33404-78-3

Basic information

• Product Name: negamycin
• Synonyms: negamycin;(3R,5R)-3,6-Diamino-5-hydroxyhexanoic acid 2-(carboxymethyl)-2-methyl hydrazide;(3R,5R)-3,6-Diamino-5-hydroxyhexanoic acid-N'-methyl-N'-(2-oxo-2-hydroxyethyl) hydrazide
• CAS NO: 33404-78-3
• Molecular Formula: C₉H₂₀N₄O₄
• Molecular Weight: 248.28
• Mol File: 33404-78-3.mol
• Article Data: 18

Chemical Properties

• Melting Point: 110-120° (dec)
• Appearance: /
• Density: 1.303g/cm³
• Refractive Index: 1.555
• PKA: pKa values after treatment with HCl-methanol: 3.55, 8.10, 9.75(
• CAS DataBase Reference: negamycin(CAS DataBase Reference)
• NIST Chemistry Reference: negamycin(33404-78-3)
• EPA Substance Registry System: negamycin(33404-78-3)

Safety Data

• Hazardous Substances Data: 33404-78-3(Hazardous Substances Data)

Usage

General Description

Negamycin is a member of a class of antibiotics known as aminoglycosides. It is produced by the bacterium Streptomyces platensis and exhibits potent antibacterial properties against a wide range of pathogens. Negamycin binds to the bacterial 30S ribosomal subunit, disrupting protein synthesis and ultimately leading to cell death. This mechanism of action makes it effective against bacteria that are resistant to other antibiotics, and it has shown promise for the treatment of multidrug-resistant infections. Research is ongoing to further explore the potential clinical applications of negamycin and to develop new derivatives with improved properties.

InChI:InChI=1/C9H20N4O4/c1-13(5-9(16)17)12-8(15)3-6(11)2-7(14)4-10/h6-7,14H,2-5,10-11H2,1H3,(H,12,15)(H,16,17)

Synthetic route

(R)-tert-butyl (R)-5-[2-(tert-butoxycarbonylamino)-3-{(tert-butoxycarbonylmethyl)methylaminocarbamoyl}propyl]-2,2-dimethyloxazolidine-3-carboxylate (1037825-22-1) → negamycin (33404-78-3)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 0℃; for 2h;	98%

[N'-((3R,5R)-3-Amino-6-benzyloxycarbonylamino-5-hydroxy-hexanoyl)-N-methyl-hydrazino]-acetic acid benzyl ester → negamycin (33404-78-3)

Conditions	Yield
With hydrogen; acetic acid; palladium on activated charcoal In methanol under 2250.2 Torr; for 12h; Ambient temperature;	96%

2-((3R,5R)-2-benzyloxycarbonyl-5-(chloromethyl)isoxazolidinyl)acetic acid (1613376-41-2) → negamycin (33404-78-3)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; acetic acid In methanol; water at 20℃; under 2068.65 Torr; for 24h;	94%

{N'-[(3R,5R)-6-Azido-5-hydroxy-3-((4S,5R)-2-oxo-4,5-diphenyl-oxazolidin-3-yl)-hexanoyl]-N-methyl-hydrazino}-acetic acid benzyl ester → negamycin (33404-78-3)

Conditions	Yield
With hydrogen; acetic acid; palladium on activated charcoal In methanol under 2068.6 Torr; for 8h; Ambient temperature;	91%

[N'-((3R,5R)-3,6-Diazido-5-benzyloxymethoxy-hexanoyl)-N-methyl-hydrazino]-acetic acid benzyl ester (119138-84-0) → negamycin (33404-78-3)

Conditions	Yield
With hydrogen; palladium on activated charcoal In methanol; acetic acid	89%

[N'-(6-amino-3-tert-butoxycarbonylamino-5-hydroxy-hexanoyl)-N-methyl-hydrazino]-acetic acid tert-butyl ester (540721-28-6) → negamycin (33404-78-3)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 20℃; for 9h;	78%

benzyl (3R,5R)-<2-isoxazolidin-3-yl>acetyl>-1-methylhydrazino>acetate (103321-73-9) → negamycin (33404-78-3)

Conditions	Yield
With hydrogen; palladium on activated charcoal In methanol; acetic acid under 2280 Torr; for 12h;	75%
With methanol; hydrogen; acetic acid; palladium on activated charcoal under 2280 Torr; for 12h;	75%

(2S,3R,6R)-6-[(R)-2-(Benzyl-benzyloxycarbonyl-amino)-3-(N'-benzyloxycarbonylmethyl-N'-methyl-hydrazinocarbonyl)-propyl]-2,3-diphenyl-morpholine-4-carboxylic acid benzyl ester (461385-14-8) → negamycin (33404-78-3)

