An Efficient Approach to Chiral C8/C9-Piperazino-Substituted 1,4-Benzodiazepin-2-ones as Peptidomimetic Scaffolds

• Published in: Journal of organic chemistry 2008-11, Vol.73 (21), p.8458-8468
• Main Authors: Butini, Stefania, Gabellieri, Emanuele, Huleatt, Paul Brady, Campiani, Giuseppe, Franceschini, Silvia, Brindisi, Margherita, Ros, Sindu, Coccone, Salvatore Sanna, Fiorini, Isabella, Novellino, Ettore, Giorgi, Gianluca, Gemma, Sandra
• Format: Article
• Language: English
• Subjects: Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Molecular Mimicry; Organic chemistry; Peptides; Peptides - chemistry; Piperazines - chemistry; Preparations and properties; Protein Binding; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo8015456

A promising way to interfere with biological processes is through the modulation of protein−protein interactions by means of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways to C6−8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9 have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate protein−protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the substrates.