The synthesis and conformational analysis of optical isomers of 4-phenyl-perhydropyrido[1,2-a]pyrazine-1,3-dione: an example of ‘solid state–frozen’ dynamics in nitrogen-bridged bicyclic 2,6-diketopiperazines

The synthesis, chemical properties, and conformational analysis of enantiopure (4R,9aS)-, (4S,9aR)-, (4S,9aS)-, and (4R,9aR)-4-phenyl-perhydropyrido[1,2-a]pyrazine-1,3-diones having potential biological activity are described. An interesting example of the coexistence of two invertomers of the (4R,9aR)-diastereomer in a single crystal unit cell is reported. The invertomers differ in the cis/trans-relationship between the fused rings and in the absolute configuration at the chiral nitrogen atom. The structure and equilibrium distributions of the respective conformers have been determined by NMR spectroscopy in both polar and non-polar solvents at various temperatures. The NMR spectra show that dynamic processes in the imide parts of the interconverting species are restrained by self-aggregation. The (4S,9aR)-diastereomer exists in a single conformation with insignificant dynamic effects.

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(2S,αR)-α-(2-Carbamoylpiperidinyl)-α-phenylacetic acid methyl esterC15H20N2O3[α]D = −125.0 (c 1, CHCl3)Source of chirality: (S)-(+)-2-(4-toluenesulfonyloxy)-phenylacetic acid methyl ester, (S)-(−)-2-piperidinecarboxamideAbsolute configuration: (2S,αR)

(2S,αS)-α-(2-Carbamoylpiperidinyl)-α-phenylacetic acid methyl esterC15H20N2O3[α]D = +3.0 (c 1, CHCl3)Source of chirality: (R)-(−)-2-(4-toluenesulfonyloxy)-phenylacetic acid methyl ester, (S)-(−)-2-piperidinecarboxamideAbsolute configuration: (2S,αS)

(4R,9aS)-4-Phenyl-perhydropyrido[1,2-a]pyrazine-1,3-dioneC14H16N2O2[α]D = −137.4 (c 1, CHCl3)Source of chirality: (2S,αR)-α-(2-carbamoylpiperidinyl)-α-phenylacetic acid methyl esterAbsolute configuration: (4R,9aS)

(4S,9aS)-4-Phenyl-perhydropyrido[1,2-a]pyrazine-1,3-dioneC14H16N2O2[α]D = −97.1 (c 1, CHCl3)Source of chirality: (2S,αS)-α-(2-carbamoylpiperidinyl)-α-phenylacetic acid methyl esterAbsolute configuration: (4S,9aS)