CN1046261C - 紫杉醇及其衍生物的合成 - Google Patents
紫杉醇及其衍生物的合成 Download PDFInfo
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- CN1046261C CN1046261C CN94192841A CN94192841A CN1046261C CN 1046261 C CN1046261 C CN 1046261C CN 94192841 A CN94192841 A CN 94192841A CN 94192841 A CN94192841 A CN 94192841A CN 1046261 C CN1046261 C CN 1046261C
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- Prior art keywords
- hydrogen
- hydroxy
- alkyl
- ocor
- carbonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 14
- 229960001592 paclitaxel Drugs 0.000 title abstract description 30
- 229930012538 Paclitaxel Natural products 0.000 title abstract description 26
- 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 abstract description 26
- 229940123237 Taxane Drugs 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 28
- 230000008569 process Effects 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims description 187
- 229910052739 hydrogen Inorganic materials 0.000 claims description 187
- 150000002431 hydrogen Chemical class 0.000 claims description 175
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 150
- 125000000217 alkyl group Chemical group 0.000 claims description 115
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 100
- 125000003342 alkenyl group Chemical group 0.000 claims description 99
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 99
- 125000000304 alkynyl group Chemical group 0.000 claims description 98
- 125000003118 aryl group Chemical group 0.000 claims description 97
- -1 cyano, hydroxy Chemical group 0.000 claims description 89
- 125000001072 heteroaryl group Chemical group 0.000 claims description 86
- 125000004043 oxo group Chemical group O=* 0.000 claims description 67
- 150000001875 compounds Chemical class 0.000 claims description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 31
- 150000002576 ketones Chemical class 0.000 claims description 31
- 239000000543 intermediate Substances 0.000 claims description 29
- 239000000741 silica gel Substances 0.000 claims description 25
- 229910002027 silica gel Inorganic materials 0.000 claims description 25
- 125000003003 spiro group Chemical group 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000006239 protecting group Chemical group 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 16
- 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 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 14
- 239000002184 metal Substances 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- 150000001299 aldehydes Chemical class 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- GBBJBUGPGFNISJ-YDQXZVTASA-N (4as,7r,8as)-9,9-dimethyltetrahydro-4h-4a,7-methanobenzo[c][1,2]oxazireno[2,3-b]isothiazole 3,3-dioxide Chemical compound C1S(=O)(=O)N2O[C@@]32C[C@@H]2C(C)(C)[C@]13CC2 GBBJBUGPGFNISJ-YDQXZVTASA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- BNHFWQQYLUPDOG-UHFFFAOYSA-N lithium;1,2,2,3-tetramethylpiperidine Chemical compound [Li].CC1CCCN(C)C1(C)C BNHFWQQYLUPDOG-UHFFFAOYSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 310
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 253
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 228
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 116
- 239000000243 solution Substances 0.000 description 109
- 235000019439 ethyl acetate Nutrition 0.000 description 104
- 229920006395 saturated elastomer Polymers 0.000 description 77
- 239000007864 aqueous solution Substances 0.000 description 72
- 229910001868 water Inorganic materials 0.000 description 62
- 239000007832 Na2SO4 Substances 0.000 description 60
- 229910052938 sodium sulfate Inorganic materials 0.000 description 60
- 239000000203 mixture Substances 0.000 description 59
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 58
- 238000005160 1H NMR spectroscopy Methods 0.000 description 55
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 55
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 55
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 52
- 238000001035 drying Methods 0.000 description 47
- 238000006243 chemical reaction Methods 0.000 description 45
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 45
- 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 description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 41
- 239000012044 organic layer Substances 0.000 description 41
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 38
- 239000007787 solid Substances 0.000 description 36
- 239000012267 brine Substances 0.000 description 31
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000003921 oil Substances 0.000 description 27
