Synthesis And Characterization Of Axially Chiral Biphenyls

Biphenyl lignans (dibenzocyclooctadienes), from Schisandra chinensis show many biological acivities. One of the most notable features of their structures is an atropisomeric biaryl moiety with axial chirality. It's very important to form the axially chiral biaryl system in natural products equipped with biphenyls and other related compounds. In this thesis, the axially chiral alkyloxy-biphenyl compounds, dibenzocyclooctadienes, were synthesized by different routes.Firstly, axially chiral alkyloxy-biphenyl having M-and P-configurations induced by chiral amino alcohol arm were prepared in a facile manner through crystallization-induced configuration transformation. Secondly, P-configuration hexamethoxybiphenyl was prepared by configuration transformation of biphenyl oxazoline moieties in the presence of CuI, and then the (P)-hexamethoxy dibenzocyclooctadiene was synthesized. Finally, the (P)-unsymmertrical biphenyl induced by chiral aryl oxazolines were obtained by cross-coupling reaction of Grignard reagents with substituted methylphenyl ethers, thus the synthesis of schiantherin analogues were established.The schisantherin D-related biphenyl, dimethyl-4,4'-dimethoxy-5,6,5',6'- bis (methylenedioxy)-biphenyl-2,2'-dicarboxylate (DDB) shows good biological activity. The four ortho-substituents of DDB inhibit rotation about the biphenyl axis, which leads to two isomers. A series of axially chiral biphenyls including nine M- and two P - configurations have been conveniently obtained from racemic 4,4'-dimethoxy- 5,6, 5',6'-bis(methylenedioxy)-2-carboxylester-2'-carboxyl-biphenyls and chiral amino alcohols (R)-alaninol, (S)-alaninol, (S)-valinol, and (S)-phenylalaninol. It was found that the yields of six optically pure crystals exceed 50%. The diastereomeric ratios were determined by HPLC. The absolute configurations (ACs) of the biphenyls have been assigned based on X-ray crystallographic analysis and their CD spectra. Further investigation of stability of these axially chiral biphenyls in solvents were studied.In a similar way, ten new 4,4′,5,5′,6,6′-hexamethoxy-2-carboxylester-2′- carboxyl-biphenyls were synthesized. Their diastereomeric excesses were determined. It was found that the axically chiral hexamethoxy biphenyls with chiral amino alcohol arm were not obtained by crystallization-induced configuration transformation.(P)-Deoxyschizandrin, a 4,4′,5,5′,6,6′-hexamethoxy-dibenzocyclooctadiene, was prepared. The P/M of biphenyl oxazolines diastereomeric ratio(92.5:7.5) was obtained with CuI in DMF for 60h. The optical purity(100%) of the (P)-4,4′,5,5′,6,6′- hexamethoxy-2,2′-di-[4-(S)-i-propyl-oxazoline]- biphenyl was reached through crystallization.Then the (P)-2,2′-dihydroxymethyl- 4,4′,5,5′,6,6′- hexamethoxy- biphenyl was obtainded from (P)-2, 2′-dioxazoline biphenyl isomer by hydrolvsis , acylatioin and reduction. Finally, the dicarbinol was transformed in a two-step process to the 4,4′,5,5′,6,6′- hexamethoxy- dibenzocyclooctadiene, which was converted to (P)-deoxyschizandrin.(P)-4,5,6,4′-Tetramethoxy-5′,6′-methenedioxy-8,8′-dihydroxymethyl-dibenzo- cyclooctadiene was prepared. The (P)-asymmertrical biphenyls obtained by the cross -coupling reaction between aryl bromides (via their Grignard reagents) and o- methoxyaryl oxazolines, could be further tansformed into the chiral (P)-2, 2′- dibromidmethyl-4,5,6,4′-tetramethoxy-5′,6′-methenedioxy-biphenyl. ((P)-4,5,6,4′- tetramethoxy- 5′,6′–methenedioxy-8,8′- dihydroxymethyl-dibenzocyclooctadiene was obtained following cyclization with diethyl succinate and reduction.The target molecule was prepared in six steps from (P)-asymmertrical biphenyl in 26% yield.