Conditions	Yield
With hydrogen; acetic acid; palladium on activated charcoal In methanol; water at 75℃; under 2068.65 Torr; for 4.25h;	75%

{N'-[(3R,5R)-3,6-Diazido-5-(tert-butyl-dimethyl-silanyloxy)-hexanoyl]-N-methyl-hydrazino}-acetic acid benzyl ester (119688-96-9) → negamycin (33404-78-3)

Conditions	Yield
With hydrogen; acetic acid; palladium on activated charcoal In methanol at 20℃;	72%
With hydrogen; palladium on activated charcoal In 1,4-dioxane; hydrogenchloride

tert-butyl 2-(2-((3R,5R)-6-azido-5-((tert-butyldimethylsilyl)oxy)-3-(1,1-dimethylethylsulfinamido)hexanoyl)-1-methylhydrazinyl)acetate → negamycin (33404-78-3)

Conditions	Yield
Stage #1: tert-butyl 2-(2-((3R,5R)-6-azido-5-((tert-butyldimethylsilyl)oxy)-3-(1,1-dimethylethylsulfinamido)hexanoyl)-1-methylhydrazinyl)acetate With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 4h; Stage #2: With hydrogenchloride In methanol; water at 20℃; for 2h;	68%

benzyl 2-(1-methylhydrazinyl)acetate (55501-33-2) + (3R,5R)-6-Azido-3-benzyloxycarbonylamino-5-(tetrahydro-pyran-2-yloxy)-hexanoic acid (81601-97-0) → negamycin (33404-78-3)

Conditions	Yield
Yield given. Multistep reaction;

2-phenyl-1,3-dioxan-4-carbaldehyde (102794-92-3) + 2-(trimethylsilyl)ethyl α-(dimethoxyphosphoryl)-N-(tert-butyloxycarbonyl)glycinate (142602-45-7) → negamycin (33404-78-3) + (Z)-2-tert-Butoxycarbonylamino-3-(2-phenyl-[1,3]dioxan-4-yl)-acrylic acid 2-trimethylsilanyl-ethyl ester (142602-50-4, 145958-03-8)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane for 2h; Ambient temperature; Yield given. Yields of byproduct given. Title compound not separated from byproducts;

(N'-{(3R,5R)-6-Amino-3-[benzyl-((R)-1-phenyl-ethyl)-amino]-5-hydroxy-hexanoyl}-N-methyl-hydrazino)-acetic acid benzyl ester → negamycin (33404-78-3)

Conditions	Yield
With hydrogen; palladium dihydroxide under 4560 Torr; Ambient temperature; Yield given;
With 20 % Pd(OH)2/C; hydrogen; acetic acid In methanol at 20℃; under 3800.26 Torr; for 22h;	331 mg

C12H24N6O3Si (942292-44-6) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ethyl chloroformate; Et3N / toluene / -5 °C 1.2: 65 percent / toluene 2.1: 72 percent / H2; aq. AcOH / Pd/C / methanol / 20 °C View Scheme

(-)-tert-butoxycarbonyl-(R)-3-amino-5-hexenoic acid → negamycin (33404-78-3)

Conditions

Yield

Multi-step reaction with 10 steps 1: 88 percent / I2; KI; aq. NaHCO3 / CH2Cl2 / 2.5 h / 20 °C 2: NaN3 / dimethylformamide / 4 h / 55 °C 3: 89 percent / aq. LiOH / methanol / 2 h / 20 °C 4: imidazole / CH2Cl2 / 18 h / 20 °C 5: 80 percent / aq. K2CO3 / methanol / 2 h / 20 °C 6: pyridine / CH2Cl2 / 24 h / 20 °C 7: 96 percent / dimethylformamide / 3 h / 20 °C 8: 70 percent / TBAF / tetrahydrofuran / 1.25 h / 20 °C 9: 90 percent / H2 / Pd/C / ethyl acetate / 3 h / 20 °C 10: 78 percent / aq. HCl / dioxane / 9 h / 20 °C View Scheme

(2-azidomethyl-6-oxo-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (540721-22-0) → negamycin (33404-78-3)

