32780-32-8

Usage

Uses

Used in Pharmaceutical Industry:
Validamine is used as a glycosidase inhibitor for its role in synthesizing enzyme inhibitor type hypoglycemic agents. Its ability to inhibit small intestinal sucrase makes it a valuable component in the development of medications aimed at managing blood sugar levels and treating diabetes.

InChI:InChI=1/C8H17NO4/c1-13-3-4-2-5(9)7(11)8(12)6(4)10/h4-8,10-12H,2-3,9H2,1H3/t4-,5+,6-,7+,8+/m1/s1

Synthetic route

benzyl ((1S,2S,3S,4R,5R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)cyclohexyl)carbamate (1316231-06-7) → validamine (32780-32-8)

Conditions	Yield
With hydrogenchloride; palladium 10% on activated carbon; hydrogen In methanol; water; ethyl acetate under 760.051 Torr; for 20h;	95%

β-D-Glucopyranosylvalidamin-octaacetat (73411-05-9, 73651-21-5) → validamine (32780-32-8)

Conditions	Yield
(i) NH3, MeOH, (ii) NaIO4, (iii) (hydrolysis); Multistep reaction;

(1S)-(+)-(1,2,4/3,5)-1-acetamido-2,3,4-triacetoxy-5-acetoxymethylcyclohexane (68108-50-9) → validamine (32780-32-8)

Conditions	Yield
With sodium methylate; hydrazine hydrate 1.) RT, 2 h, 2.) 100 deg C, 72 h; Yield given. Multistep reaction;
With sodium methylate; hydrazine hydrate 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h; Yield given. Multistep reaction;
With hydrogenchloride at 80℃; for 2h;
Multi-step reaction with 2 steps 1: 10percent NaOMe / methanol / 3 h / 25 °C 2: 80percent aq. NH2NH2 / 72 h / 100 °C / sealed tube View Scheme

N-((1S,2S,3S,4R,5R)-2,3,4-Trihydroxy-5-hydroxymethyl-cyclohexyl)-acetamide (124492-65-5) → validamine (32780-32-8)

Conditions	Yield
With hydrazine hydrate at 100℃; for 72h; sealed tube; Yield given;

(1S,2R,3R,4R,6S)-6-Amino-2,3-bis-benzyloxy-4-benzyloxymethyl-cyclohexanol → validamine (32780-32-8)

Conditions	Yield
With ammonia; sodium In tetrahydrofuran at -40℃; for 1.5h;

3-O-acetyl 4,6-O-benzylidene-N-benzyloxycarbonyl-2-O-(p-tolylsulfonyl)-5a-carba-D-glucopyranosylamine → validamine (32780-32-8) + 2-epi-Validamine (191740-46-2)

Conditions	Yield
With hydrogenchloride; sodium benzoate; barium dihydroxide 1) DMF, 140 deg C, 120 h, 2) MeOH, reflux, 30 min, 3) H2O, 80 deg C, 4 h; Yield given. Multistep reaction;

2,3-di-O-acetyl-N-benzyloxycarbonyl-4,6-di-O-(p-tolylsulfonyl)-5a-carba-D-glucopyranosylamine (191723-81-6) → validamine (32780-32-8) + 4-epi-validamine

Conditions	Yield
With sodium benzoate; barium dihydroxide 1) DMF, 140 deg C, 120 h, 2) H2O, 80 deg C, 4 h; Yield given. Multistep reaction;

validamycin A (37248-47-8) → (+)-validoxylamine A (38665-10-0) + validamine (32780-32-8) + valienamine (38231-86-6)

Conditions	Yield
With ammonium sulfate; Flavobacterium saccharophilum IFO 13984; magnesium sulfate In phosphate buffer for 96h; pH=7.1; Hydrolysis; Title compound not separated from byproducts;

valienamine (38231-86-6) → validamine (32780-32-8) + 5-epi-validamine (38231-87-7)

Conditions	Yield
With hydrogen; nickel In water at 20℃; under 2068.59 Torr; for 20h;	A 152 mg B n/a

D-Glucose (2280-44-6) + culture medium → validamine (32780-32-8) + valienamine (38231-86-6) + validoxylamine A (39318-73-5, 81691-72-7, 81739-22-2) + validamycin A (37248-47-8)

Conditions	Yield
With Streptomyces hygroscopicus var. limoneus In water at 28℃; for 168h; Further byproducts.;

D-Glucose (2280-44-6) + culture medium → validamine (32780-32-8) + valienamine (38231-86-6) + validamycin A (37248-47-8) + validamycin B

Conditions	Yield
With Streptomyces hygroscopicus var. limoneus In water at 28℃; for 168h; Further byproducts.;

