Wittig-Homer-Emmons reaction retinoid synthesis

Methods for the synthesis of retinoids (Acitretin, Etretinate, Isotretinoin, Tretinoin and Alitretinoin) derived from the tetraenoic acid platform via Wittig-Homer-Emmons reactions and photochemistry are described. Chemistry enq>loyed for synthesis of the more novel aryl/heteroaryl receptor selective retinoids (Bexarotene, Differin and Zorac ) platforms is also reported. 

The major approach for synthesis of retinoids of the tetraenoic acids involves the Wittig-Homer-Emmons reaction. The photochemical reaction has also proved viable and conditions to perform this reaction on commercial scale have been identified. Identification of receptor selective retinoids expanded the chemistry of file retinoids to aryl (Bexarotene, Adapalene) and heteroaryl (Tazarotene) platforms. These analogs are prepared rapidly and efficiently and this chemistry should facilitate both the SAR and commercial development of more novel and selective members of the retinoid class. 

The sulfone-alkylation method of Julia (1968) was a significant advance in retinoid total synthesis and has potential utility for labeled s)mthesis work. But the most useful reactions that have been adapted for the preparation of labeled retinoids are the well-developed procedures for the Wittig (Pommer, 1960) and the Homer-Emmons reactions (Bautagy and Thomas, 1974). These reactions are for synthesis of unsaturated and trans- and cw-a,p-enone compounds from the condensation of aldehydes and ketones with phosphoranes and with phos-phonoacetates, phosphonoacetonitrile, and oxophosphonates. These reactions suggest profitable application to the synthesis of retinoids, including labeled materials. 

Syntheses of the five possible dihydro derivatives of all-7ra/i -retinoic acid (3) are summarized in the equations below. In each case, a conventional coupling technique for the synthesis of retinoids was employed this was based on a Wittig reaction for (517) and on Homer-Wadsworth-Emmons reactions for (513), (514), (515), and (516) (Pawson et al., 1977). 

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