Aziridine carboxylate from d-glucose: synthesis of polyhydroxylated piperidine, pyrrolidine alkaloids and study of their glycosidase inhibition

Abstract

The D-glucose derived aziridine carboxylate 5 was obtained from (E)-ethyl-6-bromo-1,2-O-isopropylidene-3-O-benzyl-5-deoxy-alpha-D-xylo-5-eno-heptofuranuronate 4 through conjugate addition of benzylamine and in situ intramolecular nucleophilic expulsion of bromine. The regioselective aziridine ring-opening, using water as a nucleophile, resulted in the alpha-hydroxy-beta-aminoester 6, which was exploited in the synthesis of six and five membered azasugars 1b/1c and 2b/2c, respectively. The glycosidase inhibitory activity of the title compounds was evaluated.

Synthesis and Glycosidase Inhibitory Studies of Pentahydroxyindolizidines: D‐Glucose‐Derived Aziridine‐2‐carboxylate Approach

“…[2] The Wittig olefination of 7 with Ph 3 P=CHCOOEt afforded the γ-amino α,β-unsaturated ester 8 exclusively with the (E) geometry, as confirmed by 1 H NMR studies, which showed a large coupling constant of J = 16.1 Hz for protons 7-H and 6-H (Scheme 2). Dihydroxylation of 8 with potassium osmate (catalytic) and N-methylmorpholine N-oxide (NMO) in acetone/water (8:1) afforded a diastereomeric mixture of the vicinal diols 9a and 9b in a ratio of 7:3 (Table 1).…”

“…Thus, the use of AD-mix-α [10 mol-% (DHQ) 2 (Entry 3). It is worth mentioning that although the presence of the N-(Bn)Cbz functionality hindered the α-face of the double bond, the dihydroxylation occurred preferentially from the same side as this bulky group to give 9a as a major product.…”

“…This in turn was elaborated for the synthesis of the piperidine and pyrrolidine iminosugars 3a/b and 4a/b, respectively (Scheme 1). [2] As a part of our continuing interest in the area of iminosugars, [3] we envisioned the potential of aziridinecarboxylate 1 in the synthesis of polyhydroxylated indolizidine alkaloids. This class of compounds (e.g., castanospermine 5; Figure 1) and their analogues [4] have the ability to inhibit a specific class of hydrolytic enzymes that cleave different types of glycosidic linkages and have therefore been found to have applications in the treatment of diabetes, obesity, and viral infection.…”

Total Synthesis of New 8‐(Arylmethyl)berbines

“…No deprotection was observed upon treatment of either 9-cis or 9-trans with H 2 in the presence of Pd/C in ethanol. Treatment of 9-cis with ammonium formate and Pd/C in refluxing ethanol [21] afforded the O-trityl-deprotected derivative 10-cis (Scheme 4), whereas no deprotection was observed upon similar treatment of 9-trans. Finally, hydrogenolytic cleavage by pressurized H 2 (3 atm) in the presence of PtO 2 in methanol led to 1-cis and 1-trans berbines in 67 % and 30 % yield, respectively, after purification.…”

Recent Developments in the Synthesis of Pyrrolidine‐Containing Iminosugars

“…[67] Here, conversion of -glucose-derived aldehyde 120 into the key aziridine-2-carboxylate 121 and subsequent aziridine ring-opening, carboxylate reduction, and periodate cleavage gave the α-amino aldehyde 122. This versatile intermediate could then be used for the synthesis of pyrrolidine 125 via reduction of the aldehyde (122 Ǟ 123), deprotection and oxidative cleavage (123 Ǟ 124), and reductive amination/cyclisation (124 Ǟ 125).…”