| Abstract
| - In validamycin A biosynthesis, as well as that of acarbose, the valienamine and validamine moietiesare ultimately derived from a C7 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 betweenC-5 and C-6 to yield valienone. To probe the dehydration mechanism of 5-epi-valiolone to valienone,stereospecifically 6α- and 6β-monodeuterated 5-epi-valiolones were synthesized. The key step inthe 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 variouscombinations of protio- and deuteroreagents and solvents probed the mechanism of the reductivedesulfurization, which is crucial for the preparation of stereospecifically monodeuterated 5-epi-valiolones. Incorporation experiments with the labeled precursors in the validamycin A producerstrain, Streptomyces hygroscopicus var. limoneus, revealed that the dehydration of 5-epi-valioloneto valienone occurs by a syn elimination of water.
|