(1R)-(1,3,4/2,6)-1,7-O-benzylidene-4-<(benzyloxycarbonyl)amino>-6-C-(hydroxymethyl)-1,2,3-cyclohexanetriol (89859-47-2) → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 89.6 percent / pyridine / 8 h / Ambient temperature 2: 0.5 N HCl / methanol / 0.5 h / Heating 3: 4.5 g / pyridine; CH2Cl2 / 14 h / Ambient temperature 4: 1) sodium benzoate, 2) Ba(OH)2 / 1) DMF, 140 deg C, 120 h, 2) H2O, 80 deg C, 4 h View Scheme
Multi-step reaction with 3 steps 1: CH2Cl2; pyridine / 14 h / Ambient temperature 2: 4.8 g / pyridine; CH2Cl2 / 15 h / Ambient temperature 3: 1) sodium benzoate, 2) N HCl, 3) Ba(OH)2 / 1) DMF, 140 deg C, 120 h, 2) MeOH, reflux, 30 min, 3) H2O, 80 deg C, 4 h View Scheme

Acetic acid (1S,2S,3S,5R,6R)-2-acetoxy-3-benzyloxycarbonylamino-6-hydroxy-5-hydroxymethyl-cyclohexyl ester → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 4.5 g / pyridine; CH2Cl2 / 14 h / Ambient temperature 2: 1) sodium benzoate, 2) Ba(OH)2 / 1) DMF, 140 deg C, 120 h, 2) H2O, 80 deg C, 4 h View Scheme

2,3-di-O-acetyl-4,6-O-benzylidene-N-benzyloxycarbonyl-5a-carba-D-glucopyranosylamine → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 0.5 N HCl / methanol / 0.5 h / Heating 2: 4.5 g / pyridine; CH2Cl2 / 14 h / Ambient temperature 3: 1) sodium benzoate, 2) Ba(OH)2 / 1) DMF, 140 deg C, 120 h, 2) H2O, 80 deg C, 4 h View Scheme

Toluene-4-sulfonic acid (4aR,6S,7S,8S,8aR)-6-benzyloxycarbonylamino-8-hydroxy-2-phenyl-hexahydro-benzo[1,3]dioxin-7-yl ester → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 4.8 g / pyridine; CH2Cl2 / 15 h / Ambient temperature 2: 1) sodium benzoate, 2) N HCl, 3) Ba(OH)2 / 1) DMF, 140 deg C, 120 h, 2) MeOH, reflux, 30 min, 3) H2O, 80 deg C, 4 h View Scheme

(1R,2R,3S,4R,5R)-3,4-di-O-benzyl-5-benzyloxymethyl-1,2-O,O-sulfonyl-cyclohexane-1,2,3,4-tetraol (151693-59-3) → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 6 steps 1: 1.) LiN3, 2.) aq. H2SO4 / 1.) DMF, 105 deg C, 2.5 h, 2.) THF, 50 deg C, 30 min 2: 96 percent / pyridine / CH2Cl2 / 0.5 h / 0 °C 3: 89 percent / tetrahydrofuran / 3 h / 80 °C 4: 98 percent / NaOMe / methanol / 6 h / Ambient temperature 5: H2 / Raney nickel / ethyl acetate / 18 h / Ambient temperature 6: Na, NH3 / tetrahydrofuran / 1.5 h / -40 °C View Scheme

(1R,2R,3R,4S,6R)-4-Azido-1,2-di-O-benzyl-6-<(benzyloxy)methyl>-3-O-(trifluoromethylsulfonyl)-1,2,3-cyclohexanetriol (166376-50-7) → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 89 percent / tetrahydrofuran / 3 h / 80 °C 2: 98 percent / NaOMe / methanol / 6 h / Ambient temperature 3: H2 / Raney nickel / ethyl acetate / 18 h / Ambient temperature 4: Na, NH3 / tetrahydrofuran / 1.5 h / -40 °C View Scheme

(1R,2R,3R,4S,6R)-4-Azido-1,2-di-O-benzyl-6-<(benzyloxy)methyl>-1,2,3-cyclohexanetriol (166376-48-3) → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 96 percent / pyridine / CH2Cl2 / 0.5 h / 0 °C 2: 89 percent / tetrahydrofuran / 3 h / 80 °C 3: 98 percent / NaOMe / methanol / 6 h / Ambient temperature 4: H2 / Raney nickel / ethyl acetate / 18 h / Ambient temperature 5: Na, NH3 / tetrahydrofuran / 1.5 h / -40 °C View Scheme

(1R,2R,3S,4S,6R)-4-Azido-1,2-di-O-benzyl-6-<(benzyloxy)methyl>-1,2,3-cyclohexanetriol (166376-52-9) → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2 / Raney nickel / ethyl acetate / 18 h / Ambient temperature 2: Na, NH3 / tetrahydrofuran / 1.5 h / -40 °C View Scheme

