Synthesis Of Several Chiral Ligands And Their Application In The Asymmetric Synthesis Of Chiral Sulfoxide

Chiral sulfoxides play a significant role as chiral auxiliaries in the asymmetric organic synthesis. At the same time, many bioactive molecules have the structural characteristics of sulfoxide, and the feature and strength of their bioactivity are closely correlative with their stereoconfiguration. The most efficient way to prepare chiral sulfoxides is the asymmetric oxidation of prochiral sulfides catalyzed by chiral metal complexes. Among the reported chiral ligands, some require complicated synthetic processes or costive starting materials, some just fit for a narrow spectrum of substrates. We prepared several chiral ligands from natural chiral resources according to reported procedures, and firstly applied them in the asymmetric oxidation of prochiral sulfides.Two chiral ligands 1,2:5,6-di-O-isopropylidene-D-mannitol and 1,2:5,6-di-O–cyclohexylidene-D-manntiol were conveniently prepared by ketalization of D-mannitol with acetone or cyclohexanone. In the presence of chiral titanium catalyst formed in situ from Ti(Oi-Pr)₄ and the diol ligand, sulfides were oxidized to sulfoxide by TBHP in moderate yields (29%⁵3%) and moderate enantioselectivities (20%ee⁵4%ee). The best results were obtained under the following reaction conditions: sulfide/diol/Ti(Oi-Pr)₄/H₂O=1/0.1/0.05/1(mol ratio); TBHP(70% in water) as oxidant(2 equiv); CCl4 as solvent; 0℃. This catalytic protocol has showed to be fairly general for alkyl aryl sulfides including the sulfides with two bulky groups.N,N'-dibenzyl-D-tartaric acid diamide and N,N'-dicyclohexyl-D-tartaric acid diamide were synthesized by ammonolysis of D-diethyl tartrate with benzyl amine and cyclohexyl amine. Their complexes with Ti(Oi-Pr)₄ were firstly employed in the catalytic asymmetric oxidation of sulfide with TBHP as the oxidant at 0℃. The corresponding sulfoxide was obtained in 12%³2% yield and 6%ee¹5% ee. No significant improvement on either optical or chemical yields were achieved by changing the reaction conditions.4,6-bis(9-O-cinchonine)-2,5-diphenylpyrimidine and 1,4-bis(9-O-quinidine) phthalazine were easily obtained from the natural cinchona alkaloid cinchonine and quinidine. The asymmetric sulfoxidation catalyzed by these ligands and WO₃ using hydrogen peroxide as the oxidant gave nearly racemic sulfoxide. No significant improvement in enantionselectivity was achieved by changing reaction conditions. However, (S)-3-(1-Naphthoxy)-1,2-propanediol was obtained in 90%ee via asymmetric dihydroxylation of allyl 1-naphthyl ether with the above readily accessible bis-cinchona alkaloid derivative 1,4-bis(9-O-quinidine)- phthalazine as the chiral ligand. By a one pot procedure the diol was converted into (2S)-2-naphthoxymethyloxiriane, which was further transformed into (S)-propranolol hydrochloride by treatment with isopropylamine and hydrochloride.