Conditions

Yield

Multi-step reaction with 8 steps 1: 89 percent / aq. LiOH / methanol / 2 h / 20 °C 2: imidazole / CH2Cl2 / 18 h / 20 °C 3: 80 percent / aq. K2CO3 / methanol / 2 h / 20 °C 4: pyridine / CH2Cl2 / 24 h / 20 °C 5: 96 percent / dimethylformamide / 3 h / 20 °C 6: 70 percent / TBAF / tetrahydrofuran / 1.25 h / 20 °C 7: 90 percent / H2 / Pd/C / ethyl acetate / 3 h / 20 °C 8: 78 percent / aq. HCl / dioxane / 9 h / 20 °C View Scheme

(2-iodomethyl-6-oxo-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (551964-17-1) → negamycin (33404-78-3)

Conditions

Yield

Multi-step reaction with 9 steps 1: NaN3 / dimethylformamide / 4 h / 55 °C 2: 89 percent / aq. LiOH / methanol / 2 h / 20 °C 3: imidazole / CH2Cl2 / 18 h / 20 °C 4: 80 percent / aq. K2CO3 / methanol / 2 h / 20 °C 5: pyridine / CH2Cl2 / 24 h / 20 °C 6: 96 percent / dimethylformamide / 3 h / 20 °C 7: 70 percent / TBAF / tetrahydrofuran / 1.25 h / 20 °C 8: 90 percent / H2 / Pd/C / ethyl acetate / 3 h / 20 °C 9: 78 percent / aq. HCl / dioxane / 9 h / 20 °C View Scheme

6-azido-3-tert-butoxycarbonylamino-5-hydroxy-hexanoic acid (551964-18-2) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 7 steps 1: imidazole / CH2Cl2 / 18 h / 20 °C 2: 80 percent / aq. K2CO3 / methanol / 2 h / 20 °C 3: pyridine / CH2Cl2 / 24 h / 20 °C 4: 96 percent / dimethylformamide / 3 h / 20 °C 5: 70 percent / TBAF / tetrahydrofuran / 1.25 h / 20 °C 6: 90 percent / H2 / Pd/C / ethyl acetate / 3 h / 20 °C 7: 78 percent / aq. HCl / dioxane / 9 h / 20 °C View Scheme

6-azido-3-tert-butoxycarbonylamino-5-(tert-butyl-dimethyl-silanyloxy)-hexanoic acid (540721-23-1) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: pyridine / CH2Cl2 / 24 h / 20 °C 2: 96 percent / dimethylformamide / 3 h / 20 °C 3: 70 percent / TBAF / tetrahydrofuran / 1.25 h / 20 °C 4: 90 percent / H2 / Pd/C / ethyl acetate / 3 h / 20 °C 5: 78 percent / aq. HCl / dioxane / 9 h / 20 °C View Scheme

[N'-(6-azido-3-tert-butoxycarbonylamino-5-hydroxy-hexanoyl)-N-methyl-hydrazino]-acetic acid tert-butyl ester (540721-27-5) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / H2 / Pd/C / ethyl acetate / 3 h / 20 °C 2: 78 percent / aq. HCl / dioxane / 9 h / 20 °C View Scheme

C23H48N4O5Si2 → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: 80 percent / aq. K2CO3 / methanol / 2 h / 20 °C 2: pyridine / CH2Cl2 / 24 h / 20 °C 3: 96 percent / dimethylformamide / 3 h / 20 °C 4: 70 percent / TBAF / tetrahydrofuran / 1.25 h / 20 °C 5: 90 percent / H2 / Pd/C / ethyl acetate / 3 h / 20 °C 6: 78 percent / aq. HCl / dioxane / 9 h / 20 °C View Scheme

{N'-[6-azido-3-tert-butoxycarbonylamino-5-(tert-butyl-dimethyl-silanyloxy)-hexanoyl]-N-methyl-hydrazino}-acetic acid tert-butyl ester (540721-26-4) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 70 percent / TBAF / tetrahydrofuran / 1.25 h / 20 °C 2: 90 percent / H2 / Pd/C / ethyl acetate / 3 h / 20 °C 3: 78 percent / aq. HCl / dioxane / 9 h / 20 °C View Scheme

6-azido-3-tert-butoxycarbonylamino-5-(tert-butyl-dimethyl-silanyloxy)-hexanoic acid pentafluorophenyl ester (540721-25-3) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 96 percent / dimethylformamide / 3 h / 20 °C 2: 70 percent / TBAF / tetrahydrofuran / 1.25 h / 20 °C 3: 90 percent / H2 / Pd/C / ethyl acetate / 3 h / 20 °C 4: 78 percent / aq. HCl / dioxane / 9 h / 20 °C View Scheme