(1R,2R,3S,4S,6R)-3-O-Acetyl-4-azido-1,2-di-O-benzyl-6-<(benzyloxy)methyl>-1,2,3-cyclohexanetriol (166376-51-8) → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 98 percent / NaOMe / methanol / 6 h / Ambient temperature 2: H2 / Raney nickel / ethyl acetate / 18 h / Ambient temperature 3: Na, NH3 / tetrahydrofuran / 1.5 h / -40 °C View Scheme

1,2-O-isopropylidene-α-D-glucofuranurono-5-ulose-6,3-lactone (5040-08-4) → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 11 steps 1: 86 percent / KF / 6 h / 20 °C 2: 79 percent / D-camphorsulfonic acid / CH2Cl2 / 0.75 h / 25 °C 3: 83 percent / NaBH4 / propan-2-ol / 2 h / 25 °C 4: 178 mg / pyridine / CH2Cl2 / 0.5 h / 25 °C 5: 84 mg / aq.trifluoroacetic acid / 1 h / 40 °C 6: 140 mg / CsF / dimethylformamide / 0.5 h / 25 °C 7: 64 percent / p-TsOH / 2 h / 25 °C 8: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 9: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 10: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 11: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme
Multi-step reaction with 11 steps 1: 86 percent / KF / 6 h / 20 °C 2: 79 percent / D-camphorsulfonic acid / CH2Cl2 / 0.75 h / 25 °C 3: NaBH4 / ethanol / Ambient temperature 4: 178 mg / pyridine / CH2Cl2 / 0.5 h / 25 °C 5: 84 mg / aq.trifluoroacetic acid / 1 h / 40 °C 6: 140 mg / CsF / dimethylformamide / 0.5 h / 25 °C 7: 64 percent / p-TsOH / 2 h / 25 °C 8: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 9: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 10: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 11: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme

(3aR,5R,6S,6aR)-5-((R)-1-Hydroxymethyl-2-nitro-ethyl)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-ol → validamine (32780-32-8)

Conditions

Yield

Multi-step reaction with 8 steps 1: 178 mg / pyridine / CH2Cl2 / 0.5 h / 25 °C 2: 84 mg / aq.trifluoroacetic acid / 1 h / 40 °C 3: 140 mg / CsF / dimethylformamide / 0.5 h / 25 °C 4: 64 percent / p-TsOH / 2 h / 25 °C 5: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 6: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 7: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 8: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme

(3aR,3bS,6S,6aS,7aR)-6-Hydroxy-2,2-dimethyl-6-nitromethyl-tetrahydro-furo[2',3':4,5]furo[2,3-d][1,3]dioxol-5-one (152434-60-1) → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 10 steps 1: 79 percent / D-camphorsulfonic acid / CH2Cl2 / 0.75 h / 25 °C 2: 83 percent / NaBH4 / propan-2-ol / 2 h / 25 °C 3: 178 mg / pyridine / CH2Cl2 / 0.5 h / 25 °C 4: 84 mg / aq.trifluoroacetic acid / 1 h / 40 °C 5: 140 mg / CsF / dimethylformamide / 0.5 h / 25 °C 6: 64 percent / p-TsOH / 2 h / 25 °C 7: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 8: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 9: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 10: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme
Multi-step reaction with 10 steps 1: 79 percent / D-camphorsulfonic acid / CH2Cl2 / 0.75 h / 25 °C 2: NaBH4 / ethanol / Ambient temperature 3: 178 mg / pyridine / CH2Cl2 / 0.5 h / 25 °C 4: 84 mg / aq.trifluoroacetic acid / 1 h / 40 °C 5: 140 mg / CsF / dimethylformamide / 0.5 h / 25 °C 6: 64 percent / p-TsOH / 2 h / 25 °C 7: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 8: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 9: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 10: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme

C21H21NO9 → validamine (32780-32-8)

Conditions

Yield

Multi-step reaction with 6 steps 1: 140 mg / CsF / dimethylformamide / 0.5 h / 25 °C 2: 64 percent / p-TsOH / 2 h / 25 °C 3: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 4: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 5: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 6: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme

C24H25NO9 (152434-63-4) → validamine (32780-32-8)

Conditions

Yield

Multi-step reaction with 7 steps 1: 84 mg / aq.trifluoroacetic acid / 1 h / 40 °C 2: 140 mg / CsF / dimethylformamide / 0.5 h / 25 °C 3: 64 percent / p-TsOH / 2 h / 25 °C 4: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 5: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 6: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 7: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme