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000005406 washing Methods 0.000 description 21
- 229930014667 baccatin III Natural products 0.000 description 20
- 238000010898 silica gel chromatography Methods 0.000 description 20
- 239000012230 colorless oil Substances 0.000 description 19
- 238000000921 elemental analysis Methods 0.000 description 19
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- 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 15
- 125000001424 substituent group Chemical group 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 14
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 14
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 13
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 13
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 150000002009 diols Chemical class 0.000 description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 11
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000000284 extract Substances 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 150000002430 hydrocarbons Chemical group 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 229930195733 hydrocarbon Natural products 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000003835 ketolide antibiotic agent Substances 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 150000004703 alkoxides Chemical class 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 150000003952 β-lactams Chemical class 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 4
- 239000000039 congener Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
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- 239000000523 sample Substances 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- YWLXLRUDGLRYDR-LUPIKGFISA-N 7-epi-10-deacetylbaccatin iii Chemical group O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-LUPIKGFISA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
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- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
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- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- NKCVNYJQLIWBHK-UHFFFAOYSA-N carbonodiperoxoic acid Chemical compound OOC(=O)OO NKCVNYJQLIWBHK-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
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- 239000003480 eluent Substances 0.000 description 3
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- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 102220092291 rs138247915 Human genes 0.000 description 3
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- XQKBFQXWZCFNFF-UHFFFAOYSA-K triiodosamarium Chemical compound I[Sm](I)I XQKBFQXWZCFNFF-UHFFFAOYSA-K 0.000 description 3
- LGFLRHWJJKLPCC-ZDUSSCGKSA-N (2s)-2-[[4-[2-(2,4-diaminopteridin-6-yl)ethyl]benzoyl]amino]pentanedioic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 LGFLRHWJJKLPCC-ZDUSSCGKSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
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- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 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 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
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Abstract
合成紫杉醇和其它三环和四环紫杉烷的方法。
Description
本发明是在国家健康研究所提供的#CA42031号政府资助的支持下完成的。美国政府在本发明中享有一定的权利。
本发明涉及紫杉醇及其他的三环和四环紫杉烷、以及它们的新的中间体的合成方法。
萜烯族的紫杉烷类，其中包括紫杉醇，已在生物和化学领域中引起了广泛的兴趣。紫杉醇是有效的肿瘤化疗药物，它具有广谱的抗白血病和肿瘤抑制活性。紫杉醇具有如下结构：其中AC为乙酰基。目前紫杉醇主要来源是Taxus brevifollia(西部紫杉属树木)的树皮，然而，在这种生长十分缓慢的长青树的树皮中仅含有极少量的紫杉醇。所以，近来化学家们正致力于找到一种可行的合成路线，以制备紫杉醇。到目前为止，结果还不完全令人满意。
在JACS110 5917(1988)中，Greene等人描述了一种用于制备紫杉醇的半合成方法，该方法中采用了紫杉醇的同族物10-去己酰基浆果赤霉素Ⅲ，其结构如下列通式Ⅱ：
10-去乙酰基浆果赤霉素Ⅲ比紫杉醇容易得到，因为前者可从欧紫杉(Taxus baccata)的针叶中获得。根据Greene等人的方法，可经下列步骤把10-去乙酰基浆果赤霉素Ⅲ(“10-DAB”)转化为紫杉醇：在C-10位乙酰化，通过用β-氨基羧酸单位与C-13醇进行酯化，接上C-β氨基酯侧链。
Denis等人在美国专利No.4,924,011中公开了另一种制备浆果赤霉素Ⅲ或10-去乙酰基浆果赤霉素Ⅲ衍生物的方法该类衍生物有如下通式：
(Ⅴ)其中R1为氢或乙酰基。在该专利中，具下列通式的酸：
其中R1为羟基保护基，与具下列通式的紫杉烷衍生物进行缩合
(Ⅶ)
其中R2为乙酰基羟基保护基且R3为羟基保护基，且保护基R1,R3以及R2可适当地随后被氢所取代。
近年来还报导了一些其它的制备紫杉醇及具有抗肿瘤活性的其它紫杉烷的半合成的方法，但所有这些方法都需要用10-DAB或浆果赤霉素Ⅲ作为起始物。在这种情况下，紫杉醇及其他的紫杉烷衍生物的来源至少一定程度上取决于从世界偏僻的角落中生长的植物的各个部位所能收集到的叶子粗树皮等以及从中提取到的10-DAB和/或浆果赤霉素的量。
本发明的目的是提供合成紫杉醇及其它四环紫杉烷的方法，所提供的方法具有高度的非对映异构选择性，及相对高的收率；并且提供了关键的中间体以及制备这些中间体的方法。
简单地讲，本发明涉及制备紫杉醇以及其他的三环和四环紫杉烷的方法。
根据本发明，该方法包括如下步骤：
将具下列通式化合物：与BrMgN(ipr)2，醛(或酮)进行反应，随后用光气和醇处理，成具有如下结构的化合物：
其中
R1为氢或保护的羟基：R2为氢或保护的羟基；
R3为氧代，
R7b为氢，烷基、氰基，羟基，保护的羟基，或-OCOR36，
R7c及R7d各自独立地表示氢，烷基，链烯基，链炔基，芳基或杂芳基；
R9为氢，保护的羟基或氧代；
R10为-OP10；
R13为-OP13且
R36为氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基，
X8为氢，烷基，链烯基，链炔基，芳基或杂芳基；
X10为烷基，链烯基，链炔基，芳基或杂芳基；
P10及P13为羟基保护基。
根据本发明，该方法还可以包括下列步骤：
将下列通式的化合物：
与四甲基哌啶锂反应成具下列通式的化合物：
其中
R1为氢或保护的羟基；
R7c为氢，烷基，链烯基，链炔基，芳基或杂芳基；
R9为氢，保护的羟基，或氧代；且
P10和P13为羟基保护基。
