157-03-9

Basic information

• Product Name: 6-DIAZO-5-OXO-L-NORLEUCINE
• Synonyms: 6-diazo-5-oxo,l-norleucin;6-diazo-5-oxo-l-norleucin;diazo-oxo-norleucine;don(pharmaceutical);6-DIAZO-5-OXO-L-2-AMINOHEXANOIC ACID;6-DIAZO-5-OXO-L-NORLEUCINE;6-DIAZO-5-OXO-NORLEUCINE;L-DON
• CAS NO: 157-03-9
• Molecular Formula: C6H9N3O3
• Molecular Weight: 171.15
• Product Categories: Antibiotics
• Mol File: 157-03-9.mol

Chemical Properties

• Melting Point: ~145 °C (dec.)
• Boiling Point: 301.12°C (rough estimate)
• Flash Point: °C
• Appearance: light yellow/crystalline
• Density: 1.3994 (rough estimate)
• Refractive Index: 1.5800 (estimate)
• Storage Temp.: −20°C
• Solubility: DMSO (Slightly, Heated, Sonicated), Water (Slightly)
• Stability: Hygroscopic
• Merck: 13,3026
• BRN: 1725815
• CAS DataBase Reference: 6-DIAZO-5-OXO-L-NORLEUCINE(CAS DataBase Reference)
• NIST Chemistry Reference: 6-DIAZO-5-OXO-L-NORLEUCINE(157-03-9)
• EPA Substance Registry System: 6-DIAZO-5-OXO-L-NORLEUCINE(157-03-9)

Safety Data

• Hazard Codes: T
• Statements: 23/24/25
• Safety Statements: 36/37/39-45
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: RC6340000
• F: 8
• Hazardous Substances Data: 157-03-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
6-Diazo-5-oxo-L-norleucine is used as an inhibitor for glutamine synthetase–glutamine(amide)-2-oxoglutarate aminotransferase. This application is significant because it plays a crucial role in the regulation of nitrogen metabolism and has been linked to various diseases, including cancer. By inhibiting this enzyme, DON can potentially be used in the development of therapeutic strategies to target these diseases.

Biochem/physiol Actions

DON is used to study mechanisms of glutamine utilizing enzymes such as carbamoyl phosphate synthase and cytidine triphosphate synthase.

Purification Methods

Crystallise it from EtOH, H2O/EtOH, MeOH, 95% aqueous MeOH or H2O/Me2CO. [DeWald & Moor J Am Chem Soc 80 3944 1958, Dion et al. J Am Chem Soc 78 3075 1956, Beilstein 4 IV 3278.]

InChI:InChI=1/C6H9N3O3/c7-5(6(11)12)2-1-4(10)3-9-8/h3,5H,1-2,7H2,(H-,10,11,12)/b4-3+/t5-/m0/s1

Synthetic route

6-Diazo-5-oxo-N-Tfa-L-norleucine-OMe (7589-24-4) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
With sodium hydroxide In methanol for 0.5h; Ambient temperature;	88%

ethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-diazo-5-oxohexanoate (208520-02-9) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
With piperidine for 0.0333333h;	81%

(S)-N-Fmoc-6-diazo-5-oxo-norleucine → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
With piperidine for 0.0333333h; Inert atmosphere;	52%

(S)-6-diazo-5-oxo-2-(2,2,2-trifluoro-acetylamino)-hexanoic acid ethyl ester (884594-54-1) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
With sodium hydroxide

(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanedioic acid α-methyl ester (42294-25-7) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
ueber mehrere Stufen;

(S)-6-Diazo-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-hexanoic acid benzyl ester → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
With piperidine

6-diazo-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-hexanoic acid methyl ester → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
With sodium hydroxide

Fmoc-Glu(OtBu)-OH (71989-18-9) + Fmoc-Leu-OH → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: diethyl ether 2: TFA / CH2Cl2 3: N-methylmorpholine / 0 °C 4: diethyl ether 5: 4M NaOH View Scheme

N-(9-fluorenylmethoxycarbonyl)glutamic acid (O-tert-butyl) methyl ester (160002-61-9) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: TFA / CH2Cl2 2: N-methylmorpholine / 0 °C 3: diethyl ether 4: 4M NaOH View Scheme

4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-methoxy-5-oxopentanoic acid (145038-49-9) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-methylmorpholine / 0 °C 2: diethyl ether 3: 4M NaOH View Scheme

2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-isopropenyloxycarbonyloxy-5-oxo-pentanoic acid methyl ester → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: diethyl ether 2: 4M NaOH View Scheme

1-(9H-fluoren-9-ylmethyl) 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 72 percent / n-BuLi / tetrahydrofuran; hexane / 0.17 h / -105 - -100 °C 2: 81 percent / piperidine / 0.03 h View Scheme

