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Methodology development for the synthesis of iminosugars

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thesis
posted on 23.11.2021, 11:04 by Alexander Hunt-PainterAlexander Hunt-Painter

This thesis investigated the development and application of methodology for the synthesis of iminosugars. The first portion of this thesis (Chapters 2 and 3) explored the scope of previously established protecting-group-free Vasella-reductive-amination and I2-mediated carbamate annulation methodology initially developed within the Stocker-Timmer group for the synthesis of pyrrolidines and piperidines from aldose sugars. In this thesis, the Vasella-reductive-amination methodology was extended to include the use of ketose sugars as starting materials, thereby allowing for the synthesis of primary amines directly from in situ formed ketones under protecting-group-free conditions. The scope of the carbamate annulation was then explored, whereby it was determined that both steric and electronic effects appear to affect transition state energies during the annulation reaction. Here, formation of pyrrolidines with the 2,5-trans and 3,4-cis relationships are favoured, however, in circumstances were conflicting electronic- and steric-effects are present, steric-effects dominate thereby favouring the formation of the 2,5-trans product. Using a combination of this Vasella-reductive-amination and carbamate annulation methodology, 2,5-dideoxy-2,5-imino-L-iditol was thus synthesised in 6 steps and 18% overall yield from D-fructose. Next, the same methodology was applied to the synthesis of the promising molecular chaperone 2,5-dideoxy-2,5-imino-D-altritol. Thus, 2,5-dideoxy-2,5-imino-D-altritol was synthesised over 7 steps and in 22% yield from D-tagatose, which is the most efficient synthesis of this iminosugar to date.  The second part of this thesis (Chapters 4 and 5) focused on the optimisation and development of synthetic methodology that would allow for the highly efficient synthesis of a variety of iminosugars including piperidines and azepanes. To this end, modifications to existing synthetic methodology allowed for the rapid synthesis of a variety of iodoglycosides, which are important synthons. Next, reductive amination/cyclisation methodology that allowed for the direct transformation of methyl iodoglycosides or isopropylidene-protected iodoglycosides into iminosugars was developed. As such, the piperidines 1-Deoxynojirimycin, 1-Deoxymannojirimycin (DMJ), L-1-Deoxygalactojirimycin (L-DGJ), and (3R,4r,5S)-piperidine-3,4,5-triol were prepared in 4 steps and good overall yields (44%, 62%, 67%, and 53%, respectively). In the case of DMJ and (3R,4r,5S)-piperidine-3,4,5-triol, these are the most efficient syntheses of these materials to date. Factors influencing the stereochemical outcome of the reductive amination reaction were also explored, and evidence suggests that the reduction occurs from the least sterically hindered face of an intermediate cyclic imine, whereby the preferred conformation of the imine is the one which places the largest number of substituents in the pseudo-equatorial position. Using analogous methodology, the azepane (3S,4R,5S,6R)-azepane-3,4,5,6-tetraol was also prepared in 4 steps and good yield (53%).

History

Copyright Date

01/01/2018

Date of Award

01/01/2018

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Chemistry

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Doctoral

Degree Name

Doctor of Philosophy

ANZSRC Type Of Activity code

4 EXPERIMENTAL DEVELOPMENT

Victoria University of Wellington Item Type

Awarded Doctoral Thesis

Language

en_NZ

Victoria University of Wellington School

School of Chemical and Physical Sciences

Advisors

Timmer, Mattie; Stocker, Bridget