C27H29NO9 → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 2: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme
Multi-step reaction with 2 steps 1: 1.) 1percent methanolic NaOMe, 2.) pyridine / 1.) RT, 3 h, 2.) RT, 3 h 2: 1.) 1percent methanolic NaOMe, 2.) 80percent aq. NH2NH2 / 1.) RT, 2 h, 2.) 100 deg C, 72 h View Scheme

C27H28N2O11 → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 2: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 3: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme
Multi-step reaction with 3 steps 1: 50 percent / n-Bu3SnH, 2,2'-azobisisobutyronitrile / toluene / 1 h / Heating 2: 1.) 1percent methanolic NaOMe, 2.) pyridine / 1.) RT, 3 h, 2.) RT, 3 h 3: 1.) 1percent methanolic NaOMe, 2.) 80percent aq. NH2NH2 / 1.) RT, 2 h, 2.) 100 deg C, 72 h View Scheme

C21H21NO9 → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 64 percent / p-TsOH / 2 h / 25 °C 2: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 3: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 4: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 5: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme

C27H27NO12 → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 2: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 3: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 4: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme
Multi-step reaction with 4 steps 1: 1.) liq. NH3, 2.) p-TsOH 2: 50 percent / n-Bu3SnH, 2,2'-azobisisobutyronitrile / toluene / 1 h / Heating 3: 1.) 1percent methanolic NaOMe, 2.) pyridine / 1.) RT, 3 h, 2.) RT, 3 h 4: 1.) 1percent methanolic NaOMe, 2.) 80percent aq. NH2NH2 / 1.) RT, 2 h, 2.) 100 deg C, 72 h View Scheme

(3aR,3bS,6S,6aS,7aR)-6-(2-Ethoxy-ethoxy)-2,2-dimethyl-6-nitromethyl-tetrahydro-furo[2',3':4,5]furo[2,3-d][1,3]dioxol-5-one (152434-61-2) → validamine (32780-32-8)

Conditions	Yield
Multi-step reaction with 9 steps 1: 83 percent / NaBH4 / propan-2-ol / 2 h / 25 °C 2: 178 mg / pyridine / CH2Cl2 / 0.5 h / 25 °C 3: 84 mg / aq.trifluoroacetic acid / 1 h / 40 °C 4: 140 mg / CsF / dimethylformamide / 0.5 h / 25 °C 5: 64 percent / p-TsOH / 2 h / 25 °C 6: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 7: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 8: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 9: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme
Multi-step reaction with 9 steps 1: NaBH4 / ethanol / Ambient temperature 2: 178 mg / pyridine / CH2Cl2 / 0.5 h / 25 °C 3: 84 mg / aq.trifluoroacetic acid / 1 h / 40 °C 4: 140 mg / CsF / dimethylformamide / 0.5 h / 25 °C 5: 64 percent / p-TsOH / 2 h / 25 °C 6: 1.) liq.NH3, 2.) p-TsOH*H2O / 1.) THF, -78 deg C, 9 min; 2.) 25 deg C, 2 h 7: 50 percent / n-Bu3SnH, AIBN / toluene / 1 h / 110 °C 8: 1.) sodium methoxide, 2.) pyridine / 1.) MeOH, 25 deg C, 3 h; 25 deg C, 12 h 9: 1.) sodium methoxide, 2.) aq. hydrazine / 1.) MeOH, 25 deg C, 2 h; 2.) 100 deg C, 72 h View Scheme

validamine (32780-32-8) + 2,3,4,6-Tetra-O-benzyl-α-D-glucopyranosyl isothiocyanate (93173-26-3) → N-<(1S)-(1,2,4/3,5)-2,3,4-trihydroxy-5-(hydroxymethyl)cyclohexyl>-N'-(2',3',4',6'-tetra-O-benzyl-α-D-glucopyranosyl)thiourea (162414-07-5)

Conditions	Yield
In water; N,N-dimethyl-formamide for 0.666667h; Ambient temperature;	92.8%

validamine (32780-32-8) + benzyl chloroformate (501-53-1) → N-(benzyloxycarbonyl)validamine (85281-05-6)

Conditions	Yield
Stage #1: validamine; benzyl chloroformate In 1,4-dioxane; water at 0 - 20℃; for 2h; Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; water pH=7 - 7.5;	92%
In 1,4-dioxane; water at 0 - 20℃; for 1h;	88%
In 1,4-dioxane; water 1.) 0-5 deg C, 1 h, 2.) room temp., 1 h;	31.8 g

validamine (32780-32-8) + S-tert-butoxycarbonyl-2-thioxo-4,6-dimethylpyrimidine → N-(tert-butyloxycarbonyl)-validamine

