CN1221412A - 1－脱氧浆果赤霉素ⅲ,1－脱氧紫杉醇和1－脱氧紫杉醇类似物及其制备方法 - Google Patents
1－脱氧浆果赤霉素ⅲ,1－脱氧紫杉醇和1－脱氧紫杉醇类似物及其制备方法 Download PDFInfo
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 10
- 229930012538 Paclitaxel Natural products 0.000 title claims description 32
- 229960001592 paclitaxel Drugs 0.000 title claims description 32
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 title claims description 30
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 118
- -1 formula [10] compound Chemical class 0.000 claims description 67
- 238000006243 chemical reaction Methods 0.000 claims description 54
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- 229930195733 hydrocarbon Natural products 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
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- 125000000468 ketone group Chemical group 0.000 claims description 11
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 6
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- QMMMGQKKOKYDMN-UHFFFAOYSA-N lauroguadine Chemical compound CCCCCCCCCCCCOC1=CC=C(N=C(N)N)C=C1N=C(N)N QMMMGQKKOKYDMN-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- IVIIAEVMQHEPAY-UHFFFAOYSA-N tridodecyl phosphite Chemical compound CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC IVIIAEVMQHEPAY-UHFFFAOYSA-N 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims description 3
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 claims description 3
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- 239000000243 solution Substances 0.000 description 64
- 235000019439 ethyl acetate Nutrition 0.000 description 56
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 45
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- 238000005481 NMR spectroscopy Methods 0.000 description 37
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- 239000011734 sodium Substances 0.000 description 26
- 229920006395 saturated elastomer Polymers 0.000 description 25
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 21
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 19
- 238000000746 purification Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 238000003818 flash chromatography Methods 0.000 description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
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- 239000000203 mixture Substances 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 150000001721 carbon Chemical group 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 125000000304 alkynyl group Chemical group 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 150000001263 acyl chlorides Chemical class 0.000 description 8
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 8
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- 150000003952 β-lactams Chemical class 0.000 description 7
- YWLXLRUDGLRYDR-UHFFFAOYSA-N 10-deacetylbaccatin Chemical compound CC(=O)OC12COC1CC(O)C(C(C(O)C1=C(C)C(O)CC3(O)C1(C)C)=O)(C)C2C3OC(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-UHFFFAOYSA-N 0.000 description 6
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
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- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
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- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- DJOWTWWHMWQATC-KYHIUUMWSA-N Karpoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1(O)C(C)(C)CC(O)CC1(C)O)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C DJOWTWWHMWQATC-KYHIUUMWSA-N 0.000 description 3
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- 125000004432 carbon atom Chemical group C* 0.000 description 3
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 3
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- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
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- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 2
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- BDZHKUAKSMWSAJ-UHFFFAOYSA-N 2-chloro-n,n-diethyl-1,1,2-trifluoroethanamine Chemical compound CCN(CC)C(F)(F)C(F)Cl BDZHKUAKSMWSAJ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
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- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- BNHFWQQYLUPDOG-UHFFFAOYSA-N lithium;1,2,2,3-tetramethylpiperidine Chemical compound [Li].CC1CCCN(C)C1(C)C BNHFWQQYLUPDOG-UHFFFAOYSA-N 0.000 description 1
- YTJXGDYAEOTOCG-UHFFFAOYSA-N lithium;di(propan-2-yl)azanide;oxolane Chemical compound [Li+].C1CCOC1.CC(C)[N-]C(C)C YTJXGDYAEOTOCG-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
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- 239000010936 titanium Substances 0.000 description 1
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- WILBTFWIBAOWLN-UHFFFAOYSA-N triethyl(triethylsilyloxy)silane Chemical compound CC[Si](CC)(CC)O[Si](CC)(CC)CC WILBTFWIBAOWLN-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
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- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
- C07C49/727—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
- C07C49/733—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system having two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
- C07C49/727—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
- C07C49/737—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system having three rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
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- C—CHEMISTRY; METALLURGY
