Asymmetric synthesis of d-fagomine and its diastereoisomers

Journal article

A divergent strategy for the asymmetric syntheses of d-fagomine and three of its diastereoisomers has been developed. The diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester was used as the key step to install the correct configuration required for the C(5)-stereogenic centre within the targets. In situ enolate oxidation generated the corresponding anti-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-fagomine and d-3-epi-fagomine. Subsequent epimerisation of this key anti-α-hydroxy-β-amino ester upon oxidation and diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-4-epi-fagomine and d-5-epi-fagomine. Elaboration of both α-hydroxy-β-amino esters upon reduction to the corresponding aldehydes followed by aldol reaction generated the requisite C(3)-stereogenic centres within the target compounds, then cyclisation and deprotection gave the enantiopure iminosugars in good overall yields, as single diastereoisomers (>99:1 dr).

Authors: Davies, S; Fletcher, A; Kennedy, M; Roberts, P; Thomson, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Tetrahedron
• Volume: 74
• Issue: 51
• Pages: 7261-7271
• Publication date: 2018-10-31
• Acceptance date: 2018-10-27
• DOI: 10.1016/j.tet.2018.10.073
• EISSN: 1464-5416
• ISSN: 0040-4020
• Keywords: d-4-epi-fagomine; d-fagomine; d-5-epi-fagomin; d-3-epi-fagomine; lithium amide; asymmetric synthesis