Synthesis of 5-epi-[6-(2)H(2)]valiolone and stereospecifically monodeuterated 5-epi-valiolones: exploring the steric course of 5-epi-valiolone dehydratase in validamycin A biosynthesis.
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 6alpha- and 6beta-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, NiCl(2), ND(4)Cl/D(2)O, 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.
Mahmud
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Department of Chemistry, Box 351700, University of Washington, Seattle, Washington 98195-1700, USA. mahmud@chem.washington.edu
Xu
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Choi
Y U
YU
D000935:Antifungal Agents / Q000096:biosynthesis*; D002240:Carbohydrate Sequence; D006836:Hydro-Lyases / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D007294:Inositol / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000138:chemical synthesis*; D008969:Molecular Sequence Data; D009532:Nickel; D012997:Solvents; D013302:Streptomyces / Q000737:chemistry*; D015032:Zinc
C433384:5-epi-(6-(2)H2)valiolone; D000935:Antifungal Agents; D007202:Indicators and Reagents; D012997:Solvents; C030790:validamycin A; D007294:Inositol; D009532:Nickel; C433385:5-epi-valiolone dehydratase; D006836:Hydro-Lyases; D015032:Zinc