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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Abstract
1－脱氧浆果赤霉素Ⅲ,1－脱氧紫杉醇和1－脱氧紫杉醇类似物及其制备方法。
Description
本发明是在政府支持下及由国立卫生研究院(National Institutes ofHealth)奖励的NIH Grant#CA 42031下完成的。因此，政府对本发明有一定的权利。相关申请
本申请至少部分要求了临时中请60/016,927(申请日为1996年5月6日)的优先权，发明背景
本发明涉及新的用作抗肿瘤药的紫杉烷(taxane)及其制备方法。
作为萜的紫杉烷家族成员，浆果赤霉素Ⅲ和紫杉醇(taxol)已经引起生物界和化学界很大兴趣。紫杉醇是有希望的具有广谱肿瘤抑制活性的抗癌化疗剂。紫杉醇具有2’R,3’S构型和下列结构式：
其中Ac是乙酰基。由于其有希望的活性，所以目前法国和美国已将紫杉醇用于临床试验。
Colin等人在美国专利4,814,470中报告说，具有下面结构式(Ⅱ)的紫杉醇衍生物具有比紫杉醇(Ⅰ)更显著的活性，
其中R’代表氢或乙酰基，R”和R”’之一代表羟基，另一个代表叔丁氧羰基氨基和它们的立体异构体形式，及其混合物。其中R”是羟基，R”’是叔丁氧羰基氨基并具有2’R,3S’构型的上式化合物通常称为拓扑紫杉醇(taxotere)。
虽然紫杉醇和拓扑紫杉醇都是有希望的化疗剂，但它们不是普遍有效。因此，仍需要其它的化疗剂。发明概述
因此，本发明目的之一是提供新的具有抗肿瘤剂价值的紫杉烷及其制备方法。
简而言之，本发明涉及制备1-脱氧浆果赤霉素Ⅲ,1-脱氧紫杉醇和1-脱氧紫杉醇类似物的方法。该方法至少包括下列一个步骤：(a)将式[3]化合物
与过酸如间氯过苯甲酸反应，形成式[4]化合物，
其中P10是甲硅烷基羟基保护基如三乙基甲硅烷基，或酰基如苯甲酰基。在该反应中，保护的羟基-OP10迁移到邻近的碳，形成-OP9,P9与P10相同；(b)将式[5]化合物进行环氧醇裂解，包括
(ia)在过渡金属催化剂，优选四异丙氧化钛存在下，用氢过氧化物，优选t-BuOOH对烯烃基团进行环氧化反应，或
(ib)用过酸如过乙酸处理烯烃基团，然后
(ii)加入硫化物，优选二甲基硫醚，然后在过渡金属催化剂，优选四异丙氧化钛存在下加热，形成式[6]化合物，
其中P9是羟基保护基如甲硅烷基，缩酮，缩醛或不含有反应性官能团的醚；(c)将式[9]化合物
与乙烯基有机金属试剂反应，形成式[10]化合物；
(d)将式[14]化合物
与钯催化剂反应，形成式[15]化合物；
(e)将式[17]化合物
与碱，最优选甲醇中的BaO反应，并保护C7羟基取代基，例如，通过产物与TESOTf反应，形成式[18]化合物；及
和(f)将式[18]化合物
与SeO2反应，形成式[19]化合物；其中E7是氢或羟基保护基，P2,P7,P9,P10和P13是下面定义的羟基保护基。
一般而言，本发明方法可以用来制备具有以下结构式的1-脱氧浆果赤霉素Ⅲ,1-脱氧紫杉醇和1-脱氧紫杉醇类似物，
其中M包含铵或者是金属；
R2是-OT2,-OCOZ2或-OCOOZ2；
R4是-OT4,-OCOZ4或-OCOOZ4；
R6是氢，酮基，-OT6,-OCOZ6或-OCOOZ6；
R7是氢，卤素，-OT7,-OCOZ7或-OCOOZ7；
R9是氢，酮基，-OT9,-OCOZ9或-OCOOZ9；
R10是氢，酮基，-OT10,-OCOZ10或-OCOOZ10；
R6,R7,R9和R10独立地α和β立体化学构型；
R13是羟基，保护的羟基，酮基，MO-或
T2,T4,T6,T7,T9和T10独立地是氢或羟基保护基；
X1是-OX6；
X2是氢，烃，杂原子取代的烃或杂芳基；
X3和X4独立地是氢，烃，杂原子取代的烃或杂芳基；
X5是-COX10,-COOX10,-COSX10或-CONX8X10；
X6是氢，烃，杂原子取代的烃，杂芳基或羟基保护基，或增加紫杉烷衍生物水溶解性的官能团；
X8是氢，烃，杂原子取代的烃；
X10是烃，杂原子取代的烃或杂芳基；及
Z2,Z4,Z6,Z7,Z9和Z10独立地是烃，杂原子取代的烃或杂芳基。
此外，本发明还涉及具有下列结构式的化合物：
其中E7是氢或羟基保护基；Bz是苯甲酰基；P2,P3,P7,P9,P10和P13是羟基保护基；且R13定义如上。这些化合物是1-脱氧浆果赤霉素Ⅲ,1-脱氧紫杉醇和其它类似物合成的关键中间体。本发明还涉及制备这些关键中间体的方法。
本发明的其它目的和特性将在下文中陆续出现和指出。优选实施方案的详细描述
本发明方法能够由1-脱氧浆果赤霉素Ⅲ,1-脱氧-10-脱乙酰基浆果赤霉素Ⅲ或它们的类似物制备1-脱氧紫杉醇和1-脱氧拓扑紫杉醇以及1-脱氧紫杉醇和1一脱氧拓扑紫杉醇的类似物。在一优选实施方案中，这些化合物具有下列结构：
其中
M包含铵或者是金属；
R2是-OCOZ2；
R4是-OCOZ4；
R6是氢；
R7是氢，-OT7或-OCOZ7；
R9是氢，酮基，-OT9或-OCOZ9；
R10是氢，酮基，-OT10或-OCOZ10；
R13是MO-或
T7,T9和T10独立地为氢或羟基保护基；
X1是-OX6；
X2是氢；
X3是烷基，取代的烷基，链烯基，取代的链烯基，炔基，取代的炔基，芳基，取代的芳基或杂芳基；
X4是氢；
X5是-COX10或-COOX10；
X6是氢或羟基保护基；
X10是烷基，取代的烷基，链烯基，取代的链烯基，炔基，取代的炔基，苯基，取代的苯基或杂芳基；及
Z2是烷基，取代的烷基，苯基，取代的苯基或杂芳基；
Z4是苯基，取代的苯基或杂芳基；
Z7,Z9和Z10独立地为烷基，取代的烷基，苯基，取代的苯基或杂芳基。
合成1-脱氧浆果赤霉素Ⅲ的一个实例示于反应流程1。起始原料二醇1可以从商品化的patchino(通常称为B-绿叶灵(patchouline)环氧化物)制备。首先将patchino与有机金属如叔丁基锂反应，然后用有机过氧化物如叔丁基过氧化物在四异丙氧化钛存在下进行氧化反应，生成叔醇。然后将叔醇与Lewis酸如三氟化硼，在40--100℃低温下，在酸如三氟甲磺酸存在下反应。该反应流程的图示和制备二醇1的实验论述可以在美国专利4,876,399中找到。
反应流程1
1-脱氧浆果赤霉素Ⅲ在该反应流程中，P2是BOM；P3是TMS；P7在化合物12-15中是Ac，在化合物18-23中是TES；P9在化合物4-7中是TES，在化合物8-12中是TMS；P10是TES；P13在化合物7-21中是TBS，在化合物22和23中是TES。然而，应该理解，P2,P3,P7,P9,P10和P13也可以是其它羟基保护基。
一般来说，带有C13侧链的四环紫杉烷可以通过-内酰胺与有紫杉烷四环核和C13金属氧化物或铵氧化物取代基的醇盐反应，形成在C13位有β-氨基酯取代基的化合物。β-内酰胺有下列结构式：
其中X1-X5定义如上。有紫杉烷四环核和C13金属氧化物或铵氧化物取代基的醇盐有下列结构式：
其中R2,R4,R6,R7,R9,R10和R13定义如上，M包含铵或是任意选自ⅠA,ⅡA，过渡金属(包括镧系和锕系元素)，Ⅱb,ⅢA,ⅣA,ⅤA或ⅥA的金属(CAS版)。如果M包含铵，则优选四烷基铵，而且，四烷基铵取代基的烷基部分优选C1-C10烷基如甲基或丁基。
1-脱氧紫杉醇可以通过用适当羟基保护基保护1-脱氧浆果赤霉素Ⅲ24的C7羟基，然后将7-保护的浆果赤霉素Ⅲ转化成相应的醇盐，并将该醇盐与其中X1是保护的羟基，X3是苯基，X5是苯甲酰基及X2和X4是氢的β-内酰胺反应制成。保护基如2-甲氧基丙基(“MOP”),1-乙氧基乙基(“EE”)和苄氧基甲基是优选的，但其它各种标准的保护基如三烷基甲硅烷基和三芳基甲硅烷基也可以使用。
可用制备1-脱氧紫杉醇同样的方法制备1-脱氧拓扑紫杉醇，只是用1-脱氧-10-脱乙酰基浆果赤霉素Ⅲ代替1-脱氧浆果赤霉素Ⅲ，且β-内酰胺的X5是叔丁氧羰基而不是苯甲酰基。1-脱氧-10-脱乙酰基浆果赤霉素Ⅲ可以如反应流程2中那样制备，原料为化合物22。
反应流程2
带有其它侧链取代基的1-脱氧紫杉醇和1-脱氧拓扑紫杉醇的类似物可以用其它适当取代的β-内酰胺制备。例如，在C3’位有烷基，链烯基，炔基，取代的芳基，杂芳基或取代的杂芳基取代基的1-脱氧紫杉醇和1-脱氧拓扑紫杉醇类似物可以用其中X3是烷基，链烯基，炔基，取代的芳基，杂芳基或取代的杂芳基的β-内酰胺制备。或者，β-内酰胺的X5可以是-COX10,-COOX10,-COSX10或-CONX8X10，其中X8和X10定义如上。
紫杉醇的1-脱氧-10-脱乙酰氧基类似物可以从相应的浆果赤霉素Ⅲ的1-脱氧-10-脱乙酰氧基衍生物和10-DAB的1-脱氧-10-脱氧基衍生物制备。正如反应流程3所示，这些衍生物可以通过1-脱氧-浆果赤霉素Ⅲ或1-脱氧-10-DAB(或它们的衍生物)与碘化亚钐反应制成。有C10离去基团的四环紫杉烷与碘化亚钐之间的反应可以在0℃和溶剂如四氢呋喃中进行。有利的是，碘化亚钐选择性地除去C10离去基团；四环核上的C13侧链和其它取代基不变。反应流程3
带有其它C9取代基的1-脱氧紫杉醇和1-脱氧拓扑紫杉醇的类似物可以通过选择性地还原1-脱氧紫杉醇，1-脱氧-10-DAB,1-脱氧浆果赤霉素Ⅲ或本发明公开的其它中间体之一的C9酮取代基，生成相应的9-β-羟基-1-脱氧衍生物来制备。还原剂优选硼氢化物，最优选四丁基硼氢化铵(Bu4NBH4)或三乙酰氧基氢化硼。
正如反应流程4所示，1-脱氧浆果赤霉素Ⅲ24与Bu4NBH4在二氯甲烷中反应生成9-脱氧-9β-羟基-1-脱氧浆果赤霉素Ⅲ25。C7羟基被适当保护基保护之后，正如本文他处所述，适当的侧链可以连到7-保护的-9β-羟基-1-脱氧衍生物26上。因此，除去留下的保护基得到9β-羟基-脱氧-1-脱氧紫杉醇或其它有C13侧链的9β-羟基-1-脱氧四环紫杉烷。反应流程4
或者，7-保护的-9β-羟基-1-脱氧衍生物26的C13羟基可以用一个保护基保护，所说保护基可以根据反应流程5所述相对C7羟基保护基被选择性地除去，使得可以进一步选择性地操作紫杉烷的各种取代基。例如，7,13-保护的-9β-羟基-1-脱氧衍生物27与KH的反应引起乙酸酯基团从C10向C9迁移，同时羟基从C9向C10迁移，因而生成10-脱乙酰基衍生物28。10-脱乙酰基衍生物28被保护基保护后形成衍生物29。从衍生物29选择性地除去C13羟基保护基，得到衍生物30。如上所述，衍生物30上可以附着适当侧链。反应流程5
如反应流程6所示，10-氧代衍生物31可以通过10-脱乙酰基衍生物28的氧化反应得到。之后，C13羟基保护基可以被选择性地除去。然后如上述附着侧链，得到9-乙酰氧基-10-氧代-紫杉醇或其它有C13侧链的9-乙酰氧基-10-氧代-四环紫杉烷。或者，可以通过10-氧代衍生物31与还原剂如碘化亚钐的还原反应选择性地除去C9乙酸酯基，生成9-脱氧-10-氧代衍生物32，再从衍生物32中选择性地除去C13羟基保护基，然后如上述附着侧链，得到9-脱氧-10-氧代-1-脱氧紫杉醇或其它有C13侧链的9-脱氧-10-氧代-1-脱氧四环紫杉烷。反应流程6
反应流程7描述了还原1-脱氧-10-DAB生成四醇33的反应。然后，四醇33的C7和C10羟基可以用保护基选择性的保护，得到二醇34，如上所述，二醇34上可以附着C13侧链，或者，在进一步修饰四环取代基之后附着侧链。反应流程7
有C9和/或C10酰氧基取代基而不是乙酰氧基的紫杉烷可以用1-脱氧-10-DAB作为起始原料按反应流程8所述制备。用适当保护基保护了1-脱氧-10-DAB的C7羟基后得到7-保护的1-脱氧-10-DAB35，然后7-保护的1-脱氧-10-DAB35的C10羟基取代基可以很容易地用任何标准酰化剂如酰氯酰化，生成有新的C10酰氧基取代基的衍生物36。用类似的氯甲酸酯代替酰氯可以得到相应的碳酸酯。将C7羟基脱保护，接着用四丁基硼氢化铵对衍生物36的C9酮基取代基进行选择性还原反应，然后进行C7羟基的保护反应，得到9β-羟基衍生物37，其上面可以附着C13侧链。或者，引发上面反应流程5所述的C10和C9基团的迁移。反应流程8
另外，有C2和/或C4酯的紫杉烷可以用浆果赤霉素Ⅲ和10-DAB作原料制备。可以用还原剂如LAH或Red-Al将浆果赤霉素Ⅲ和10-DAB的C2和/或C4酯选择性地还原成相应的醇，然后，用标准酰化剂如酸酐和酰氯与胺如吡啶，三乙胺，DMAP或二异丙基乙胺联合处理取代成新的酯。或者，通过用适当的碱如LDA处理C2和/或C4醇形成相应的醇盐然后用酰化剂如酰氯处理，将C2和/或C4醇转化成新的C2和/或C4酯。见美国专利5,399,726，该文关于有不同C2和C4酰氧基取代基的紫杉烷的制备方法在此引作参考。
在反应流程9中，7,10,13-保护的10-DAB38用氢化锂铝转化成二醇39。用LDA将二醇39脱质子化，接着与酰氯选择性地反应，得到C2酯40。用LDA对C2酯40进行脱质子化反应，接着与酰氯反应，得到C2,C4酯41。如果用氯甲酸酯代替酰氯，得C2或C4碳酸酯(-OCOOZ2或-OCOOZ4)。反应流程9