根据本发明，该方法还可包括如下步骤，将下列通式的化合
与四甲基哌啶锂和樟脑磺酰氧杂氮丙啶反应，形成具下列通式的化合物：
其中R9为氢，保护的羟基，或氧化；R7c为氢，烷基，链烯基，链炔基，芳基或杂芳基；且P10和P13为羟基保护基。
根据本发明，该方法可由如下步骤构成：将具有下列通式的化合物：与氢化物还原剂反应，较可取的为Red-AL，形成具下列通式的化合物：
其中R9为氢，保护的羟基，或氧代；R7c为氢，烷基，链烯基，链炔基，芳基或杂芳基；且P10和P13为羟基保护基。
根据本发明，该方法可由如下步骤构成，将具有下列通式的化合物：
与二异丙基酰胺锂反应，生成具有下列通式的化合物：
其中R为低级烷基，R1为氢，保护的羟基，或R1和R2一起构成碳酸酯，R2为氢，保护的羟基，或R1和R2一起构成碳酸酯；R9为氢，保护的羟基，或氧代；P10和P13为羟基保护基。
根据本发明，该方法包括如下步骤，将具下列通式的化合物：
与DBU反应，生成具下列通式的化合物：与DBU反应，生成具下列通式的化合物：
其中
R1为氢，羟基；保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31，或与R1一同构成碳酸酯；
R4a为氢，烷基，羟基，或保护的羟基，或与R2一同构成碳酸酯；
R4b为羟亚甲基；
R5为-OMs,OTs或溴；
R7a为氢，保护的羟基，或-OCOR34，或与R9一同构成碳酸酯；
R9为氢，氧代，羟基，保护的羟基，或-OCOR33，或与R79或R10一同构成碳酸酯；
R10为氢，氧代，羟基，保护的羟基，或-OCOR29，或与R9一同
R29,R30,R31,R33及R34为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基或杂芳基；和
X10为烷基，链烯基，链炔基，芳基或杂芳基。
根据本发明，该方法包括下列步骤，将具有下列通式的化合物：
与KOtBu和(phseO)2O反应形成具有下列通式的化合物：
在另外加入KOtBu，并有硅胶，或其它的酸或碱存在下，或加热后，上述化合物重排，得到具有如下通式的化合物：
其中，
R1为氢，羟基，保护的羟基，或-OCOR30或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，或-OCOR31，或与R1或R4a一同构成碳酸酯；
R4a为氢，烷基，羟基，保护的羟基，或-OCOR27，与R4b构成氧代，或与R2,R4b或R5一同构成碳酸酯；
R4b为氢，烷基，链烯基，链炔基，芳基，杂芳基，或氰基，与R4a构成氧代，与R4a或R5一同构成碳酸酯，或与R5及它们所接的碳一同构成螺[4,4]二氧乙烷(oxetane)。
R5为氢，保护的羟基，-OCOR37，为R4a或R4b一同构成碳酸酯，或与R4b及所连的碳一起构成螺[4,4]二氧己烷；
R7a为氢，卤素，保护的羟基，或-OCOR34；
P13为羟基保护基，
R27,R30,R31,R34及R37为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基，杂芳基，或杂原子取代的烷基，链烯基，链炔基，芳基或杂芳基；和
X10为烷基，链基，链炔基，芳基，杂芳基，或杂原子取代的烷基，链烯基，链炔基，芳基或杂芳基。
通常，本发明中的方法可用于制备具有下列通式的紫杉烷类：
其中：
R1为氢，羟基，保护的羟基，或-OCOR30；
R2为氢，羟基，-OCOR31，或氧代；
R4a为氢，烷基，链烯基，链炔基，芳基，杂芳基，氰基，羟基，-OCOR27，或与R4b一同构成氧代，环氧乙烷或亚甲基；
R4b为氢，与R4a一同构成氧代，环氧乙烷或亚甲基，或与R5及所连的碳一同构成螺[4,4]二氧乙烷。
R5为氢，卤素，羟基，保护的羟基，-OCOR37，氧代，或与R4b及所连的碳一同构成螺[4,4]二氧己烷；
R6为氢，烷基，链烯基，链炔基，芳基或杂芳基，羟基，保护羟基或与R6a一起形成氧代；
R6a为氢，烷基，链烯基，链炔基，芳基或杂芳基，羟基，保护羟基或与R6一起形成氧代；
R7a为氢，卤素，羟基，保护的羟基，-OCOR34，氧代或-OR28；
R9为氢，羟基，保护的羟基，酰氧基，或氧代；
R10为氢，-OCOR29，羟基，保护的羟基，或氧代；
R13为羟基，保护的羟基，MO-或
R14为氢，烷基，链烯基，链炔基，芳基或杂芳基；
R14a为氢，烷基，链烯基，链炔基，芳基或杂芳基，羟基，保护羟基或与R1一起形成碳酸酯；
R28为增加紫杉烷熔解度的功能基；
R27,R29,R30,R31,R34及R37为独立的氢，烷基，链烯基，链炔基，单环芳基或单环杂芳基；
X1为-OX6,-SX7或-NX8X9；
X2为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X3和X4为独立的氢，烷基，链烯基，链炔基，芳基或杂芳基；
X9为氨基保护基；
X10为烷基，链烯基，链炔基，芳基，杂芳基，或杂原子取代的烷基，链烯基，链炔基，芳基或杂芳基；
X11为烷基，链烯基，链炔基，芳基，杂芳基，-OX10，或-NX8X14；
X14为氢，烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或金属，
另外本发明还涉及制备三环或四环紫杉烷中所用的具有下列通式的中间体：
其中
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31，或与R1一同构成碳酸酯；
R3为氢，羟基，保护的羟基，-OCOR32或氧代；
R8为氢，烷基，链烯基，链炔基，芳基或杂芳基；
R9为氢，保护的羟基，氧代，或-OCOR33，或与R10一同构成碳酸酯；
R10为氢，羟基，保护的羟基，氧代，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35或MO-；
R29,R30,R31,R32,R33，及R35为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或金属。
本发明进一步涉及制备三环四环紫杉烷中所用的具有下列通式的中间体：
其中
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31，或与R1一同构成碳酸酯；
R3为氢，羟基，保护的羟基，-OCOR32，或氧代或与R7b一同构成碳酸酯；
R7b为氢，烷基，氰基，羟基，保护的羟基，或-OCOR36，或与R3或R9一同构成碳酸酯；
R7c及R7d为独立氢，烷基，链烯基，链炔基，芳基或杂芳基；
R9为氢，保护的羟基，氧代，或-OCOR33，或与R7b或R10一同构成碳酸酯；
R10为氢，羟基，保护的羟基，氧代，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35或MO-；
R29,R30,R31,R32,R33,R35及R35为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或金属。
本发明进一步涉及制备三环四或环紫杉烷中所用的具有下列通式的中间体：
本发明进一步涉及制备三环四或环紫杉烷中所用的具有下列通式的中间体：
其中
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31，或与R1一同构成碳酸酯；
R3为氢，羟基，保护的羟基，-OCOR32；
R7b为氢，烷基，氰基，羟基，保护的羟基，或-OCOR36，或与R3或R9一同构成碳酸酯；
R7c氢，烷基，链烯基，链炔基，芳基或杂芳基；
R9为氢，保护的羟基，氧代，或-OCOR33，或与R10一同构成碳酸酯；
R10为氢，羟基，保护的羟基，氧代，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35或MO-：
R29,R30,R31,R32,R33,R35及R36为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或金属。
本发明进一步涉及制备三环四环紫杉烷中所用的具有下列通式的中间体：
其中
R为C1-C8烷基，
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31，或与R1一同构成碳酸酯；或与R4一同构成碳酸酯；
R4a为氢，烷基，羟基，保护的羟基，或-OCOR27，或与R2一同构成碳酸酯；
R7a为氢，卤素，羟基，保护的羟基，OR28,-OCOR34，或与R9一同构成碳酸酯；
R9为氢，氧代，羟基，保护的羟基，-OR28，或-OCOR33，或与R7a或R10一同构成碳酸酯；
R10为氢，氧代，羟基，保护的羟基，-OR28，或-OCOR28，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35或MO-；
R28为增加紫杉烷衍生物溶解度的功能基；
R29,R30,R31,R32,R33，及R35为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或金属。
本发明进一步涉及制备三环四环紫杉烷中所用的具有下列通式的中间体：
其中
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31，或与R1一同构成碳酸酯；或与R4一同构成碳酸酯；
R4a为氢，烷基，羟基，保护的羟基，或-OCOR27，与R4b构成氧代，或与R2,R4b或R5一同构成碳酸酯；
R4b为氢，烷基，链烯基，链炔基，芳基，杂芳基，或氰基，与R4a一同构成氧代，与R4a或R5一同构成碳酸酯，与R5及所连的碳一同构成螺[4,4]二氧乙烷；
R5为氢，保护的羟基，-OCOR37，氧代，与R4a或R4b一起构成碳酸酯，或与R4b及所连的碳一同构成螺[4,4]二氧乙烷；
R7a为氢，卤素，羟基，保护的羟基，-OR28，或-OCOR34，或与R9一同构成碳酸酯；
R9为氢，氧代，羟基，保护的羟基，-OR28，或-OCOR33，或与R7a或R10一同构成碳酸酯；
R10为氢，氧代，羟基，保护的羟基，-OR28，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35或MO-；或
R28为增加紫杉烷衍生物溶解度的功能基；
R27,R29,R30,R31,R32,R33,R34,R35及R37为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10单环芳基或单环杂芳基；
X1为-OX6,-SX7，或-NX8X9；
X2为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X3和X4为独立的氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X5为-COX10,-COOX10,-COSX10,-CONX8X10，或-SO2X11；
