Preparation of (all‐E)‐ and (11Z)‐12‐Haloretinals and (11Z,13Z)‐ and (13Z)‐14‐Haloretinals by the C15 + C5 Route − Exploring the Possibility of Preparing any Retinoid Rationally Chemically Modified at any Position in the Conjugated Tail

Abstract In this paper we describe how chemically modified ylides can be prepared by electrophilic substitution in a simple way. A subsequent Horner−Emmons reaction gives access to ( all ‐ E )‐ and (11 Z )‐12‐chloro‐, ‐12‐bromo‐, and ‐12‐iodoretinal. It could be expected that many more retinals chemically modified at the 12‐position could be prepared in this manner. Selectfluor ® , a good reagent for introducing a fluorine atom by electrophilic substitution, does not give the 12‐fluororetinal system. However, 14‐fluororetinal is simply available by reaction of the anion with Selectfluor ® . Cl, Br and I atoms were also introduced at the 14‐position of retinal both in the (11 Z ,13 Z )‐ and (13 Z )‐isomeric forms. This strategy could be extended to a whole range of electrophilic‐substitution reactions. We also developed a novel method to prepare 4‐hydroxy‐substituted Horner−Emmons derivatives, which could be converted into the 4‐fluoro derivatives by reaction with (diethylamino)sulfur trifluoride (DAST). This system could simply be converted into 12‐fluororetinal in the ( all ‐ E )‐ and (11 Z )‐isomeric forms and we think that this strategy has a good scope to prepare a whole series of 12‐modified retinals. We have also explored the essential steps to give access to retinoids modified at any position of the conjugated chain. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)