C7二氢和其它C7取代的紫杉烷可以按反应流程10,11和12制备。
反应流程10
反应流程12
如反应流程11所述，在室温和THF溶液中用FAR处理可以将1-脱氧-浆果赤霉素Ⅲ转化成7-氟1-脱氧-浆果赤霉素Ⅲ。其它有游离C7羟基的1-脱氧-浆果赤霉素衍生物的情况与此类似。或者，可以用含有过量三乙胺盐酸盐的甲磺酰氯和三乙胺的二氯甲烷溶液处理浆果赤霉素Ⅲ来制备7-1-脱氧-氯浆果赤霉素Ⅲ。
有C7酰氧基取代基的紫杉烷可以按反应流程12制备。通过选择性地除去C13保护基并用金属如锂取而代之将7,13-保护的10-氧代-衍生物42转化成其相应的C13醇盐。然后将醇盐与β-内酰胺或其它侧链前体反应。然后C7保护基水解引起C7羟基取代基向C10迁移，C10氧代基取代基向C9迁移，及C9酰氧基取代基向C7迁移。
有其它C6取代基的1-脱氧紫杉烷可以用Liang等人，《四面体通讯(Tetrahedron Letters)》，第36卷，No.17,pp.2901-2904(1995)所述反应制备，但用1-脱氧-10,13-保护的10-DAB代替紫杉醇作为起始原料。根据该反应流程，用CF3SO2Cl将1-脱氧-10,13-保护的10-DAB转化成7-0-三氟甲磺酸酯。用1,8-二氮杂双环(5,4,0)-十一-7-烯(DBU)处理7-0-三氟甲磺酸酯，得到7-脱氧中间体。将其与OsO4然后与酰氯(或氯甲酸酯)反应后生成相应的C6酯或碳酸酯。
本文所用术语“Ar”指芳基；“Ph”酯苯基；“Bz”指苯甲酰基；“Me”指甲基；“Et”指乙基；“iPr”指异丙基；“tBu”和“t-Bu”指叔丁基；“R”指低级烷基，除非另有定义；“Ac”指乙酰基；“Py”指吡啶；“TES”指三乙基甲硅烷基；“TMS”指三甲基甲硅烷基；“TBS”指Me2t-BuSi-；“Tf”指-SO2CF3；“BMDA”指BrMgNiPr2；“Swern”指(COCl)2,Et3N；“LTMP”指四甲基哌啶锂；“MOP”指2-甲氧基-2-丙基；“BOM”指苄氧基甲基；“LDA”指二异丙基氨基锂；“LAH”指氢化锂铝；“Red-Al”指双(2-甲氧基乙氧基)氢化铝钠；“Ms”指CH3SO2-；“TASF”指二氟三甲基硅酸三(二乙氨基)锍；“Ts”指甲苯磺酰基；“TBAF”指四丁基氢化铵；“TPAP”指过钌酸四丙基铵；“DBU”指二氮杂双环十一烷；“DMAP”指对-二甲氨基吡啶；“LHMDS”指六甲基二硅氮化锂；“DMF”指二甲基甲酰胺；“AIBN”指叠氮-(双)-异丁腈；“10-DAB”指10-脱乙酰基浆果赤霉素Ⅲ；“FAR”指2-氯-1,1,2-三氟三乙胺；“mCPBA”指间氯过苯甲酸；“DDQ”指二氰基二氯醌；“巯基保护基”包括(但不限于)半硫缩醛如1-乙氧基乙基和甲氧基甲基半硫缩醛，硫酯或硫代碳酸酯；胺保护基”包括(但不限于)氨基甲酸酯，例如，2,2,2-三氯乙基氨基甲酸酯或四丁基氨基甲酸酯；“保护的羟基”指-OP，其中P是羟基保护基；及“羟基保护基”包括(但不限于)有2-10个碳原子的缩醛，有2-10个碳原子的缩酮，醚如甲基，叔丁基，苄基，对甲氧基苄基，对硝基苄基，烯丙基，三苯甲基，甲氧基甲基，甲氧基乙氧基甲基，乙氧基乙基，四氢吡喃基，四氢硫代吡喃基醚，以及三烷基甲硅烷基醚如三甲基甲硅烷基醚，三异丙基甲硅烷基醚，二甲基芳基甲硅烷基醚，三乙基甲硅烷基醚和叔丁基二甲基甲硅烷基醚；酯如苯甲酰基，乙酰基，苯基乙酰基，甲酰基，一-，二-和三卤代乙酰基如氯乙酰基，二氯乙酰基，三氯乙酰基，三氟乙酰基；碳酸酯包括(但不限于)有1-6个碳原子的烷基碳酸酯如甲基，乙基，正丙基，异丙基，正丁基，叔丁基，异丁基和正戊基酯；有1-6个碳原子并被一个或多个卤原子取代的烷基碳酸酯，如2,2,2-三氯乙氧基甲基和2,2,2-三氯乙基酯；有2-6个碳原子的烯基碳酸酯如乙烯基和烯丙基酯；有3-6个碳原子的环烷基碳酸酯如环丙基，环丁基，环戊基和环己基酯；在环上任意被一个或多个C1-6烷氧基或硝基取代的苯基或苄基碳酸酯。其它羟基，巯基和胺保护基可以在T.W.Greene的《有机合成中的保护基》，John Wiley and Sons,1981中查到。
本文所说的“烃”部分是只包括元素碳和氢的有机化合物或基团。这些部分包括烷基，链烯基，炔基和芳基部分。这些部分还包括被其它脂族或环烃基团取代的烷基，链烯基，炔基和芳基部分，例如，烷芳基，烯芳基和炔芳基。这些部分优选含有1-20个碳原子。
本文所述烷基优选在主链上含有1-6个碳原子并至多有20个碳原子的低级烷基。它们可以是直链或支链的，包括甲基，乙基，丙基，异丙基，丁基，己基等。它们可以被脂族或环烃基团取代或被本文定义的各种取代基杂取代。
本文所述链烯基优选在主链上含有2-6个碳原子并至多有20个碳原子的低级烯基。它们可以是直链或支链的，包括乙烯基，丙烯基，异丙烯基，丁烯基，异丁烯基，己烯基等。它们可以被脂族或环烃基团取代或被本文定义的各种取代基杂取代。
本文所述炔基优选在主链上含有2-6个碳原子并至多有20个碳原子的低级炔基。它们可以是直链或支链的，包括乙炔基，丙炔基，丁炔基，异丁炔基，己炔基等。它们可以被脂族或环烃基团取代或被本文定义的各种取代基杂取代。
本文所述芳基部分含有6-20个碳原子并包括苯基。它们可以是烃或被本文定义的各种取代基杂取代。苯基是更优选的芳基。
本文所述杂芳基部分是与芳族化合物或基团类似的并且总共含有5-20个原子，通常是5-6个环原子，并且至少有一个原子不是碳的杂环化合物或基团，例如，呋喃基，噻吩基，吡啶基等。杂芳基部分可以被烃，杂取代的烃或杂原子取代，其中取代基中的杂原子选自氮，氧，硅，磷，硼，硫和卤素。这些取代基包括低级烷氧基如甲氧基，乙氧基，丁氧基；卤素如氯或氟；醚；缩醛；缩酮；酯；杂芳基如呋喃基或噻吩基；烷氧基；羟基；保护的羟基；酰基；酰氧基；硝基；氨基和酰氨基。
本文所述杂取代的烃部分是指被至少一个非碳原子取代的烃部分，包括碳链原子被杂原子如氮，氧，硅，磷，硼，硫或卤原子取代的部分。这些取代基包括低级烷氧基如甲氧基，乙氧基，丁氧基；卤素如氯或氟；醚；缩醛；缩酮；酯；杂芳基如呋喃基或噻吩基；烷氧基；羟基；保护的羟基；酰基；酰氧基；硝基；氨基和酰氨基。
本文所述酰基部分包括烃，取代的烃或杂芳基部分。
本文所述烷氧基羰基氧基部分包括低级烃或取代的烃部分。
下列实施例用以说明本发明。
实施例
反应流程1
羟基酮2。在0℃氮气下30分钟时间内向搅拌的3,10-二醇1(3.49g,14.78mmol)的35mL DMF溶液中分3批加入固体重铬酸吡啶鎓(“PDC”)(7.209,19.15mmol)，然后将反应混合物温热至室温。6小时后将反应混合物倒入500mL H2O中，并三次用200mL 15％乙酸乙酯/己烷萃取。合并有机相并用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(10％EtOAc/己烷)，得到3.349(97％产率)所要羟基酮2，为白色固体。
2:mp:73-74℃；1H NNR(300MHz,CDCl3)δ(ppm)0.96(s,3H,Me16),1.06(s,3H,Me17),1.20(d,J=7.1Hz,3H,Me19),1.38(d,J=14.8Hz,1H,H2α),1.70(d,J=1.7Hz,3H,Me18),1.76(t,J=6.0Hz,1H,H1),2.00(br d,J=18.1Hz,1H,H14α),2.07(dd,J=19.2,7.7Hz,1H,H9β),2.45(br d,J=18.1Hz,1H,H14β),2.61(ddq,J=11.5,7.7,7.1Hz,1H,H8α),2.66(dd,J=14.8,6.0Hz,1H,H2β),2.72(dd,J=19.2,11.5Hz,1H9α),2.81(s,1H,OH3),5.43(m,1H,H13)；13C NMR(75MHz,CDCl3)δ(ppm)16.40,21.44,21.75,25.46,33.48,38.29,44.68,44.77,47.06,48.41,73.07,94.19,121.72,138.34,217.54；IR(CCl4)υ3520,3000,2960,2900,2820,1730,1440,1330,990,970cm-1；MS(CI)235(M++1,100),217(65).
三乙基甲硅烷基烯醇醚3。在-78℃氮气下沿烧瓶壁向搅拌的0.94MLDA的THF溶液(1.41mL,1.33mmol)中滴加羟基酮2(156mg,0.667mmol)在1.5mL THF中的溶液和0.23mL HMPA(1.33mmol)。0.5h后沿烧瓶壁以0.1mL/分钟的速率滴加0.1M TESCL的THF溶液(6.67mL,0.667mmol)。加完后搅拌反应混合物5分钟，然后迅速倒入剧烈搅拌的50mL饱和NaHCO3水溶液中。用50mL己烷萃取混合物三次，合并的有机相用20mL H2O洗涤，用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(10％EtOAc/己烷)，得到225mg三乙基甲硅烷基烯醇醚3(97％产率)，为无色油。
3:1H NMR(300MHz,CDCl3)δ(ppm)0.71(q,J=7.7Hz,6H,TES CH2)0.89(s,3H,Me16),0.98(t,J=7.7Hz,9H,TES CH3),1.06(d,J=7.1Hz,3H,Me19),1.13(s,3H,Me17),1.28(d,J=14.3Hz,1H,H2α),1.66(dd,J=6.0,5.5 Hz,1H,H1),1.76(dd,J=2.2,1.7Hz,3H,Me18),1.95(br d,J=18.7Hz,1H,H14α),2.33(ddd,J=14.3,6.0,2.2Hz,1H,H2β),2.42(br d,J=18.7Hz,1H,H14β),2.72(qd,J=7.7,2.1Hz,1H,H8α),3.08(s,1H,OH3),4.45(d,J=2.1Hz,1H,H9),5.50(m,1H,H13)；13C NMR(75MHz,CDCl3)δ(ppm)4.51,6.46,16.10,21.58,22.76,25.10,33.57,43.78,44.11,45.13,45.16,71.32,91.75,106.27,120.82,140.25,151.77；IR(CCl4)υ3510,3010,2960,2910,2880,2830,1630,1440,1330,1310,1230,1150,1040,1010,880,700cm-1；MS(CI)349(M++1,54),331(100).
三乙基甲硅烷氧基酮4。在0℃氮气下0.5小时内向搅拌的三乙基甲硅烷基烯醇醚3(5.335g,15.33mmol)的300mL己烷溶液中分4批加入6.427g NaHCO3(76.55mmol)和4.533g间氯过氧苯甲酸(67％纯度，17.60mmol)。2.5小时后用200mL己烷稀释反应混合物，然后倒入400mL 1∶1的饱和NaHCO3水溶液和饱和Na2S2O3水溶液的混合物中。分离有机相，水相用各100mL的己烷萃取两次。合并的有机相用100mL H2O洗涤，用无水Na2SO4干燥，并减压浓缩，得到5.7g黄色油。该物质用快速色谱纯化(5％EtOAc/己烷)，得到5.495g三乙基甲硅烷氧基酮4(98％产率)，为无色油。
4:1H NMR(300MHz,CDCl3)δ(ppm)0.65(q,J=7.7Hz,6H,TES CH2),0.90(s,3H,Me16),0.97(t,J=7.7Hz,9H,TES CH3),1.06(s,3H,Me17),1.11(d,J=7.7Hz,3H,Me19),1.39(d,J=14.8Hz,1H,H2α),1.76(d,J=1.7Hz,3H,Me18),1.76(dd,J=6.1,5.5Hz,1H,H1),2.17(br d,J=18.7Hz,1H,H14α),2.33(dq,J=9.3,7.7Hz,1H,H8α),2.46(br d,J=18.7Hz,1H,H14β),2.64(ddd,J=14.8,6.1,2.2Hz,1H,H2β),2.79(br s,1H,OH3),3.85(d,J=9.3Hz,1H,H9),5.54(m,H,H13)；13C NMR(75MHz,CDCl3)δ(ppm)4.90,6.48,13.98,21.47,21.94 26.94,33.42,44.33,44.49,46.79,48.59,70.51,83.33,90.04,121.71,138.66,214.42；IR(CCl4)υ3520,3000,2960,2920,2880,2830,1730,1450,1330,1220,1160,1105,980,960,920,700cm-1；MS(CI)365(M++1,34),347(100),335(42),233(35).
