Novel Chemistry Of Chiral 1,4,4-Tetrasubstituted Butanetetraols

TADDOLs and their derivatives have been developed into a versatile chiral auxiliaries and chiral ligands. They are also used as organic small molecule catalyst in asymmetric synthesis in recent years. TADDOLs are generally prepared via reactions of dialkyl tartrates protected by aldehydes or ketones with Grignard reagents, but the deprotection of TADDOLs is difficult. The study on chiral 1,1,4,4-tetrasubstituted butanetetraol, which is the parent compound of TADDOLs, is extremely rare. In this thesis, a convenient route to synthsize chiral 1,1,4,4-tetrasubstituted butane tetraol is eatablished and selective functional group transformation of chiral 1,1,4,4-tetrasubstituted butanetetraols is studied. And the synthesized derivatives of chiral 1,1,4,4-tetrasubstituted butanetetraols are applied to asymmetric synthesis.The thesis is devided into 6 chapters.In chapter 1, the preparation and application of TADDOLs and its derivatives to asymmetric synthesis are reviewed, and the research strategies of the thesis are outlined.In chapter 2, synthesis of chiral 1,1,4,4-tetrasubstitued butanetetraol was investigated. Three routes to synthesize chiral 1,1,4,4-tetrasubstitued butanetetraol were designed:reaction of diethyl tartrate protected by phenylboric acid with Grignard reagents, reaction of diethyl tartrate protected by borate ester with Grignard reagents and directly reaction of diethyl tartrate with Grignard reagents. "One-pot" and one step synthesis of chiral 1,1,4,4-tetrasubstitued butanetetraol was established and several chiral 1,1,4,4-tetrasubstitued butanetetraol were synthesized.In chaper 3, selective 1,4-cycloetheration reaction of chiral 1,1,4,4-tetraphenylbutane-tetraol was studied. And the chiral induction ability of the prepared chiral tetrahydrofurandiol was investigated.In heterogeneous conditions, chiral 1,1,4,4-tetraphenylbutanetetraol underwent highly regioselective 1,4-cycloetheration reaction with halogen acid to give chiral tetrahydrofuran-diol. While in homogeneous conditions, chiral 1,1,4,4-tetraphenylbutanetetraol underwent rearrangement and furnished a cyclic isomer. The structure of chiral tetrahydrogenfurandiol and its isomer were confirmed by X-ray diffraction analysis.Chiral tetrahydrogenfurandiol was used as chiral additive in asymmetric aldol and Michael addition reaction catalyzed by L-proline, it was found that chiral tetrahydrogenfuran-diol displayed excellent asymmetric induction ability.In chapter 4, selective 2,3-cyclosulfuration reaction of chiral 1,1,4,4-tetraphenyl-butanetetraol was studied and properties of the prepared chiral cyclic sulfites were investigated.Chiral 1,1,4,4-tetraphenylbutanetetraol underwent highly regioselective 2,3-cyclo-sulfuration reaction with thionyl chloride in the presence of excess tertiary amine, such as pyridine or triethylamine, and offered three different cyclic sulfites, including 4,5-bis-(diphenylhydroxymethyl)-1,3,2-dioxathiolane 2-oxide,4-diphenylchloromethyl-5-diphenylhydroxymethyl-1,3,2-dioxathiolane 2-oxide and 4,5-bis-(diphenylchloromethyl)-1,3,2-dioxathiolane 2-oxide. They could be obtained via contralling thionyl chloride loading in high yield separately. Cyclic sulfites are stable to common solvents, water and even acid, but they are easy to desulphurize in alkaline liquor.Crystallography of cyclic sulfites was studied, and an ultrashort S=O bond was discovered. Bond length of the S=O in dichloride of the cyclic sulfite is only 1.228 A, and it may be the shortest one known to date. Electrostatic repulsion interaction between chlorine atoms and the bond-forming atoms of S=O, which compressed the S=O, resulting in ultrashortenation. It is the first time for revealing considerable effect of electrostatic repulsion interation of the surrouding electronegative atoms to the S=O bond.The performance of 4,5-bis-(diphenylchloromethyl)-1,3,2-dioxathiolane 2-oxide in alkaline liquor is peculiar. It could be specifically oxidized into cyclic sulfate by oxygen in the air at room temperature, while desulphurization would take place to offter chiral bi-epoxyethane in the absence of oxygen.Reaction behaviour of 4,5-bis-(diphenylchloromethyl)-1,3,2-dioxathiolane 2-oxide and sodium sulfide was also studied. It was found that the reaction was influenced greatly by reaction solvents. Chiral tetrahydrothiophenediol was offered when the reaction occurred in dry THF in absence of oxygen; but 1,1,4,4-tetraphenyl-1,4-dihydroxy-2-butanene was obtained in high yield when the reation was allowed to carry out in DMF.In chapter 5, selective cycloboration of chiral 1,1,4,4-tetraphenylbutanetetraol was studied. Highly regioselective 1,3-cycloboration reaction took place between chiral 1,1,4,4-tetraphenylbutanetetraol and alkylboronic acid to offer chiral bicyclo[4.4.0]diborates. A series of chiral diborates were prepared and their chiral induction ability was investigated.In contrast, chiral 1,1,4,4-tetraphenylbutanetetraol reacted with trialkyl borate via 2,3-cycloboration to give chiral spiroboronic acid 21. Three chiral spiroboronate compound 22, 23 and 24 were separated from one-pot reaction of chiral 1,1,4,4-tetraphenylbutanetetraol, tributyl borate and L-proline in refluxing tolunene and discovered that chiral spiroboronic L-proline salts readily underwent decarboxylation reaction in polar protic solvents to furnish pyrrolidinium spiroborate in high yield. The X-ray diffraction analysis for three chiral spiroborate salts revealed that complicated hydrogen bonding interaction existed in their molecules.Preliminary investigation indicated that chairal spiroboronate 22 could effectively promote the Michael addition reaction, but the stereoselctivity of the reaction was low.In chapter 6, selective cyclophosphoration reaction of chiral 1,1,4,4-tetraphenyl-butanetetraol was studied. Chiral 1,1,4,4-tetraphenylbutanetetraol was allowed to react with phosphorus oxychloride to give chiral phosphoric acid containing two hydroxyl groups via selective 1,3-cyclophosphoration reaction. Its composition and structure has been confirmed by the single-crystal X-ray diffraction analysis.Asymmetric Biginelli reaction catalyzed by the chiral phosphoric acid and several chiral amino acid was studied, and medium yield and stereoselctivity was obtained when the chiral phosphoric acid was used as catalyst. In comparation, chiral amino acid had very low catalytic activity to Biginelli reaction.