Synthesis Of Valiolamine And Some Chiral Epoxy Intermediates Starting From （-）-Shikimic Acid And CuCl₂-promoted Regeneration Of Carbonyl Compounds From Oximes And Hydrazones

This dissertation contains the following three parts:(1) In the first part,(+)-valiolamine and its epimer (-)-1-epi-valiolamine were synthesized from the naturally abundant (-)-shikimic acid:Starting from (-)-shikimic acid, ethyl shikimate I-B-2was first prepared in97%yield, and then was treated with thionyl chloride in N,N-dimethylformamide (DMF). Because of the better reaction of the hydroxyl group at the allylic (C-3) position than the other two hydroxyls at C-4and C-5, a highly regioselective chlorination of the C-3hydroxyl took place. Then, both hydroxyls at C-4and C-5were masked by formyl groups. As a result, compound I-B-3was obtained in91%yield. Ethyl shikimate I-B-2was first treated with PhCHO to give an acetal I-B-21, which was then treated with NBS to afford bromide I-B-22in90%yield. When both compounds I-B-3and I-B-22were treated with K2CO3,3,4-epoxido compound I-B-4could be smoothly obtained after deblocking and intermolecular substitution. Methanesulfonylation of epoxide I-B-4gave I-B-5, which then underwent ring-opening in aqueous CF3COOH to give compound I-B-6in93%yield. Compound I-B-6was treated with sodium azide in the presence of0.5equivalent of AcOH by using dimethylsulfoxide (DMSO) as the solvent. A typical SN2-type nucleophilic substitution occurred smoothly to afford compound I-B-7a in83%yield, and the (R) configuration of C-5was inverted to (S) via a Walden-type inversion. In contrast, when compound I-B-6was treated with sodium azide at reflux by using ethanol as the solvent, compound I-B-7b was obtained in84%yield, but the (R) configuration of C-5retained during the substitution. Subsequently, protection of hydroxyl groups at the allyllie (C-3) position of compounds I-B-7a and I-B-7b by TBDPS, reduction of ester groups, and acylation of the other hydroxyl groups smoothly afforded compounds I-B-9a and I-B-9b. Then, Ru-catalyzed asymmetric dihydroxylation of compounds I-B-9a and I-B-9b was proceeded smoothly to afford compounds I-B-10a and I-B-10b. Finally, after removal of all the protecting groups followed by Pd/C-catalyzed hydrogenation of the azido group,(+)-valiolamine I-A-1and (-)-1-epi-valiolamine I-A-4were obtained accordingly.In conclusion, by using the naturally abundant (-)-shikimic acid as the starting matrial, the first target compound (+)-valiolamine I-A-1was synthesized via12steps in35%overall yield, and the second target compound (-)-1-epi-valiolamine I-A-4via12steps in30% overall yield.(2) In the second part, syntheses of four important chiral epoxy intermediates from the naturally abundant (-)-shikimic acid were described:(a) Starting from (-)-shikimic acid, we first prepared cyclic sulfite intermediate Ⅱ-B-1by protecting3,4-dihydroxyl groups with SOCl2Methanesulfonylation of hydroxyl at C-5of compound Ⅱ-B-1gave compound Ⅰ-B-2in96%yield. Compound Ⅱ-B-2was treated with powdered potassium carbonate in anhydrous methanol, and cascade methanolysis of cyclic sulfite and intramolecular SN2-type reaction took place smoothly to afford the desired epoxide Ⅱ-A-1.(b) Compound Ⅱ-B-2was treated with aqueous concentrated hydrochloric acid, the cyclic sulfite functional group of compounds Ⅱ-B-2was thus removed, and compound Ⅱ-B-7was obtained in95%yield. Regioselective mono-tosylation of the less-hindered hydroxyl group at C-3of compound Ⅱ-B-7with toluenesulfonyl chloride produced tosylate Ⅱ-B-8. After the treatment of compound Ⅱ-B-8with a mixture of benzoic acid and triethylamine (BzOH/Et3N=3:2), nucleophilic substitution of OTs group at C-3allylic position of compound Ⅱ-B-8afforded benzoate Ⅱ-B-9in85%yield. When compound Ⅱ-B-9was treated with potassium carbonate, epoxide formation and a simultaneous deblocking of benzoyl group took place smoothly to give the desired epoxide Ⅱ-A-2in93%yield.(c) Protection of hydroxyl group at C-5of compound Ⅱ-B-1with BzCI afforded compound Ⅱ-B-11. Then treatment with aqueous concentrated hydrochloric acid to remove the cyclic sulfite functional group of compounds Ⅱ-B-11provided compound II-B-12. Compound Ⅱ-B-12reacted with methanesulfonyl chloride to produce the bismesylated compound Ⅱ-B-13. Compound Ⅱ-B-13was treated with a mixture of AcOH and DBU (AcOH/DBU=3:1), where a selective SN2-type replacement of the OMs group at C-3position by an OAc group took place smoothly to afford compound Ⅱ-B-14in86%yield. Treatment of compound Ⅱ-B-14with K2CO3furnished the desired epoxide Ⅱ-A-3.(d) Compound Ⅱ-B-12was exposed to p-hlorobenzoyl chloride, and selective protection of the less hindered hydroxyl at allylic C-3position took place smoothly to afford compound Ⅱ-B-18in88%yield. Methanesulfonylation of hydroxyl group at C-4of compound Ⅱ-B-18with methanesulfonyl chloride produced compound Ⅱ-B-19. Then removal of the protecting groups followed by an intramolecular substitution finally furnished epoxide Ⅱ-A-4in90%yield.In summary, we have successfully developed novel asymmetric syntheses of four useful chiral epoxides Ⅱ-A-1, Ⅱ-A-2, Ⅱ-A-3, Ⅱ-A-4from (-)-shikimic acid in79%(over4steps). 56%(7steps),64%(7steps) and65%(7steps) overall yields, respectively.(3) In the third part, we described a green method for the regeneration of carbonyl compounds from oximes and hydrazones by using cupric chloride dihydrate as a recoverable promoter for hydrolysis:We investigated the hydrolysis of oximes and hydrazones with various cupric salts in different solvents to obtain the corresponding carbonyl compounds. The best condition was found as follows:2molar equivalent of cupric chloride dihydrate (CuCl2·2H2O) used in an aqueous acetonitrile (CH3CN/H2O=4:1) at reflux. The comesponding carboxyl compounds were obtained in85-98%yields. This method is tolerant with various sensitive groups (sulfides, aldehydes, etc). In addition, cupric salt could readily be recovered in almost quantitative yield via the complete precipitation of Cu(OH)2, which could be reused for the above hydrolysis after being converted int.