β Scribed by Seiichiro Ogawa; Kenji Washida
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In order to elucidate the essential core structure of potent the five stereoisomers thus obtained for the six glycosidases has demonstrated the 2/3,4,5) and (1,2,3,4,5/0) isomers Ξ±-mannosidase inhibitors, e.g. mannostatin A, 5-amino-5-Cmethyl-1,2,3,4-cyclopentanetetrols 4-8 were designed and to be moderate Ξ±-mannosidase inhibitors, suggesting that the all-cis configuration of the amino and three hydroxy groups synthesized by a base-catalyzed nitro aldol condensation of nitroethane and the dialdehyde derived by periodate on the cyclopentane ring plays a role in exhibiting inhibitory activity. oxidation of
followed by reduction and deprotection. Biological assay of Discovery of the potent and specific Ξ±-mannosidase in-seemed of interest to elucidate the influence of the C-methyl functions toward the inhibitory potentials, comparing the hibitor mannostatin A [1] (1) has stimulated us to develop new glycosidase inhibitors composed of 5-amino-1,2,3,4-activities of 7 and 8 with those of 2 and 3. cyclopentaneterols, which are thought to act as transition Dialdehyde/nitromethane cyclization has established itstate mimickings of glycopyranosyl cations postulated to self as a generally applicable synthetic method for prepform during hydrolysis of glycosides [2] . Concerning conforaration of aminocyclitols and amino sugars. [8] Some nitromational feature of the transition state mannopyranosyl alkanes and alkanols have successfully been applied [9] [10] in cation predicted in hydrolysis of mannopyranosides, it the reaction of glutaraldehyde, producing some unaccessible seemed rather difficult to correlate the structures of the branched-chain aminocyclitols. In the present study, nitro known potent inhibitors conformationally to the postulated aldol cyclization between nitroethane and a dialdehyde destructure of mannopyranosyl cation [3] . Recently, Winkler rived by treatment of ο€ο¬-1,2-O-cyclohexylidene-myo-inosiand his coworkers [4] have proposed adequate corretol [11] with excess of sodium metaperiodate has been carried lationship by comparing the structures of some Ξ±-mannoout for synthesis of the target compounds. No cyclization sidase inhibitors to their flap up mannopyranosyl cation product was formed when sodium methoxide, sodium hymodel.
droxide, barium hydroxide, sodium carbonate, or sodium hydrogen carbonate was used as a base catalyst. Only, under We have so far investigated synthetic studies [5] on glycosiinfluence of DBU, the reaction occurred smoothly to give dase inhibitors containing 5-amino-1,2,3,4-cyclopentanetea mixture of the nitro diols, in practically acceptable yields, trols, being initially motivated by our results [6] of the strucwhich was subsequently reduced in the presence of Raney ture and inhibitory activity relationship of trehalase innickel and acetic anhydride, followed by acetylation with hibitor trehazolin. [7] Among twenty four stereoisomers [5] of acetic anhydride in pyridine, giving an inseparable mixture 5-amino-1,2,3,4-cyclopentanetetrols and its branched-chain of the 2,3-O-cyclohexylidene derivatives of 5-acetamidoderivatives, which were assayed inhibitory activity toward 1,4-di-O-acetyl-5-C-methyl-1,2,3,4-cyclopentanetetrol. Deseveral glycosidases, only 1ο€-and 1ο¬-(1,2,3,5/4) (2), and O-acetylation of the compounds under Zemple Β΄n con-(1,2,3,4,5/0) isomers (3) have been shown to be weak inhibiditions [12] led to a separable mixture of products, and, after tors of Jack beans Ξ±-mannosidase (IC 50 Ο 1Οͺ10 Ο« 10 Οͺ5 ο).
silica gel chromatography, three stereoisomers of the 5-acet-In fact, compounds 2 and 3 are likely to resemble mannosamido-5-C-methyl-1,2,3,4-cyclopentanetetrol derivatives 9, tatin A in configurations the all-cis relationships of the 10, and 11 were obtained in 16, 10, and 1% yields, respecamino and consecutive three hydroxy groups, suggesting tively, based on the inositol derivative used [13] . Their structhat these core structures are essential for generation of intures were assigned by the 1 H-NMR spectra and NOE hibitory potential toward Ξ±-mannosidase, and furthermore experiment, together with those of the corresponding di-Othey should conceivably be constituted the simple and close acetyl derivatives 9a, 10a, and 11a. mimickings of the transition state mannopyranosyl cation. In the present paper, the five branched-chain analogs 4Ψ8 Thus, eight stereoisomers (2 chiral and 4 meso) are theoretically possible to be obtainable by the present preparative of 5-amino-5-C-methyl-1,2,3,4-cyclopentanetetrol were synthesized and their enzyme inhibitory activity assayed. It reaction. By analogy with the results of a similar cyclization
π SIMILAR VOLUMES
Three selectively labeled propynes were prepared either with deuterium or carbon-13 at position 3 and doubly labeled with carbon-13 at positions 1 and 2 by an alkylation reaction from the corresponding labeled or unlabeled monolithio acetylides and dimethylsulfates. Their lithiation with nBuLi gave