Solid-phase Synthesis of 2,3,5-Triketopiperadine

Abstract

The synthesis of 2,3,5-triketopiperadines on solid-support has been achieved for the first time. Cyclization of 4 using oxalyl diimidazole proceeded excellently with N-methyl amino acids except for Sarcosine (Sar). On the other hand, this cyclization did not proceed well when amino acids without N-methyl substitution were used. This can be explained by the lower energy difference between the trans and cis configurations of oxalyl amide 5 by the introduction of N-methyl substitution, because cis conformation is necessary for the cyclization to proceed. This cyclization also worked well with amino acids with a six-membered ring such as tetrahydroisoquinoline-3-carboxylic acid (Tic) and piperidine-2-carboxylic acid (Pic), which are N-alkylated amino acids. Although the purity of the target compounds was found to be low in the case of Sar and amino acids with a five-membered ring such as proline (Pro) and thiazolidine-4-carboxylic acid (Thz) under the same cyclization conditions, we were able to successfully optimize the reaction conditions to give the target compounds with good purity. Furthermore, it was demonstrated that 2,3,5-triketopiperadines with three points diversity could be prepared on solid-support with high purity, showing the generality of this method.

N-(2-Methylphenyl)-2-nitrobenzamide

“…The benzanilide core is present in compounds with such a wide range of biological activities that it has been called a privileged structure. Benzanilides serve as intermediates towards benzothiadiazin-4-ones (Makino et al, 2003), quinazoline-2,4-diones (Makino et al, 2001) and benzodiazepine-2,5-diones (Ho et al, 2002) and 110 kinase inhibitors 2,3-disubstituted 3H-quinazoline-4-ones (Zhichkin et al, 2007). Benzanilides have established their efficacy as centroid elements of ligands that bind to a wide variety of receptor types.…”

Recent Advances in the Solid-Phase Combinatorial Synthetic Strategies for the Quinoxaline, Quinazoline and Benzimidazole Based Privileged Structures

“…Similarly, they have also reported synthesis of 2,1,3-benzothiadiazin-4-one 2-oxides using SynPhase Lanterns [88]. SynPhase Lantern bearing 4aminobenzoic acid ester (75) was reacted with 2-fluoro-5nitrobenzoic acid to obtain the linked amide (76).…”

N-(3-Chlorophenyl)-2-nitrobenzamide

“…For related literature, see: Capdeville et al (2002); Ho et al (2002); Igawa et al (1999); Jackson et al (1994); Makino et al (2001Makino et al ( , 2003; Manley et al (2002); Zhichkin et al (2007).…”

“…The benzanilide core is present in compounds with such a wide range of biological activities that it has been called a privileged structure. Benzanilides serve as intermediates towards benzothiadiazin-4-ones (Makino et al, 2003), quinazoline-2,4-diones (Makino et al, 2001) and benzodiazepine-2,5-diones (Ho et al, 2002) and δ kinase inhibitors 2,3disubstituted 3H-quinazoline-4-ones (Zhichkin et al, 2007). Benzanilides have established their efficacy as centroid elements of ligands that bind to a wide variety of receptor types.…”