Towards the stereoselective synthesis of bicyclic and tricyclic alkaloid natural products

Abstract

In this thesis we discuss the stereoselective synthesis of natural products containing bicyclic heterocycle with a bridgehead nitrogen atom. The unique structural feature of this core skeleton has inspired interest regarding to their stereochemistry and biological properties. The first chapter describes efforts in the stereoselective total synthesis of amphorogynine C, a new class of pyrrolizidine alkaloids, which have not been reported in New Caledonian plants before. The key steps involve the stereoselective construction of cis-2,5-disubstituted isoxazolidines and the NO bond cleavage of cis-2,5-disubstituted isoxazolidines to form the cis-1,3-amino-alcohol which can further cyclise to pyrrolidines by an intramolecular nucleophilic substitution. In chapter 2, we report studies towards the stereoselective total synthesis of hydroxyindolizi-dine, an alkaloid isolated from the ant Myrmicaria melanogaster (Emery). The use of N,O-heterocycles, tetrahydro-1,2-oxazines, as synthetic intermediates to control the regio-and stereochemistry, is discussed. The key steps involve a tandemdeprotection-intramolecular Michael addition and a tandem double hydrogenationlactamization. In chapter 3, we report studies towards the total synthesis of tuberostemospironine, an alkaloid extracted from the roots of Stemona tuberosa (Stemonaceae). Tuberostemospironine is a unique structure feature containing a spiro[furan-2-(5H), 9[9H]pyrrolo[1,2-a]-azepin]-5-one nucleus which displays a spiro-γ-lactone at the basic azabicyclic nucleus. Three stereogenic centres of this natural product comprise a spiro-γbutyro-lactone ring and the last chiral centre contains at the basic azabicyclic nucleus. v LIST OF ABBREVIATIONS Å angstrom Ac acetyl Acac acetylacetonyl AIBN azobisisobutyronitrile Anal. elemental analysis aq aqueous Ar aryl Bn benzyl Boc tert-butyloxycarbonyl b.p. boiling point br. broad °C degree Celsius CAN ceric ammonium nitrate cat. catalytic Calcd. Calculated Cbz benzyloxycarbonyl cm-1 wave number unit COSY correlated spectroscopy Conc. Concentrated CSA camphorsulfonic acid d doublet (spectral) dd double doublets (spectral) vi LIST OF ABBREVIATIONS (Cont.