(S)-5-Oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-(9H-fluoren-9-ylmethyl) ester → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 61 percent / n-BuLi / tetrahydrofuran; hexane / 0.17 h / -105 - -100 °C 2: piperidine View Scheme

L-glutamic acid γ-benzyl ester (1676-73-9) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 4 steps 2: 95 percent / 1) H2, 5percent palladium-carbon / 1) 95percent Ethanol, room temperature, 1 h, 2) Diethylether, cooling, overnight 3: 16 percent / 1) Oxalyl chloride / 0 °C / 1) methylene dichloride, 2) ether, 0.5 h 4: 88 percent / 1.0 N sodium hydroxide / methanol / 0.5 h / Ambient temperature View Scheme

γ-OBzl-N-Tfa-L-Glu-OMe (84369-01-7) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / 1) H2, 5percent palladium-carbon / 1) 95percent Ethanol, room temperature, 1 h, 2) Diethylether, cooling, overnight 2: 16 percent / 1) Oxalyl chloride / 0 °C / 1) methylene dichloride, 2) ether, 0.5 h 3: 88 percent / 1.0 N sodium hydroxide / methanol / 0.5 h / Ambient temperature View Scheme

N-Tfa-L-Glu-OMe-γ-Dcha Salt (84344-29-6) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 16 percent / 1) Oxalyl chloride / 0 °C / 1) methylene dichloride, 2) ether, 0.5 h 2: 88 percent / 1.0 N sodium hydroxide / methanol / 0.5 h / Ambient temperature View Scheme

N-Tfa-L-Glu anhydride (1535-57-5) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 22 percent / 1) Methanol / 1) methanol, room temperature, 48 h, 2) THF, 2 h and standing overnight in a refrigerator 2: 16 percent / 1) Oxalyl chloride / 0 °C / 1) methylene dichloride, 2) ether, 0.5 h 3: 88 percent / 1.0 N sodium hydroxide / methanol / 0.5 h / Ambient temperature View Scheme

(S)-4-Chlorcarbonyl-2-(trifluor-acetylamino)butansaeureethylester (367-95-3) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: diethyl ether 2: aq.-ethanolic NaOH View Scheme

L-glutamic acid (56-86-0) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 140 - 150 °C / Erhitzen des Reaktionsprodukts mit Acetanhydrid auf 100grad 2: methanol 3: ueber mehrere Stufen View Scheme

N-phthaloyl-L-glutamic anhydride (25830-77-7) → 6-diazo-5-oxo-L-norleucine (157-03-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol 2: ueber mehrere Stufen View Scheme

6-diazo-5-oxo-L-norleucine (157-03-9) → (S)-5-oxo-2-piperidinecarboxylic acid (146467-21-2)

Conditions	Yield
With Ru(CO)(TPPS) In water at 25℃; for 6h; Inert atmosphere;	73%

6-diazo-5-oxo-L-norleucine (157-03-9) + 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid (19741-14-1) → 4-amino-4-deoxy-N10-methylpteroyl-(6-diazo-5-oxo)-L-norleucine

Conditions	Yield
With benzotriazol-1-ol; dicyclohexyl-carbodiimide 1.) DMSO, THF, 0 deg C, 1 h; room temperature, 1 h, 2.) 3 h; Yield given. Multistep reaction;

6-diazo-5-oxo-L-norleucine (157-03-9) → (S)-2-Amino-6-bromo-5-oxo-hexanoic acid

Conditions	Yield
With hydrogen bromide; acetic acid

6-diazo-5-oxo-L-norleucine (157-03-9) → (S)-2-Amino-6-chloro-5-oxo-hexanoic acid

Conditions	Yield
With hydrogenchloride In diethyl ether

6-diazo-5-oxo-L-norleucine (157-03-9) → 4-amino-4-deoxy-N10-methylpteroyl-(6-chloro-5-oxo)-L-norleucine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 1-hydroxybenzotriazole, dicyclohexylcarbodiimide / 1.) DMSO, THF, 0 deg C, 1 h; room temperature, 1 h, 2.) 3 h 2: 98 percent / HCl / dimethylformamide / 1 h / 4 °C View Scheme

6-diazo-5-oxo-L-norleucine (157-03-9) + C22H22N2O6 (1147093-55-7) → C24H26N4O6

Conditions	Yield
With triethylamine In tetrahydrofuran; water at 0℃; for 2h;

6-diazo-5-oxo-L-norleucine (157-03-9) + C16H16N2O8 (65581-50-2) → C18H20N4O8

Conditions	Yield
With triethylamine In tetrahydrofuran; water at 0℃; for 2h;

