Lactam & amide acetals XXI. Use of pyroglutamic acid and proline in chiral synthesis of conformationally constrained piperazinones

Article abstract of DOI:10.1016/S0040-4020(01)81592-1

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, o 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.