The amphidinolides are a family of structurally-related cytotoxic natural products
which have shown powerful antitumour activity against murine lymphoma (LI210),
human epidermoid carcinoma (KB) and human colon tumor cells (HCT116). They
occur naturally in only minute amounts, in specific strains of the microscopic marine
dinoflagellate amphidinium sp. Total synthesis therefore becomes an important
potential source of these natural products. Chapter One presents the amphidinolide
family and specifically the isolation, structural features, biosynthesis and elucidation
of the absolute configuration of amphidinolides C, F and U, then goes on to review
the syntheses of specific fragments of amphidinolides C and F. Finally, we discuss
our retrosynthetic approach towards amphidinolide C. Chapter Two begins with our
approach to the synthesis of the (C18-C25) THF-fragment, including a successful 9-
step route which utilizes an asymmetric dihydroxylation-iodoetherification strategy.
We continue with the installation of the simple side chain of amphidinolide F via a
Wittig reaction and the synthesis of the (C18-C29) dithiane in three steps. We then go
on to present our approaches towards the synthesis of the (C18-C34) fragment of
amphidinolides C and U. Firstly, we investigated a Stille-NHK coupling approach
towards the installation of the side chain of amphidinolides C and U which was
unsuccessful. Secondly, we examined a Stille coupling approach for the synthesis of
the (C27-C34) fragment by using Carreira's enantioselective formation of propargylic
alcohols and Negishi carboalumination. Although we installed the C29 stereocentre
with excellent enantioselectivity, application of the carboalumination reaction failed.
Thirdly, we examined a Stille coupling for the synthesis of the (C27-C34) fragment
by using cuprate chemistry and asymmetric CBS-reduction. This approach showed
success in the synthesis of the complex side chain, but epimerization at the C29
stereocentre was observed at the final step. The fourth approach attempted was a three
step synthetic transformation of the simple side chain of amphidinolides C and U
which involved a diene-allylic hydroxylation, oxidation and NHK coupling. This
route was finally chosen for the installation of the side chain. We then discuss our
approach towards the (C10-C17) fragment of amphidinolides C and F which involves
a dithiane alkylation approach. We show the syntheses of the (C15-C17)-dithiane in 5
steps starting from the (5)-Roche ester and the (Cl l-C14)-epoxide in 7 steps starting
from D-malic acid or from the but-2-yne-l,4-diol and we then go on to talk about the dithiane coupling. Chapter Three reviews the findings presented in Chapter Two and
describes the route towards the total synthesis of the three natural products. Chapter
Four gives full experimental details, spectroscopic and physical data for all new
compounds prepared.