(-)-Agelastatin A (1) is a tetracyclic alkaloid recently isolated from the marine sponge Agelas dendromorpha. It has powerful antitumour properties in vitro and in vivo, and is a selective inhibitor of the ubiquitous enzyme, glycogen synthase kinase 3(3. It also exhibits insecticidal properties. In this thesis, we describe an enantiospecific total synthesis of the cyclopentenone (-)- 175, an advanced intermediate whose racemate had previously been converted into ( )-agelastatin A by Weinreb and co-workers. Our strategy exploited the chiral oxazolidinone 150 as a key intermediate, and commenced from the Hough-Richardson aziridine 234 (which is itself obtainable from D-glucosamine hydrochloride). Noteworthy reactions in the route to 150 include the regioselective trans-diaxial ring-opening of 234 with azide ion to set up the vicinal diamido functionality present in (-)-175, and the Grubbs-Hoveyda ring-closing metathesis reaction that is used to fashion its cyclopentene core. We also describe a new synthetic endgame for converting (-)-150 to (-)-agelastatin A via cyclopentenone 307. This new endgame has so far allowed 223 mg of (-)-agelastatin A to be prepared for detailed toxicological and biological evaluation. Some of the results of these studies are presented in this thesis.

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Detailed herein is the tethered Biginelli condensation between irninium ion 201 and beta keto ester 206 leading to a model tricyclic ring system representative of the guanidinium core of cylindrospennopsin alkaloids. This was achieved in a biosynthetically-inspired manner in 12 steps and 8.3% overall yield from simple, commercially available 1,5-pentanediol 172. Also discussed is the adaption of this methodology to allow for the highly efficient stereoselective synthesis of all 3 of the cylindrospermopsin alkaloids and the preparation of the advanced synthetic intermediate nitro-alcohol 223.

A new asymmetric synthetic route to (-)-galanthamine (1.01), a potent Amaryllidaceae alkaloid used in the symptomatic treatment of early on-set Alztheimer's disease (AD), was successfully developed with complete stereocontrol. Key to achieving high chemo-and stereo-selectivity in this approach was the use of transition metal (IM) mediated reactions, in the form of an enyne RCM; a Heck coupling and a titanium based asymmetric allylation. Additionally, application of an asymmetric imino-aldol reaction resulted in the short total synthesis of two Lupin-type alkaloids, tashiromine (3.01) and epilupinine (3.02).