Conditions	Yield
In 1,4-dioxane; water at 0 - 20℃; for 18h;	88.4%

dihydroxyacetone (96-26-4) + validamine (32780-32-8) → N-<2-hydroxy-1-(hydroxymethyl)ethyl>validamine (83470-79-5)

Conditions	Yield
With hydrogenchloride; sodium cyanoborohydride In N,N-dimethyl-formamide at 50 - 60℃; for 15h;	55%

validamine (32780-32-8) + acetic anhydride (108-24-7) → (1S)-(+)-(1,2,4/3,5)-1-acetamido-2,3,4-triacetoxy-5-acetoxymethylcyclohexane (68108-50-9)

Conditions	Yield
With pyridine; dmap Inert atmosphere;	52%
With pyridine; dmap for 24h; Ambient temperature; Yield given;

Cellobiose (133-99-3, 490-37-9, 2152-98-9, 4482-75-1, 5965-66-2, 13299-27-9, 13360-52-6, 14641-93-1, 15548-43-3, 16462-44-5, 16984-36-4, 16984-38-6, 20869-27-6, 22688-72-8, 27452-49-9, 29276-55-9, 30608-12-9, 34481-13-5, 37169-60-1, 37169-64-5, 64234-01-1, 64234-02-2, 75281-88-8, 80446-85-1, 84413-57-0, 92344-56-4, 93221-87-5, 93301-77-0, 94799-29-8, 100427-98-3, 100428-00-0, 101312-82-7, 102046-24-2, 102046-25-3, 109432-00-0, 109432-02-2, 109432-04-4, 109432-08-8, 135268-49-4, 138231-26-2, 140461-59-2, 145414-22-8, 145414-26-2, 146339-75-5, 146339-76-6, 149116-55-2, 528-50-7) + validamine (32780-32-8) → 1-O-β-D-glucopyranosyl-1L-(1,3,4/2,6)-4-amino-6-hydroxymethyl-1,2,3-cyclohexanetriol (73410-98-7, 145554-75-2) + validamine 2-β-glucoside (139541-64-3) + 7-O-β-D-glucosyl validamine (145531-76-6, 145554-76-3)

Conditions	Yield
In water at 27℃; for 72h; β-glucosidase (from Rhodotorula lactosa);	A 48 mg B 51 mg C 125 mg

Maltose (133-99-3, 490-37-9, 2152-98-9, 4482-75-1, 5965-66-2, 13299-27-9, 13360-52-6, 14641-93-1, 15548-43-3, 16462-44-5, 16984-36-4, 16984-38-6, 20869-27-6, 22688-72-8, 27452-49-9, 29276-55-9, 30608-12-9, 34481-13-5, 37169-60-1, 37169-64-5, 64234-01-1, 64234-02-2, 75281-88-8, 80446-85-1, 84413-57-0, 92344-56-4, 93221-87-5, 93301-77-0, 94799-29-8, 100427-98-3, 100428-00-0, 101312-82-7, 102046-24-2, 102046-25-3, 109432-00-0, 109432-02-2, 109432-04-4, 109432-08-8, 135268-49-4, 138231-26-2, 140461-59-2, 145414-22-8, 145414-26-2, 146339-75-5, 146339-76-6, 149116-55-2, 6363-53-7) + validamine (32780-32-8) → validamine 7-α-isomaltoside (145531-77-7) + validamine 4-α-glucoside (73410-98-7, 145554-75-2) + validamine 7-α-glucoside (145531-76-6, 145554-76-3)

Conditions	Yield
In water at 27℃; for 72h; α-glucosidase (from Rhodotorula lactosa);	A 22 mg B 44 mg C 106 mg

validamine (32780-32-8) + acetic anhydride (108-24-7) + Methyl 3,4-anhydro-α-D-galactopyranoside (24578-12-9) → Acetic acid (2R,3R,4R,5R,6S)-5-acetoxy-2-acetoxymethyl-6-methoxy-4-((1S,2S,3S,4R,5R)-2,3,4-triacetoxy-5-acetoxymethyl-cyclohexylamino)-tetrahydro-pyran-3-yl ester + Acetic acid (2S,3R,4S,5R,6S)-3-acetoxy-6-acetoxymethyl-2-methoxy-5-((1S,2S,3S,4R,5R)-2,3,4-triacetoxy-5-acetoxymethyl-cyclohexylamino)-tetrahydro-pyran-4-yl ester

