Abstract:
The biological activity of azasugars has largely been attributed to their ability to mimic
the oxocarbenium ion-like transition state formed during reactions with carbohydrate-processing
enzymes and, for this reason, functional and stereochemical modifications
of the azasugar scaffold have led to the development of specific and potent glycosidase
inhibitors. Given the potential of azasugars as glycosidase inhibitors, we were interested
in developing efficient methodology for their synthesis.
This thesis highlights synthetic methodology developed to produce amino-imino-hexitols
as azasugar scaffolds. Key in the synthesis of the amino-imino-hexitols
was the application of a stereoselective Strecker reaction, without the need for chiral
Lewis acids or catalysts, and an extension of an I2-mediated carbamate annulation to
cyclise functionalised and protected alkenylamines. Sixteen amino-imino-hexitols were
synthesized, including ten previously undisclosed substrates with the D-galacto, D-talo,
and L-altro configurations. The novel amino-imino-hexitols were then tested for their
ability to act as glycosidase inhibitors and substrates of the D-talo configuration showed
promising inhibitory effects.
Mechanistic considerations of the I2-mediated carbamate annulation are discussed and
although the exact annulation mechanism has yet to be determined, experimental studies
have revealed that an aziridine is not an intermediate in the reaction. Factors influencing
the diastereoselectivity of the carbamate annulation are also explored. Furthermore, an
in depth analysis of the high cis-selectivity of the carbamate annulation is investigated
using density functional theory to calculate the transition states of iodocyclisations
en route to the formation of carbamates. Taken as a whole, the applicability of the
carbamate annulation to a variety of alkenylamines and an understanding of the factors
controlling the diastereoselectivity of the reaction should make this methodology a
valuable addition to the synthetic chemist’s toolbox.
