LACTAM AND AMIDE ACETALS .21. USE OF PYROGLUTAMIC ACID AND PROLINE IN CHIRAL SYNTHESIS OF CONFORMATIONALLY CONSTRAINED PIPERAZINONES

Making use of amide activation chiral synthesis of (+)-(1S, 5R)- and (-)-(1R, 5S)-3, 8-diazabicyclo[3.2.1]octan-2-ones (1 and 2) has been achieved from L- and D-pyroglutamates, and of (-)-(2R, 6S)-, (-)-(2S, 6S)-, (+)-(2S,6R)- and (+)-(2R, 6R)-2-methyl-1, 4-diazabicyclo[4.3.0]nonan-5-ones (3a, 3b, 4a and 4b) from L & D-proline methyl esters respectively. The key step of the synthesis involves a stereo-selective catalytic hydrogenation, accompanied with spontaneous cyclisation, of the nitroenamines 11, 14, 17 and 19. While this reaction was stereospecific in the case of pyro-Glu derived nitroenamines (11 and 14), with N-acetyl-proline derived nitroenamines (17 and 19) both 2R and 2S diastereoisomers were obtained with 40%d.e. of the diastereomer with 2-CH3 oriented cis to the 6-H. The piperazinones 1 and 2 on treatment with methanolic HCl at room temperature yielded the corresponding optically pure 5-aminomethylprolines 12 and 15 respectively.