Conditions	Yield
With pyridine 1.) isopropanol, 120 deg C, 6 d, 2.) room temp., overnight; Yield given. Multistep reaction. Yields of byproduct given;

validamine (32780-32-8) → (1S,5S,7R,8S,1''R)-3-(5a'-carba-α-D-glucopyranosylamino)-7-(1'',2''-dihydroxyethyl)-2,6-dioxa-4-azabicyclo<3.3.0>oct-3-en-8-ol (162414-09-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92.8 percent / dimethylformamide; H2O / 0.67 h / Ambient temperature 2: 94.8 percent / HgO / diethyl ether / 46 h / Ambient temperature 3: 85.7 percent / Na / liquid ammonia; tetrahydrofuran / 0.25 h / -78 °C View Scheme

validamine (32780-32-8) → (1S,3R,4R,5S,6S)-3-hydroxymethyl-8-(2',3',4',6'-tetra-O-benzyl-α-D-glucopyranosylamino)-7-oxa-9-azabicyclo<4.3.0>non-8-ene-4,5-diol (162414-08-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92.8 percent / dimethylformamide; H2O / 0.67 h / Ambient temperature 2: 94.8 percent / HgO / diethyl ether / 46 h / Ambient temperature View Scheme

Upstream product

• 73411-05-9 β-D-Glucopyranosylvalidamin-octaacetat 
• 68108-50-9 (1S)-(+)-(1,2,4/3,5)-1-acetamido-2,3,4-triacetoxy-5-acetoxymethylcyclohexane 
• 124492-65-5 N-((1S,2S,3S,4R,5R)-2,3,4-Trihydroxy-5-hydroxymethyl-cyclohexyl)-acetamide 
• 191723-81-6 2,3-di-O-acetyl-N-benzyloxycarbonyl-4,6-di-O-(p-tolylsulfonyl)-5a-carba-D-glucopyranosylamine 
• 5040-08-4 1,2-O-isopropylidene-α-D-xylo-5-hexulofuranurono-6,3-lactone 
• 1316231-06-7 benzyl ((1S,2S,3S,4R,5R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)cyclohexyl)carbamate 
• 38665-10-0 (+)-validoxylamine A 
• 119951-72-3 Benzoic acid (1R,4S,5R,6R)-4,6-diacetoxy-5-benzyloxy-2-nitro-cyclohex-2-enylmethyl ester 
• 119951-74-5 Benzoic acid (1R,2R,3S,4S,5S)-2,4-diacetoxy-5-acetylamino-3-benzyloxy-cyclohexylmethyl ester 
• 152434-61-2 (3aR,3bS,6S,6aS,7aR)-6-(2-Ethoxy-ethoxy)-2,2-dimethyl-6-nitromethyl-tetrahydro-furo[2',3':4,5]furo[2,3-d][1,3]dioxol-5-one 
• 152434-63-4 C₂₄H₂₅NO₉ 
• 152434-60-1 (3aR,3bS,6S,6aS,7aR)-6-Hydroxy-2,2-dimethyl-6-nitromethyl-tetrahydro-furo[2',3':4,5]furo[2,3-d][1,3]dioxol-5-one 
• 166376-51-8 (1R,2R,3S,4S,6R)-3-O-Acetyl-4-azido-1,2-di-O-benzyl-6-<(benzyloxy)methyl>-1,2,3-cyclohexanetriol 
• 166376-52-9 (1R,2R,3S,4S,6R)-4-Azido-1,2-di-O-benzyl-6-<(benzyloxy)methyl>-1,2,3-cyclohexanetriol 

Downstream Products

• 73410-98-7 1-O-β-D-glucopyranosyl-1L-(1,3,4/2,6)-4-amino-6-hydroxymethyl-1,2,3-cyclohexanetriol 
• 139541-64-3 validamine 2-β-glucoside 
• 145531-76-6 7-O-β-D-glucosyl validamine 
• 145531-77-7 validamine 7-α-isomaltoside 
• 73410-98-7 validamine 4-α-glucoside 
• 145531-76-6 validamine 7-α-glucoside 
• 83470-79-5 N-<2-hydroxy-1-(hydroxymethyl)ethyl>validamine 
• 85281-05-6 N-(benzyloxycarbonyl)validamine 
• 162414-07-5 N-<(1S)-(1,2,4/3,5)-2,3,4-trihydroxy-5-(hydroxymethyl)cyclohexyl>-N'-(2',3',4',6'-tetra-O-benzyl-α-D-glucopyranosyl)thiourea 
• 68108-50-9 (1S)-(+)-(1,2,4/3,5)-1-acetamido-2,3,4-triacetoxy-5-acetoxymethylcyclohexane 
• 162414-09-7 (1S,5S,7R,8S,1''R)-3-(5a'-carba-α-D-glucopyranosylamino)-7-(1'',2''-dihydroxyethyl)-2,6-dioxa-4-azabicyclo<3.3.0>oct-3-en-8-ol 
• 162414-08-6 (1S,3R,4R,5S,6S)-3-hydroxymethyl-8-(2',3',4',6'-tetra-O-benzyl-α-D-glucopyranosylamino)-7-oxa-9-azabicyclo<4.3.0>non-8-ene-4,5-diol 
• 83465-22-9 (1S,2S,3R,4S,5S)-1-amino-5-hydroxymethyl-2,3,4,5-tetrahydroxycyclohexane 
• 85240-30-8 1L(1R)-(1,3,4/2)-<(benzyloxycarbonyl)amino>-6-methylene-1,2,3-cyclohexanetriol 

