Abstract EN:

Bridged biaryls are ubiquist natural compounds of biological interest, including, bisbenzocyclooctadiene lignans, dihydrophenantrenes, and several classes of alkaloids like aporphines, homoaporphines, dibenzazocines or colchicine derivatives. We have discovered that ruthenium dioxide in fluoroacid-boron trifluoride etherate medium constituted efficient conditions in non-phenolic biaryl coupling of dibenzylbutanolides, diarylbutanes and phenylalkylisoquinolines. The method was applied to the synthesis of many bridged biaryls such as (a) Trans-bisbenzocyclooctadiene lignan lactones, e. G. , steganolide A, neoisostegane, and related compounds (10 examples); (b) Non-natural cis-bisbenzocyclooctadiene lactones; (c) Unnatural bisbenzocyclooctatriene lactones; (d) Bisbenzocyclooctadiene lignans, e. G. , deoxyschizandrin, its diastereoisomers and analogues; (e) Aporphinic alkaloids, e. G. , glaucine and thalicsimidine; (t) Homoaporphinic alkaloids, e. G. , homoglaucine; and, (g) Dibenzazocine (one example). Surprisingly, oxidative aryl-benzyl coupling of diarylbutanes occurred in (d), giving the corresponding phenyl tetralins as major by-products. Conditions of occurence of the latter coupling versus biaryl coupling were studied. In the case of oxidative phenolic coupling, very good results were obtained by using Ru02, 2H20 in the above described media as well as in trifluoromethanesulfonic acid-boron trifluoride etherate mixture. Ultrasound assistance was also tested and showed encouraging results, more particularly in the lowering of Ru02, 2H20 ratio. Thus, a regio and stereoselective intramolecular phenolic coupling of presteganes A et B -two natural dibenzylbutanolides bearing meta phenols- was performed. Thus, the high-yield formation of the expected bisbenzocyclooctadiene lignan lactones was confirmed by high resolution PMR studies and comparison of the methylated derivatives of the latters with the above described compound. These results provides a possible explanation of the biogenetic pathway of the formation of the cyclolignans in the steganacin series. Phenolic, no methoxylated dibenzylbutanolide precursors such as HPMF (enterolactone) failed to react. Unfortunately, many attempts of access to the azafluoranthene skeleton from the corresponding phenolic and non-phenolic phenylisoquinoline precursors were unsuccessful. Stereostructure of the above synthetized compounds were established with the help of high resolution PMR. Structure elucidation of conformers of cis and trans deoxyschizandrins and discovering of a particular conformation of homoglaucine versus glaucine, in solution, were our most outstanding results obtained in this area. Most of this compounds were submitted to the National Cancer lnstitute (U. S. A. ) for a cytotoxicity screening on the KB cells. Some other pharmacological evaluations are in progress.