X6为氢，烷基，链烯基，链炔基，芳基，杂芳基，羟基保护基，或增加紫杉烷衍生物水溶解度的功能基；
X7为烷基，链烯基，链炔基，芳基，杂芳基或巯基保护基；
X8为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X9为氨基保护基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；
X11为烷基，链烯基，链炔基，芳基，或杂芳基，-OX10或-NX8X14；
X14为氢，烷基，链烯基，链炔基，芳基，或杂芳基，且指乙基；“ipr”系指异丙基；“tBu”及“t-Bu”系指叔丁基；“R”系指低级烷基，有特殊注明时例外；“Ac”系指乙酰基；“Py”系指吡啶；“TES”系指三乙基甲硅烷基；“TMS”系指三甲基甲硅烷基；“TBS”系指Me2t-BuS-；“Tf”系指-SO2CF3；“BMDA”系指BrMgNiPr3；“Swern”系指(COCL)2,Et3N；“LTMP”系指四甲基吡啶锂；“MOP”系指2-甲氧基-2-丙基；“BOM”系指苄氧甲基；“LDA”系指二异丙酰胺锂；“LAH”系指氢化铝锂；“Red-Al”系指双(2-甲氧乙氧基)氢化铝锂；“Ms”系指“CH3SO2”；“TASF”系指三(二乙氨基)锍二氟三甲基硅酸盐；“Ts”系指甲苯磺酰基；“TBAF”系指氢化四丁基铵；“TPAP”系指四丙基-铵过钌酸盐；“DBU”系指二偶氮双环十一烷；“DMAP”系指对-二甲基氨基吡啶；“LHMDS”系指六甲基二硅叠氮化锂；“DMF”系指二甲基甲酰胺；“AIBN”系指偶氮-(双)-异丁腈；“10-DAB”系指10-去乙酰基浆果赤霉素Ⅲ；“FAR”系指2-氯-1.1.2-三氟三乙胺；“mCPBA”“系指间氯过苯甲酸；DDQ”系指二氰基二氯醌；“巯基保护基”包括(但不局限于)硫代半缩醛，例如1-乙氧乙基及甲氧甲基，硫代酯或硫代碳酸酯；“氨基保护基”包括(但不局限于)氨基甲酸酯，例如，2.2.2.-三氯乙基氨基甲酸酯或氨基甲酸叔丁酯；“保护的羟基”系指-OP，其中P为羟基保护基；且“羟基保护基”包括(但不局限于)具有2-10个碳原子的缩醛，具有2-10个碳原子的缩酮，醚类，如甲基，叔丁基，苄基，对甲氧苄基，对硝基苄基，烯丙基，三苯甲基，甲氧甲基，甲氧乙氧甲基，乙氧乙基，四氢吡喃基，四氢硫代吡喃基，及三烷基甲硅醚，如，三甲基甲硅醚，三乙基甲硅醚，二甲芳基甲硅醚，三异丙基甲硅醚，及叔丁基二甲基甲硅醚；酯类，例如，苯甲酰基，乙酰基，苯乙酰基，甲酰基，一，二及三卤代乙酰基，如氯乙酰基，二氯乙酰基，三氯乙酰基，三氟乙酰基；以及碳酸酯，包括(但不局限于)具有1-6个碳原子的烷基的碳酸酯，例如，甲基，乙基，正丙基，异丙基，正丁基，叔丁基，异丁基及正戊基；具有1-6个碳原子且被一或多个卤原子取代的烷基碳酸酯，例如2,2,2,-三氯乙氧甲基和2,2,2，-三氯乙基；具有2-6个碳原子的链烯基碳酸酯，如乙烯基和烯丙基；具有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；以及任意地在环上有一或多个C1-6烷氧基，或硝基取代基的苯基或苄基碳酯酯。其它的羟基，巯基及氨基的保护基参见由T.W.Greene所著，Johm Wileyand Sons公司1981年出版的“Protection Groups in OrganicSynthesis”。
本文中所述的烷基较可取的是主链在1-6碳原子内，且15个碳原子以内的低级烷基。它们可以是直链的或支链的，包括甲基，乙基，丙基，异丙基，丁基，己基等等。它们可以是烃或被杂原子取代的烃(在本文所定义的各种取代基的范围内，包括杂取代的烷基，链烯基，杂取代的链烯基，链炔基，杂原子取代的链炔基，芳基，杂原子芳基及杂原子取代的杂芳基)。
本文中所述的链烯基较可取的是主链在2-6个碳原子内，且15个碳原子以内的低级链烯基。它们可以是直链的或支链的，包括乙烯基，丙烯基，异丙烯基，丁烯基，异丁烯基，己烯基等等。它们可以是被烃或杂原子取代的(在本文所定义的各种取代基的范围内，包括烷基，杂原子取代的烷基，杂原子取代的链烯基，炔基，杂原子取代的链炔基，芳基，杂芳基，及杂原子取代的杂芳基)。
本文中所定义的链炔基较可取的是主链在2-6碳原子内，且15个碳原子以内的低级烷基。它们可以是直链的或支链的，包括甲基，乙基，丙基，异丙基，丁基，己基等等。它们可以是烃或被杂原子取代的烃(在本文所定义的各种取代基的范围内，包括烷基，杂原子取代的烷基，链烯基，杂原子取代的链烯基，杂原子取代的链炔基，芳基，杂芳基及杂原子取代的杂芳基)。
本文中所述的杂芳基片断含有6-15碳原子且包括苯基，它们可以是烃或杂原子取代的烃(在本文定义的各种取代基的范围内，包括烷基，杂原子取代的烷基，链烯基，杂原子取代的链烯基，链炔基，杂原子取代的链炔基，杂芳基，以及杂原子取代的杂芳基)。苯为最可取的芳基。
本文中所述的芳基片断含有5-15碳原子且包括呋喃基，噻吩基，吡啶基等等。它们可以是烃或杂原子取代的烃。各种取代基的定义见本文所述，且包括烷基，杂取代的烷基，链烯基，杂原子取代的链烯基，链炔基，杂原子取代的链炔基，杂芳基，以及杂原子取代的杂芳基)。
本文中的酰基片断包括烷基，链烯基，链炔基，芳基或杂芳基。
本文中的烷基羰氧片断包括有低级烷基，链烯基，链炔基或芳基。
本文中所述的烃取代基可以是烷基，链烯基，链炔基，或芳基，以及本文中所述的杂原子取代的烷基，链烯基，链炔基，芳基的杂原子取代基及杂芳基片断的杂原子取代基含有氮，氧，硫，卤素和/或1-6个碳原子，且包括低级烷氧基如甲氧基，乙氧基，丁氧基，卤素，如氯或氟，及硝基，杂芳基如，呋喃基或噻吩基，羰基，羟基，保护的羟基，酰基，酰氧基，硝基，氨基和酰胺基。
在下列反应路线A中叙述了合成浆果赤霉素Ⅲ或10-DAB的实例。可以从Patchino[此商品名为B-经绿叶灵环氧化物(B-Patchouline epoxide)]制备起始物二醇2,Patchino可从市场上买到。Patchino首先与有机金属物，如叔丁锂反应，而后用有机过氧化物，如叔丁基过氧化物，在四异丙氧化钛存在下进行氧化后生成叔醇。然后，将该叔醇与Lewis酸，如三氟化硼在低温下，如40℃至-100℃下，在酸存在下，如三氟甲磺酸，进行反应。二醇2的反应路线图及实验条件，见美国专利4,876,399。反应路线A 
在反应路线A中，P5是TMS,P7是MOP或BOM,P10为TES,P13为TBS，且在化合物6和7中，R是乙基，在化合物15,16及17中R为甲基，在化合物24aa及26a中R为Ms，以及在化合物26aa中R为Ts。然而，同样可以认为P5,P7,P10及P13也可以是其它的羟基保护基，而且在化合物6,7,15,16和17中的R可包括其它的低级烷基取代基。
可在生成化合物18和29之间对反应路线A进行修改，得到如下反应路线A′。反应路线A′ 
在反应路线A′中，P5为TMS或Ac,Pa7为MOP或BOM,P10为TES,P13为TBS且P520为缩醛或缩酮，较可取的为丙酮化合物。然而，同样可以认为P5,P7,P10及P520可以是其它的羟基保护基。
通常，带有C13侧链的三环或四环紫杉烷可经下列步骤制备：将β-内酰胺与具有紫杉烷的三环或四环核以及C-13位有金属氧化物取代基的烷氧化物进行反应，生成在C13上有β-内酰胺酯取代基的化合物，该β-内酰胺具有如下结构式：
其中X1-X5同上定义。具有紫杉烷的三环或四环核以及C-13有金属氧化取代基或铵氧化物取代基的烷基化物具有如下结构式：
其中R1,R2,R4a,R4b,R5,R6,R6a,R7a,R9及R10同前定义，R13为一OM。M代表铵或金属，该金属可任意选自ⅠA,ⅡA，过渡元素(包括镧系元素和锕系元素)，ⅡB,ⅢA,ⅣA,ⅤA或ⅥA族金属(CAS定义)。如果M包括铵，四烷基铵较为可取，且四烷基铵中的烷基较可取的为C1-C10烷基，如甲基或丁基。更可取的是烷氧化物具有四环紫杉烷核，且符合如下结构式：
其中M,R2,R4a,R7a,R9及R10同前定义。
像在反应路线A中所阐述，可按如下步骤制备紫杉醇，将7-保护的浆果赤霉素Ⅲ35转化为相应的烷氧化物，将该烷氧化物与β-内酰胺(其中X1为保护的羟基，X3为苯基，且X5为苯甲酰基)进行反应。较可取的保护基有2-甲氧丙基(“MOP”),1-乙氧乙基(“EE”)，但也可用其它各种标准的保护基，如三乙基甲硅烷基或其它的三烷基(或芳基)甲硅烷基。具有可供选择的侧链取代基的紫杉烷可经具有可供选择的取代基的β-内酰胺来制备。
具有可供选择的C9取代基的紫杉烷类，可经选择性地还原紫杉醇，10-DAB，浆果赤霉素Ⅲ或本文中公开的其它中间体之一的C9酮取代基，而后得到相应的C9β-羟基衍生物。可取的还原剂为硼氢化物，且最可取的为四丁基铵硼氢化物(Bu4NBH4)或三乙酰氧基硼氢化物。
如反应路线1中所示，浆果赤霉素Ⅲ与Bu4NBH4在二氯甲烷中反应，生成9-去氧-9β-羟基浆果赤霉素Ⅲ5。在C7羟基用三乙基甲硅烷保护后，可按本文别的地方描述的那样，将7-保护-9β-羟基衍生物6中引入合适的侧链。除去剩余的保护基后，得到具有C13侧链的9β-羟基-去氧紫杉醇，或具有C13侧链的9β-羟基四环紫杉烷。
反应路线1
另外，7-保护-9β-羟基衍生物6中的C13羟基也可被三甲基甲硅烷或者其它的保护基保护，其相关于C7羟基保护基，能被选择性地除去。如下面的反应路线2所示，从而能够进一步选择性地控制紫杉烷结构上不同的取代基。例如，将7,13-保护的9β-羟基衍生物7与KH反应，使得乙酰基从C10移到C9，同时羟基从C9移动到C10，从而产生10-去乙酰基衍生物8。将10-去乙酰基衍生物8上的C10羟基用三乙基甲硅烷保护，得到衍生物9。从衍生物9选择性地除去C13保护基，得到衍生物10，衍生物10可按上述方法接上合适的侧链。
反应路线2
如反应路线3所示，10-氧化衍生物11可通过10-去乙酰基衍生物8提供。此后，C13羟基保护基能被选择性地除去，接着连接上述侧链，便产生9-乙酰氧基-10-氧化-紫杉醇或其它的具有C13侧链的9-乙酰氧基-10-氧代四环紫杉烷类。另外，使用还原剂碘代亚钐还原10-氧化衍生物11,C9乙酸酯基团能被选择性地除去，生成9-去氧化-10-氧代衍生物12，从后者C13羟荃保护荃能被选择性地除去，接着连接上述侧链，便产生9-去氧代-10-氧代紫杉醇或其它具有C13侧链的9-去氧化-10-氧代四环紫杉烷类。
反应路线3
在反应路线4中叙述了一个反应，10-DAM被还原，生成五醇13(Pentaol)。五醇13的C7和C10羟基可选择性地被三乙基甲硅烷基或其它保护荃保护，生成三醇14,C13侧链可与其相连接或在四环取代化合物经进一步修饰后与其相连。
反应路线4
反应路线4
