A novel method for the stereoselective synthesis of all-E-, 13Z-and 9Z-retionic acid esters was developed by palladiumcatalyzed cross coupling reactions of tetraenyl stannanes with E-or Z-vinyl triflates in good yields. Applying this methodology, 13-substituted all-E-and 9Z-retinoic acids were prepared in satisfactory yields.all-E-Retinoic acid 1 and 9Z-retinoic acid 2 are the metabolites of vitamin A (retinol) and act as ligands of small molecular hormons that regulate the gene transcription through the activation of the retinoic acid receptors (RARa, b and g) and retinoid X receptors (RXR a, b and g), respectively. 1 The RARs and RXRs are members of nuclear receptor superfamily and exhibit the significant biological functions including cell differentiation, cell proliferation, embryonic development etc. 2 In particular, the RXRs play an important role as heterodimer with other proteins of the nuclear receptors such as the RARs, the thyroid hormone receptor (TR), the vitamin D receptor (VDR) and the peroxisome proliferator-activated receptors (PPAR) in a myriad of biological functions. Currently great efforts have been found for the preparation of receptor-selective retinoid in order not only to define the functions of each receptor but also to develop the therapeutic agents. 3 In connection with our study on the stereoselective synthesis of retinoids, 4,5 we wish to describe here a novel synthesis of 13-substituted all-E-and 9Z-retinoic acids using palladium-catalyzed cross-coupling reaction. 6Our synthetic strategy is based on the coupling reaction of two fragments A and B (Scheme 1). The fragment A was derived from b-ionylideneacetaldehydes C, whose stereoselective synthesis have been already accomplished by Bennani 7 and us, 4c,5 and fragment B was easily obtained from ethyl acetoacetate by the reported method. 8 (9E)-b-Ionylideneacetaldehyde 3 was converted to the alkyne 5 by the Wittig reaction with (iodomethyl)triphenylphosphonium iodide followed by elimination of hydrogen iodide using sodium bistrimetylsilylamide (NaN(TMS) 2 ) in 70% yield. Stannylcupration of 5 with lithium butyltributylstannylcyanocuprate 9 at -78°C in tetrahydrofuran (THF) afforded the tetraenylstannane 7 with excellent both regio and stereoselectivities. As all our attempts to isolate 7 were unsuccessful, and thus 7 was used for the next step without further purification after usual workup. 10 The same procedure was employed for the synthesis of the stannane 8 from the (9Z)-b-ionylideneacetaldehyde 4.In a preliminary study, we tested the palladium catalyzed coupling reaction of 7 with the vinyl triflate 10a 8 in various solvents using 5 mol% of tris(dibenzylideneacetone)dipalladium (0) (Pd 2 (dba) 3 ) and triphenylarsine (AsPh 3 ) as a ligand 11,12 at room temperature (Table 1). It is well known that in a Stille coupling reactions between vinyl triflates and vinyl stannane, polar solvents such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP) enhance the reaction rate extremely and afford the coupling product in high yield. 11 ...
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