A new facile synthetic method of heterocyclic compounds using palladium catalyzed carbonylation to an aryl or vinyl halide which was developed by us has been extended to the syntheses of the natural compounds. Sendaverine, which was isolated by Manske and possesses a tetrahydroisoquinoline skeltone was synthesized by the insertion of carbon monoxide to 2-bromophenethylamine derivative (10). It was found that the diazepine derivatives were easily prepared from o-bromoaniline and amino acid by use of this carbonylation. Thus, the compound(24) was synthesized from o-bromoaniline and proline. And moreover, the key intermediate(38) of the synthesis of the antibiotics, tomaymycin(19) and SEN-215(20) was also synthesized from 2-bromo-4-methoxy-5-tosyloxy aniline(32) and L-hydroxy proline(33). For the application of the new synthesis of α-methylene-β-lactams, (±)-3-aminonocardicinic acid which is an important starting material for the synthesis of nocardicin A(42) and other biologically active analogues, has been synthesized. Palladium catalyzed carbonylation to the amine(48) which was prepared fron DL-p-hydroxyphenyl glycine (44) was smoothly proceeded under 4 atm pressure of carbon monoxide to afford the desired α-methylene-β-lactam(49b) in a good yield. α-Methylene group was converted to 3-amino group through four stages. The hydrotosylate(54b TsOH)of one isomer of the diastereomers was fully identical to an authentic sample kindly provided by Professor Wasserman.
