A Biomimetic Total Synthesis of the Alkaloid Gracilamine

Abstract

In 2005 Ünver and Kaya reported that ethanolic extraction of the dried and powdered total plant material derived from Galanthus gracilis, a Turkish member of the Amaryllidaceae family, lead to the isolation of gracilamine and to which the unprecedented structure 1.1 was assigned on the basis of extensive NMR spectroscopic and mass spectrometric analyses. This compound represents the first example of a pentacyclic dinitrogenous alkaloid isolated from the Amaryllidaceae family. It embodies five rings and seven stereocentres. The ethyl ester moiety associated with compound 1.1 is almost certainly an artifact of the isolation process, the naturally occurring alkaloid presumably being either another ester or the corresponding free acid. This rather complex structure together with the author’s previous [BSc(Hons.)] studies made its total synthesis a topic of considerable interest. Chapter One provides a brief introduction to the isolation, structural elucidation, proposed biogenesis, and previous total syntheses of gracilamine. It also details earlier relevant work carried out by the author. Chapter Two details a model study involving a Pd-catalysed intramolecular Alder-ene (IMAE) reaction that delivers a substrate used for testing the crucial intramolecular [3+2]cycloaddition process. By such means the basic framework, 2.24, of gracilamine was established. Chapter Three outlines the difficulties encountered in efforts to extend the abovementioned model studies in establishing a total synthesis of gracilamine. Despite this, one of these “difficulties” could be parlayed in the establishment of a ten-step total synthesis of the racemic modification of the alkaloid (±)-3-O-demethylmacronine (1.68). Chapter Four details the completion of a total synthesis of gracilamine. The final route proceeded in just eleven steps and so representing the shortest route to the title alkaloid reported thus far in this active area of research. Chapter Five presents the experimental procedures and data underpinning all of the work and conclusions detailed in Chapters Two, Three and Four. Show more