【作者】 宋志光；

【导师】 李叶芝； 黄化民； 沈家骢；

【作者基本信息】 吉林大学 ， 有机化学， 2005， 博士

【摘要】 本论文提出了一种新的紫杉醇AB 环骨架的化学合成方法。以价格便宜、原料易得的α-蒎烯为原料来进行合成,获得了一些创新性的结果。主要内容包括: 以价格便宜的原料易得的α-蒎烯为原料来进行合成马鞭烯酮,通过(+)-α-蒎烯,(-)-α-蒎烯氧化后光照合成(+)-菊花烯酮、(-)-异菊花烯酮,改进文献方法,使产率大大提高,为紫杉醇全合成奠定好的开始。研究(±)-α-蒎烯在Co(4-MeC5H4N)2Br2 催化下合成(±)-马鞭烯酮,(±)-马鞭烯酮在光照下在石英装置中反应得到(+)-菊花烯酮和(-)-异菊花烯酮。由外消旋的(±)-马鞭烯酮在光照下重排合成光学产物,文献上未见报道,是首次发现。通过(+)-菊花烯酮进行Baeyer-Villiger 反应得到内酯,通过内酯水解产物的结构验证,证明(+)-菊花烯酮进行Baeyer-Villiger 反应中氧原子插入位置的机理。通过对内酯的还原得到伯仲醇,选择保护伯醇后对仲醇氧化,并通过一系列反应证明手性碳的空间位置。通过烯醇硅醚与羰基缩合的反应增加了三个碳,此方法与文献方法不同,是我们在文献基础上加以改进首次提出的。通过乙二醇保护羰基后对伯醇进行氧化为醛基,进行Reformatsky 反应增加两个碳原子,之后进行分子内缩合形成紫杉醇AB 环。反应中合成了24 个新的化合物,对新化合物中基团的空间位置及结构通过IR,1H NMR、X-衍射及化学反应等进行了证明。更多还原

