Synthesis of 1-Deoxynojirimycin and N-Butyl-1-deoxynojirimycin

Abstract

1-Deoxynojirimycin (1) is a natural alkaloid with several biological activities; the analog N-butyl-1-deoxynojirimycin (4), for example has shown potent anti HIV-1 and HIV-2 activity without cytotoxicity. As part of a program to synthesize compounds with biological activity against retroviruses, we developed an efficient route for the preparation of 1 and 4 employing as raw material glucose and others inexpensive reagents.The polyhydroxylated piperidine alkaloid 1-deoxynojirimycin (1), and its derivatives have been studied in numerous scientific investigations because they have demonstrated interesting antidiabetic, 1 anticancer, 2 anti-HIV I and HIV II 3 properties.The N-butyl derivative 4 has been shown to possess potent inhibitory activity of glycosidase enzymes, 4 and within a group including several natural and synthetic amino sugars and bicyclic alkaloids such as the indolizidine castanospermine and pyrrolizidine alexine, it presented the highest cytopathic effect (CPE) at a concentration which did not demonstrate cytotoxicity. 3 This compound is under clinical evaluation as an agent for the chemotherapy of AIDS. 5The compound 1-deoxynojirimycin (1) can be obtained from nojirimycin 6 and L-sorbofuranose 7 by varied chemical transformations. This alkaloid has also been isolated from natural sources such as plants of the genus Morus (Mori cortex, 8 Morus bombycis 9 ) and strains of Bacillus. 10 Regarding synthetic procedures for obtaining 1 and its derivatives, we can cite three different preparative strategies: the first involves as starting materials natural aldohexoses and ketohexoses; 11-16 the second employs a large number of steps using as starting material a chiral C 2 -symmetrical diol, the readily available diethyl L-tartarate; 17 and the third approach uses enzymes to build the skeleton of the desired alkaloid 1. 18,19 The latter synthetic methodology and related techniques of research represent a special field in modern synthetic organic chemistry involving microbiology, biochemistry and immunochemistry; these enantioselective syntheses have been developed employing enzymes isolated from mammals and bacteria. 20,21 The step of ring-closure to make piperidine alkaloids developed by some groups employed dicarbonyl sugar intermediates 22,23 with reductive amination to generate the desired diastereoisomer with high stereoselectivity, initiated by the attack of hydrogen from the bottom face resulting in the formation of the C 4 -C 5 bond in the more favorable trans configuration. As part of a research program to produce anti-retrovirus drugs with potential biological activity we were stimulated by all these representative results to design a straightforward and inexpensive synthesis to deoxynojirimycin (1) and N-butyl-1-deoxynojirimycin (4) employing reductive amination as the key step.The synthesis of 1 and 4 started with 2,3,4,6-tetra-O-benzyl-α-glucopyranose (5) which was converted to the desired 1,5-diol 6, in the form of a colorless viscous syrup, in quantitative yield, by reduction of the hemiketa...

N-Butyldeoxygalactonojirimycin Induces Reversible Infertility in Male CD Rats

“…The synthesis of N-butyl-1-deoxynojirimycin (NB-DNJ, Figure 2) and N-butyl-1-deoxygalactonojirimycin (NB-DGJ, Figure 2) was accomplished following known procedures (detailed in SI, Schemes S1 and S2, Figures S1 and S2) using 2,3,4,6-tetra-O-benzyl-α-glucopyranose and 2,3,4,6-tetra-O-benzyl-d-galactopyranose, respectively, as the starting materials [31,32]. Since the iminosugars are likely to be administered orally to men in a single dose, we selected a once a day oral drug dosing regimen for our study.…”

“…While testis obtained from vehicle group showed normal spermatid with elongated head, both NB-DNJ and NB-DGJ treated mice testis had rounded, abnormally shaped spermatid heads (Figure 3a). (detailed in SI, Schemes S1 and S2, Figures S1 and S2) using 2,3,4,6-tetra-O-benzyl-α-glucopyranose and 2,3,4,6-tetra-O-benzyl-D-galactopyranose, respectively, as the starting materials [31,32]. Since the iminosugars are likely to be administered orally to men in a single dose, we selected a once a day oral drug dosing regimen for our study.…”

Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors

“…For accessing compounds 11 and 12 , depicted in Scheme 1 , the key intermediate is per- O -benzylated 1-DNJ 6 , which was accessed in a 5-step linear pathway (36% overall yield), following the procedure reported in the literature 42 , starting from commercially-available methyl α- d -glucopyranoside 1 ( Scheme 1 ). Such procedure involves fully O -protection, acidic hydrolysis of the glycoside moiety, reduction of the masked aldehyde of 3 , Swern oxidation 43 , and fast reductive amination of transient unstable dicarbonyl compound 5 ; the last step consists of a double reductive amination (DRA), a cascade reaction that provides a straightforward methodology for accessing polyhydroxylated piperidines 44 .…”

Design, Synthesis, and Activity Evaluation of Novel N-benzyl Deoxynojirimycin Derivatives for Use as α-Glucosidase Inhibitors

“…1-DNJ were synthesized according to the methods of Wennekes and Matos with slight modification (shown as Scheme 1) using 2,3,4,5-tetra-O-benzyl- d -glucopyranose (compound 1 in Scheme 1) as the starting compound [13,17,18].…”