Synthesis of labelled carotenoids

This C25-aldehyde 82 is elongated to spheroidene (97) by coupling in an Horner-Emmons reaction with the anion of C -phosphonate 44 and subsequent reduction with DIBAH to the Cio-aldehyde 83. This aldehyde can be converted in one step into spheroidene (97) by a Wittig reaction with the Cio-phosphonium salt 58 and BuLi as base. The overall yield, based on acetonitrile in the first coupling reaction, is 32%. 

In each of the coupling reactions, a mixture of ( /Z)-isomers is formed. The product of every step is predominantly the (all- )-form, but with about 20% of the (Z)-isomer. Mixtures of (E/Z)-isomers of the nitriles cannot easily be separated but are reduced with DIBAH and the isomers of the resultant aldehyde separated. The fZ)-isomers can be effectively converted into the f j-isomers by irradiation with visible light in hexane in the presence of a trace of iodine. This procedure is repeated after each Horner-Emmons coupling / DIBAH reduction step. In this way, the product consists mainly ( 85%) of the f /Z)-isomer. Repeated crystallization from petroleum ether affords the pure (all- )-spheroidene (97). 

Retinals singly or multiply labelled with or at predetermined positions have been synthesized [29-38]. Based on this work, symmetrically labelled P,p-carotene (3) can easily be synthesized in 90% yield (50% after crystallization) by reductive dimerization of retinal (88) 

Deuterium can be introduced at the 15 position by reducing the unlabelled C2o-nitrile 89 with DIBA- H in petroleum ether at -70°C, to give the deuterium-labelled aldehyde 77d in 76% yield with a deuterium incorporation of 98%. DIBA- H is not commercially available, but can be prepared by reacting Li H with diisobutylaluminium chloride [57]. This reaction scheme is more facile and convenient than that which starts from an ester. The ester first has to be reduced by LiApH4 and subsequently reoxidized to the aldehyde by Mn02. 

The procedure is repeated a deuterium label is introduced at the 15 position by coupling the anion of deuterated acetonitrile to the C2o-aldehyde 80, quenching the resulting tertiary alkoxide with acetic anhydride, and elimination of acetic acid, giving the C22-nitrile 90e in 81% yield and with a deuterium incorporation of 96%. Reduction with DIBA- H introduces 

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Chemical synthesis does allow labelling at specific positions with high isotopic enrichment. There are four constraints on the synthesis of labelled carotenoids. 

Combination of these reactions allows the labelling of the polyene chain at any position or any combination of positions. Examples of the application of these reactions in the synthesis of labelled carotenoids are given in the next Sections. 

In this Section, the preparation of some unlabelled synthons for use in the synthesis of labelled carotenoids is discussed. 

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