Diastereoselective synthesis of 1-deoxy-L-nojirimycins: A treatise on stereoselective hydroxylations of 6-membered rings

Saara Tiuri

Research output: ThesisDoctoral ThesisMonograph

Abstract

Glycosidases are an important and broad class of ubiquitous enzymes involved in the modification and processing of carbohydrates and glycoconjugates. Understanding the function and inhibition mechanisms of these enzymes is thus a desirable goal not only for medicinal and pharmaceutical purposes, but it has also found applications in food and biotechnology. Naturally occurring iminosugars, also known as azasugars, are monosaccharides with the heterocyclic oxygen replaced by nitrogen. Several iminosugars exhibit important therapeutic properties through selectively inhibiting carbohydrate-degrading enzymes, such as glycosidases. Nojirimycin was the first member of this class of compounds to be discovered and identified; it was isolated from several Streptomyces species in the 1960's. Soon after the discovery of nojirimycin, its 1-deoxyderivative 1-deoxynojirimycin was also isolated from Nature and found to have intriguing antibiotic and glycosidase-inhibiting properties. Numerous syntheses for different 1-deoxy-iminosugars have been published utilizing strategies based on chiral pool or enantioselective reactions. However, many of these methods only aim at producing a single or only a few of the possible diastereomers. The aim of this doctoral thesis was to diastereoselectively synthesize all eight diastereomers of 1-deoxy-l-nojirimycin utilizing a library-type synthesis based on two diastereomeric cyclic intermediates. These intermediates were in turn synthesized starting from l-serine-derived Garner's aldehyde. The thesis begins with a literature part aiming to give the reader a general picture of the history of nojirimycin analogs and the most common strategies used for their prior synthesis. The latter part of this thesis describes the author's own work on the diastereoselective synthesis of 1-deoxy-l-nojirimycins. To the best of our knowledge, all eight diastereomers from one enantiomeric series of 1-deoxynojirimycin were for the first time selectively synthesized from common intermediates. In addition, the first highly selective synthesis of 1-deoxytalonojirimycin without using sugars as starting material was described. The protected products were obtained either as single diastereomers or as major components in a mixture of diastereomers. Although the main objective was reached, there remains some room for improvement in optimizing the yields of three products and the diastereoselectivity of one of these. In addition, the purification of the final iminosugar products could be improved on. The thesis also gives a comprehensive view on the behavior of cyclic 6-membered alkenes in various diasteroselective hydroxylation reactions. The remarkable difference in the selectivities demonstrated by two diastereomeric substrates with an equatorial or an axial allylic alcohol are discussed.
Translated title of the contribution1-Deoksi-L-nojirimysiinien diastereoselektiviinen synteesi - Tutkielma stereoselektiivisestähydroksylointireaktioista 6-renkaissa
Original languageEnglish
QualificationDoctor's degree
Awarding Institution
  • Aalto University
Supervisors/Advisors
  • Koskinen, Ari, Supervisor
  • Koskinen, Ari, Advisor
Publisher
Print ISBNs978-952-60-8786-3
Electronic ISBNs978-952-60-8787-0
Publication statusPublished - 2019
MoE publication typeG4 Doctoral dissertation (monograph)

Keywords

  • 1-deoxynojirimycin
  • diastereoselective synthesis
  • amino acid
  • hydroxylation

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