Phosphine-free Palladium Catalyzed Heck Reaction For The Synthesis Of Stilbene Retinoids

Retinoic acid is nonsteroidal small molecule hormone and plays a key role in the maintenance and differentiation of epithelial tissue and is very important for the treatment of acne and skin damaged by UV-light. Furthermore, it has been evaluated for their possible beneficial effects in several cancerous conditions.The actions of retinoids are mediated through binding and activation of the retinoic acid receptors (RARs) or retinoid X receptors (RXRs), which function as ligand dependent transcription factors. Therefore development of receptor-selective retinoid which has a stable structure, cause chemist's great interest.The aim of this thesis is to research structural design and synthetic methods of novel stilbene receptor-selective retinoids. And development of a efficient synthesis for the important pharmaceutical intermediates-Sartanbiphenyl.Two results obtained were sum- marized as follows:First, a phosphane-free palladium-catalyst conditions for the Heck reaction using dicyclohexylamine as the ancillary ligands was investigated, establish a new phosphane-free palladium-catalyst Heck reaction system. This system can be high-yield(72%～84%), high-stereoselective(83%～95%)synthesis of the disubstituted and trisubstituted stilbene compounds. Four novel stilbene derivatives arotinoid methyl ester (3a,3b,4a,4b) were synthesized by above method using 2,4,5-trimethoxystyrene andα-asarone as starting material.Their hydrolysates arotinoic acid (5a,5b,6a,6b) were easily accessible under mild hydrolysis conditions using the LiOH, THF:H2O = 5:1 system.Second, a highly efficient 2-step synthesis of the Sartanbiphenyl (7) was developed, 68% of total yield. The most important features are the following: (1) using MnCl2 as a catalyst for cross-coupling reaction, have avoid the use of the palladium catalyst and reduced the cost greatly; (2) in the presence of MnCl2, Grignardreagents can easy react with aryl chlorides which has an electron withdrawing activating group(CN,CH=NR,oxazoline),and can effectively protect CN group; (3) The possible origins of by-product were discussed, and the reaction condition were optimized; (4) the purified process of the products has been improved, and we describe a step-by-step crystallization of the purification process. This process to avoid expensive chromatographic purification and vacuum distillation . We have synthesized 12 compounds and 8 retinoid compounds were not reported in literatures until now. Their structures were characterized and confirmed by IR, 1H NMR, 13C NMR and MS spectra.