The stereoselective synthesis of 13C2-labelled 11Z-retinals and the total synthesis of (-)-galanthamine

Abstract

Rhodopsin a G-protein coupled receptor (GPCR), consists of the apoprotein opsin and a 11Z-retinylidene chromophore and is responsible for dim light vision. On adsorption of a photon, the 11Zretinylidene chromophore specifically photoisomerises to all-E-retinylidene in approximately 200 fs. To allow investigation by solid state NMR into how the protein environment accelerates and controls this specific isomerisation and of the photointermediates, synthetic strategies to a series of ¹³C₂ labelled 11Z-retinals were devised. [9,10-¹³C₂]-11Z-Retinal (2.45), [10,11-¹³C₂]-11Z-retinal (2.53) and [11,12-¹³C₂]-11Z-retinal (2.81) were successfully synthesised, employing a novel Weinreb amide analogue and a labelled ethoxy analogue of the Bestmann-Ohira reagent (2.78) as key reagents.

(-)-Galanthamine (3.1) is a naturally occurring tertiary alkaloid, with its hydrobromide salt used in the treatment of mild to moderate Alzheimer’s disease. Two synthetic routes to (-)-galanthamine (3.1) were investigated. The first synthetic route used a Heck cross-coupling and an enzyme metathesis to form rings B and C respectively. An azepine ring closure completed the synthesis giving (-)-galanthamine (3.1). Investigation of the second route was commenced. Efforts to synthesise a 1,3-anti-diol fragment were explored, using the Sharpless asymmetric epoxidation to induce asymmetry.

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