9‐Demethyl‐9‐haloretinals by Wadsworth−Emmons Coupling − Easy Preparation of Pure (all‐E), (9Z) and (11Z) Isomers

Abstract

Abstract5‐(2′,6′,6′‐Trimethyl‐1′‐cyclohexen‐1′‐yl)‐4‐penten‐2‐yn‐1‐al has been prepared in a one‐pot process starting from β‐ionone in almost quantitative yield. Using 1,4‐nucleophilic addition reactions, the corresponding 9‐Cl, 9‐Br, 9‐I β‐ionylideneacetaldehyde systems could be obtained in one step in quantitative yield as a mixture of (9Z) and (all‐E) isomers. Even the corresponding fluoro derivative could be obtained in good yield as (9Z) and (all‐E) isomers. In the case of a double bond having a halogen substituent, the IUPAC rules have the (E) nomenclature for a cis double bond and the (Z) for a trans double bond. Simple column chromatography gave the pure (9Z) and (all‐E) form. Optimizing the Wadsworth−Emmons coupling gave the corresponding (all‐E)‐ and (9Z)‐retinonitriles in quantitative yield. Subsequent DIBAL‐H reduction gave the corresponding retinals. For the preparation of the (11Z) isomers essential to vision, we found that Wadsworth−Emmons reactions with the diphenyl phosphonate group gave retinonitriles in quantitative yield, where the newly formed double bond is predominantly the (11Z) form (> 60%), together with the (9Z) isomer as minor component. The nitriles could be isolated in pure (9Z,11Z) and (9Z) forms by simple column chromatography. In the case of the (9Z,11Z)‐9‐demethyl‐9‐halo systems, a complication arose due to the unprecedented acid lability of these (9Z,11Z) aldehydes. By adjusting the DIBAL‐H reduction workup procedure, these aldehydes are now available in pure form. We used this strategy to rationally synthesize (11Z)‐retinal starting from β‐cyclocitral as a first test for the generality of our new approach. β‐Ionylideneacetaldehyde could be prepared in the (all‐E) form in almost quantitative yield. Extending the conjugated chain of this molecule gave an almost quantitative yield of a mixture containing 80% (11Z)‐retinal and 20% (all‐E) as the minor component. Simple column chromatography gave pure (11Z)‐retinal in 75% overall yield. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)