Synthesis of Enantiomeric Polyhydroxyalkylpyrrolidines from 1,3-Dipolar Cycloadducts. Evaluation as Inhibitors of a β-Galactofuranosidase

Abstract

Enantiomeric 2,3,4-tris(hydroxyalkyl)-5-phenylpyrrolidines have been synthesized from the major cycloadducts obtained by the 1,3-dipolar cycloaddition of sugar enones with azomethine ylides derived from natural amino acids. Reduction of the ketone carbonyl group of the cycloadducts, which possess a basic structure of bicyclic 6-(menthyloxy)hexahydropyrano[4,3-c]pyrrol-7(6H)one, afforded a number of pyrrolidine-based bicyclic systems. A sequence of reactions, which involved hydrolysis of the menthyloxy substituent, reduction, N-protection, and degradative oxidation, afforded varied pyrrolidine structures having diverse configurations and patterns of substitution; in particular, polyhydroxylated derivatives have been obtained. The unprotected products were isolated as pyrrolidinium trifluoroacetates. Because of the furanose-like nature of the target trihydroxyalkyl pyrrolidines, these molecules have been evaluated as inhibitors of the β-galactofuranosidase from Penicillium fellutanum. The compounds showed practically no inhibitory activity for concentration of pyrrolidines in the range of 0.1-1.6 mM.

Synthesis of Highly Substituted and Enantiomerically Pure 2,3,4-Tris(hydroxyalkyl)pyrrolidines Using a 1,3-Dipolar Cycloaddition Reaction as Key Step

“…The formation of 6 a was indicative that the attack of the hydride took place from the Si face of the carbonyl, to lead to the suitable disposition of the resulting hydroxyl group to lactonize with the methyl carboxylate substituent. As shown in Scheme , the alcohols 7 a–c (with S ‐configuration) were the main products in the reduction of all the respective adducts 4 a–c , following a tendency previously observed in analogous systems . In fact, no lactone product was isolated in the reduction of 5 a–c and alcohols 8 a–c were the only products obtained.…”

“…The diasteroselectivity observed in the reduction of the carbonyl group of pyranone derivatives may be mostly attributed to the axial orientation of the menthyloxy group due to the anomeric effect . Such diastereoselectivity is probably reinforced by the substitution pattern of the pyrrolidine ring (i. e., the change of the methyl group in 4 a–c by a bulkier benzyl group in 5 a–c ) that could modify its conformation.…”

“…In connection with our work on the synthesis of polyhydroxypyrrolidines, by chemical modifications of the cycloadducts obtained via the 1,3‐dipolar cycloaddition of sugar derivatives with azomethine ylides, we report here the synthesis of enantiomerically pure pyrrolidines containing hydroxyalkyl substituents in three adjacent positions of the ring and a tetrasubstituted stereocenter in one of the carbons vicinal to the ring nitrogen atom and a phenyl group on the other.…”

Benzyl Glycosides of Thiodisaccharides. Influence of C‐2 Configuration of the Reducing End and Substitution at Benzyl on the Inhibition of the E. coli β‐Galactosidase.

“…The diastereoselectivity seems to be controlled by p ‐nitrobenzyloxy substituent, which is axially oriented because of the anomeric effect [29] and induces the approach of the thioaldose 2 from the opposite face of the pyranone ring. This is evidenced by the relatively small coupling constant values of H‐4 with the vicinal methylene protons at C‐5 and C‐3 (H‐5a [ J =3.0 Hz], H‐5b [ J =4.0 Hz] and H‐3a [ J =5.6 Hz], H‐3b [ J =4.3 Hz], respectively).…”

Current Trends towards the Synthesis of Bioactive Heterocycles and Natural Products Using 1,3-Dipolar Cycloadditions (1,3-DC) with Azomethine Ylides

“…A series of polyhydroxyalkylpyrrolidines 153 and ent-153, as potential inhibitors of a β-galactofuranosidase, were described by Varela et al employing a silver-catalyzed 1,3-DC from imino esters and (S)-or (R)-sugar pyranone as dipolarophiles (Scheme 45). 69 A sequence of reactions com-…”