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The Asymmetric Synthesis Of Methyl Shikimate, 5a-Carba-β-D-gulopyranose, Tadalafil And Stavudine

Posted on:2009-08-02Degree:DoctorType:Dissertation
Country:ChinaCandidate:S L LiuFull Text:PDF
GTID:1101360245986257Subject:Pharmaceutical Engineering and Technology
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This dissertation included three parts:In the first part of this dissertation, we studied the synthesis of (-)-methyl shikimate and 5a-Carba-β-D-gulopyranose.(4R,5S,6R)-5,6-Bis-allyl-6-aldehyde-γ-hexanelactone I-145 was prepared from D-arabinose by six steps. Compound I-145 underwent Mukaiyama-type intramolecular aldolization to produce bicyclooctane I-147 stereospecifically. (-)-Methyl shikimate (-)-I-48 was prepared stereospecifically from the bicyclooctane I-147 by three steps. 5a-Carba-β-D-gulopyranose I-151 was prepared stereospecifically from the bicyclooctane I-147 by four steps. This method provided a new strategy for the stereoselective synthesis of carbasugar.In the second part of this dissertation, we studied the stereoselectivity of the Pictet-Spengler reaction of D-tryptophan methyl ester with piperonal and the synthesis of tadalafil.We discovered that the best stereoselectivity of the Pictet-Spengler (cis/trans=92:8) was obtained, when the reaction of D-tryptophan methyl ester II-33 with piperonal II-34 in acetic acid was catalyzed by benzoic acid at room temperature.The Pictet-Spengler reaction of D-tryptophan methyl ester hydrochloride II-42 with piperonal II-34 in various solvents was extensively studied. The best stereoselectivity (cis/trans=99:1) was obtained using nitromethane or acetonitrile as the solvent.The mechanism of the epimerization between the cis isomer(II-50) and the trans isomer(II-51) was elucidated. The mechanism involed scission of the carbon-nitrogen bond, rotation of the carbon-carbon bond and reformation of a carbon-nitrogen bond.The ratio of solubility of cis isomer(II-50) and trans isomer(II-51) was 1:11, while the stereoselectivity was 32:1. So the cis isomer(II-50) was more stable than the trans isomer(II-51).An epimerization equilibrium between the compound II-50 and the compound II-51 existed during the reaction. For the large solubility difference of the compound II-50 and the compound II-51 in the solvent used, the compound II-50 precipitated from the reaction mixture and induced transformation of II-51 into II-50. The cis isomer(II-50) was more thermodynamically stable than the trans isomer(II-51), which promote also the transformation of II-51 to II-50. The high cis/trans stereoselectivities was thus achieved due to the both factors.Tadalafil II-1 was prepared from D-tryptophan acid via methyl ester formation, Pictet-Spengler reaction, acylation and cyclization in 80% overall yield. A base-catalyzed epimerization at 12a-position of Tadalafil II-1 in a DMSO-containing solvent was also exploited. In the deutieum solvent system, Tadalafil II-1 was subjected to K2CO3 affording deuterium-labeled Tadalafil II-58 and 12a-epi-Tadalafil II-57.In the third part of this dissertation, we studied the synthesis of the anti-HIV drugs: zidovudine and stavudine.At first, the zidovudine III-1 and stavudine III-2 were prepared fromβ-thymidine. The key of the route is the synthesis of the 2, 3′-anhydro-5′-O-trityl thymidine III-7 via three steps. The zidovudine III-1 was prepared from III-7 via the reaction with sodium azide and the deprotection of a trytyl group in a 70% overall yield fromβ-thymidine. The stavudine III-2 was prepared from III-7 viaβ-elimination and deprotection in a 74% overall yield fromβ-thymidine.Then, stavudine III-2 was prepared fromβ-thymidine through another route via three steps in 69% overall yield.β-Thymidine was treated with toluenesulfonyl chloride to form ditoluenesulfonate III-77b, which was subjected to formation of the cyclic ether in the presence of a base to form III-44, followed byβ-elimination in KOH-t-BuOH system, and finally afforded stavudine III-2.At last, we developed a novel synthesis of stavudineIII-2. The stavudine was prepared from 5-methyluridine via six steps in 34% overall yield, in which the key step is the selective acylation of 5-methyluridine by propionyl chloride. In summary, a novel, ecnomic and convenient synthesis of the d4T from readily available 5-methyluridine has been developed. This method provided a new strategy for the synthesis of other unsaturated nucleosides.
Keywords/Search Tags:(-)-methyl shikimate, 5a-carba-β-D-gulopyranose, tadalafil, zidovudine, stavudine
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