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Acarviosin 441


Compounds 441-448

derivatives [259], and analogs of acarviosin and methyl acarviosin having a-d-manno configurations and saturated cyclohexane rings [260,261]. Another report by this group describes the synthesis of methyl 1'-epi-acarviosin and its 6-hydroxy analog [262]. Various other 1,6-anhydro acarviosins, including 2'-substituted derivatives having the 2'-hydroxyl group replaced with NH2 or F, as well as a diastereomeric methylacarviosin and its hydroxylated analog, have also been synthesized by the same group [263,264].

The total synthesis of the trehalose inhibitor salbostatin 451 was achieved by the coupling reaction of the a-valienamine derivative 449 with 1,5:2,3-dihydro-d-mannitol (450) under forcing conditions (sealed tube, 120°C) in a protic solvent [265] (compounds 449-451 ).

K. Aminocyclopentitol Aminoglycosides: Trehazolin and Trehalostatin

The total syntheses of the trehalose inhibitors trehazolin (452) [266,267] and its 5-epi analog trehalostatin (453) [266,268] have been described by two different groups. The 5-epi derivative 453 possesses much weaker inhibitory activities than trehazolin toward two trehalases. Another publication by Boiron et al. [269] reports a synthesis of trehazolin 452 from d-glucose. In this synthesis three chiral centers of the starting compound, d-glucose, are conserved and the remaining two chiral centers of treha-zolamine 456 are formed stereoselectively by reductive cyclization of the ketoxime ether 454. Reduction of this oxide ether leads to formation of the title compound 456 (compounds 452-456 ).

In addition, different research groups have described syntheses of (+)-treha-zolin [270,271], (+)-6-epitrehazolin [271], a tetrahydropyrano-[2,3-d] oxazol analog

449 450 451

Compounds 449-451

452 R1 = OH, R2 = H 454 455 Trehazolamine 456

Compounds 452-456

of trehazolin [272], and a series of trehazolin derivatives in which the a-D-gluco-pyranose unit was replaced by other mono- and disaccharide or carba sugar units [273]. The inhibitory activity results revealed that the four hydroxyl groups of the D-glucopyranosyl moiety of trehazolin are topologically essential for the hydrogen binding of the inhibitor to the active site of the enzyme. Furthermore, it appeared that the ß-D-glucopyranosyl residue is likely to facilitate the uptake of the compound into the cell [273].

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