具有C9和/或C10酰氧基取代基而不是乙酸酯基的紫杉烷可按反应路线5所述的以10-DAM作起始原料来制备。10-DAB与三乙基甲硅烷基氯化物在吡啶中的反应，产生7位保护的10-DAB15。7位保护的10-DAB15的C10羟基取代基可以与任何标准的酰化剂容易地进行酰化反应，生成具有新的C10酰氧取代基的衍生物16。衍生基物16C9酮取代基的选择性还原，生成9β-羟基衍生物17,C13侧链可与其相连。另外，C10和C9基团可按上述反应路线2中所述的过程被引起迁移。
反应路线5
具有C2和/或C4酯的紫杉烷可用浆果赤霉素Ⅲ和10-DAB作超始原料来制备。浆果赤霉素Ⅲ和10-DAB的C2和/或C4酯可使用如LAH或Red-Al之类的还原剂，被选择性地还原成相应的醇，使用标准的酰化剂，如酸酐和酰氯(与胺如吡啶，三乙胺，DMAP，或二异丙基乙基胺相结合的)可取代新酯。另外，通过用合适的碱，如LDA处理醇，然后用酰化剂如酰氯处理之形成相应的烷氧化物，可使C2和/C4醇转化成新的C2和/或C4酯。
在C2和/或C4上具有不同取代基的浆果赤霉素Ⅲ和10-DAB同类物可按所述的反应路线6-10来制备。为简化描述，以10-DA作起始原料。然而应该懂得浆果赤霉素Ⅲ衍生物或其同类物可用相同的反应体系(除C10羟基基团的保护)来制备，所不同的仅仅是用浆果赤霉素Ⅲ代替10-DAB来作起始原料。在C2和/或C4上，具有不同取代基的浆果赤霉素Ⅲ9-脱氧衍生物和10-DAB同类物可通过还原这些同类物的C9酮取代基以及进行上述其它反应来制备。
在反应路线6中，用氢化铝锂可使保护的10-DAB3转化成三醇18。使用溶于吡啶中的CL2CO以及随后的亲核试剂(例如Grig-nard试剂或烷基锂试剂)可使三醇18转化可相应的C4酯。
反应路线6
反应路线6
用LDA，再引入酰氯使三醇18去质子化可以选择性地给出C4酯。例如，使用乙酰氯，按反应路线7可使三醇18转化成1,2-二醇4。
三醇18可以很容易地转化成1,2碳酸酯19。按反应路线8所述的在活泼的标准条件下，碳酸酯19的乙酰化反应可提供碳酸酯21；如向反应路线6所述，向碳酸酯19中加入烷基锂或Grignard试剂可以给出C2酯，其在C4位上具有游离羟基。
反应路线7和反应路线8
反应路线7
反应路线8
如反应路线9所示，其它C4取代基能被提供其是通过碳酸酯19与酰氯和叔胺反应，生成碳酸酯22，然后可进一步与烷基锂或Grignard试剂反应生成C2上具有新取代基的10-DAB衍生物。
反应路线9
反应路线9
另外，浆果赤霉素Ⅲ可以用作起始原料，并接反应路线10所示进行反应。在C7和C13被保护后，浆果赤霉素Ⅲ可用LAH还原成1,2,4,10四醇24。用CL2CO和吡啶使四醇24转化成碳酸酯15，然后用酰氯和吡啶使碳酸酯25在C10上进行酰化，生成碳酸酯26(如所示)，或者也可以用醋酸酐和吡啶作酰化剂(在此未显示)。在活泼的标准条件下进行的碳酸酯26的乙酰化给出碳酸酯27，其可进一步与烷基锂反应，生成C2和C10上具有新取代基的浆果赤霉素Ⅲ衍生物。
反应路线10
反应路线10
使浆果赤霉素Ⅲ或10-DAB(或其衍生物)与碘化亚钐进行反应可以制得浆果赤霉素Ⅲ的10-去乙酰氧基衍生物和10-DAB的10-脱氧衍生物。在具有C10离去基团的四环紫杉烷与碘化亚钐之间的反应可在0℃下，于THF等溶剂中进行。碘化亚钐占优势地选择性进攻C10离去基团；四环核上的C13侧链和其它取代基保持不变。因此，正如所述的C9酮取代基可被还原生成相应的9-脱氧-9β-羟基-10-脱乙酰氧基或10-脱氧衍生物。
C7二氢或其它C7取代的紫杉烷可按反应路线11,12和12a所述方法来制备。
反应路线11
反应路线11
反应路线12
反应路线12a
反应路线13
如反应路线12所述，在室温下，于THF溶液中用FAR对浆果赤霉素Ⅲ进行处理，可使之转化成7-氟浆果赤霉素Ⅲ。其它具有游离C7羟基基团的浆果赤霉素衍生物具有相似的性质。另外，在含有过量三乙胺盐酸盐的CH2CL2中，用甲磺酰氯和三乙胺处理浆果赤霉素Ⅲ，可以制得7-氯浆果赤霉素Ⅲ。
按反应路线12a所述，可制得具有C7酰氧取代基的紫杉烷。通过选择性地除去C13保护基团并用金属，如锂来取代之，可使7,13-保护的10-氧代-衍生物11转化成其相应的C13烷氧化物。然后此烷氧化物与β-内酰胺或其它侧链前体进行反应。随后，C7保护基团的水解可引起C7羟基取代基向C10的迁移，C10氧化取代基向C9的迁移，以及C9酰氧取代基向C7的迁移。
如反应路线13所示，通过三甲基氧翁四氟化硼酸盐在CH2CL2溶液中的作用，7-O-三乙基甲硅烷基浆果赤霉素Ⅲ可以转化成三环紫杉烷。然后，产物二醇与四醋酸铅反应，得到相应的C4酮。
反应路线13反应路线13
反应路线4中的亚反应步骤可用于不同阶段，例如，化合物30至化合物33的转化步骤可以应用于任何在C10上具有羟基及C9上两个氢原于的中间体，例如，用于引入C9和C10羰基和羟基基团的方法步骤可以应用于合适保护的中间体4-29。
同样，引入CL和C2含氧功能团(反应路线A中6-13的转化)的步骤可以应用于具C3羰基基团的任何中间体。
相似的，如反应路线6-10中所举例的C2和C4酰基基团的引入步骤，可应用于任何具有C1-C2碳酸酯的中间体。
同样，在反应路线A由24a至27a转化中举例的形成螺[4,4]环氧己烷的步骤，可应用于具C4羰基基团的各种中间体。
在反应路线A5至6的转化中举例的醛醇，步骤可应用于任何具有C3羰基基团和C8a氢原子合适保护的中间体。在此步骤中，各种酮或醛可作为反应剂。
任何中间体中的1,2或1,3-二醇亚单位形成环碳酸酯的反应，可使用光气(碳酰氯)作为反应剂来进行。羰基基团可用氢化试剂或金属物质还原生成相应的醇。使用反应路线中举例的各种氧化剂对醇进行氧化。可使之生成相应的羰基基团。
在本发明中公开的化合物具有几个不对称碳原子，因此能以非对映体，外消旋体或光学活性形式存在。所有这些形式均被视为在本发明范围内。更具体地说，本发明包括对映体，非对映体，外消旋混合物以及这里分开发表的化合物的其它混合物。
下列实例将说明本发明。
实例
反应路线A
三乙基甲硅烷氧基醇3，室温下，向二醇2(3.16g,13.4mmol)及DMAP(70mg,0.57mmol)的CH2CL2(65ml)溶液中加入三乙胺(3.7ml,26.6mmol)，然后滴加TESCL(2.7ml,16.1mmol)。1.75小时后，用150ml己烷稀释反应混合物，然后倾入100ml饱和NaH-CO3水溶液和150ml己烷中。有机相用饱和NaHCO3水溶液(100ml×2)及100ml水洗涤，无水Na2So4干燥，减压浓缩，得4.88g三乙基甲硅烷氧基醇3粗品。供分析使用的样品可通过塞过滤(短的硅胶垫)来实现，以己烷作洗涤液，然后用5％乙酸乙酯的己烷溶液来洗脱化合物3(P10=TES)(无色油状)的纯品。3(P10=TES):1H NMR(300MHz,CDCl3)δ0.61(q,J=7.7Hz,6H,TES CH2),0.89(s,3H,CH3 16),0.96(t,J=7.7Hz,9H,TES CH3),1.03(d,J=7.1Hz,3H,CH3 19),1.07(s,3H,CH3 17),1.23(d,J=14.3Hz,1H,H2α),1.56(dd,J=6.0,6.0Hz,1H,H7),1.76(ddd,J=5.0,11.0,13.7Hz,1H,H9),1.90(ddd,J=2.2,8.8,15.4Hz,1H,H9),1.96(m,1H,H14α),2.37(m,2H,H2β,H14β),2.51(ddd,J=7.7,7.7,10.4Hz,1H,H8α),2.94(s,1H,OH-3),4.21(dd,J=2.2,5.0Hz,1H,H10),5.43(dd,J=2.8,2.8Hz,1H,H13).13C NMR(75MHz,CDCl3)δ(ppm)4.8(TES CH2),6.7(TES CH3),15.02(CH3 19),23.0(CH3 17),26.2(CH3 18),28.0(CH3 16),33.6(C14),41.5(C8),44.2(C2),45.0(C1),45.2(C15),45.8(C9),69.6(C11),74.9(C10),96.0(C3),123.0(C13),143.7(C12)；IR(CHCl3)υ3530,2970,2930,2900,1460,1340,1140,1100,1080,1045,1010,970,915,650cm-1；MS(CI)351(M+1,58),333(100),219(34).
羟基酮4,0℃且有氮气氛中，向剧烈搅拌的化合物3(P10=TES)粗品的无水CH2CL2(30ml)溶液中加入Ti(oipr)4(13.5ml,43.1mmol)溶液。然后滴加无水2M+-BuOOH的己烷(18ml,36mmol)溶液。45分钟后在5分钟内慢慢加入二甲硫(15ml)，溶液在0℃下搅拌10分钟，然后室温下放置15分钟，再移至55℃的热溶上回流8小时。减压蒸除溶剂生成的原浆状物溶于乙酸乙酯(850ml)中，在剧烈搅拌下滴加3.5mlH2O。生成的混合物于室温下搅拌1小时，经硅藻土过滤，进一步用乙酸乙酯(100ml×2)洗涤。减至蒸除溶剂，得一油状物，其经短硅胶填充柱过滤，以10％乙酸乙酯的己烷溶液作洗脱液，得4.78g羟基酮4(P10=TES)(无色油状物)纯品。4(P10=TES):1H NMR(300MHz,CDCl3)δ0.58(q,J=7.7Hz,6H,TES CH2),0.94(t,J=7.7Hz,12H,CH3 19,TES CH3),0.98(s,3H,CH317),1.31(s,3H,CH3 16),1.71(dd,J=5.0,11.5Hz,1H,H2α),1.85(m,3H,H1,H9β,H14β),1.96(s,3H,CH3 18),2.15(d,J=12.1,1H,OH-13),2.22(ddd,J=4.9,13.2,15.9Hz,1H,H9α),2.56(dddd,J=3.8,7.1,13.7,13.7Hz,1H,H8α),2.75(dd,J=2.2,11.0Hz,1H,H2β),2.80(ddd,J=4.4,7.7,11.0Hz,1H,H14β),4.10(t,J=11.0HZ,1H,H13β),4.56(d,J=5.0Hz,1H,H10β)；13C NMR(75MHz,CDCl3)δ(ppm)4.3(TES CH2),6.5(TES CH3),13.4(CH3 18),18.4(CH3 19),25.8(CH3 17),27.1(CH3 16),34.7(C14),38.2(C15),38.8(C2),44.0(C8),44.2(C9),47.8(C1),67.3(C13),69.7(C10),137.3(C11),138.8(C12),219.2(C3)；IR(CHCl3)υ3550,2960,2880,1660,1460,1410,1240,1200,1160,1140,1080,1050,1000,980,900,810cm-1；MS(CI)367(M+1,2),349(100),331(55).
