5845-66-9

Usage

InChI:InChI=1/C11H12N2O3/c14-8-3-1-7(2-4-8)5-9-11(16)12-6-10(15)13-9/h1-4,9,14H,5-6H2,(H,12,16)(H,13,15)

Synthetic route

cyclo(L-tyrosine(OBn)-glycine) (1628630-12-5) → 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;	92%

CF3CO2H*H-L-Tyr-Gly-OMe → 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Conditions	Yield
With 4-methyl-morpholine; acetic acid In iso-butanol at 120℃; for 3h;	43%

N-Gly-Tyr (658-79-7) → 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Boc-Tyr-Gly-OEt (67208-98-4) → 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Conditions	Yield
With 4-methyl-morpholine; hydrogenchloride; acetic acid 1.) dioxane, r.t., 30 min; 2.) 2-butanol, reflux, 3 h; Yield given. Multistep reaction;

Boc-Tyr-OH (3978-80-1) → 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / N,N'-dicyclohexylcarbodiimide, 1-hydroxybenztriazole 2: 1.) 4N HCl; 2.) N-methylmorpholine / 2.) 0.1M AcOH / 1.) dioxane, r.t., 30 min; 2.) 2-butanol, reflux, 3 h View Scheme
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: dichloromethane / 1 h / 20 °C / Inert atmosphere 3: acetic acid; 4-methyl-morpholine / iso-butanol / 3 h / 120 °C View Scheme

FLQLYGLPETGY-isoacyl-Hse(Bz)-NH2 (1594922-38-9) + GGGGAEW-NH2 (1594873-76-3) → C22H26N4O6 (1594962-96-5) + C11H14N2O3 (1195407-21-6) + 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Conditions	Yield
With recombinant sortase A In aq. buffer at 21℃; pH=8;

BOC-Tyr(OBzl)-Gly-OEt (40356-35-2) → 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: water; methanol / 0.17 h / 170 °C / Microwave irradiation 2: hydrogen; palladium 10% on activated carbon / methanol / 20 °C View Scheme

O-benzyl-N-tert-butoxycarbonyl-L-tyrosine (2130-96-3) → 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 2: water; methanol / 0.17 h / 170 °C / Microwave irradiation 3: hydrogen; palladium 10% on activated carbon / methanol / 20 °C View Scheme

Boc-L-Tyr-Gly-OMe (7733-20-2) → 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 1 h / 20 °C / Inert atmosphere 2: acetic acid; 4-methyl-morpholine / iso-butanol / 3 h / 120 °C View Scheme

L-tyrosine ethyl ester (949-67-7) + chloroacetyl chloride (79-04-9) → 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9)

Conditions	Yield
With ammonia Multistep reaction;

prenyl bromide (870-63-3) + 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9) → cyclo-(glycyl-t-tyrosyl) 4,4-dimethylallyl ether (112900-76-2)

Conditions	Yield
With caesium carbonate; tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide at 20℃; for 12h;	73%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;	46%
With sodium hydride In dimethyl sulfoxide 0 deg C, then room t., 20 h;	23 mg

dimethyl sulfate (77-78-1) + 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9) → 3-<(4-methoxyphenyl)methyl>-1,4-dimethylpiperazine-2,5-dione (128520-01-4)

Conditions	Yield
With sodium hydride DMSO-THF; Multistep reaction;

3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9) + methyl iodide (74-88-4) → 3-<(4-methoxyphenyl)methyl>-1,4-dimethylpiperazine-2,5-dione (128520-01-4)

Conditions	Yield
With sodium hydride In dimethyl sulfoxide for 18h; Ambient temperature;

N-(2,4-dinitro-5-fluorophenyl)-L-alaninamide + 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (5845-66-9) → Gly-L-FDAA + DAA-L-Tyr-OH

Conditions	Yield
Stage #1: 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione With hydrogenchloride In water at 125℃; for 24h; Stage #2: N-(2,4-dinitro-5-fluorophenyl)-L-alaninamide With sodium hydrogencarbonate In water; acetone at 40℃; for 1h;

