Synthesis of bicyclic alkaloids from the iridoid antirrhinoside

The present thesis describes the isolation of the iridoid glucoside antirrhinoside from Antirrhinum majus, and the approaches made towards its transformation into analogues of biologically active compounds, with special interest in syntheses of bicyclic alkaloids.A synthetic piperidine monoterpene alkaloid was prepared from antirrhinoside by means of an enzymatic cleavage to afford the aglucone, followed by a double reductive amination with benzylamine hydrochloride and sodium cyanoborohydride. The resulting piperidine was modified by opening of the epoxide on the cyclopropane ring by azide or by reduction using lithium aluminum hydride. The piperidines were subjected to hydrogenation to remove the N-benzyl group. The compounds were tested for hypoglycaemic activity by Novo Nordisk, but no activity was observed.Another approach towards a synthetic piperidine monoterpene was attempted. The strategy involved preparation of a diol, which through treatment of its ditosyl derivative with an amine would afford a piperidine monoterpene. Antirrhinoside was protected as its 5,6-O-monoacetonide via its 5,6:4',6'-O-diacetonide. The 5,6-O-isopropylidene-derivative was hydrogenated to give the 3,4-dihydro-analogue and enzymatically cleaved by b-glucosidase to afford the 3,4-dihydro-5,6-O-isopropylidene antirrhinoside aglucone. Unfortunately, the subsequent sodium borohydride reduction of the aglucone proved difficult, affording a mixture of the expected diol and a product with a 2-oxo[3.2.1]octane framework. The latter strategy was therefore abandoned.A one-pot reaction involving ozonolysis and subsequent reduction of the 5,6-O-isopropylidene-2',3',4',6'-tetra-O-acetyl antirrhinoside yielded a diol, which was considered a potential intermediate in the preparation of enantiopure 3-azabicyclo[3.3.0]octane alkaloids. The corresponding ditosyl derivative was treated with benzylamine to afford a bicyclic N-benzylated pyrrolidine. An alternative starting material was prepared from 5,6:4',6'-di-O-isopropylidene antirrhinoside by reduction with lithium aluminum hydride. Subsequent ozonolysis and sodium borohydride gave the expected triol. The corresponding ditosyl derivative was treated with benzylamine or 2-methoxy-benzylamine to afford bicyclic pyrrolidines in 54-66% yield. The isopropylidene protection was removed and the unprotected pyrrolidine was acylated with benzoyl chloride to afford a potential Substance P antagonist.In addition antirrhinoside has been used as starting material for preparation of a new isolate from Antirrhinum majus. The 3,4-dihydro-5,6-O-isopropylidene antirrhinoside aglucone was oxidised with RuO4 and treated with triethylamine to afford a 5,6-O-isopropylidene lactone. The isopropylidene protection was removed to afford a lactone, which proved to be identical to the natural product. Preparation of the known pyrrolidine 2,5-dideoxy-2,5-imino-D-glucitol (DGDP) was accomplished from L-gulono-1,4-lactone through an 11 step synthesis. This work was performed during a stay at The Dyson Perrins Laboratory, Oxford University and it is described at the end of this thesis as a separate study.