酮5。-23℃氮气氛中，向羟基酮4(P10=TES)的无水吡啶(25ml)溶液中滴加TBSOTf(3.2ml,13.9mmol)。5分钟后，将烧瓶移至冰溶上，搅拌1.75小时，0℃下用75ml己烷稀释溶液，然后将其从不溶性的油状物中倾析入饱和NaHCO3水溶液(200ml)中。用己烷75ml×3)对剩下的油状物进行提取，合并有机相，依次用饱和NaHCO3水溶液(50ml×2)、50ml水洗涤，无水Na2SO4干燥，减压浓缩。所得的黄色油状物经短硅胶填充柱过滤，以10％乙酸乙酯的己烷溶液作洗脱液，得4.78g酮5(P10=TES,P13=TBS)纯品(从2计产率为94％)。
元素分析：C27H52O3Si2
理论值：C,67.44；H,10.90
实侧值：C,67.31；H:10.785(P10=TES,P13=TBS):1H NMR(300MHz,CDCl3)δ0.03(s,3H,TBS CH3),0.05(s,3H,TBS CH3),0.57(q,J=8.2Hz,6H,TES CH2),0.93(t,J=82Hz,9H,TES CH3)0.93(s,9H,TBS t-Bu),0.96(d,J=1.8Hz,3H,CH3 19),1.06(s,3H,CH3 17),1.33(s,3H,CH316),1.68(dd,J=5.5,11.5Hz,1H,H2α),1.84(m,2H,H1,H93),1.89(s,3H,CH3 18)1.92(dd,J=6.0,14.3Hz,1H,H14α),2.21(ddd,J=5.5,13.2,15.4Hz,1H,H9α),2.39(ddd,J=8.2,10.4,14.3Hz,1H,H14β),2.52(ddd,J=3.9,7.1,13.6Hz,1H,H8α)2.66(dd,J=2.8,115Hz 1H,H2β),4.45(dd,J=5.5,10.4Hz,1H,H13β),4.61(d,J=5.0Hz,1H,H10β):13C NMRδ(ppm)-5.4(TBS CH3),-4.6(TBS CH3),4.3(TES CH2),6.5(TESCH3),14.1(CH3 18),17.9(TBS C(CH3)3),19.1(CH3 19),25.4(CH3 17),25.8(TBSC(CH3)3),26.8(CH3 16),33.5(C14),38.6(C15),39.4(C2)43.7(C8),44.4(C9),47.5(C1)67.5(C13),69.5(C10),136.8(C11),138.8(C12),213.5(C3)；IR(CHCl3)υ2950,2900,1680,1460,1420,1395,1365,1250,1200,1110,1080,1000,900,860,840cm-1；MS(CI)481(M+1,3),463(16),349(100),331(50)；
酮碳酸酯6。在室温氮气氛下，向搅拌着的二异丙胺(0.60ml,4.28mmol)的THF(11ml)溶液中加入1.26ml3.1M(3.89mmol)MeMgBr的乙醚溶液。3小时后，于室温下滴加酮5(P10=TES,P13=TBS)(750mg,1.56mmol)的THF(3.5ml)溶液。1.5小时后，将混合物冷却至-23℃，沿瓶壁滴加4-戊烯醛(327mg,3.89mmol)的THF(4ml)溶液。1小时后，加入10ml饱和NH4CL溶液，2分钟后，用100ml己烷稀释，然后倾入100mlH2O中。有机层依次用100ml水，100ml盐水洗涤，无水Na2SO4干燥，减压浓缩得0.92g黄色油状物。-23℃且氮气氛下，向此粗品的CH2CL2(10ml)和吡啶(10ml)混合溶液中中滴加入2.3ml4M碳酰氧的甲苯溶液，反应混合物温热至-10℃,30分钟后，加入乙醇(3.7ml)，生成的混合物搅拌30分钟，然后用300ml己烷稀释，依次用200ml饱和NaHCO3水溶液，200ml10％CuSO4溶液，200ml水，200ml饱和NaHCO3水溶液及200ml盐水洗涤，无水Na2SO4干燥，减压浓缩得1.05g黄色固体，基经硅胶过滤，以10％乙酸乙酯己烷溶液作洗脱液，得965mg白色固体，进一步经硅胶层析纯化，以2％乙酸乙酯的己烷溶液作洗脱液，得745mg(75％)的酮碳酸酯6(P10=TES,P13=TBS,R=Et)，其为白色固体，此产品可分离出比例为6∶1的构象异构体，下列的NMR数据是主要异构体的数据。
元素分析：C35H64O6Si2
理论值：C,65.99；H,10.13
实侧值：C,65.88；H:10.176(P10=TES,P13=TBS,R=Et):mp103-104℃；1H NMR(500MHz,CDCl3)δ0.08(s,3H,TBS CH3),0.08(s,3H,TBS CH3),0.56(q,J=7.8Hz,6H,TES CH2),0.94(t,J=7.8Hz,9H,TES CH3),0.96(s,9H,TBS t-Bu),1.08(s,3H,CH3 17),1.29(m,1H,H6),1.38(s,3H,CH3 19),1.42(s,3H,CH3 16),1.66(dd,J=4.6,12.5Hz,1H,H9α),1.83(s,3H,CH318),1.85(dd,J=4.5,4.5Hz,1H,H14α),2.05(m,1H,H5),2.06(dd,J=6.4,14.2Hz,1H,H5),2.47(m,2H,H9α,H6),3.01(dd,J=3.7,12.3Hz,1H,H14β),4.20(m,2H,H2α,H2β),4.47(d,J=7.3Hz,1H,H13β),4.50(dd,J=4.6,11.4Hz,1H,H10β),4.91(dd,J=1.83,10.1Hz,1H,H20),4.97(dd,J=1.8,16.9Hz,1H,H20),5.29(dd,J=0.9,10.1Hz,1H,H7),5.73(dddd,J=6.9,6.9,10.5,16.9Hz,1H,H4)；13C NMRδ(ppm)-5.3(TBSCH3),-4.5(TBS CH3),4.8(TES CH2),6.5(TES CH3),14.0(OEt CH3),15.5(CH3 19),15.9(CH3 18),18.1(TBS C(CH3)3),25.8(CBS C(CH3)3),27.6(CH3 17),28.2(CH3 16),30.4,30.5(C5,C6),34.1(C14),39.0(C15),41.1(C2),47.1(C1),47.5(C9),55.1(C8),63.8(OEt CH2),66.3(C13),68.3(C10),84.0(C7),114.8(C20),134.8(C11),138.1(C4),144.9(C12),155.7(Etnylcarbonate C=O),214.8(C3)；IR(CCl4)υ3000,2950,2900,1770,1700,1490,1390,1280,1140,1100,1030,910,880,860cm-1；MS(EI)636(M,100),593(20),538(34),409(33)；
羟基酮7,-35℃氮气氛下，10分钟内，沿瓶壁向搅拌着的酮碳酸酯6(P10=TES,P13=TBS,R=Et)(4.00g,6.28mmol)的THF(65ml)溶液中加入50ml,0.2MLDA(10mmol)的THF溶液。30分钟，将其冷却至-78℃，沿瓶壁滴加入2.29g(R)-樟脑磺酰基氧杂氮丙啶(10mmol)的THF(18ml)溶液。30分钟后，用300ml饱和NaHCO3水溶液终止反应，然后依次用500ml及150ml25％乙酸乙酯己烷溶液提取。合并有机层，盐水洗涤，无水Na2SO4干燥，减压浓缩，得7g蜡状固体。此物经闪柱层析纯化，以3％乙酸乙酯己烷溶液洗脱，得3.50g羟基酮7(P10=TES,P13=TBS,R=Et),(85％)。7(P10=TES,P13=TBS,R=Et):1H NMR(500MHz,CDCl3)δ0.01(s,3H,TBS CH3),0.03(s,3H,TBS CH3),0.50(q,J=7.8Hz,6H,TES CH2),0.87(t,J=7.8Hz,9H,TESCH3),0.90(s,9H,TBS t-Bu),1.03(s,3H,CH3 17),1.25(t,J=7.0Hz,3H,OEt CH3),1.35(s,3H,CH3 19),1.40(m,1H,H6),1.41(s,3H,CH3 16),1.66(dd,J=4.6,12.8Hz,1H,H9β),1.77(d,J=1.4Hz,3H,CH3 18),1.83(dd,J=6.0,14.7Hz,1H,H14α),1.97(dd,J=4.1,8.5Hz,1H,H1),2.02(m,2H,H5,H5),2.44(dd,J=11.9,11.9Hz,1H,H9α),2.75(d,J=10.5Hz,1H,OH-2),4.14(q,J=14.2Hz,2H,OEt CH2),4.35(dd,J=6.0,8.7Hz,1H,H13),4.42(dd,J=4.6,11.0Hz,1H,H10),4.49(dd,J=4.1,10.1Hz,1H,H2),4.86(dd,J=1.8,10.3Hz,1H,H20),4.92(dd,J=1.8,16.9Hz,1H,H20),5.23(dd,J=1.4,10.1Hz,1H,H7),5.67(dddd,J=6.9,6.9,10.5,16.9Hz,1H,H4)；13C NMRδ(ppm)-5.3(TBS CH3),-4.5(TBS CH3),4.7(TES CH2),6.5(TES CH3),14.0(OEt CH3),15.0(CH319),16.0(CH3 18),18.0(TBS C(CH3)3),25.8(TBS C(CH3)3),27.5,27.8(CH3 17),28.1(CH3 16),30.4,30.5(C5,C6),36.9(C15),47.3(C9),54.5(C1),54.7(C8),63.9(OEt CH2),66.2(C13),67.8(C10),70.3(C2),83.6(C7),114.9(C20),135.4(C11),137.9(C4’),144.5(C12),155.6(Ethylcarbonate C=O),217.8(C3)；IR(CCl4)υ3600,2950,2900,1750,1700,1660,1470,1400,1370,1240,1080,1050,1000,840,680cm-1；MS(CI)653(M+1,8),564(100),431(69),389(67).