Relevant academic research and scientific papers

Preparation method of high-purity validamine

Validamine and valienamine are important chemical raw materials but have high separation cost and complex separation process. The invention discloses a preparation method validamine, which includes the steps of: 1) hydrolyzing validoxylamine A through an NBS chemical method by adding the validoxylamine A and NBS to water as a solvent according to certain molar ratio, and performing a reaction for 4 h at 25 DEG C; 2) carrying out adsorption separation to the reaction product through a weak-acidic cation exchange resin, and concentrating the product to obtain a mixture of the validamine and valienamine; 3) under catalysis by a heavy metal catalyst, performing hydrogenation to the mixture, performing adsorption separation to the reaction product through a weak-acidic cation exchange resin, concentrating the product, and vacuum-drying the concentrate to obtain a high-quality validamine sample.

Methods of producing validamycin A analogs and uses thereof

This disclosure relates to validamycin A biosynthesis and in particular, to methods of producing validamycin A analogs and uses thereof. In a particular example, a method for making a validamycin A analog includes transforming a host cell with one or more recombinant DNA vectors to produce a valN-inactivated mutant; and culturing the valN-inactivated mutant in a culture medium to produce a validamycin A analog, such as 1,1′-bis-valienamine and validienamycin, and their conversion to valienamine. The present disclosure further relates to compositions including such compounds as well as methods of using the compositions, such as for antifungal agents.

Pseudoglycosyltransferase catalyzes nonglycosidic C-N coupling in validamycin a biosynthesis

Glycosyltransferases are ubiquitous in nature. They catalyze a glycosidic bond formation between sugar donors and sugar or nonsugar acceptors to produce oligo/polysaccharides, glycoproteins, glycolipids, glycosylated natural products, and other sugar-containing entities. However, a trehalose 6-phosphate synthase-like protein has been found to catalyze an unprecedented nonglycosidic C-N bond formation in the biosynthesis of the aminocyclitol antibiotic validamycin A. This dedicated 'pseudoglycosyltransferase catalyzes a condensation between GDP-valienol and validamine 7-phosphate to give validoxylamine A 7′-phosphate with net retention of the 'anomeric configuration of the donor cyclitol in the product. The enzyme operates in sequence with a phosphatase, which dephosphorylates validoxylamine A 7′-phosphate to validoxylamine A.

METHODS OF PRODUCING VALIDAMYCIN A ANALOGS AND USES THEREOF

This disclosure relates to validamycin A biosynthesis and in particular, to methods of producing validamycin A analogs and uses thereof. In a particular example, a method for making a validamycin A analog includes transforming a host cell with one or more recombinant DNA vectors to produce a valN-inactivated mutant; and culturing the valN-inactivated mutant in a culture medium to produce a validamycin A analog, such as 1,1′-bis-valienamine and validienamycin, and their conversion to valienamine. The present disclosure further relates to compositions including such compounds as well as methods of using the compositions, such as for antifungal agents.

Biosynthesis of the validamycins: Identification of intermediates in the biosynthesis of validamycin A by Streptomyces hygroscopicus var. limoneus

To study the biosynthesis of the pseudotrisaccharide antibiotic, validamycin A (1), a number of potential precursors of the antibiotic were synthesized in 2H, 3H-, or 13C-labeled form and fed to cultures of Streptomyces hygroscopicus var. limoneus. The resulting validamycin A from each of these feeding experiments was isolated, purified and analyzed by liquid scintillation counting, 2H- or 13C NMR or selective ion monitoring mass spectrometry (SIM-MS) techniques. The results demonstrate that 2-epi-5-epi-valiolone (9) is specifically incorporated into 1 and labels both cyclitol moieties. This suggests that 9 is the initial cyclization product generated from an open-chain C7 precursor, D-sedoheptulose 7-phosphate (5), by a DHQ synthase-like cyclization mechanism. A more proximate precursor of 1 is valienone (11), which is also incorporated into both cyclitol moieties. The conversion of 9 into 11 involves first epimerization to 5-epi-valiolone (10), which is efficiently incorporated into 1, followed by dehydration, although a low level of incorporation of 2-epi-valienone (15) is also observed. Reduction of 11 affords validone (12), which is also incorporated specifically into 1, but labels only the reduced cyclitol moiety. The mode of introduction of the nitrogen atom linking the two pseudosaccharide moieties is not clear yet. 7-Tritiated valiolamine (8), valienamine (2), and validamine (3) were all not incorporated into 1, although each of these amines has been isolated from the fermentation, with 3 being most prevalent. Demonstration of in vivo formation of [7-3H]validamine ([7-3H]-3) from [7-3H]-12 suggests that 3 may be a pathway intermediate and that the nonincorporation of [7-3H]-3 into 1 is due to a lack of cellular uptake. We thus propose that 3, formed by amination of 12, and 11 condense to form a Schiff base, which is reduced to the pseudodisaccharide unit, validoxylamine A (13). Transfer of a D-glucose unit to the 4′-position of 13 then completes the biosynthesis of 1. Other possibilities for the mechanism of formation of the nitrogen bridge between the two pseudosaccharide units are also discussed.