2R,5R,6S-2-(2'-(benzylamino)pent-4'-enyl)-5,6-diphenylmorpholine-4-carboxylic acid benzyl ester → negamycin (33404-78-3)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 80 percent / NaOH / dioxane; H2O / 12 h / 0 - 5 °C 2.1: O3 / methanol; CH2Cl2 / -78 °C 2.2: 73 percent / (C6H5)3P / methanol; CH2Cl2 / 20 °C 3.1: 97 percent / pyridinium dichromate / dimethylformamide / 12 h / 20 °C 4.1: 80 percent / 1-hydroxybenzotriazole; (C2H5)3N; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / CH2Cl2 / 12 h / 20 °C 5.1: 75 percent / CH3COOH; H2 / Pd/C / methanol; H2O / 4.25 h / 75 °C / 2068.65 Torr View Scheme

2R,2'R,5R,6S-2-(2'-((benzyl)(benzyloxycarbonyl)amino)-4'-oxobutyl)-5,6-diphenylmorpholine-4-carboxylic acid benzyl ester (461385-12-6) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 97 percent / pyridinium dichromate / dimethylformamide / 12 h / 20 °C 2: 80 percent / 1-hydroxybenzotriazole; (C2H5)3N; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / CH2Cl2 / 12 h / 20 °C 3: 75 percent / CH3COOH; H2 / Pd/C / methanol; H2O / 4.25 h / 75 °C / 2068.65 Torr View Scheme

2R,5R,6S-2-(2'-((benzyl)(benzyloxycarbonyl)amino)pent-4'-enyl)-5,6-diphenylmorpholine-4-carboxylic acid benzyl ester → negamycin (33404-78-3)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: O3 / methanol; CH2Cl2 / -78 °C 1.2: 73 percent / (C6H5)3P / methanol; CH2Cl2 / 20 °C 2.1: 97 percent / pyridinium dichromate / dimethylformamide / 12 h / 20 °C 3.1: 80 percent / 1-hydroxybenzotriazole; (C2H5)3N; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / CH2Cl2 / 12 h / 20 °C 4.1: 75 percent / CH3COOH; H2 / Pd/C / methanol; H2O / 4.25 h / 75 °C / 2068.65 Torr View Scheme

2R,2'R,5R,6S-2-(2'-((benzyl)(benzyloxycarbonyl)amino)-3'-carboxypropyl)-5,6-diphenylmorpholine-4-carboxylic acid benzyl ester (461385-13-7) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / 1-hydroxybenzotriazole; (C2H5)3N; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / CH2Cl2 / 12 h / 20 °C 2: 75 percent / CH3COOH; H2 / Pd/C / methanol; H2O / 4.25 h / 75 °C / 2068.65 Torr View Scheme

(R)-5-{(R)-2-[Benzyl-((R)-1-phenyl-ethyl)-amino]-3-carboxy-propyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (181772-92-9) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 96 percent / DCC, Et3N, HOBt / Ambient temperature 2: aq. TFA / tetrahydrofuran 3: H2 / Pd(OH)2/C / 4560 Torr / Ambient temperature View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 0.17 h / -15 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 0.58 h / -15 - 0 °C / Inert atmosphere 3.1: trifluoroacetic acid / 0.5 h / 0 - 20 °C 3.2: 16 h / 20 °C 3.3: pH 9 4.1: 20 % Pd(OH)2/C; hydrogen; acetic acid / methanol / 22 h / 20 °C / 3800.26 Torr View Scheme
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide / dichloromethane / 5.25 h / 0 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / 0.5 h / 0 - 20 °C 2.2: 16 h / 20 °C 2.3: pH 9 3.1: 20 % Pd(OH)2/C; hydrogen; acetic acid / methanol / 22 h / 20 °C / 3800.26 Torr View Scheme

3''-pentyl (R,R,R)-3-[N-benzyl-N-(α-methylbenzyl)amino]-4-[2',2';-dimethyl-N(3')-tert-butoxycarbonyl-1',3'-oxazolidin-5'-yl]butanoate (181772-74-7) → negamycin (33404-78-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 82 percent / aq. LiOH / methanol; tetrahydrofuran 2: 96 percent / DCC, Et3N, HOBt / Ambient temperature 3: aq. TFA / tetrahydrofuran 4: H2 / Pd(OH)2/C / 4560 Torr / Ambient temperature View Scheme
Multi-step reaction with 5 steps 1.1: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 24 h / Reflux 1.2: 20 °C 2.1: triethylamine / dichloromethane / 0.17 h / -15 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.58 h / -15 - 0 °C / Inert atmosphere 4.1: trifluoroacetic acid / 0.5 h / 0 - 20 °C 4.2: 16 h / 20 °C 4.3: pH 9 5.1: 20 % Pd(OH)2/C; hydrogen; acetic acid / methanol / 22 h / 20 °C / 3800.26 Torr View Scheme
Multi-step reaction with 4 steps 1.1: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 24 h / Reflux 1.2: 20 °C 2.1: benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide / dichloromethane / 5.25 h / 0 - 20 °C / Inert atmosphere 3.1: trifluoroacetic acid / 0.5 h / 0 - 20 °C 3.2: 16 h / 20 °C 3.3: pH 9 4.1: 20 % Pd(OH)2/C; hydrogen; acetic acid / methanol / 22 h / 20 °C / 3800.26 Torr View Scheme

