Palladium catalyzed cross coupling reactions of (arylvinyl)tributyl stannanes with vinyl triflates resulted in the production of stereochemically pure trisubstituted E-and Z-olefins in very good yields. These olefins were transformed to the corresponding all-E-and 9Z-heteroaryl-retinoic acid analogs via Horner-Emmons reaction and subsequent basic hydrolysis in excellent yields.It is well known that all-E-retinoic acid and 9Z-retinoic acid (Scheme 1) are the ligand molecules for retinoic acid receptors (RARa, b, g) and retinoid X receptors (RXRa, b, g), respectively. 1 They are members of the nuclear receptor superfamily and exhibit significant biological functions which include cell differentiation, cell proliferation, embryonic development etc. through gene transcription. 2 In biological system, RXRs form functional heterodimers 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). These heterodimers bind to co-activator or co-repressor proteins with changing their conformation depending on the nature of the ligand molecule, and then activate or repress a wide variety of gene transcription. Currently great efforts have been found for the preparation of receptor-selective retinoids 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 report a convenient synthesis of all-E-and 9Z-heteroaryl-retinoic acid analogs 12 and 14 (Scheme 3), which replace the 2,6,6-trimethylcyclohexene ring of retinoic acid by the heterocyclic rings in order not only to decrease a hydrophobic character of analogs but also to investigate the interaction between the ligand and the receptor protein, by the application of a stereoselective, palladium catalyzed cross coupling reaction of (arylvinyl)-tributyl stannanes with E-and Z-vinyltriflates. 6,7 As the conversion of b-ionylideneacetaldehyde analog A to the corresponding retinoic acid has been already established using Horner-Emmons or Wittig reaction, 3,4 key step in our synthetic strategy is based on the coupling reaction of two segments B and C. Segment C was obtained from ethyl acetoacetate by the reported method 8 and the separation of two stereoisomers was easily performed by column chromatography (Scheme 1). Scheme 1Our synthetic approach toward heteroaryl-retinoic acids starts from the synthesis of (arylvinyl)tributyl stannanes 3 (Scheme 2). The arylaldehydes 1 were transformed to the acetylenes 2 by the standard procedure using carbon tetrabromide and triphenylphosphine and subsequent treatment with n-butyllithium. 9 Hydrostannylation 10 of 2 with n-Bu 3 SnH in the presence of a catalytic amount of AIBN at 50 °C for 12-16 hours afforded the corresponding (arylvinyl)tributyl stannanes 3 11 in moderate to good yields.Stille coupling reaction of 3a with (E)-vinyl triflate 5 8 in the presence of a catalytic amo...
Synthesis of all-E-and 9Z-Heteroaryl-retinoic Acid Applying Palladium Catalyzed Coupling Reaction of (Arylvinyl)tributyl Stannane with Vinyl Triflate. -Stille-type cross-coupling of stereodefined (E)-and (Z)-vinyl triflates (II) and (VII) with vinylstannanes (I) produces stereopure (E)-and (Z)-olefins in good yields. These products [cf. (III)] are readily transformed to hetaryl analogues (VI) of retinoic acid. -(WADA,
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