三乙基甲硅烷氧基二醇5。在0℃氮气下向搅拌的0.263g(6.932mmol)氢化铝锂的30mL乙醚悬浮液中加入2.527g(6.932mmol)三乙基甲硅烷氧基酮4的20mL乙醚溶液。将反应混合物温热至室温。在室温2h后重新将混合物冷却到0℃，用50mL乙醚稀释，然后滴加2.5mL H2O淬灭反应。在室温搅拌2h后用100mL乙酸乙酯稀释所得白色悬浮物，用无水Na2SO4干燥，并经0.5英寸硅藻土垫过滤。减压浓缩滤液，得到2.434g三乙基甲硅烷氧基二醇5(96％产率)，为白色固体，无需进一步纯化即可使用。
5:mp:62-63℃；1H NMR(300MHz,CDCl3)δ(ppm)0.62(q,J=7.7Hz,6H,TES CH2),0.97(t,J=7.7Hz,9H,TES CH3),1.08(s,3H,Me16),1.09(d,J=7.1Hz,3H,Me19),1.18(d,J=14.8Hz,H,H2α),1.20(s,3H,Me17),1.48(dd,J=6.6,6.1Hz,1H,H1),1.84(d,J=1.7Hz,3H,Me18),1.97(dq,J=8.8,7.1Hz,1H,H8α),2.17(br d,J=18.7Hz,1H,H14α),2.43(br d,J=18.7Hz,1H,H14β),2.47(ddd,J=14.8,6.1,2.2Hz,1H,H2β),2.74(br s,1H,OH3),4.01(dd,J=8.8,8.2Hz,1H,H9β),4.28(d,J=8.2Hz,1H,H10),5.55(m,1H,H13)；13C NMR(75MHz,CDCl3)δ(ppm)5.16,6.60,12.82,21.96,23.63,27.76,33.88,44.16,44.96,45.31,48.27,63.33,81.46,83.37,122.03,141.62；IR(CCl4)υ3640,3550,3020,2970,2920,2890,2850,1450,1330,1240,1160,1140,1120,1100,1080,1040,1000,970,960,860,840,710cm-1；MS(CI)367(M++1,21),349(100),337(22),319(42).
三乙基甲硅烷氧基酮二醇6。在0℃氮气下向剧烈搅拌的三乙基甲硅烷氧基二醇5(886mg,2.42mmol)的25mL CH2Cl2溶液中加入1.08mL(3.63mmol)Ti(Oi-Pr)4，接着滴加2M t-BuOOH的己烷溶液1.82ml(3.63mmol)。2h后加入2.5mL二甲基硫醚，并将反应混合物在42℃浴中加热回流12h。减压蒸发溶剂。室温下将剩余物溶解于200mLTHF，并在剧烈搅拌的同时滴加0.5mL H2O。2h后用无水Na2SO4干燥所得白色悬浮液，然后经0.5英寸硅藻土垫过滤，并用两份50mL乙酸乙酯稀释。减压浓缩滤液，得到黄色油。该油经快速色谱纯化(10％EtOAc/己烷)，得到866.7mg三乙基甲硅烷氧基酮二醇6(94％产率)，为白色固体。
6:mp 106-107℃；1H NMR(300MHz,CDCl3)δ(ppm)0.71(q,J=7.7Hz,6H,TES CH2),1.01(t,J=7.7Hz,9H,TES CH3),1.01(s,3H,Me17),1.07(d,J=7.1Hz,3H,Me19),1.53(s,3H,Me16),1.73(s,3H,Me18),1.80-1.94(m,3H,H1,H2β,H14α),2.02(d,J=3.3Hz,1H,OH10),2.22(dq,J=9.9,7.1Hz,1H,H8α),2.52(d,J=12.1Hz,1H,OH13),2.81(dd,J=11.5,3.3Hz,1H,H2α)2.83(m,1H,H14β),4.08(br t,J=11.5Hz,H,H13),4.16(dd,J=9.9,8.8Hz,1H,H9),4.56(dd,J=8.8,3.3Hz,1H,H10)；13C NMR(75MHz,CDCl3)δ(ppm)5.36,6.72,15.84,17.96,26.11,29.30 34.83,38.44,41.00,45.98,54.49,66.94,77.15,77.21,137.66,140.65,215.86；IR(CCl4)υ3650,3550,3460,2980,2900,2870,1670,1455,1410,1370,1280,1240,1210,1160,1090,1050,1030,1010,960,860,720cm-1；MS(EI)382(M+,2),353(10),335(5),307(4),250(4),215(67),75(100).
叔丁基二甲基甲硅烷氧基酮7。在0℃氮气下向搅拌的三乙基甲硅烷氧基酮二醇6(883mg,2.31mmol)的35mL吡啶溶液中滴加0.485mL(2.771mmol)TBSOTf，然后将溶液温热至室温。在室温2h后用100mL己烷稀释溶液，并将其倒入150mL饱和NaHCO3水溶液中。分离有机相，水相用两份100mL己烷萃取。合并有机相，先后用50mL 10％CuSO4水溶液和20mL水洗涤并用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(2.5％EtOAc/己烷)，得到1.122g叔丁基二甲基甲硅烷氧基酮7(98％产率)，为白色固体。
7:mp:128-130℃；1H NMR(300MHz,CDCl3)δ(ppm)0.04(s,3H,TBS CH3),0.06(s,3H,TBS CH3),0.63q,J=7.7Hz,6H,TES CH2),0.93(s,9H,TBS t-Bu),1.01(t,J=7.7Hz,9H,TES CH3),1.06(d,J=7.1Hz,3H,Me19),1.09(s,3H,Me17),1.56(s,3H,Me16),1.66(d,J=1.1Hz,3H,Me18),1.82(m,1H,H1),1.85(m,1H,H2β),1.90(d,J=3.3Hz,1H,OH10),1.93(dd,J=14.3,5.5Hz,1H,H14α),2.16(dq,J=10.4,7.1Hz,1H,H8α),2.49(ddd,J=14.3,7.8,2.2Hz,1H,H14β),2.72(dd,J=12.1,2.7Hz,1H,H2α),4.19(dd,J=10.4,8.8Hz,1H,H9),4.46(ddd,J=7.8,5.5,1.1,1H,H13),4.58(dd,J=8.8,3.3Hz,1H,H10)；13C NMR(75MHz,CDCl3)δ(ppm)-5.48,-4.54,5.33,6.68,15.30,16.42,17.77,25.65,27.15,27.38,33.93 38.94,41.26,45.83,53.87,67.27,77.23,77.61,135.08,142.06,209.77；IR(CCl4)υ3530,2950,2930,2870,1670,1460,1250,1090,1030,1010,970,910,870,830,770,740cm-1；MS(CI)497(M++1,16),479(100),365(28),346(35),307(22),205(91).
三甲基甲硅烷基二醇醚8。在室温氮气下向搅拌的叔丁基二甲基甲硅烷氧基酮7(287mg，0.55mmol)的2.5mL THF溶液和0.3mL HMPA(3.3mmol)中滴加0.44M LDA的THF溶液(3.8mL,1.65mmol)。在室温搅拌10分钟后以0.1mL/分钟的速率滴加1.0M TMSCl(1.7mL,1.65mmol)的THF溶液。加完后搅拌反应物2分钟，然后加入2.5mL三乙胺。将反应混合物倒入150mL饱和NaHCO3水溶液。水相用三份50mL己烷萃取。合并的有机相用50mL H2O洗涤，无水Na2SO4干燥，并减压浓缩，得到370mg三甲基甲硅烷基烯醇醚8(99％产率)，为无色油。该物质无需进一步纯化即可用于下步反应。
8:1H NMR(500MHz,CDCl3)δ(ppm)0.08(s,3H,TBS CH3),0.11(s,3H,TBS CH3),0.14(s,9H,TMS CH3),0.16(s,9H,enol TMS CH3),0.63(q,J=7.5Hz,6H,TESCH2),0.81(d,J=7.0Hz,3H,Me19),0.92(s,9H,TBSt-Bu),0.98(t,J=7.5Hz,9H,TES CH3),1.09(s,3H,Me17),1.23(ddd,J=14.0,10.5,5.5Hz,1H,H14α),1.24(s,3H,Me16),1.81(d,J=1.5Hz,3H,Me18),1.96(ddd,J=10.5,8.5,5.5Hz,1H,H1),2.30(dq,J=7.0,7.0Hz,1H,H8α),2.5(ddd,J=14.0,10.5,7.5Hz,1H,H14β),3.77(dd,J=7.0,6.4Hz,1H,H9),4.63(d,J=6.4Hz,1H,H10),4.67(ddd,J=10.5,7.5,1.5Hz,1H,H13),4.95(d,J=8.5Hz,1H,H2)；13C NMR(75MHz,CDCl3)δ(ppm)-5.27,-4.71,1.06,0.53,4.96,6.86,12.94,15.72,18.11,25.77,28.76,32.02,37.54,40.70,41.79,41.90,69.53,78.61,80.96,112.22,139.48,139.87,155.26；IR(CHCl3)υ2960,2880,2870,1680,1630,1460,1250,1130,1080,1000,900,880,830cm-1；MS(CI)641(M++1,9),551(65),508(100),379(80).
羟基酮9。在0℃氮气下向搅拌的321mg(0.501mmol)三甲基甲硅烷基烯醇醚8的15mL THF溶液中分三批加入216mg(80％纯度，1.00mmol)间氯过氧苯甲酸固体。3h后用50mL己烷稀释反应混合物，并将其倒入200mL 1∶1的饱和NaHCO3水溶液和饱和Na2S2O3水溶液的混合物中。分离有机相，水相用三份100mL己烷萃取。合并的有机相用100mL H2O洗涤，无水Na2SO4干燥，并减压浓缩，得到332mg相应的三甲基甲硅烷氧基环氧化物，为白色固体。该物质无需进一步纯化即可用于下步反应。
将332mg上述三甲基甲硅烷氧基环氧化物(约0.501mmol)在5mL甲醇和0.5mL CHCl3中的溶液在室温搅拌24h。除去溶剂后用快速色谱纯化(5％EtOAc/己烷)，得到266mg羟基酮9，为白色固体(从三甲基甲硅烷基烯醇醚8算起产率为91％)。
9:mp:111-112℃；1H NMR(300MHz,CDCl3)δ(ppm)0.04(s,3H,TBS CH3),0.07(s,3H,TBS CH3),0.18(s,9H,TMS CH3),0.62(q,J=7.7Hz,6H,TES CH2),0.93(s,9H,TBS t-Bu),0.97(t,J=7.7Hz,9H,TES CH3),1.06(d,J=7.1Hz,3H,Me19),1.08(s,3H,Me17),1.35(s,3H,Me16),1.65(s,3H,Me18),1.81(dd,J=14.8,4.4Hz,1H,H14α),1.95(dd,J=7.7,3.8Hz,1H,H1),2.26(ddd,J=14.8,10.4,7.7Hz,1H,H14),2.30(dq,J=0.4,7.1Hz,1H,H8α),3.30(d,J=8.3Hz,1H,OH2),4.22(dd,J=10.4,8.8Hz,1H,H9),4.35(br dd,J=10.4,4.4Hz,1H,H13),4.41(dd,J=8.3,3.8Hz,H,H2),4.54(d,J=8.8Hz,1H,H10)；13C NMR(75MHz,CDCl3)δ(ppm)-5.44,-4.52,0.95,4.85,6.8,15.46,17.62,17.83,25.65,26.22,28.21,28.39,36.69,52.19,54.33,66.94,71.25,75.74,77.43,137.10,140.25,211.59；IR(CCl4)υ3530,2960,2890,2870,1680,1460,1240,1160,1120,1080,1060,1020,1000,990,880,830cm-1；MS(CI)585(M++1,34),584(69),567(13),453(100),363(30),323(52).