【Abstract】 The Taxol is a natural product with anti-cancer activity and special action mechanism, which was found twenty years ago. It was approved by the FDA of the United States as a medicine for ovary cancer and galactophore cancer. And it appeared on market in 1992. Since it’s function shows more and more evident, investigating its synthesis method and origin is more and more valued by the chemist and biochemist. In this thesis, we use readily available α-Pinene as starting material, and synthesized AB ring of Taxol after many steps. Content is as follow (1) We synthesized (+)-Verbenone 2 from (+)-α-Pinene in presence of Co(4-Me(C5H4N)2)Br2 as catalyst. Then we synthesized (+)-Chrysanthenone from 2 under the irradiation of ultraviolet light. On base of literatures, we changed reaction condition, improved yield and process oxidation without purification. 2 (+)-VerbenoneOO1 (+)-α-Pinene 3 (+)-ChrysanthenoneCo(4-Me(C5H4N)2)Br2O2hv (2) We synthesized (-)-Isochrysanthenone 6 from (-)-α-Pinene 4 via (-)-Verbenone 5 under the irradiation of ultraviolet light. We first found that (+)-Chrysanthenone is not enantiomer of (-)-Isochrysanthenone 6. OO6 (-)-IsochrysanthenoneO4 (-)-α-Pinene5 (-)-verbenonehv (3) (-)-Isochrysanthenone 6 could been converted into chrial hydroxyl acid 2,2,4-trimethyl-5-hydroxy-3-cyclohenemethanoic acid 8. The structure of compound 8 was confirmed by X-ray diffraction analysis. OOOOHCOOHH2O6 7 8Baeyer-Villiger氧化 (4) We first synthesized (+)-Chrysanthenone and (-)-Isochrysanthenone via the rearrangement of racemic Verbenone, which has not been not reported in literature before. We knowed that (+)-Chrysanthenone and (-)-Isochrysanthenone were 75.6% e.e and 90.6% e.e separately via HPLC analysis. OO12 34567HHOO(±)-α-pineneracemic verbenone(5R)-3(5S)-6+1 2 34657hvquartz flask (5) We testified the structures of (+)-Chrysanthenone 3 and (-)-Isochrysanthenone through chemistry method.O O CNO3NO3OOH3 (6) (+)-Chrysanthenone 3 could been converted into lactone 9 via Baeyer-Villiger oxidation. After hydrolysizing, lactone 9 could been converted into chrial hydroxyl acid 10. The experiment result also proved the structure of compound 3. Since Baeyer-Villiger oxidation did not change steric configuration, the structures of compound 9 and 10 were correct. OOOHCOOHO 3 (+)-ChrysanthenoneCH3COOHH2O2H2O9 10 (7) Compound 8 and 10 could been converted into lactones 7 and 9 separately. The experiment result illuminated hydroxyl and carboxyl were on the same side of the ring. OOOHCOOHOOHOCOOH81097(8) Compound 8 could been converted into compound 14 via oxidation. We synthesized hydroxyl acid 15 from compound 14 in presence of NaBH4 via reduction. Hydroxyl acid 15 could been converted into lactone 16, which illuminated hydroxyl and carboxyl were on the same side of the ring. OHCOOH COOHOCOOHHOOOPCC NaBH4 -H2O814 15 16 (9) In view of steric configuration, compound 16 and 9, compound 10 and 15 were separately enantiomer, because their optical rotation were contrary. In addition, their optical activity were near, which demonstrate they were enantiomer. This enantiomers were obtained via chemistry synthesis first. (10) Lactones 7 and 9 could been reduced separately into chrial δ-diol in presence of LiAlH4. δ-diol was reported as chrial catalyst in literature. Compound 16 and 17 were chrial catalyst or not, which needed more investigation. OOOH9CH2OH17LiAlH4OOOHCH2OHLiAlH47 20(11) After protecting the primary alcohols of chrial δ-diol 17 and 20 with TBSCl, chrial δ-diol 17 and 20 were turned into conjugate chrial diketones 19 and 22 through oxidizing secondary alcohol in the presence of oxalyl chloride at -78℃. Chrial conjugate ketone 19 was intermediate that we synthesized further in this thesis. OH17CH2OHO19CH2OTBSOH18CH2OTBSTBSCl C2Cl2O2OH20CH2OHO22CH2OTBSOH21CH2OTBSTBSCl C2Cl2O2 (12) Compound 19 reacted with enol silyl ether of methyl pyruvate and was converted into chrial compound 23 via Mukiayama reaction. Compound 23 had more three carbons than compound 19. This was new method to add three carbons via Mukaiyama reaction. CH3CCOOCH2CH3O+ TMSCl CH2=CCOOCH2CH3OTMSDMF O19 CH2OTBSCH2OTBSOHCOOC2H5+ CH2=CCOOC2H5OOTMS23 (13) Compound 23 could been converted into conjugate diketone 24 via oxidation in presence of PCC. Compound 24 was an intermediate that we synthesized further in this thesis. CH2OTBSOHCOOC2H5O23CH2OTBSCOOC2H5O24OPCCH H (14) We protected the two carbonyl groups in compound 24 with ethylene glycol in presence of iron sulfate hydrate. Protecting carbonyl group with iron sulfate hydrate was found first by our experimental laboratory. CH2OTBSCOOC2H5O24OCH2OTBSCOOC2H525OO O OH HHO OH (15) After compound 26 was deprotected and oxidized in sequence, additional two carbons were introduced in compound 25 via Reformatsky reaction.CH2OTBSCOOC2H525OO O OCH2OHOCOOC2H5O O OCHOOCOOC2H5O O O26OCOOC2H5O O OCOOC2H528 OH 27 (16) Under nitrogen atmosphere, compound 28 was converted into AB ring of Taxol in xylene solution containing rare NaH. This method to synthesiz AB ring of Taxol has not been not reported in literature. We fisrt synthesized AB ringof Taxol via Dieckmam condensation. OCOOC2H5O O OCOOC2H5OHOOOOOHOCOOC2H52829 (17) After threeteen steps we synthesized AB ring of Taxol from α-Pinene. In literature, Mukiayama synthesized B ring of Taxol from 2,2-dimethyl-3-hydroxy acryl acid ester after more than twenty steps. Our synthesis route was short more than seven steps than Mukiayama’s. What’s more we used readily available chemical reagent.更多还原