Stereoselective oxygenation of a double bond: Design and synthesis of azasugar inhibitors of glucoconjugate processing enzymes.

Persistent Link:
http://hdl.handle.net/10150/187332
Title:
Stereoselective oxygenation of a double bond: Design and synthesis of azasugar inhibitors of glucoconjugate processing enzymes.
Author:
Sames, Dalibor.
Issue Date:
1996
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
A novel methodology for the synthesis of amino sugars and aza-sugars, important inhibitors of glycosidases, is described. This is accomplished via the intermediacy of N-diphenylmethylene-protected a-amino esters. This methodology can be divided into three major phases. First, the reduction-alkenylation reaction with DIBAL-TRIBAL and oxygenated alkenyllithium nucleophiles provides unsaturated 1,2-amino alcohols with excellent threo-selectivity (>20: 1). Second, optimization of catalytic osmylation conditions with regards to chemical yield, stereoselectivity, and osmium content is described. A mixture of 1.2 mol% of osmium tetroxide in the presence of 3 eq. of potassium ferricyanide (K₃Fe(CN)₆) as an oxidant, 3 eq. of K₂CO₃ and 3 mol% of (DHQ)₂PHAL chiral ligand represents optimized dihydroxylation conditions. Depending upon the substrate, good to excellent antiselectivities are observed. The separation of diastereomeric mixtures of protected amino tetrols is accomplished by flash chromatography on silica gel. Thus, four contiguous chiral centers are established efficiently in two steps. The third stage involves manipulation of the protecting groups and subsequent cyclization. Deprotection of the silyl protecting group in the presence of acyl groups is complicated by migration. The cyclization is accomplished via the reductive amination of acyclic amino aldehydes with NaBH3CN. D-N-methyl-fucosamine is prepared from protected L-serine. Depending on the order of osmylation and cyclization steps, this methodology provides either Lazafucose or L-azagulose from protected L-alanine in 8 steps. Furthermore, 1-cyano-L-azafucose is prepared via treatment of acyclic amino aldehydes with HCN (Strecker reaction).
Type:
text; Dissertation-Reproduction (electronic)
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Chemistry; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Polt, Robin L.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleStereoselective oxygenation of a double bond: Design and synthesis of azasugar inhibitors of glucoconjugate processing enzymes.en_US
dc.creatorSames, Dalibor.en_US
dc.contributor.authorSames, Dalibor.en_US
dc.date.issued1996en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractA novel methodology for the synthesis of amino sugars and aza-sugars, important inhibitors of glycosidases, is described. This is accomplished via the intermediacy of N-diphenylmethylene-protected a-amino esters. This methodology can be divided into three major phases. First, the reduction-alkenylation reaction with DIBAL-TRIBAL and oxygenated alkenyllithium nucleophiles provides unsaturated 1,2-amino alcohols with excellent threo-selectivity (>20: 1). Second, optimization of catalytic osmylation conditions with regards to chemical yield, stereoselectivity, and osmium content is described. A mixture of 1.2 mol% of osmium tetroxide in the presence of 3 eq. of potassium ferricyanide (K₃Fe(CN)₆) as an oxidant, 3 eq. of K₂CO₃ and 3 mol% of (DHQ)₂PHAL chiral ligand represents optimized dihydroxylation conditions. Depending upon the substrate, good to excellent antiselectivities are observed. The separation of diastereomeric mixtures of protected amino tetrols is accomplished by flash chromatography on silica gel. Thus, four contiguous chiral centers are established efficiently in two steps. The third stage involves manipulation of the protecting groups and subsequent cyclization. Deprotection of the silyl protecting group in the presence of acyl groups is complicated by migration. The cyclization is accomplished via the reductive amination of acyclic amino aldehydes with NaBH3CN. D-N-methyl-fucosamine is prepared from protected L-serine. Depending on the order of osmylation and cyclization steps, this methodology provides either Lazafucose or L-azagulose from protected L-alanine in 8 steps. Furthermore, 1-cyano-L-azafucose is prepared via treatment of acyclic amino aldehydes with HCN (Strecker reaction).en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairPolt, Robin L.en_US
dc.contributor.committeememberGlass, Richard S.en_US
dc.contributor.committeememberMash, Jr., Eugene A.en_US
dc.contributor.committeememberWalker, F. Annen_US
dc.contributor.committeememberWigley, David E.en_US
dc.identifier.proquest9620392en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.