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

Abstract

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.

Genetically engineered production of 1,1′-bis-valienamine and validienamycin in Streptomyces hygroscopicus and their conversion to valienamine

“…Preliminary studies were carried out by the groups of Rinehart, Floss, and Mahmud (Dong et al 2001, Mahmud et al 2001a, Mahmud et al 2001b, Toyokuni et al 1987), mainly by feeding experiments with isotopically labeled precursors , resulting in the identification of a number of cyclitols believed to be involved in the biosynthesis of validamycin A. The active pharmacophores of validamycin A, valienamine and validamine, are derived from 2- epi -5- epi- valiolone, the product of an intramolecular aldol cyclization of sedoheptulose 7-phosphate (Dong et al 2001, Yu et al 2005).…”

Biosynthesis of the C7-cyclitol Moiety of Acarbose inActinoplanes Species SE50/110

“…Fig. 1) (6,7). In contrast, similar feeding experiments revealed 2-epi-5-epi-valiolone to be the only precursor that was incorporated into acarbose (8).…”

“…1) (6). Therefore, the biosynthesis of the two C 7 -cyclitol units (valienamine and validone) seemed to occur without initial phosphorylation by direct epimerization and dehydration or reduction (7). Also, the incorporation of the nitrogen into validamycin must occur on another route because, in acarbose, it is introduced via formation of a dideoxyaminohexose (see below).…”

The effects of C–S and C–Se bonds on torquoselectivity: stereoselective olefination of α-thio and α-selenoketones with ynolates

“…Attempts at desulfurization of the olefins with activated ZnNiCl 2 -NH 4 Cl aq 14 provided the unconjugated b,g-unsaturated esters in only the Z-form (Scheme 5). Since, even in the absence of a conjugated phenyl group (Scheme 5b) or a conjugated carbonyl group (Scheme 5c), the double bond was isomerized by the desulfurization, the trisubstituted olefins are therefore preferable to the tetrasubstituted olefins, probably due to the steric strain in the transition states of the protonation of the allylic radical or anion species.…”