Stereospecific Synthesis of Pyrrolidines with Varied Configurations via 1,3-Dipolar Cycloadditions to Sugar-Derived Enones

Abstract

Enantiomerically pure pyrrolidines have been obtained by 1,3-dipolar cycloaddition of stabilized azomethine ylides and sugar enones (dihydropyranones) derived from pentoses. Thus, the S-enone (menthyl 3,4-dideoxy-(1S)-pent-3-enopyranosid-2-ulose) was prepared from D-xylose, while the R analogue was obtained from L-arabinose. The dipoles were generated in situ from α-arylimino esters of common amino acids (glycine, alanine, or phenylalanine) and aromatic aldehydes (benzaldehyde, 3-formylpyridine and 4-methoxybenzaldehyde). Under optimized conditions, the cycloaddition reactions were highly diastereo- and regioselective to yield, in most of the cases, a very major adduct of the 16 theoretically possible. The diastereoselectivity relies on the strict stereocontrol exerted by the stereogenic center of the pyranone. Thus, the (S)-enone, derived from D-xylose, gave tetrasubstituted pyrrolidines having a defined stereochemistry for the four stereocenters of the ring, while they had the opposite configuration when starting from the (R)-dihydropyranone. Furthermore, some endo-cycloadducts underwent isomerization of the carbons vicinal to the nitrogen atom to afford pyrrolidines with a rather unusual stereochemistry for the direct dipolar cycloadditions.

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

“…Now, we were able to confirm by X-ray crystallography the structure of compounds 2a and 2b , which had been previously assigned on the basis of NMR data . Suitable crystals of 2a and 2b could be obtained using acetonitrile as recrystallization solvent, and the X-ray diffraction analysis confirmed the absolute configuration assigned to these two key cycloadducts (Figure ).…”

“…The 1,3-dipolar cycloaddition is one of the most powerful tools for the synthesis of heterocyclic scaffolds, and the reaction has been applied in diverse fields like drug discovery, polymers and materials . We have employed the 1,3-dipolar cycloaddition reaction of stabilized azomethine ylides and sugar-derived enones ( 1a and 1b ) to afford cycloadducts of the type of 2a or 2b , as shown in Scheme . The stereogenic center ( S ) or ( R ) of the sugar pyranone ( 1a or 1b , respectively) exerts a strict diastereocontrol during the [3 + 2]-cycloaddition.…”

“…The cycloadduct 2a – e (1.00 mmol) was dissolved in anhydrous EtOH (15 mL). In some cases, smooth heating was necessary to achieve complete dissolution.…”

“…As a continuation of our project on the synthesis of sugar mimetics as inhibitors of glycosidases, we report here the synthesis of enantiomeric pyrrolidines substituted in three adjacent positions of the ring with hydroxyalkyl groups. These compounds were obtained by chemical transformations performed on cycloadducts generated by 1,3-dipolar cycloaddition of azomethine ylides and sugar enones . Some representative compounds were evaluated as inhibitors of the β-galactofuranosidase from Penicillium fellutanum .…”

Divergent Entry to Gelsedine-Type Alkaloids: Total Syntheses of (−)-Gelsedilam, (−)-Gelsenicine, (−)-Gelsedine, and (−)-Gelsemoxonine

“…With the above analysis in mind, we first investigated the asymmetric Michael addition, as shown in Scheme . Taking inspiration from Varela’s seminal work, we decided to choose (−)-menthol-derived enone 15 (readily accessible from l -arabinose in four steps with dr > 98:2) as the Michael acceptor, in the hope of accessing serviceable stereocontrol. Initial attempts to treat indole fragment 13 (easily prepared from gramine in three steps) and dihyropyranone 15 with a variety of organic bases all met with failure, leading to decomposition of both coupling partners in most cases.…”