三醇10。在-78℃氮气下向4-溴-4-戊烯-1-醇(770.0mg,4.7mmol)的20mL Et2O溶液中加入1.7M t-BuLi(8mL,13.6mmol)的己烷溶液，然后将该溶液在0℃搅拌2h。冷却到-10℃后加入羟基酮9(370mg,0.63mmol)的5mL Et2O溶液。在-10℃搅拌0.5h后将溶液倒入150mL NaHCO3饱和水溶液中。用EtOAc萃取水相(100mL，三次)。合并的有机相用无水Na2SO4干燥，并减压除去溶剂。剩余物用快速色谱纯化(20％EtOAc/己烷)，得到400mg(95％产率)所要三醇10，为无色油。
10:1H NMR(500MHz,CDCl3):δ(ppm)0.136(s,12H,TMS CH3,TBS CH3),0.159(s,3H,TBS CH3),0.669(qd,J=8.0,1.5Hz,6H,TES CH2),0.770(d,J=7.0Hz,3H,Me19),0.921(s,9H,TBS t-Bu),0.991(t,J=8.0Hz,9H,TES CH3),1.038(s,3H,Me17),1.488(s,3H,Me16),1.702(t,J=6.0Hz,1H,OH7),1.729(s,3H,Me18),1.779-1.830(m,3H,2xH6,H8),1.869(dd,J=9.0,2.8Hz,1H,H1),2.101(m,2H,2xH5),2.134(d,J=16.0Hz,1H,H14α),2.545(dt,J=16.0,9.0Hz,1H,H14β),2.905(br,1H,OH2),3.473(s,1H,OH3),3.670-3.726(m,2H,2xH7),4.060(m,1HH2),4.070(dd,J=8.0,6.5Hz,1H,H9β),4.250(d,J=8.0Hz,1H,H10α),4.322(d,J=9.0Hz,1H,H13β),4.968(s,1H,1xH20),5.190(s,1H,1xH20)；13C NMR(75MHz,CDCl3):δ(ppm)-5.19,-4.57,0.89,5.05,6.83,13.10,17.74,19.33,25.54,26.18,28.64,29.94,30.97,34.40,35.78,45.27,51.44,62.31,68.88,73.80,73.87,83.83,109.95,135.03,142.32；IR(CHCl3):υ2950,2870,1090,1060,980,890cm-1 MS(CI):653(M++1-H2O),539,521,503,449,431,407,390,316,294,244.
碳酸酯11。在-78℃氮气下向三醇10(405mg,0.60mmol)的20mLCH2Cl2溶液中加入4.7mL(60.0mmol)吡啶，接着加入COCl2(6.0mL,6.0mmol)的甲苯溶液。将混合物温热至0℃并在此温度搅拌50分钟。用100mL EtOAc稀释混合物，倒入200mL NaHCO3饱和水溶液中。分离有机相，用EtOAc萃取水相(100mL，三次)。合并有机相并用无水Na2SO4干燥，除去溶剂后得到所要碳酸酯11，为淡黄色油，无需进一步纯化即可使用。
11:1H NMR(500MHz,CDCl3):δ(ppm)0.085(s,3H,TBS CH3),0.100(s,12H,TBS CH3,TMS CH3),0.652(qd,J=7.5,1.5Hz,6H,TES CH2),0.912(s,9H,TBS t-Bu),0.950(d,J=6.0Hz,3H,Me19),0.984(t,J=7.5Hz,9H,TES CH3),1.199(s,3H,Me17),1.434(ddd,J=18.5,9.0,4.5Hz,1H,H14α),1.481(s,3H,Me16),1.637(m,1H,1xH6),1.722(m,1H,1xH6),1.786(d,J=1.0Hz,3H,Me18),2.192-2.349(m,4H,2xH5,H1,H14β),2.396(qd,J=6.0,5.0Hz,1H,H8),3.658(qd,J=6.5,3.0Hz,2H,2xH47),3.982(dd,J=8.0,5.0Hz,1H,H9β),4.509(d,J=8.0Hz,1H,H10α),4.771(td,J=9.0,1.0Hz,1H,H13β),4.858(d,J=4.0Hz,1H,H2),5.275(s,2H2xH20).
乙酸酯12。在室温氮气下向上述碳酸酯11的5mL吡啶溶液中加入Ac2O(0.6mL,6.3mmol)。在室温搅拌9h后用100mL 20％EtOAc/己烷稀释该溶液，并倒入100mL饱和NaHCO3水溶液中。分离有机相，水相用20％EtOAc/己烷萃取(100mL，三次)。合并有机相并用无水Na2SO4干燥，除去溶剂后用快速色谱纯化(8％EtOAc/己烷)，得到433.2mg(98％产率)所要乙酸酯12，为无色油。
12:1H NMR(500MHz,CDCl3):δ(ppm)0.085(s,3H,TBS CH3),0.097(s,12H,TMS CH3,TBS CH3),0.654(qd,J=8.0,2.0Hz,6H,TES CH2),0.913(s,9H,TBS t-Bu),0.935(d,J=7.5Hz,3H,Me19),0.985(t,J=8.0Hz,9H,TES CH3),1.201(s,3H,Me17),1.429(m,1H,H14α),1.480(s,3H,Me16),1.711(m,1H,1xH6),1.788(s,3H,Me18),1.820(m,1H,1xH6),2.041(s,3H,COCH3),2.153-2.351(m,4H,H1,2xH5,H14β),2.403(dq,J=8.0,7.5Hz,1H,H8),3.977(dd,J=8.0,5.5Hz,1H,H9β),4.075(t,J=6.5Hz,2H,2xH7),4.510(d,J=8.0Hz,1H,H10α),4.771(t,J=8.0Hz,1H,H131β),4.835(d,J=4.0Hz,1H,H2β),5.253(s,1H,1xH20),5.286(s,1H,1xH20)；13C NMR(75MHz,CDCl3):δ(ppm)-5.37,-4.74,0.79,4.98,6.74,12.93,15.61,17.92,20.53,25.63,27.36,28.27,29.77,32.34,32.98,36.48,39.11,48.96,63.55,68.84,73.02,79.66,88.61,92.86,114.68,137.48,141.39,150.56,154.08,171.14；IR(CHCl3):υ2950,2850,1790,1713,1020,880,815cm-1；MS(CI):739(M++1),691,665,607,563,503,473,431.
羟基烯烃13。在0℃向乙酸酯12(433.0mg,0.586mmol)的2mLCH3CN溶液中加入5.0mL 48％HF/吡啶/CH3CN(1∶8∶8)溶液。在0℃搅拌3h后用50mL EtOAc稀释该溶液，然后倒入100mL NaHCO3饱和水溶液中。分离有机相，用EtOAc萃取水相(100mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后得到淡黄色油，无需进一步纯化即可使用。
在室温氮气下向上述油的4mL CH2Cl2溶液中先后加入Et3N(0.32mL,2.3mmol)和TESCl(0.20mL,1.2mmol)。在室温搅拌1.5h后用100mL 20％EtOAc/己烷稀释该溶液，然后倒入100mL NaHCO3饱和水溶液中。分离有机相，用20％EtOAc/己烷萃取水相(100mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(15％EtOAc/己烷)，得到351.0mg所要羟基烯烃13(90％产率)，为淡黄色油，以及2.3％起始原料12和1.1％9,10-二醇。
13:1H NMR(500MHz,CDCl3):δ(ppm)0.090(s,3H,TBS CH3),0.104(s,3H,TBS CH3),0.662(qd,J=8.0,1.5Hz,6H,TES CH2),0.915(s,9H,TBS t-Bu)0.965(d,J=7.5Hz,3H,Me19),0.989(t,J=8.0Hz,9H,TES CH3),1.197(s,3H,Me17),1.486(s,3H,Me16),1.434(dd,J=9.54.7Hz,1H,H14α),1.780(m,1H,1xH6),1.810(d,J=1.5Hz,3H,Me18),1.942(m,1H,1xH6),2.045(s,3H,COCH3),2.191(m,1H,1xH5),2.208(d,J=2.5Hz,1H,OH9),2.262-2.333(m,3H,1xH5,H1,H8),2.360(m,1H,H14β),3.986(m,1H,H9β),4.112(td,J=6.5,2.5Hz,2H,2xH7),4.512(d,J=8.5Hz,1H,H10α),4.760-4.791(m,2H,H13β,H2),5.201(s,1H,1xH20),5.320(s,1H,1xH20)；13C NMR(75MHz,CDCl3):δ(ppm)-5.41,-4.72,4.64,5.49,11.23,15.89,17.88,20,52,25.60,27.13,27.44,28.09,32.49,33.16,36.72,36.83,49.11,63.52,68.78,70.99,79.13,86.15,92.71,114.00,136.37,141.98,147.57,154.21,171.20；IR(CHCl3):υ2960,2780,1795,1735,1000,865cm-1；MS(CI):667(M++1),649,523,605,587,535,473.
酮14。在室温氮气下向羟基烯烃13(343.0mg,0.515mmol)和200mg3埃分子筛在5mL CH2Cl2中的混合物中先后加入4-甲基-吗啉(180mg,1.54mmol)和四丙基过钌酸铵(18mg,0.05mmol)。在室温搅拌2h后混合物经硅胶短柱过滤。用200mL 15％EtOAc/己烷洗涤硅胶。除去溶剂后得到338.5mg所要酮14(99％产率)，为无色油，无需进一步纯化即可使用。
14:1H NMR(500MHz,CDCl3):δ(ppm)0.116(s,3H,TBS CH3),0.132(s,3H,TBS CH3),0.635(qd,J=7.5,4.0Hz,6H,TES CH2),0.936(s,9H,TBS t-Bu),0.961(t,J=7.5Hz,9H,TES CH3),1.051(d,J=7.0Hz,3H,Me19),1.203(s,3H,Me17),1.232(s,3H,Me16),1.534(m,1H,H14α),1.807(m,1H,1xH6),1.885-1.981(m,2H,1xH5,1xH46),1.942(d,J=1.5Hz,3H,He18),2.059(s,3H,COCH3),2.242(ddd,J=15.5,10.5,4.0Hz,1H,1xH5),2.333-2.418(m,2H,H14β,H1),3.523(q,J=7.0Hz,1H,H8),4.103(t,J=6.0Hz,2H,2xH7),4.773(d,J=4.5Hz,1H,H2β),4.868(m,1H,H13β),4.935(s,1H,H10α),5.282(s,1H,1xH20),5.320(s,H,1xH20)；13C NMR(75MHz,CDCl3):δ(ppm)-5.44,-4.78,4.60,6.34,15.11,15.54,17.91,20.53,25.60,25.68,27.01,28.00,32.35,32.8836.69,42.40,47.82,63.46,68.70,79.56,85.00,90.58,115.91,134.62,143.46,145.91,153.47,171.15,209.74；IR(CHCl3):υ2960,2880,1800,1750,1000,865cm-1；MS(CI):665(M++1),648,637,621,533,489.
