limoneus, revealed that the dehydration of 5-epi-valiolone to valienone occurs by a syn elimination of water.
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页码:5066 / 5073
页数:8
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