6-diazo-5-oxo-L-norleucine (157-03-9) + C21H20N2O5 (1147093-66-0) → C23H24N4O5

Conditions	Yield
With triethylamine In tetrahydrofuran; water at 0℃; for 2h;

Cbz-Gly-ONSuc (2899-60-7) + 6-diazo-5-oxo-L-norleucine (157-03-9) → C16H18N4O6

Conditions	Yield
With triethylamine In tetrahydrofuran; water at 0℃; for 2h;

Upstream product

• 884594-54-1 (S)-6-diazo-5-oxo-2-(2,2,2-trifluoro-acetylamino)-hexanoic acid ethyl ester 
• 42294-25-7 (2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanedioic acid α-methyl ester 
• 7589-24-4 6-Diazo-5-oxo-N-Tfa-L-norleucine-OMe 
• 208520-02-9 ethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-diazo-5-oxohexanoate 
• 71989-18-9 Fmoc-Glu(OtBu)-OH 
• 160002-61-9 N-(9-fluorenylmethoxycarbonyl)glutamic acid (O-tert-butyl) methyl ester 
• 145038-49-9 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-methoxy-5-oxopentanoic acid 
• 1676-73-9 L-glutamic acid γ-benzyl ester 
• 84369-01-7 γ-OBzl-N-Tfa-L-Glu-OMe 
• 84344-29-6 N-Tfa-L-Glu-OMe-γ-Dcha Salt 
• 1535-57-5 N-Tfa-L-Glu anhydride 
• 367-95-3 (S)-4-Chlorcarbonyl-2-(trifluor-acetylamino)butansaeureethylester 
• 56-86-0 L-glutamic acid 
• 25830-77-7 N-phthaloyl-L-glutamic anhydride 

Downstream Products

• 82972-54-1 4-amino-4-deoxy-N¹⁰-methylpteroyl-(6-diazo-5-oxo)-L-norleucine 
• 146467-21-2 (S)-5-oxo-2-piperidinecarboxylic acid 

Related news

A mechanism behind the antitumour effect of 6-DIAZO-5-OXO-L-NORLEUCINE (cas 157-03-9) (DON): disruption of mitochondria - release of cytochrome c from mitochondria blocked (see comments)09/30/2019

6-diazo-5-oxo-l-norleucine (DON) exerts a growth inhibitory effect selectively on the neuroendocrine tumour cell line BON and is proposed as an antitumour drug. The mechanism behind this has not yet been clarified. In the present study, transmission electron microscopy was used for the assessmen...detailed

Bioanalysis of 6-DIAZO-5-OXO-L-NORLEUCINE (cas 157-03-9) in plasma and brain by ultra-performance liquid chromatography mass spectrometry09/29/2019

Glutamine is an abundant amino acid that plays pivotal roles in cell growth, cell metabolism, and neurotransmission. Dysregulation of glutamine-using pathways has been associated with pathological conditions such as cancer and neurodegenerative diseases. 6-Diazo-5-oxo-l-norleucine (DON) is a rea...detailed

Relevant articles and documents

Inhibition of Escherichia coli glucosamine synthetase by novel electrophilic analogues of glutamine - Comparison with 6-diazo-5-oxo-norleucine

A series of electrophilic glutamine analogues based on 6-diazo-5-oxo-norleucine has been prepared, using novel synthetic routes, and evaluated as inhibitors of Escherichia coli. glucosamine synthetase. The γ-dimethylsulphonium salt analogue of glutamine was found to be one of the most potent inactivators of this enzyme yet reported, with an apparent second order rate constant (k2/K(i)) of 3.5 x 105 M-1 min-1. (C) 2000 Elsevier Science Ltd.

Chemical reactivity of 6-diazo-5-oxo-l-norleucine (DON) catalyzed by metalloporphyrins (Fe,Ru)

The transfer of the metallocarbene derived from N- and O-protected 6-diazo-5-oxo-l-norleucine (DON) catalyzed by metalloporphyrins undergoes dimerization, cyclopropanation, N-H and S-H insertion reactions, respectively. An efficient and direct synthesis of 5-oxo-l-pipecolic acid from DON is described from unprotected 6-diazo-5-oxo-l-norleucine.

The Reaction of Lithium Trimethylsilyldiazomethane with Pyroglutamates - a Facile Synthesis of 6-Diazo-5-oxo-norleucine and Derivatives

The reaction of carbamate derivatives of pyroglutamic acid esters with the lithium salt of trimethylsilyldiazomethane below -100 deg C gives good yields of the corresponding substituted 6-diazo-5-oxo-norleucine esters; cleavage of Fmoc-substituted products provides a safe, convenient route to the parent acid.