Polyhydroxylated isoquinuclidines mimicking the boat conformation of pyranosides are strong and selective inhibitors of a retaining b-mannosidase.According to the principle of stereoelectronic control, 1 heterolytic cleavage of an acetal C-O bond requires an antiperiplanar orientation of a doubly occupied, non-bonding orbital. This antiperiplanar lone pair hypothesis (ALPH) means that hydrolysis of b-D-pyranosides involves a conformational change of the tetrahydropyran ring from a chair to a twist-boat or boat resulting in a pseudoaxial orientation of the aglycon (Fig.
Duilio Arigoni, in dankbarer und freundschaftlicher Verbundenheit, zum 75. herzlich zugeeignet Racemic and enantiomerically pure manno-configured isoquinuclidines were synthesized and tested as glycosidase inhibitors. The racemic key isoquinuclidine intermediate was prepared in high yield by a cycloaddition (tandem Michael addition/aldolisation) of the 3-hydroxy-1-tosyl-pyridone 10 to methyl acrylate, and transformed to the racemic N-benzyl manno-isoquinuclidine 2 and the N-unsubstituted mannoisoquinuclidine 3 (twelve steps; ca. 11% from 10). Catalysis by quinine of the analogous cycloaddition of 10 to (À)-8-phenylmenthyl acrylate provided a single diastereoisomer in high yield, which was transformed to the desired enantiomerically pure d-manno-isoquinuclidines ()-2 and ()-3 (twelve steps; 23% from 10). The enantiomers (À)-2 and (À)-3 were prepared by using a quinidine-promoted cycloaddition of 10 to the enantiomeric ()-8-phenylmenthyl acrylate. The N-benzyl d-manno-isoquinuclidine ()-2 is a selective and slow inhibitor of snail b-mannosidase. Its inhibition strength and type depends on the pH (at pH 4.5: K i 1.0 mm, mixed type, a 1.9; at pH 5.5: K i 0.63 mm, mixed type, a 17). The N-unsubstituted d-manno-isoquinuclidine ()-3 is a poor inhibitor. Its inhibition strength and type also depend on the pH (at pH 4.5: K i
Duilio Arigoni, in dankbarer und freundschaftlicher Verbundenheit, zum 75. herzlich zugeeignetThe d-gluco-isoquinuclidines 3 and 4 were prepared and tested as inhibitors of the b-glucosidases from Caldocellum saccharolyticum and from sweet almonds; the results are compared to the inhibition of snail bmannosidase by the d-manno-isoquinuclidines 1 and 2. Exploratory experiments in the racemic series showed that treatment of the ester epoxide 6 with benzyl alcoholates leads only to epimerisation, transesterification, and formation of the cyclopropane 9. Ring opening of the reduced epoxide 13 by NaN 3 proceeded regioselectively to provide 14. Treatment of the C(6)ÀO-triflate 16 with AcOCs induced a rearrangement; the reaction with NaN 3 gave the C(5)-azido derivative 14. The acetoxy triflate 18, however, reacted with AcOCs to provide the desired gluco-isoquinuclidine 19. Similarly, the enantiomerically pure acetoxy triflate 22 provided the d-glucoisoquinuclidine 24, which was reduced and deprotected to provide 3 and 4. The deoxy analogues 30 and 31 were obtained by reductive deiodination of the iodide 27, derived from 22. The d-gluco-isoquinuclidines 3, 4, 30, and 31 are much weaker inhibitors of b-glucosidases than the d-manno-analogues 1 and 2 of snail b-mannosidase. The N-benzyl derivative 3 is a weaker inhibitor than the N-unsubstituted analogue in the gluco-series, while it is a much stronger inhibitor in the manno-series. A consideration of the pK HA values of the isoquinuclidines 1 ± 4 and the pH value of the enzyme assays suggests that the d-gluco-isoquinuclidines are poor mimics of the shape of a reactive, enzyme-bound gluco-conformer, while the d-manno-analogues are reasonably good mimics of a reactive, enzyme-bound manno-conformer. The inhibition results may also suggest that the glycosidase induced lengthening of the scissile bond and rehybridisation of the anomeric centre are more strongly correlated with the change of the ground-state conformation during hydrolysis of b-d-glucopyranosides than of b-d-mannopyranosides.
We report the synthesis of a modified 8mer RNA sequence, (C‐C‐C‐C‐A‐C‐C‐(2′‐thio)A)‐RNA 5′‐(dihydrogen phosphate) (9) containing a 3′‐terminal 2′‐thioadenosine (Schemes 2 and 3), and its spontaneous and site‐specific aminoacylation with the weakly activated amino acid thioester HPheSPh (12). This reaction, designed in analogy to the ‘native chemical ligation’ of oligopeptides, occurs efficiently in buffered aqueous solutions and under a wide range of conditions (Table). At pH values between 5.0 and 7.4, two products, the 3′‐O‐monoacylated and the 3′‐O,2′‐S‐diacylated RNA sequences 10 and 11 are formed fast and quantitatively (Scheme 4). At pH 7.4 and 37°, the 3′‐O‐monoacylated product 10 is formed as major product in situ by selective hydrolysis of the O,S‐diacylated precursor 11. Additionally, the preparation and isolation of the relevant 3′‐O‐monoacylated product 10 was optimized at pH 5. The here presented concept could be employed for a straightforward aminoacylation of analogously modified tRNAs.
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