Pyrroles as Building Blocks for the Enantioselective Synthesis of Indolizidines

Charles   W.   Jefford

doi:10.2174/1385272003376355

Abstract

We describe how pyrrole derivatives derived from naturally occurring a-amino acids, and ß-amino acids prepared from aspartic acid, can be efficiently converted into enantiomerically pure indolizidines by application of a three-part method. First, an optically pure, correctly substituted amino acid is condensed with tetrahydro-2,5-dimethoxyfuran to give the corresponding 1-pyrrolylacetic acid derivative. Second, through the intermediacy of a diazoketone, an alkylated bicyclic pyrrole-cyclohexanone is created by Rh2(OAc)4-catalyzed decomposition to the carbenoid which inserts into the a-position of the pyrrole ring. Alternatively, the 1-pyrrolyl derivative obtained from glutamic ester is directly cyclized by BBr3-promoted intramolecular acylation to the ester-substituted bicyclic pyrrole-cyclohexanone with retention of configuration. Third, catalytic hydrogenation of the bicyclic entities is entirely directed by the resident stereocenter to give the penultimate indolizidine intermediate or final prod uct in an enantiomerically pure state. In the former case, transformation of the ring-substituent or substituents delivers the finished indolizidine in a few steps. As an illustration of the power of the methodology, the syntheses of some rare alkaloids of exotic origin, namely, indolizidines 167B, 209D, 209B, piclavine, and monomorine, are presented. By way of comparison, some other synthetic strategies leading to the same alkaloids, except piclavine, are outlined.

Keywords: Pyrroles, Enantioselective synthesis, Indolizidines, Ipalbidine, Monomorine, D Norvaline, L Alanine, Modified clauson kaas reaction, 5 Alkylindolizidines, Piclavine A, L Glutamate ester, Indolizidine of 167B, Aspergillus niger, Enantiomericaly pure monomorine, 5 Alkyl 8 methylindolizidines