negamycin (33404-78-3) → δ-Hydroxy-β-lysin

Conditions	Yield
With hydrogenchloride Heating;

negamycin (33404-78-3) + 2-benzyloxycarbonylsulfanyl-4,6-dimethyl-pyrimidine (42116-21-2) → Di-N-Z-negamycin

Conditions	Yield
With triethylamine In 1,4-dioxane; water

Upstream product

• 461385-13-7 2R,2'R,5R,6S-2-(2'-((benzyl)(benzyloxycarbonyl)amino)-3'-carboxypropyl)-5,6-diphenylmorpholine-4-carboxylic acid benzyl ester 
• 102794-92-3 2-phenyl-1,3-dioxan-4-carbaldehyde 
• 142602-45-7 2-(trimethylsilyl)ethyl α-(dimethoxyphosphoryl)-N-(tert-butyloxycarbonyl)glycinate 
• 119138-84-0 [N'-((3R,5R)-3,6-Diazido-5-benzyloxymethoxy-hexanoyl)-N-methyl-hydrazino]-acetic acid benzyl ester 
• 103321-73-9 benzyl (3R,5R)-<2-<methyl>isoxazolidin-3-yl>acetyl>-1-methylhydrazino>acetate 
• 55501-33-2 benzyl 2-(1-methylhydrazinyl)acetate 
• 81601-97-0 (3R,5R)-6-Azido-3-benzyloxycarbonylamino-5-(tetrahydro-pyran-2-yloxy)-hexanoic acid 
• 119688-96-9 {N'-[(3R,5R)-3,6-Diazido-5-(tert-butyl-dimethyl-silanyloxy)-hexanoyl]-N-methyl-hydrazino}-acetic acid benzyl ester 
• 72278-45-6 6-Azido-3-benzyloxycarbonylamino-5-oxo-hexanoic acid benzyl ester 
• 72278-44-5 benzyl N-carbobenzoxy-dl-3-amino-5-oxo-6-chlorohexanoate 
• 119688-92-5 {N'-[2-((3aR,5S,6aR)-2,2-Dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-acetyl]-N-methyl-hydrazino}-acetic acid benzyl ester 
• 118117-15-0 ((3aR,5S,6aR)-2,2-Dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-acetic acid 
• 58475-20-0 3,5-dideoxy-1,2-O-isopropylidene-α-D-erythro-hexofuranose 
• 119680-73-8 methyl 5-<<(benzyloxycarbonyl)amino>methyl>-N-(2,3:5,6-O-dicyclohexylidene-D-gulofuranosyl)isoxazolidine-3-carboxylate 

Downstream Products

• 58773-43-6 [N'-((3R,5S)-3,6-Bis-benzyloxycarbonylamino-5-hydroxy-hexanoyl)-N-methyl-hydrazino]-acetic acid methyl ester 
• 58773-31-2 [N'-((3R,5S)-3,6-Bis-benzyloxycarbonylamino-5-hydroxy-hexanoyl)-N-methyl-hydrazino]-acetic acid 

Relevant articles and documents

A total synthesis of (+)-negamycin through isoxazolidine allylation

The β-amino acid antibiotic (+)-negamycin has been synthesised in ten steps from epichlorohydrin via Sakurai allylation of an isoxazolidine intermediate. The key allylation reaction proceeded with complete trans-selectivity, which is attributed to electrostatic attraction between the chlorine atom and the iminium ion in the Sakurai intermediate. This journal is the Partner Organisations 2014.

Efficient total synthesis of (+)-negamycin, a potential chemotherapeutic agent for genetic diseases

Herein, we describe an efficient strategy for the total synthesis of (+)-negamycin using commercially available achiral N-Boc-2-aminoacetaldehyde as starting material with 42% overall yield for a limited number of steps. The Royal Society of Chemistry.