Upstream product

• 40356-35-2 BOC-Tyr(OBzl)-Gly-OEt 
• 2130-96-3 O-benzyl-N-tert-butoxycarbonyl-L-tyrosine 
• 7733-20-2 Boc-L-Tyr-Gly-OMe 
• 1080-06-4 L-Tyr-OMe 
• 65160-62-5 N^α-t-butyloxycarbonyl-glycyl-L-tyrosine methyl ester 
• 658-79-7 N-Gly-Tyr 
• 67208-98-4 Boc-Tyr-Gly-OEt 
• 3978-80-1 Boc-Tyr-OH 
• 1594922-38-9 FLQLYGLPETGY-isoacyl-Hse(Bz)-NH₂ 
• 1594873-76-3 GGGGAEW-NH₂ 
• 1628630-12-5 cyclo(L-tyrosine(OBn)-glycine) 
• 96935-86-3 H-Gly-Tyr-OMe 
• 949-67-7 L-tyrosine ethyl ester 
• 79-04-9 chloroacetyl chloride 

Downstream Products

• 112900-76-2 cyclo-(glycyl-t-tyrosyl) 4,4-dimethylallyl ether 
• 128520-01-4 3-<(4-methoxyphenyl)methyl>-1,4-dimethylpiperazine-2,5-dione 

Relevant academic research and scientific papers

Histamine H3 receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aβ oligomerisation

Alzheime?s disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where β-amyloid structures (Aβ) build toxic oligomers. Design of disease modifying multi target directed ligand (MTDL) has been performed, which disable PPI on the one hand and on the other hand, act as procognitive antagonists at the histamine H3 receptor (H3R). The synthetized compounds are structurally based on peptidomimetic amino acid-like structures mainly as keto, diketo-, or acyl variations of a piperazine moiety connected to an H3R pharmacophore. Most of them showed low nanomolar affinities at H3R and some with promising affinity to Aβ-monomers. The structure–activity relationships (SAR) described offer new possibilities for MTDL with an optimized profile combining symptomatic and potential causal therapeutic approaches in AD.

Synthesis and anti-cancer activity of naturally occurring 2,5-diketopiperazines

Three naturally occurring oxyprenylated diketopiperazines were synthesized and preliminarily tested as growth inhibitory agents in vitro against various cancer cell lines. The compounds were tested on six human cancer cell lines with different sensitivity to proapoptotic stimuli using the MTT colorimetric assay. The data revealed that of the chemicals under study only deoxymicelianamide (11) displayed the highest activity, recording mean IC50 growth inhibitory values ranging from 2 to 23 μM. A comparative study with the non-geranylated saturated derivative of (11) revealed the importance of the presence of the geranyloxy side chain and the exocyclic 2,5-DPK double bond moiety for the observed activity.

Synthesis and conformational characterization of diketopiperazines bearing a benzyl moiety

Diketopiperazines bearing a benzyl moiety with different para-substituents were synthesized and analyzed by 1HNMR spectroscopy. All of these diketopiperazines were found to adopt a folded conformation according to the upfield chemical shift of the cis-proton (cis to the benzyl moiety) due to a shielding effect in the 1HNMR spectra. An intramolecular CH-π interaction appears to be an important factor for the folded conformation due to the effects of para-substituents on the benzyl group.

Irreversible sortase a-mediated ligation driven by diketopiperazine formation

Sortase A (SrtA)-mediated ligation has emerged as an attractive tool in bioorganic chemistry attributing to the remarkable specificity of the ligation reaction and the physiological reaction conditions. However, the reversible nature of this reaction limits the efficiency of the ligation reaction and has become a significant constraint to its more widespread use. We report herein a novel set of SrtA substrates (LPETGG-isoacyl-Ser and LPETGG-isoacyl-Hse) that can be irreversibly ligated to N-terminal Gly-containing moieties via the deactivation of the SrtA-excised peptide fragment through diketopiperazine (DKP) formation. The convenience of the synthetic procedure and the stability of the substrates in the ligation buffer suggest that both LPETGGisoacyl- Ser and LPETGG-isoacyl-Hse are valuable alternatives to existing irreversible SrtA substrate sequences.

THREE PIPERAZINEDIONES AND A DRIMANE DITERPENOID FROM PENICILLIUM BREVI-COMPACTUM

Three new piperazinedione metabolites isolated from cultures of Penicillium brevi-compactum are described.A drimane derivative similar to macrophorin A was isolated and characterized.

New Piperazinedione Metabolites of Gliocladium deliquescens

The phenol (3), its γγ-dimethylallyl ether (7), and bisdethiobis(methylthio)dehydrogliotoxin (10), together with the hydroxy-acid (13), have been isolated from Gliocladium deliquescens.