羟基碳酸酯8,-78℃氮气氛下，沿瓶壁向剧烈搅拌的羟基酮7(P10=TES,P13=TBS,R=Et)(2.69g,4.12mmol)的甲苯(117ml)溶液中滴加85ml,0.97M Red-Al(82.4mmol)的甲苯溶液。6小时后，-78℃下，于6小时内使之逐渐升至室温，再重新冷却至-10℃，沿瓶壁滴加125ml 2M乙酸(250mmol)的THF溶液。将此浑浊混合物搅拌10分钟，倾入1200ml50％乙酸乙酯的己烷溶液中，用IL饱和NaHCO3水溶液洗涤，水相用乙酸乙酯(500ml×4)提取，合并有机层，用盐水洗涤，无水Na2SO4干燥，减压浓缩，得2.29g2,3,7三醇，其为白色固体，此物无须纯化即可用于下一步反应。
-78℃氮气氛下，向剧烈搅拌的三醇(2.29g,3.93mmol)在CH2CL2(157ml)和吡啶(15.7ml)的溶液中快速加入7.6ml3.0M碳酰氯(23mmol)的甲苯溶液。1小时内使之升至室温，然后倾入250ml乙酸乙酯中，用125ml×2饱和NaHCO3水溶液及100ml盐水洗涤，无水Na2SO4干燥，减压浓缩得2.52g黄色油状物。此物经2英寸硅胶垫过滤，以50％乙酸乙酯的己烷溶液作洗脱液，减压浓缩，得2.39g(95％，从7起始计)羟基碳酸酯8(P10=TES,P13=TBS)，其为白色固体。
元素分析：C33H60O6Si2
理论值：C,64.92；H,9.90
实侧值：C,65.13；H:9.888(P10=TES,P13=TBS):mp155-157℃,1H NMR(500MHz,CDCl3)δ0.09(s,3H,TBSCH3),0.10(s,3H,TBS CH3),0.59(q,J=8.2Hz,6H,TES CH2),0.96(t,J=8.2Hz,9H,TES CH3),0.97(s,9H,TES t-Bu),1.11(s,3H,CH3 19),1.14(s,3H,CH3 17),1.30(s,3H,CH3 16),1.39(dd,J=4.1,13.3Hz,1H,H9β),1.65(m,2H,H6,H6),1.99(dd,J=6.4,15.1Hz,1H,H14α),2.01(d,J=9Hz,3H,CH3 18),2.04(d,J=3.7Hz,1H,H1),2.11-(ddd,J=7.3,15.6,15.6Hz,1H,H5),2.28(ddd,J=9.6,9.6,14.2Hz,1H,H14β),2.34(dd,J=12.4,13.3Hz,1H,H9β),2.41(m,1H,H5),3.87(dd,J=0.9,10.5Hz,1H,H7),3.95(d,J=3.7Hz,1H,H2),4.59(dd,J=3.7,11.4Hz,1H,H10β),4.40(s,1H,H3),4.55(dd,J=6.4,8.7Hz,1H,H13),5.03(d,J=10.5Hz,1H,H20),5.07(dd,J=1.5,17.0Hz,1H,H20),5.77(m,1H,H4)；13C NMRδ(ppm)-5.4(TBS CH3),-4.4(TBS CH3),4.8(TESCH2),6.5(TES CH3),15.5(CH3 18),17.9(TBS C(CH3)3),18.2(CH3 19),25.6(TBSC(CH3)3),25.9(CH3 16),27.5(CH3 17),28.3(C6),28.4(C5),29.8(C14),30.8(C15),36.5(C8),36.8(C9),37.3,50.8(C1),66.6(C10),678(C13),70.5(C2),91.9(C3),91.9(C7),116.3(C20),123.7(C11),137.9(C4’),142.6(C12),148.0(cyciic carbonate C=O)；IR(CCl4)υ3450,2950,2870,1750,1460,1380,1350,1220,1120,1080,1040、980,900,820,710cm-1；MS(CI)625(M+1-H2O,6),551(11),477(100),459(12),433(8),344(90)；
酮碳酸酯9,-78℃氮气氛下，向剧烈搅拌的二甲亚砜(2.41ml,34mmol)的CH2CL2(57ml)溶液中加入8.5ml2.0M草酰氧(17.0m-mol)的CH2CL2溶液。10分钟后，沿瓶壁滴加羟基碳酸酯8(P10=TES,P13=TBS)(3.45g,5.67mmol)的16mlCH2CL2溶液。30分钟后，-78℃下，加入三乙胺(6.8ml,49mmol)，然后使之升至室温。用200ml己烷稀释，用饱和NaHCO3水溶液(75ml×2)及盐水洗涤，无水Na2SO4干燥，减压浓缩得3.45g黄色固体。此物经1英寸硅胶垫过滤，以10％乙酸乙酯己烷溶液洗脱，再用己烷重结晶，得2.62g酮碳酸酯9，其为白色结晶。母液经硅胶层析纯化，以10％乙酸乙酯己烷溶液洗脱，再用乙烷重结晶，又得0.58g，酮碳酸酯9(P10=TES,P13=TBS)总产率：3.20g 93％)。
元素分析：C33H58O6Si2
理论值：C,65.30；H,9.63
实侧值：C,65.23；H:9.669(P10=TES,P13=TBS):mp140.0-141.5℃；1H NMR(500MHz,CDCl3)δ0.11(s,3HTBS CH3),0.12(s,3H,TBS CH3),0.60(q,J=7.8Hz,6H,TES CH2),0.96(t,J=7.8Hz,9H,TES CH3),0.98(s,9H,TBS t-Bu),1.06(s,3H,CH3 19),1.17(s,6H,CH3 16,CH3 19),1.42(dd,J=3.7,14.2Hz,1H,H9β),1.63(m,2H,H6,H6),2.12(m,1H,H5),2.38(d,J=0.9Hz,3H,CH3 18),2.47(dd,J=11.4,13.3Hz,1H,H9α),2.65(d,J=8.2,1H,H1),3.94(dd,J=1.4,10.4Hz,1H,H7),4.44(dd,J=3.7,11.4Hz,1H,H10),4.49(s,1H,H3),4.64(dd,J=6.9,7.8Hz,1H,H13),5.04(dd,J=1.4,11.9Hz,1H,H20),5.07(dd,J=1.8,17.4Hz,1H,H20),5.76(m,1H,H4)；13C NMRδ(ppm)-5.4(TBS CH3),-4.5(TBS CH3),4.8(TES CH2),6.5(TES CH3),15.7(CH3 18),17.8(CH3 19),17.9(TBS C(CH3)3),25.5(TBSC(CH3)3),28.2(CH3 16),28.3(CH3 17).28.3(C6),29.6(C5),30.4(C14),37.7(C15),38.0(C8,C9),62.1(C1),66.5(C10),67.5(C13),91.3(C3),91.5(C7),116.4(C20),132.8(C11),137.0(C4’),145.4(C12),146.6(cyclic carbonatc C=O),206.8(C2)；IR(CCl4)υ2930,2860,1760,1670,1450,1380,1340,1240,1180,1170,1120,1090,1060,1040,980,890,860,820,700,650cm-1；MS(CI)607(M+1,6),549(11),475(100),431(4),347(45)；
2-酮-3-羟基内酯10,-25°下，沿瓶壁向搅拌着的3.7-环碳酸酯9(P10=TES,P13=TBS)(2.246g,3.70mmol)的THF(9ml)溶液中滴加入19.4ml0.2M LTMP(3.88mmol)的THF溶液。30分钟内使之升至-10℃。将其倾入100ml10％乙酸水溶液中，用100ml10％乙酸乙酯的己烷溶液提取，有机相用50ml饱和NaHCO3水溶液及50ml盐水海洗涤。合并水相，用10％乙酸乙酯的己烷溶液(20ml×2)提取。合并有机相，无水Na2SO4干燥，减压浓缩，得2.4g黄色油状物。此物经硅胶层析纯化，以5％，后10％的乙酸乙酯的己烷溶液洗脱，得2.033g(90％)羟基内酯10(P10=TES,P13=TBS)，其为泡沫状固体以及0.207g(7.2g)的3-氨基甲酸酯。
元素分析：C33H58O6Si2
理论值：C,65.30；H,9.63
