Design And Synthesis Of DNJ Derivatives

The natural product 1-deoxynojirimycin(DNJ)is a kind of efficient a-glucosidase inhibitor.It has been one of the hotspots of DNJ by structural modification to increase its inhibitory activity to α-glucosidase.In this paper,a series of DNJ-C-6,C-4,deuterated and N-alkylated derivatives were synthesized through the structural modification.The key steps in the route were optimized to improve the reaction yield.The main contents are as follows:(1)Two different routes were designed by using DNJ as the raw material to synthesize the key intermediate 2.4 with only C-6 hydroxyl not protected by any group.Then on the basis of compound 2.4,the reaction of etherification,esterification and halogenation was explored,at last the compounds 2.4a,2.6 were further processed by deprotection by hydrogen in the presence of Pd/C to give the target compounds 2,5,2.7.(2)The intermediate 3,3 with only C-4 hydroxyl group not protected by benzyl was prepared by the four-step reaction using DNJ as the starting material,then a series of 4-O-alkylated-l-deoxynojirimycins were synthesised on the basis of the compound 3.3.Besides,we not only improved the total yield from 31%to 68%compared to literatures,but also avoided the using of 1,4-dioxane,sodium cyanoborohydride-HCl(4M in 1,4-dioxane)such highly toxic reagents via designing and optimizing the reaction.(3)We synthesized the C-6-deuterated-DNJ by using compound 2.4 as raw material via PCC oxidation,deuterated sodium borohydride reduction,deprotection by hydrogen in the presence of Pd/C.In addition,we also prepared a one-deuterated and three-deuterated N-methyl-DNJ from DNJ.(4)The N-alkylation reaction was explored by using DNJ as starting materials,and N-allyl-DNJ was synthesized with 717 anion exchange resin instead of the traditional inorganic base.