羟基酮15。在室温氮气下向0.1M Pd(acac)2/n-Bu3P(1∶1)的DMF(1mL,0.1mmol)溶液中先后加入2.37M HCOOH/Et3N(1∶1)的DMF(10.2mL,24.2mmol)溶液和酮14(320.0mg,0.48mmol)的5mL DMF溶液。在室温搅拌19h后用100mL Et2O稀释该溶液，然后倒入100mLNaHCO3饱和水溶液中。分离有机相，水相用Et2O萃取(100mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(15％EtOAc/己烷)，得到280.5mg(94％产率)所要羟基酮15，为无色油。
15:1H NMR(500MHz,CDCl3):δ(ppm)0.138(s,3H,TBS CH3),0.149(s,3H,TBS CH3),0.628(qd,J=7.5,3.0Hz,6H,TES CH2),0.892(d,J=7.0Hz,3H,Me19),0.953(s,9H,TBS t-Bu),0.962(t,J=7.5Hz,9H,TES CH3),1.104(s,3H,Me17),1.201(s,3H,Me16),1.409(ddd,J=14.5,4.5,4.0Hz,1H,H14α),1.464(q,J=6.0Hz,1H,1xH5),1.783(br,1H,OH2),1.805-1.863(m,2H,2xH6),1.910(d,J=1.0Hz,3H,Me18),2.054(m,1H,H1),2.063(s,3H,COCH3),2.367-2.473(m,3H,E14β,1xH5,H3),3.024(dq,J=9.0,7.0Hz,1H,H8),3.880(ddd,J=9.5,2.5,2.0Hz,1H,H2β),4.102(m,1H,1xH7),4.154(m,1H,1xH17),4.790(ddd,J=9.0,4.5,1.0Hz,1H,H13β),4.899(s,1H,H10α),5.012(s,1H,1xH20),5.097(s,1H,1xH20).
羟基酮16。在室温氮气下向羟基酮15(450.0mg,0.72mmol)的15mLCH2Cl2溶液中先后加入二异丙基乙胺(1.25mL,7.2mmol)和四丁基碘化铵(265.0mg,0.72mmol)和苄氧基甲基氯(0.5mL,3.6mmol)。在室温搅拌24h后再先后加入1.25mL(7.2mmol)二异丙基乙胺和0.5mL(3.6mmol)苄氧基甲基氯。将溶液在室温再搅拌24h，然后在40℃加热2h。重新冷却到室温后用50mL THF和5mL MeOH稀释，然后加入0.1N NaOH水溶液(10mL,1.0mmol)。在室温搅拌1.5h后用100mL 20％EtOAc/己烷稀释该溶液，然后倒入50mL NaHCO3饱和水溶液中。分离有机相，用20％EtOAc/己烷萃取水相(100mL，三次)。合并有机相，用50mL饱和NH4Cl水溶液和50mL NaHCO3饱和水溶液洗涤，然后用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(20％EtOAc/己烷)，得到430.0mg(85％产率)所要羟基酮16，为无色油。
16:1H NMR(500MHz,CDCl3):δ(ppm)0.140(s,3H,TBS CH3),0.150(s,3H,TBS CH3),0.636(qd,J=8.0,4.0Hz,6H,TES CH2),0.939(d,J=7.0Hz,3H,Me19),0.949(t,J=8.0Hz,9H,TES CH3),0.967(s,9H,TBS t-Bu),1.078(s,3H,Me17),1.202(s,3H,Me16),1.450(ddd,J=15.0,8.5,5.0Hz,1H,H14α),1.661(t,J=6.0Hz,1H,OH20),1.695-1.821(m,2H,2xH6),1.910(d,J=1.0Hz,3H,Me18),2.055(m,1H,1xH5),2.174(m,1H,H1),2.258(m,1H,1xH5),2.317(m,1H,H14β),2.473(dd,J=10.0,7.0Hz,1H,H3),3.100(dq,J=7.0,7.0Hz,1H,H8α),3.615-3.693(m,2H,2xH7),3.967(dd,J=10.0,3.0Hz,1H,H2β)4.548(d,J=12.0Hz,H,1HxBOM),4.596(d,J=12.0Hz,1H,1HxBOM),4.601(d,J=7.0Hz,1H,1HxBOM),4.710(d,J=7.0Hz,1H,1HxBOM),4.836(br td,J=8.5,1.0Hz,1H,H13β),4.868(s,1H,H10α),5.009(br s,1H,1xH20),5.014(brs,1H,1xH20),7.277-7.346(m,5H,5HxBOM)；13C NMR(75MHz,CDCl3):δ(ppm)-5.34,-4.69,4.61,6.48,15.57,17.88,18.03,25.74,26.01,30.05,32.40,32.73,36.60,37.27,47.32,53.74,62.22,69.32,69.69,79.84,82.51,94.65,113.60,127.57,127.70,128.52,135.67,138.25,141.04,148.02,215.16.
酮醛17。在室温氮气下向羟基酮16(130.0mg,0.186mmol)和150mg3埃分子筛在5mL CH2Cl2中的混合物中先后加入4-甲基-吗啉(65.0mg,0.55mmol)和四丙基过钌酸铵(7.0mg,0.02mmol)。在室温搅拌2分钟后混合物经硅胶短柱过滤。用50mL 10％EtOAc/己烷洗涤硅胶。除去溶剂后得到116.8mg(90％产率)所要酮醛17，为无色油，无需进一步纯化即可使用。
17.1H NMR(300MHz,CDCl3):δ(ppm)0.128(s,3H,TBS CH3),0.139(s,3H,TBS CH3),0.615(qd,J=8.1,2.1Hz,6H,TES CH2),0.919(d,J=6.6Hz,3H,Me19),0.948(t,J=8.1Hz,9H,TES CH3),0.952(s,9H,TBS t-Bu),1.058(s,3H,Me17),1.197(s,3H,Me16),1.413(m,1H,H14α),1.900(br s,3H,Me18),2.159(m,1H),2.239-2.387(m,2H),2.422-2.700(m,4H),3.094(qd,J=6.6,6.6Hz,1H,H8),3.954(dd,J=9.6,2.7Hz,1H,H2),4.513(d,J=12.0Hz,1H,1HxBOM),4.574(d,J=7.2Hz,1H,1HxBOM),4.595(d,J=12.0Hz,1H,1HxBOM),4.704(d,J=7.2Hz,1H,1HxBOM),4.821(br t,J=8.4Hz,1H,H13),4.848(s,1H,H10),4.905(br s,1H,1xH20),5.029(br s,1H,1xH20),7.278-7.360(m,5HxBOM),9.724(t,J=1.5Hz,1H,CHO).
烯烃18。在室温氮气下向0.08M BaO的MeOH(10.0mL)溶液中加入酮醛17(116.8mg,0.167mmol)。在室温搅拌9h后将溶液减压浓缩。加入30mL EtOAc和20mL饱和NaHCO3水溶液。分离有机相，水相用EtOAc萃取(30mL,5次)。合并有机相并用Na2SO4干燥。除去溶剂后得到110.0mg(94％产率)粗产物，为淡黄色油，无需进一步纯化即可使用。
在0℃氮气下向上述粗产物(110.0mg,0.158mmol)的2mL吡啶溶液中加入TESOTf(0.11mL,0.47mmol)。在0℃搅拌1h后用30mL 10％EtOAc/己烷稀释该溶液，然后倒入30mL饱和NaHCO3水溶液中。分离有机相，用10％EtOAc/己烷萃取水相(30mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(2％EtOAc/己烷)，得到100.0mg(从羟基酮16算起总产率为78％)所要烯烃18，为无色油。
18:1H NMR(500MHz,CDCl3):δ(ppm)0.099(s,3H,TBS CH3),0.131(s,3H,TBS CH3),0.565(q,J=8.0Hz,6H,TES CH2),0.635(qd,J=8.0,2.5Hz,6H,TES CH2),0.925(s,9H,TBS t-Bu),0.943(t,J=8.0Hz,9H,TES CH3),0.960(s,3H,Me17),0.995(t,J=8.0Hz,9H,TES CH3),1.136(s,3H,Me19),1.155(s,3H,Me16),1.561(m,1H,H6β),1.637(dd,J=15.0,5.5Hz,1H,H14α),1.794(br d,J=9.0Hz,1H,H1),1.915(m,1H,H6α),2.043(d,J=1.5Hz,3H,Me18),2.106-2.162(m,2H,2xH5),2.500(dt,J=15.0,9.0Hz,1H,H14β),3.244(br d,J=4.0Hz,H,H3),3.785(br dd,J=4.0,1.0Hz,1H,H2β),4.173(dd,J=11.0,4.5Hz,1H,H7α),4.565(m,1H,H13),4.579(s,2H,2HxBOM),4.680(d,J=7.0Hz,1H,1HxBOM),4.703(d,J=7.0Hz,1H,1HxBOM),4.929(br s,1H,1xH20),5.363(s,1H,H10α),5.489(t,J=2.0Hz,1H,1xH20),7.270-7.343(m,5H,5HxBOM)；13C NMR(75MHz,CDCl3):δ(ppm)-5.33,-4.54,4.89,5.92,6.62,6.71,11.5 3,17.27,17.78,24.95,25.65,31.09,32.40,32.79,37.63,37.83,47.44,49.34,62.19,68.53,70.05,75.00,76.36,78.90,93.74,113.68,127.73,127.90,12 8.54,136.72,137.17,138.11,143.93,209.62.
烯丙醇19。在室温氮气下向烯烃18(80.0mg,0.0985mmol)的5mLCH2Cl2溶液中先后加入1.0mL t-BuOOH(90％纯度，9.8mmol)和SeO2(109.0mg,0.985mmol)。在室温搅拌10h后用50mL 20％EtOAc/己烷稀释该溶液，然后倒入20mL饱和NaHCO3水溶液中。分离有机相，水相用20％EtOAc/己烷萃取(20mL，三次)。合并有机相，用10mL水洗涤，然后用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(3％EtOAc/己烷)，得到75.0mg(92％产率)所要烯丙醇19，为无色油。
19:1H NMR(500MHz,CDCl3):δ(ppm)0.135(s,3H,TBS CH3),0.162(s,3H,TBS CH3),0.571(q,J=8.0Hz,6H,TES CH2),0.640(qd,J=8.0,1.5Hz,6H,TES CH2),0.927(s,3H,Me17),0.943(s,9H,TBS t-Bu),0.959(t,J=8.0Hz,9H,TES CH3)0.995(t,J=8.0Hz,9H,TES CH3),1.109(s,3H,Me19),1.163(s,3H,Me16),1.564-1.632(m,2H,H6β,H14α),1.792(br d,J=8.5Hz,1H,H1),2.108(br,1H,OH5),2.123(d,J=1.0Hz,3H,Me18),2.155(m,1H,H6α),2.550(dt,J=15.0,8.5Hz,1H,H14β),3.785(brd,J=2.0Hz,1H,H2β),3.931(br t,J=2.0Hz,1H,H3),4.180(t,J=3.0Hz,1H,H5β),4.570(s,2H,2HxBOM),4.597(dd,J=11.5,4.5Hz,1H,H7α),4.613(br t,J=8.5Hz,1H,H13β),4.675(d,J=7.0Hz1H,1HxBOM),4.697(d,J=7.1Hz,1H,1HxBOM),5.166(t,J=2.0Hz,1H,1xH20),5.414(s,1H,H10α),5.742(t,J=2.0Hz,1H,1xH20),7.268-7.347(m,5H,5HxBOM).
