Asymmetric synthesis of amino polyols

Thesis

This thesis is concerned with the development of methodology for the asymmetric synthesis of a range of amino polyol containing compounds.

Chapter 1 highlights the abundance of the amino polyol motif in nature, the wide range of biological activities displayed by amino polyol containing compounds, and their occurrence in drug molecules. A variety of different methods for the synthesis of stereodefined amino polyols is then discussed.

Chapter 2 details a full investigation into the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to enantiopurealpha,beta-unsaturated esters which contain a dioxolane unit. The “matched” conjugate addition reactions were further coupled with a highly diastereoselective in situ enolate oxidation using camphorsulfonyloxaziridine for the synthesis of keyalpha-hydroxy-beta-amino ester intermediates. Subsequent cyclisation and further elaboration allowed access to a range of amino polyol containing compounds including imino sugars, amino sugars, and amino acids.

Chapter 3 extends the investigation into the doubly diastereoselective lithium amide conjugate addition reaction to enantiopure alpha,beta-unsaturated esters which contain two dioxolane units. A full assessment into the conjugate addition of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a series of D-pentose derived alpha,beta-unsaturated esters is reported. Subsequent elaboration of thebeta-amino ester products of these conjugate addition reactions resulted in the synthesis of (2'S,3'S,4'R)-dihydroxyhomoproline and (2'S,3'R,4'S)-dihydroxyhomoproline.

Chapter 4 describes the asymmetric syntheses of protected forms of APTO and AETD, the 2,4,5-trihydroxy substitutedbeta-amino acid residues found within the hexapeptide marine natural products microsclerodermins C, D and E. The optimised synthetic routes to APTO and AETD involved three key steps: a diastereoselective aminohydroxylation [via conjugate addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide to an achiralalpha,beta-unsaturated ester followed by in situ enolate oxidation with camphorsulfonyloxaziridine], a diastereoselective dihydroxylation, and an olefination.

Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3 and 4.

Authors: Foster, E

• Publication date: 2012
• DOI: 10.5287/ora-w4xgnz2vo
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: conjugate addition; lithium amide; doubly diastereoselective; imino sugar; microsclerodermin; dihydroxyproline; amino sugar; amino acid
• Subjects: Natural products; Organic synthesis; Synthetic organic chemistry; Organic chemistry