Synthesis of [7-3H]valienamine, [7-3H]valienone, [7-3H]valiolamine and [7-3H]valiolone from validamycin A

To investigate the biosynthetic pathway to the cyclitol moieties of acarbose and validamycin A, [7-3H]valienamine, [7-3H]valienone, [7-3H]valiolamine and [7-3H]valiolone were synthesized as plausible precursors. Valienamine together with validamine was isolated from the degradation of validamycin A by Flavobacterium saccharophilum and served as starting material for the synthesis. Validamine was removed partially at the stage of tritylation and completely after the oxidation of the primary hydroxy group at C-7 to the aldehyde. The resulting valienamine aldehyde was reduced with tritiated sodium borohydride to produce [7-3H]valienamine. The latter was converted to [7-3H]valiolamine by a synthetic route described in the literature. The 3H-labeled amines were oxidized to [7-3H]valienone and [7-3H]valiolone, respectively, using 3,5-di-tert-butyl-1,2-bezoquinone (DBQ) followed by hydrolysis with oxalic acid.

Preparation and biological activity of manno- and galacto-validamines, new 5a-carba-glycosylamines as α-glycosidase inhibitors

Manno- and galacto-validamines, which are epimers of validamine, were semi-synthesized by the configurational inversion of validamine, a pseudo-sugar analogue of α-D-glucopyranose that has inhibitory activity for α-glucosidases. The inhibitory activities of these analogues were determined against several mannosidases and galactosidases. Manno-validamine shows potent inhibition for the α-mannosidases (competitive, K(i) = 4.6 x 10-5 M for jack beans, and competitive, K(i) = 2.8 x 10-5 M for almonds), and galacto-validamine shows weak inhibition for the α-galactosidases (coffee bean and E. coli). The inhibitory effect of the epimers on the N-linked oligosaccharide-processing mannosidases involved in glycoprotein biosynthesis and lysosomal mannosidase from rat liver were also examined. Mannovalidamine shows potent inhibition on the endoplasmic reticulumal α-mannosidase (competitive, K(i) = 1.2 x 10-6 M), Golgi mannosidases IA, II (competitive, K(i) = 2.8 X 10-5 M), and lysosomal α-mannosidase (competitive, K(i) 1.7 x 10-5 M).

Pseudosugars, 36: Synthesis of methyl 5a′-carbamaltoses linked by imino, ether and sulfide bridges and unsaturated derivatives thereof

Methyl 5a′-carbamaltoses linked by imino, ether, and sulfide bridges were synthesized by coupling of an amino carbasugar with a sugar epoxide and of the carbasugar epoxide with the oxide anion or thioacetate derived from sugar derivatives. Their unsaturated derivatives related to a potent α-glucosidase inhibitor, methyl acarviosin, were also synthesized. Moderate inhibitory activity against baker's yeast α-glucosidase was observed only for the imino-linked compounds 2 and 5. VCH Verlagsgesellschaft mbH, 1996.

Stereoselective conversion of D-glucuronolactone into pseudosugar: Synthesis of pseudo-α-D-glucopyranose, pseudo-β-D-glucopyranose, and validamine

Two optically active pseudo-sugars, pseudo-α-D-glucopyranose (12) and pseudo-β-D-glucopyranose (13), were synthesized from D-glucuronolactone in favorable overall yields by using a stereoselective nitromethane addition reaction and a reductive elimination of an ethoxyethoxyl moiety with NaBH4 as key steps. Furthermore, a biologically active pseudo-aminosguar, validamine (18) was efficiently synthesized via a substitution reaction for an acetoxyl group at the β-position of nitro group in a nitrocyclitol derivative (14) which was prepared from a synthetic intermediate (9) of pseudo-d-glucopyranoses (12,13).