二醇甲磺酸酯20。在0℃氮气下向烯丙醇19(14.0mg,0.017mmol)的0.7mL吡啶溶液中加入MsCl(0.05mL,0.645mmol)。将溶液在0℃搅拌2h后，先后加入1.5mL Et2O和0.22mL(0.034mmol)0.157M OsO4的THF溶液。将混合物保持在-20℃12h，然后用5mL THF稀释。接着先后加入30mg NaHCO3和0.5mL H2O。在室温搅拌8h后用50mLEtOAc稀释该溶液，然后倒入50mL饱和NaHCO3水溶液中。分离有机相，水相用EtOAc萃取(20mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后得到15mg所要二醇甲磺酸酯20，为淡黄色油，无需进一步纯化即可使用。
20:1H NMR(500MHz,CDCl3):δ(ppm)0.122(s,3H,TBS CH3),0.173(s,3H,TBS CH3),0.558(q,J=8.0Hz,6H,TES CH2),0.640(qd,J=8.0,5.0Hz,6H,TES CH2),0.949(t,J=8.0Hz,9H,TES CH3),0.964(s,9H,TBS t-Bu),0.978(t,J=8.0Hz,9H,TES CH3),1.070(s,3H,Me16),1.085(s,3H,Me17),1.174(s,3H,Me19),1.935(m,1H,H6β),1.977-2.037(m,2H,H14α,H1)2.123(d,J=1.0Hz,3H,Me18),2.244(dt,J=15.0,4.5Hz,1H,H6α),2.316(dt,J=14.0,9.0Hz,1H,H14β),2.381(dd,J=10.5,1.5Hz,1H,OH20),3.147(s,3H,SO2CH3),3.575(d,J=6.5Hz,1H,H3),3.607(t,J=10.5Hz,1H,1xH20),3.940(dd,J=10.5,1.5Hz,1H,1xH20),3.990(dd,J=6.5,2.5Hz,1H,H2β),4.133(s,1H,OH4),4.228(dd,J=11.5,4.5Hz,1H,H7α),4.613(s,2H,2HxBOM),4.766(d,J=7.0Hz,1H,1HxBOM),4.825(m,1H,H13β),4.839(d,J=7.0Hz,1H,1HxBOM),4.895(m,1H,H5β),5.276(s,1H,H10α),7.298-7.357(m,5H,5HxBOM).
氧杂环丁烷21。在室温氮气下向上述二醇甲磺酸酯20的1.0mL甲苯溶液中加入DBU(0.06mL,0.04mmol)，然后将溶液加热到120℃(油浴温度)15分钟，并保持在120℃15分钟。除去溶剂后用快速色谱纯化(15％EtOAc/己烷)，得到12.5mg氧杂环丁烷21(从烯丙醇19算起总产率为87％)为无色油。
21:1H NMR(500MHz,CDCl3):δ(ppm)0.143(s,3H,TBS CH3),0.154(s,3H,TBS CH3),0.580(q,J=8.0Hz,6H,TES CH2),0.635(qd,J=8.0,2.5Hz,6H,TES CH2),0.952(t,J=8.0Hz,9H,TES CH3),0.971(s,3H,TBS t-Bu),0.977(s,3H,Me17),0.992(t,J=8.0Hz,9H,TES CH3),1.116(s,3H,Me16),1.532(s,3H,Me19),1.944(m,1H,H1),1.945(d,J=1.5Hz,3H,Me18),2.000(m,1H,H14α),2.030(m,1H,H6β),2.407(dt,J=15.5,9.5Hz,1H,H14β),2.465(m,1H,H6α),2.990(s,1H,OH4),3.050(d,J=5.5Hz,1H,H3),3.888(dd,J=5.5,2.5Hz,1H,H2β),4.042(dd,J=11.5,6.5Hz,1H,H7α),4.358(d,J=8.0Hz,1H,H20α),4.513(d,J=12.0Hz,1H,1HxBOM),4.555(ddd,J=9.5,4.5,1.5Hz,1H,H13β),4.608(d,J=12.0Hz,1H,1HxBOM),4.640(d,J=8.0Hz,1H,H20β),4.645(d,J=6.5Hz,1H,1HxBOM),4.713(d,J=6.5Hz,1H,1HxBOM),4.730(dd,J=10.0,4.0Hz,1H,H5α),5.153(s,1H,H10α),7.270-7.355(m,5H,5HxBOM)；13C NMR(75MHz,CDCl3):δ(ppm)-5.21,-4.39,4.99,5.77,6.60,6.68,10.32,16.28,17.98,24.45,25.84,30.73,31.31,37.53,37.68,45.36,50.59,58.88,68.15,70.28,73.33,74.74,76.30,78.73,81.39,86.61,94.82,127.69,128.01,128.69,136.43,137.67,137.83,207.89.
二醇22。室温下向氮杂环丁烷21(60.0mg,0.071mmol)的0.1mLCH3CN溶液中加入1.0mL 48％HF/吡啶/CH3CN(1∶3.5∶3.5)溶液。在室温搅拌24h后用50mL EtOAc稀释该溶液，然后倒入20mL饱和NaHCO3水溶液中。分离有机相，水相用EtOAc萃取(20mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后得到四醇，为淡黄色油，无需进一步纯化即可使用。
在室温向上述油的1mL吡啶溶液中加入TESCl(0.06mL,0.355mmol)。在室温搅拌21h后用10mL EtOAc稀释该溶液，然后倒入20mL饱和NaHCO3水溶液中。分离有机相，水相用EtOAc萃取(20mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(5％EtOAc/己烷)，得到所要的二醇22(48.Omg，总产率93％)，为无色油。
22:1H NMR(500MHz,CDCl3):δ(ppm)0.538(qd,J=8.0,1.0Hz,6H,TES CH2),0.707(q,J=8.0Hz,6H,TESCH2),0.919(t,J=8.0Hz,9H,TES CH3),1.001(s,3H,Me17),1.011(s,3H,Me16),1.026(t,J=8.0Hz,9H,TESCH3),1.605(s,3H,Me19),1.964-2.037(m,3H,H1,H14α,H6β),2.019(d,J=1.5Hz,3H,Me18),2.392(m,1H,H6α),2.452(m,1H,H14β),3.090(d,J=6.0Hz,1H,H3),3.150(s,1H,OH4),3.873(dd,J=6.0,3.0Hz,1H,H2),3.988(dd,J=11.5,7.5Hz,1H,H7α),4.140(d,J=3.0Hz,1H,OH10),4.396(d,J=7.5Hz,1H,H20α),4.527(d,J=11.5Hz,1H,1HxBOM),4.599(br m,1H,H13),46.621(d,J=11.5Hz,1H,1HxBOM),4.626(d,J=7.5Hz,1H,H20β),4.656(d,J=6.5Hz,1H,1HxBOM),4.729(d,J=6.5Hz,H,1HxBOM),4.787(dd,J=9.5,4.0Hz,1H,H5α),5.106(d,J=3.0Hz,1H,H10),7.284-7.363(m,5H,5HxBOM)；13C NMR(75MHz,CDCl3):δ(ppm)4.672,4.945,6.433,6.645,9.878,16.509,23.976,29.500,30.775,31.791,37.406,45.222,50.655,58.288,68.259,70.292,73.494,74.754,75.133,78.639,81.158,86.804,94.907,127.687,128.067,128.704,136.337,137.597,140.025,212.474.
双-乙酸酯23。在室温向二醇22(5.0mg,0.007mmol)的0.5mL吡啶溶液中先后加入4-二甲氨基吡啶(2.0mg,0.014mmol)和Ac2O(0.01mL,0.1mmol)。在室温搅拌21h后用10mL EtOAc稀释该溶液，然后倒入20mL饱和NaHCO3水溶液中。分离有机相，水相用EtOAc萃取(20mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后用速色谱纯化(5％EtOAc/己烷)，得到所要的双-乙酸酯23(3.4mg,60％产率)，为无色油。
23:1H NMR(500MHz,CDCl3):δ(ppm)0.518(q,J=8.0,1.0Hz,6H,TES CH2)0.600(qd,J=8.0,5.0Hz,6H,TES CH2),0.912(t,J=8.0Hz,9H,TES CH3),0.951(t,J=8.0Hz,9H,TES CH3),1.042(s,3H,Me17),1.109(s,3H,Me16),1.484(m,1H,H14α),1.653(s,3H,Me19),1.918(ddd,J=14.0,10.5,2.5Hz,1H,H6β),2.107(d,J=1.0Hz,3H,Me18),2.138(s,3H,OAc10),2.162-2.207(m,2H,H1,H14β),2.538(m,1H,H6α),2.626(s,3H,OAc4),3.628(d,J=6.5Hz,1H,H3),3.999(dd,J=6.5,2.5Hz,1H,H2),4.496(d,J=12.0Hz,1H,1HxBOM),4.538(d,J=8.5Hz,1H,H20β),4.578-4.627(m,3H,H7α,H20α,1HxBOM),4.652(d,0=6.5Hz,1H,1HxBOM),4.709(m,1H,H13β),4.733(d,J=6.5Hz,1H,1HxBOM),4.943(dd,J=9.5,2.5Hz,1H,H5α),6.394(s,1H,H10),7.284-7.369(m,5H,5HxBOM).
1-脱氧-浆果赤霉素Ⅲ。室温下向双-乙酸酯23(3.4mg,0.0042mmol)的0.5mL EtOAc和0.5mL t-BuOH溶液中加入4.0mg 10％钯/炭。在H2下搅拌45分钟后用10mL EtOAc稀释该混合物，并用硅藻土短柱过滤。除去溶剂后得到无色油，然后将油溶解于0.5mL CHCl3，并装入硅胶柱。在室温2h后用EtOAc洗涤该柱。除去溶剂后得到所要的粗产物，无需进一步纯化即可使用。
在室温向上述粗产物的0.5mL吡啶溶液中先后加入4-吡咯烷基-吡啶(1.8mg,0.012mmol)和0.5mL(0.5mmol)1.0M BzCl的吡啶(0.5mL)溶液。在室温搅拌26h后用10mL EtOAc稀释该溶液，然后倒入20mL饱和NaHCO3水溶液中。分离有机相，水相用EtOAc萃取(20mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后得粗苯甲酸酯，无需进一步纯化即可使用。
室温下向上述粗苯甲酸酯的0.1mL CH3CN溶液中加入0,5mL 48％HF/吡啶/CH3CN(1∶3.5∶3.5)溶液。在室温搅拌27h后用10mL EtOAc稀释该溶液，然后倒入20mL饱和NaHCO3水溶液中。分离有机相，水相用EtOAc萃取(10mL，三次)。合并有机相并用无水Na2SO4干燥。除去溶剂后用快速色谱纯化(60％EtOAc/己烷)，得到所要的1-脱氧-浆果赤霉素Ⅲ(1.4mg，从双-乙酸酯23算起总产率为59％)。
1-脱氧浆果赤霉素Ⅲ:1H NMR(500MHz,CDCl3):δ(ppm)1.069(s,3H,Me17),1.204(s,3H,Me16),1.667(s,3H,Me19),1.730(ddd,J=15.0,7.5,1.0Hz,1H,H14α),1.890(ddd,J=15.0,6.0,2.0Hz,1H,H6β),1.978(d,J=5.5Hz,1H,OH13),2.034(ddd,J=9.0,3.5,1.0Hz1H,H1),2.085(d,J=1.0Hz,3H,Me18),2.227(s,3H,OAc10),2.290(s,3H,OAc4),2.387(d,J=4.5Hz,1H,OH7),2.516(ddd,J=15.0,10.0,9.0Hz,1H,H14β),2.583(ddd,J=15.0,10.0,7.0Hz,1H,H6α)3.738(d,J=6.5Hz,1H,H3α)4.156(dd,J=8.5,1.0Hz,1H,H20β),4.373(d,J=8.5Hz,1H,H20α),4.471(ddd,J=10.0,7.0,4.5Hz,1H,H7α),4.712(dddd,J=10.0,7.5,5.5,1.0Hz,1H,H13β),5.023(ddd,J=9.5,2.0,1.0Hz,1H,H5α),5.643(dd,J=6.5,3.5Hz,1H,H2β),6.320(s,1H,H10α),7.472(t,J=8.0Hz,2H,苯甲酸酯-m),7.597(dd,J=8.0,1.0Hz,1H，苯甲酸酯-p),8.085(dd,J=8.0,1.0Hz,2H，苯甲酸酯-o).
