A Concise Synthesis of 6-Amino-6-deoxy-DNJ and 6-Amino-1,6-dideoxy-l-­talonojirimycin

Abstract

A concise and straightforward synthesis of two amino-DNJ derivatives, 6-amino-6-deoxy-DNJ and 6-amino-1,6-dideoxy-l-talonojirimycin is described from a commercial and cheap starting material. The methodology employed takes advantage of dia­stereoselective reductive amination to achieve the two non-natural iminosugars in three and five steps, respectively.

Key words

carbohydrates - inhibitors - alkaloids - azasugars - stereoselectivity

References and Notes

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4

Zavesca^® or Miglustat^® (N-butyl-1-deoxynojirimycin) for Gaucher’s disease.

5

Miglitol^® [(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol] for diabetes.

10

Synthesis of (2 R ,3 R ,4 R ,5 S )-2-(aminomethyl)-3,4,5-piperidinetriol dihydrochloride [(6-amino-6-deoxy-DNJ) or (6-amino-1,5-imino-1,5,6-trideoxy- d -glucitol) 4] from diazido intermediate 6: A solution of 6 (206 mg, 0.76 mmol) in 50% aq TFA (3 mL) was stirred at r.t. for 24 h. The mixture was evaporated and codistilled with water and toluene several times. The final residue was subjected to a short flash chromatography column (Et₂O) to give 10, which was used directly in the next step without further purification. IR: 3399 (OH), 2109 (N₃) cm^-¹.
A solution of compound 10 (142 mg, 0.62 mmol)in anhydrous MeOH (20 mL) was hydrogenated at 60 psi over 10% Pd/C (35 mg) for 24 h. The catalyst was filtered off, washed with MeOH and the resulting filtrate evaporated. The residue was transferred to a Dowex 50W×8 (200-400 mesh) column that was eluted with MeOH (30 mL), H₂O (20 mL) and 7% NH₄OH (40 mL), consecutively. After evaporation of the solvent the residue was acidified with 10% aqueous HCl (10 mL) and then evaporated to afford 4 (94 mg, 65% from 6) as a reddish foam; [α]_D ^²³ +10 (c 0.25, H₂O). ^¹H NMR (500 MHz, D₂O): δ = 3.67 (ddd, J _1,2 = 9.5, J _{1 ′ ,2} = 11.8, J _2,3 = 5.2 Hz, 1 H, H-2), 3.56 (t, J _3,4 = J _4,5 = 9.3 Hz, 1 H, H-4), 3.49-3.37 (m, 4 H, H-1,3,5,6), 3.29 (dd, J _5,6 = 4.4, J _{6,6 ′} = 13.2 Hz, 1 H, H-6′), 2.90 (t, J _{1,1 ′} = 11.8 Hz, 1 H, H-1′). ^¹³C NMR (125 MHz, D₂O): δ = 78.3 (C-3), 73.5 (C-4), 68.9 (C-2), 57.8 (C-5), 48.8 (C-1), 41.9 (C-6). HRMS (ES): m/z [M + H]⁺ calcd for C₆H₁₅N₂O₃: 163.1083; found: 163.1079

13

Synthesis of (2 S ,3 R ,4 S ,5 S )-2-(aminomethyl)-3,4,5-piperidinetriol dihydrochloride [(6-amino-1,6-dideoxy- l - talo nojirimycin) or (6-amino-1,5-imino-1,5,6-trideoxy- l -talitol) 5] from diazido intermediate 7: A solution of 7 (216 mg, 0.8 mmol) in 50% aqueous TFA (4 mL) was stirred at r.t. for 18 h. The mixture was evaporated and codistilled with water and toluene several times. The final residue was subjected to a short flash chromatography column (Et₂O) to give 12, which was used directly in the next reaction without further purification. IR (KBr): 3391 (OH), 2106 (N₃) cm^-¹.
A solution of compound 12 (95 mg, 0.41 mmol)in anhydrous MeOH (20 mL) was hydrogenated at 60 psi over 10% Pd/C (25 mg) for 24 h. The catalyst was filtered off, washed with MeOH and evaporated. The residue was transferred to a Dowex 50W×8 (200-400 mesh) column that was eluted with MeOH (30 mL), H₂O (20 mL) and 7% NH₄OH (40 mL), consecutively. After evaporation of the solvent, the residue was acidified with 10% aqueous HCl (10 mL) and then evaporated to afford 5 (71 mg, 73%) as a reddish foam; [α]_D ^²4 +33 (c 0.25, H₂O).^¹H NMR (400 MHz, D₂O): δ = 4.31 (br s, 2 H, H-2,4), 3.96 (t, J _3,4 = J _2,3 = 3.3 Hz, 1 H, H-3), 3.79 (m, 1 H, H-5), 3.67-3.59 (m, 2 H, H-1,6), 3.50 (dd, J _5,6 = 5.7, J _{6,6 ′} = 13.9 Hz, 1 H, H-6′), 3.40 (br d, 1 H, H-1′). ^¹³C NMR (100 MHz, D₂O): δ = 70.2 (C-2 or 4), 69.5 (C-3), 68.4 (C-2 or 4), 58.3 (C-5), 51.0 (C-1), 40.6 (C-6). HRMS (ES): m/z [M + H]⁺ calcd for C₆H₁₅N₂O₃: 163.1083; found: 163.1082