433285-21-3

Upstream product

• 2393-23-9 4-methoxy-benzylamine 
• 269717-62-6 dimethyl (-)-(S)-2-[N-benzyl-N-(2-chloroacetyl)amino]pentanedioate 
• 56-86-0 L-glutamic acid 
• 23150-65-4 L-glutamic dimethyl ester hydrochloride 
• 84453-20-3 dimethyl (S)-2-(2-chloroacetylamino)pentanedioate 
• 6525-53-7 L-glutamic acid dimethyl ester 
• 882994-23-2 (-)-methyl (S)-[4-(4-methoxybenzyl)-3,6-dioxopiperazin-2-yl]propanoate 
• 100-39-0 benzyl bromide 
• 192655-69-9 dimethyl (S)-2-(benzylamino)pentanedioate 
• 100-52-7 benzaldehyde 

Downstream Products

• 960599-40-0 (-)-(1S,2R,5S)-6-benzyl-2-methoxy-8-(4-methoxybenzyl)-2-(trimethylsiloxy)-6,8-diazabicyclo[3.2.2]nonane-7,9-dione 

Relevant academic research and scientific papers

Homologous piperazine-alcanols: Chiral pool synthesis and pharmacological evaluation

Starting with the proteinogenic amino acids (S)-aspartate and (S)-glutamate the homologous piperazine-alcanols 3 and 4 were prepared in a five step synthesis. The diversity was introduced by N-1 alkylation of the piperazinediones 5 and 6 with various alkyl halides. Subsequent LiAlH 4 reduction of the dioxopiperazine-esters 7 and 8 provided the alcohols 3 and 4. The ethanol derivatives 3 show similar σ1 affinity as the methanol derivatives 2, but increased selectivity over the σ2 subtype. The corresponding propanol derivatives 4 are considerably less potent. A benzyl or dimethylallyl residue at N-1 appears to be optimal for high σ1 affinity.

Synthesis of bicyclic σ receptor ligands with cytotoxic activity

All possible stereoisomeric alcohols (6-benzyl-8-(4-methoxybenzyl)-6,8- diazabicyclo[3.2.2]nonan-2-ol) and methyl ethers (6-benzyl-2-methoxy-8-(4- methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane) are prepared from (R)- and (S)-glutamate. A Dieckmann analogous cyclization, which makes use of trapping the primary cyclization product with Me3SiCl, generates the bicyclic framework. Stereoselective LiBH4 reduction and Mitsunobu inversion establish the configuration in position 2. Enantiomeric alcohols 15 (1S,2S,5R) and ent-15 (1R,2R,5S) as well as diastereomeric methyl ethers ent-17 (1R,2R,5S) and ent-22 (1R,2S,5S) display high σ1 receptor affinity. Cell growth inhibition of the stereoisomeric alcohols and methyl ethers against five human tumor cell lines is investigated. In particular, at a concentration of 20 μthe four methyl ethers stop completely the cell growth of the small cell lung cancer cell line A-427, indicating a specific target in this cell line. The IC50-values of methyl ethers ent-17 and ent-22 are in the range of the antitumor drugs cisplatin and oxaliplatin. Binding assays show that the investigated tumor cell lines express considerable amounts of σ1 and σ2 receptors.

Synthesis of chiral non-racemic 3-(dioxopiperazin-2-yl)propionic acid derivatives

Starting with the proteinogenic amino acid (S)-glutamate (3) a facile, high yielding synthesis of the chiral non-racemic 3-(dioxopiperazin-2-yl)propionates 6, 11, and 14 is presented. Key intermediates in the synthesis of N1-benzyl substituted (dioxopiperazin-2yl)propionates 11 and 14 are the N-monobenzylglutamate 8 and the chloroacetamide 12, which allow introduction of various substituents in position 4 of the piperazine ting. In receptor binding studies with radioligands the 3-(piperazin-2-yl)propanol 15 was found to have promising affinity for σ1-receptors (Ki=66.1 nM).