从上面所述可以看出，本发明的几个目的均已实现。
可以对上述内容进行各种变化而不脱离本发明范围，即包含在上面说明书中的所有情况都被认为是解释而非限制本发明。
Claims (14)
1．一种制备用于1-脱氧浆果赤霉素Ⅲ,1-脱氧紫杉醇和1-脱氧紫杉醇类似物合成的中间体的方法，该方法至少包括下列一个步骤：(a)将式[9]化合物
与乙烯基有机金属试剂反应，形成式[10]化合物；
(b)将式[14]化合物
与钯催化剂反应，形成式[15]化合物；(c)将式[17]化合物
与碱，最优选甲醇中的BaO反应，并保护C7羟基取代基，例如，通过产物与TESOTf反应，形成式[18]化合物；及
和(d)将式[18]化合物
与SeO2反应，形成式[19]化合物；
其中E7是氢或羟基保护基，P2,P7,P9,P10和P13是羟基保护基。
2．下式化合物，
其中
M包含铵或者是金属；
R2是-OT2,-OCOZ2或-OCOOZ2；
R4是-OT4,-OCOZ4或-OCOOZ4；
R6是氢，酮基，-OT6,-OCOZ6或-OCOOZ6；
R7是氢，卤素，-OT7,-OCOZ7或-OCOOZ7；
R9是氢，酮基，-OT9,-OCOZ9或-OCOOZ9；
R10是氢，酮基，-OT10,-OCOZ10或-OCOOZ10；
R6,R7,R9和R10独立地有α和β立体化学构型；
R13是酮基，MO-，羟基，保护的羟基，或
T2,T4,T6,T7,T9和T10独立地为氢或羟基保护基；
X1是-OX6；
X2是氢，烃，杂取代的烃或杂芳基；
X3和X4独立地为氢，烃，杂取代的烃或杂芳基；
X5是-COX10,-COOX10,-COSX10或-CONX8X10；
X6是氢，烃，杂取代的烃，杂芳基或羟基保护基，或增加紫杉烷衍生物水溶解性的官能团；
X8是氢，烃，杂取代的烃；
X10是烃，杂取代的烃或杂芳基；及
Z2,Z4,Z6,Z7,Z9和Z10独立地为烃，杂取代的烃或杂芳基。
3．权利要求2的化合物，其中R10是羟基，保护的羟基或-OCOZ10，且Z10是烷基，取代的烷基，苯基，取代的苯基或杂芳基。
4．权利要求2的化合物，其中R9是酮基。
5．权利要求2的化合物，其中R7是羟基或保护的羟基。
6．权利要求2的化合物，其中R6是氢。
7．权利要求2的化合物，其中R4是-OCOZ4，且Z4是苯基，取代的苯基或杂芳基。
8．权利要求2的化合物，其中R2是-OCOZ2，且Z2是烷基，取代的烷基，苯基，取代的苯基或杂芳基。
9．权利要求2的化合物，其中R13是羟基或保护的羟基。
10．权利要求2的化合物，其中R13是MO-或
及M,X1,X2,X3,X4和X5定义同权利要求2。
11．权利要求2的化合物，其中R2是-OCOZ2；R4是-OCOZ4；R7是羟基或保护的羟基；R9是酮基；R10是羟基，保护的羟基或-OCOZ10；Z2,Z4和Z10定义同权利要求2。
12．权利要求2的化合物，其中R2是苯甲酰氧基；R4是乙酰氧基；R6是氢；R7是羟基或保护的羟基；R9是酮基；R10是羟基，保护的羟基或乙酰氧基；R13是羟基或保护的羟基。
13．权利要求2的化合物，它是1-脱氧紫杉醇。
14．选自如下的化合物：(a)
其中R9是氢，羟基或保护的羟基；R10是羟基，保护的羟基或酮基；(b)
其中R10是羟基或保护的羟基；(c)其中R2是氢，羟基或保护的羟基；R9是羟基或保护的羟基；R10是羟基或保护的羟基；及R13是羟基或保护的羟基；(d)
其中R3是羟基或保护的羟基；R9是羟基或保护的羟基；R10是羟基或保护的羟基；及R13是羟基或保护的羟基；(e)其中R2是羟基或保护的羟基，或与R3一起形成碳酸酯；R3是氢，羟基或保护的羟基，或与R2一起形成碳酸酯；R7是羟基，保护的羟基或酮基；R9是羟基，保护的羟基或酮基；R10是羟基或保护的羟基；及R13是羟基或保护的羟基；(f)其中R2是羟基或保护的羟基；R4是羟基或保护的羟基，或与R4a一起形成酮基；R4a是-CH2OH，或与R4一起形成酮基；R5是羟基，保护的羟基或CH3SO2-；R7是羟基或保护的羟基；R10是羟基或保护的羟基；及R13是羟基或保护的羟基；(g)
其中R2是羟基或保护的羟基；R4是羟基，保护的羟基或乙酰氧基；R7是羟基或保护的羟基；R10是羟基，保护的羟基或乙酰氧基；及R13是羟基或保护的羟基。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1692796P | 1996-05-06 | 1996-05-06 | |
| US60/016,927 | 1996-05-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1221412A true CN1221412A (zh) | 1999-06-30 |
Family
ID=21779772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97195321A Pending CN1221412A (zh) | 1996-05-06 | 1997-05-05 | 1－脱氧浆果赤霉素ⅲ,1－脱氧紫杉醇和1－脱氧紫杉醇类似物及其制备方法 |
Country Status (8)
| Country | Link |
|---|---|
| US (3) | US6545168B1 (zh) |
| EP (1) | EP0927175A4 (zh) |
| JP (1) | JP2000510470A (zh) |
| CN (1) | CN1221412A (zh) |
| AU (1) | AU724499B2 (zh) |
| CA (1) | CA2253513A1 (zh) |
| IL (1) | IL126856A0 (zh) |
| WO (1) | WO1997042181A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093315A (zh) * | 2010-12-23 | 2011-06-15 | 上海大学 | C7，c10修饰的1-去羟基紫杉醇类似物及其制备方法 |
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| JP2000510470A (ja) * | 1996-05-06 | 2000-08-15 | フロリダ・ステイト・ユニバーシティ | １―デオキシバッカチンｉｉｉ、１―デオキシタキソールおよび１―デオキシタキソール類似体、ならびにこれらの製造方法 |
| US5739359A (en) * | 1997-01-24 | 1998-04-14 | Virginia Tech Intellectual Properties, Inc. | Methods for preparing 1-deoxy paclitaxels |
| ES2195378T3 (es) | 1997-08-21 | 2003-12-01 | Univ Florida State | Procedimiento para la sintesis de taxanos. |
| IL145643A0 (en) | 2000-02-02 | 2002-06-30 | Univ Florida State Res Found | C7 carbamoyloxy substituted taxanes as antitumor agents |
| CO5280224A1 (es) | 2000-02-02 | 2003-05-30 | Univ Florida State Res Found | Taxanos sustituidos con ester en c7, utiles como agentes antitumorales y composiciones farmaceuticas que los contienen |
| US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
| WO2001057033A1 (en) | 2000-02-02 | 2001-08-09 | Florida State University Research Foundation, Inc. | C10 carbamoyloxy substituted taxanes as antitumor agents |
| IL145637A0 (en) | 2000-02-02 | 2002-06-30 | Univ Florida State Res Found | C7 carbonate substituted taxanes as antitumor agents |
| US6673833B2 (en) | 2000-02-02 | 2004-01-06 | Fsu Research Foundation, Inc. | C7 heterosubstituted acetate taxanes |
| CN1362876A (zh) | 2000-02-02 | 2002-08-07 | 佛罗里达州立大学研究基金有限公司 | C10杂取代的乙酸基紫衫烷抗肿瘤剂 |
| CZ20013405A3 (cs) | 2000-02-02 | 2002-03-13 | Florida State University Research Foundation, Inc. | C10 karbonátem substituované taxany jako protinádorová činidla |
| SV2006002010A (es) | 2004-02-13 | 2006-08-23 | Univ Florida State Res Found | Taxanos sustituidos con esteres de ciclopentilo en c10 |
| CN1960721A (zh) | 2004-03-05 | 2007-05-09 | 佛罗里达州立大学研究基金有限公司 | C7乳酰氧基取代的紫杉烷类 |
| EP2276755A4 (en) | 2008-03-31 | 2011-05-04 | Univ Florida State Res Found | C (10) -ETHYESTER- AND C (10) -CYCLOPROPYLESTER-SUBSTITUTED TAXANES |
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-
1997
- 1997-05-05 JP JP09540115A patent/JP2000510470A/ja not_active Ceased
- 1997-05-05 AU AU29966/97A patent/AU724499B2/en not_active Ceased
- 1997-05-05 EP EP97924581A patent/EP0927175A4/en not_active Withdrawn
- 1997-05-05 WO PCT/US1997/007569 patent/WO1997042181A1/en not_active Application Discontinuation
- 1997-05-05 US US08/850,942 patent/US6545168B1/en not_active Expired - Fee Related
- 1997-05-05 CN CN97195321A patent/CN1221412A/zh active Pending
- 1997-05-05 IL IL12685697A patent/IL126856A0/xx unknown
- 1997-05-05 CA CA002253513A patent/CA2253513A1/en not_active Abandoned
-
2002
- 2002-09-06 US US10/236,798 patent/US6620950B2/en not_active Expired - Fee Related
-
2003
- 2003-08-07 US US10/636,017 patent/US7019150B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093315A (zh) * | 2010-12-23 | 2011-06-15 | 上海大学 | C7，c10修饰的1-去羟基紫杉醇类似物及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0927175A1 (en) | 1999-07-07 |
| US20040029976A1 (en) | 2004-02-12 |
| US6620950B2 (en) | 2003-09-16 |
| AU2996697A (en) | 1997-11-26 |
| US7019150B2 (en) | 2006-03-28 |
| CA2253513A1 (en) | 1997-11-13 |
| AU724499B2 (en) | 2000-09-21 |
| EP0927175A4 (en) | 2002-05-22 |
| WO1997042181A1 (en) | 1997-11-13 |
| US6545168B1 (en) | 2003-04-08 |
| IL126856A0 (en) | 1999-09-22 |
| US20030028039A1 (en) | 2003-02-06 |
| JP2000510470A (ja) | 2000-08-15 |
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