Synthesis of Imidazolo-Piperidinopentoses as Nagstatine Analogues

Abstract

The syntheses of the four imidazolo-piperidino-pentoses 3−6, which belong to the D-series, and of their L-enantiomers, ent-3 to ent-6, are reported. Ascorbic acid and isoascorbic acid were converted over several steps into the L-threo/ L-erythro-and the D-erythro/D-threo-configured aldotetroses, respectively, which are the key building blocks for the eight target imidazolo-pentoses cited above. Nucleophilic addition of a metallated imidazole to any one of these four aldotetroses gave the corresponding two diastereomeric adducts, intramolecular cyclisation of which provided the expected bicyclic target molecules, with some protection and deprotection steps being unavoidable prerequisites. The structures and configurations of all eight piperidinoses in Scheme 1 were determined unambiguously, by a combination of 1 H/ 13 C NMR spectroscopy, circular dichroism (CD)

Samarium diiodide-induced reductive coupling of chiral nitrones prepared from D-isoascorbic acid with methyl acrylate

“…We are currently extending the scope of this synthetically useful reaction to various chiral sugar derived nitrones. 12 were prepared by literature procedure. …”

“…8 The nitrones 3 and 5 possessing C−2/C−3 threo configuration were found to effectively undergo an SmI 2 induced reductive coupling to methyl acrylate affording γ-N-hydroxylamino esters 4 and 6 with high diastereomeric control (Scheme 2). On the other hand, the coupling of the nitrones 7 and 10 possessing C−2/C−3 erythro configuration with methyl acrylate proceeded slower, the expected γ-N-hydroxylamino esters 8 and 11 were obtained as minor products along with products resulting from unusual reductive deoxygenation 9 and dimethyl adipate (12), the product of the radical dimerisation/addition step involving the acrylate (Scheme 3). …”

Discovery of new β‐D‐galactosidase inhibitors via pharmacophore modeling and QSAR analysis followed by in silico screening

“…2 and Table A) were collected from recently published literature. [17][18][19][20][21] The in vitro bioactivities of the collected inhibitors were determined by using identical bioassay conditions and were expressed as K i values (inhibition constants, lM), which allowed us to pool them for pharmacophore and QSAR analysis. The logarithm of measured 1/K i values were used in the three-dimensional quantitative structure activity analysis (3D-QSAR), thus correlating the data linear to the free energy change.…”

“…Such transition states feature extensive sp 2 hybridization and partial positive charge (predominantly along the bond between the anomeric carbon and endocyclic oxygen) and likely involve pyranoside distortion to half-chair or boat conformations. 16 Some of the most powerful glycosidase inhibitors contain imidazole moieties, [17][18][19][20][21] such as the cyclohexylethyl-substituted glucoimidazole 12 (Supporting Information Figs. 1 and 2, Table A), which display a flattened transition state-mimicking conformation resulting from fusion of the planar imidazole ring to the ''glycon.''…”

Stereomeric Pyrrolidinopentoses Bearing an Imidazole Ring − Synthesis, Chiroptical Properties, and Evaluation as Potential Sugar-Mimic Glycosidase Inhibitors

“…[11] Retrosynthetic analysis of its enantiomer ent-2 (Scheme 2) required the -threo derivative 6 Ϫ a compound that we had prepared previously [12] Ϫ as the chiral starting material and an imidazol-4-yl anion, the preparation of which had been described and discussed in detail elsewhere. [13Ϫ15] Suffice it to say that a solution of EtMgBr in diethyl ether had to be added to 4-iodo-1-tritylimidazole in dry CH 2 Cl 2 to give the C(4)-metallated imidazole building block, which was not isolated.…”