实侧值：C,65.38；H:9.6410(P10=TES,P13=TBS):1H NMR(500MHz,CDCl3)δ0.12(s,3H,TBS CH3),0.14(s,3H,TBS CH3),0.61(q,J=7.8Hz,6H,TES CH2),0.92(s,9H,TBS t-Bu),0.97(t,J=7.8Hz,9H,TES CH3),1.11(s,3H,CH3 17),1.22(s,3H,CH3 19),1.27(s,3H,CH3 16),1.32(dd,J=3.2,13.3Hz,1H,H9β),1.64(ddd,J=2.3,6.9,9.2Hz,1H,H6),2.07(m,2H,H6,H5),2.17(m,1H,H14α),2.33(m,1H,H5),2.65(m,2H,H14β,H1),2.74(dd,J=12.4,12.4Hz,1H,H9α),3.92(dd,J=2.8,11.5Hz,1H,H7),4.47(dd,J=3.2,11.0Hz,1H,H10),4.55(dd,J=2.8,9.6Hz,1H,H13),5.02(d,J=10.1Hz,1H,H20),5.07(dd,J=1.4,16.9Hz,1H,H20),5.81(dddd,J=6.9,6.9,10.5,16.9Hz,1H,H4)；13C NMRδ(ppm)-5.2(TBS CH3),-4.5(TBS CH3),4.8(TES CH2),6.6(TES CH3),16.4(CH3 18),17.9(TBSC(CH3)3),24.2(CH3 19),25.7(TBS C(CH3)3),26.9(CH3 16),30.1(CH3 17),30.4(C5),32.7(C6),32.9(C14),39.1(C15),40.6(C9),48.1(C8),62.0(C1),673(C10),67.6(C13),87.9(C3),91.1(C7),115.8(C20),137.7(C11),138.5(C4’),143.0(C12),173.5(C4),207.6(C2)；IR(CCl4)υ3500,2970,2900,1780,1700,1480,1360,1260,1210,1160,1070,1010,910,890,840cm-1；MS(EI)606(M,100),549(69),474(27),431(65),417(40)；
酮内酯11，向2-酮-3-羟基内酯10(P10=TES,P13=TBS)(1.10g,1.83mmol)中加入0.1M SmI2的THF溶液(82ml,8.2mmol)。生成的深兰色溶液于室温下氦气下搅拌4小时。冷却至0℃后，加入HCL(0.66M；4.2ml,2.77mmol)的醚溶液，5分钟后，打开烧瓶，反应混合物用200ml冷的乙酸乙酯稀释，然后倾入50ml，冰冷的02.NlCH溶液中。分出有机层，依次用50ml5％的柠檬酸水溶液，饱和NaHCO3水溶液(50ml×2)以及50ml盐水洗涤，无水Na2SO4干燥，减压浓缩。将生成物溶于100ml己烷中，加硅胶(230-400目；4.3g)，混合物在室温下剧烈搅拌65分钟，然后经1英寸硅胶垫过滤，以300ml20％乙酸乙酯的己烷溶液洗脱。减压蒸除溶剂，残渣经硅胶展析纯化，以10％乙酸乙酯的己烷溶液洗脱，得822mg(77％)顺式一酮内酯11以及164mg(15％)相应的反式异构体。
0℃氮气下，向搅拌着的反式2-酮内酯(611mg,1.03Hmmol)的10mlTHF溶液中沿瓶壁加入6.8ml0.6M叔-BuOK(4.1mmol)的THF溶液。生成物搅拌1.5小时，沿瓶壁加入10ml10％乙酸的THF溶液。搅拌5分钟后，用200ml己烷稀释，倾入100ml饱和NaHCO3水溶液中。有机层用水，盐水洗涤，无水Na2SO4干燥，减压浓缩，得615mg灰棕色油状物。将此油溶于10ml己烷中，加入硅胶(3.0g)，混合物剧烈搅拌15分钟，经1/2英寸的硅胶垫过滤，以20％乙酸乙酯的己烷溶液洗脱，减压浓缩，得576mg灰黄色油状物。此物经硅胶层析纯化，以10％，后20％的乙酸乙酯的己烷溶液洗脱，得472mg(77g)纯顺式-2-酮内酯11(P10=TES,P13=TBS),84mg(13％)纯反式-异构体以及24mg6∶1的顺式：反式异构体。
元素分析：C33H58O6Si2
理论值：C,65.07；H,9.89
实侧值：C,65.97；H:9.9111(P10=TES,P13=TBS):mp=86.5-88.0℃；1H NMR(500MHz,CDCl3)δ0.05(s,3H,TBS CH3),0.07(s,3H,TBS CH3),0.54(q,J=7.8Hz,6H,TES CH2),0.84(s,9H,TBSt-Bu),0.90(t,J=7.8Hz,9H,TES CH3),1.03(s,3H,CH3 17),1.11(s,3H,CH3 16),1.15(s,3H,CH3 19),1.35(dddd,J=4.6,4.6,7.3,14.2Hz,1H,H6),1.43(dd,J=3.7,12.8Hz,1H,H9β,),1.67(dddd,J=3.2,7.3,10.1,13.7Hz,1H,H6),1.83(dd,J=4.6,16.0Hz,1H,H14α),2.03(m,1H,H5),2.07(d,J=1.4Hz,3H,CH3 18),2.25(m,1H,H5),2.30(dd,J=11.9,12.3Hz,1H,H9α),2.45(d,J=8.2Hz,1H,H1),2.58(ddd,J=8.7,9.2,16.0Hz,1H,H14β),3.93(dd,J=2.8,11.4Hz,1H H7β),4.03(s,1H,H3α),4.37(dd,J=3.7,11.0Hz,1H,H10β),4.46(ddd,J=1.4,4.6,9.2Hz,1H,H13β),4.96(dd,J=1.4,10.1Hz,1H,H20),5.01(dd,J=1.4,17.4Hz,1H,H20),5.73(dddd,J=6.4,7.3,10.5,16.9Hz,1H,H4)；13CNMRδ(ppm)-5.3(TBS CH3),-4.6(TBS CH3),4.5(TES CH2),6.5(TES CH3),15.0(CH318),18.0(TBS C(CH3)3),25.7(TBS C(CH3)3),28.9(CH3 19),29.2(CH3 16),29.8(C5),29.9(CH3 17),30.3(C6),32.8(C14),38.5(C15),44.2(C8),44.9(C9),60.6(C3),61.2(C1),66.9(C10),67.8(C13),91.9(C7),115.7(C20),137.7(C11),138.5(C4’),142.4(C12),174.7(C4),204.8(C2)；IR(CCl4)υ2975,2899,1780,1705,1460,1355,1260,1180,1070,1060,1000,830cm-1；MS(CI)591(M+1,5),523(6),459(100),441(5)；
1-羟基-2-酮-内酯12,-10℃氮气下，向34.2ml，搅拌着的0.2M LTMP(6.84mmol)的THF溶液中，沿瓶壁滴加入酮内酯11(P10=TES,P13=TBS),(1.008g,1.71mmol)的10mlTHF溶液。0.5小时后，将混合物冷却至-40℃，沿瓶壁滴加入(土)樟脑磺酰基氧杂氮丙啶(1.96g,8.55mmol)的THF(10ml)溶液，20分钟后，将混合物冷却至-78℃，用200ml己烷稀释，迅速倾入250ml剧烈搅拌着的饱和NH4CL水溶液中。水相用己烷(50ml×2)提取，有机层合并，无水Na2SO4干燥，减压浓缩，得1.4g蜡状固体。此物经层析(先用CH2CL2，后用含比例渐增至10％乙酸乙酸的己烷作洗脱液)得0.882g羟基酮内酯12(P10=TES,P13=TBS),(85％)，其为白色固体，0.083g相应的反式羟基酮内酯(8％)，其为固体，以及31mg回收的酮内酯11(3％)。
元素分析：C33H58O6Si2
理论值：C,65.30；H,9.63
实侧值：C,65.19；H:9.6012(P10=TES,P13=TBS):mp124-126℃；1H NMR(C6D6)δ(ppm)0.09(s,3H,CH3 inTBDMS),0.17(s,3H,CH3 in TBDMS),0.62(q,J=7.78Hz,6H CH2’s in TES),1.03(t,J=7.78,9H CH3’s in TES),1.05(s,3H,CH3 19),1.13(s,9H,t-Bu in TBS),1.20(s,3H,CH3 17),1.39(m,1H,H6),1.42(s,3H,CH3 16),1.44(dd,J=0.92,13.28Hz,Hi,H9β),1.98(dd,J=9.61,12.82Hz,1H,H14β),2.05(m,1H,H5),2.06(broad,1H,OH1,D2Oexchangable),2.25(m,1H,H6),2.27(d,J=0.91Hz,3H,CH3 18),2.29(m,1H,H5),2.41(dd,J=10.98,13.28Hz,1H,H9α),2.56(dd.J=3.21,12.82Hz,1H,H14α),3.83(dd,J=2.75,11.90Hz,1H,H7),4.04(s,1H,H3),4.47(dd,J=0.92,10.98Hz,1H,H10),4.60(ddq,J=0.91,3.21,9.61Hz,1H,H13),5.11(brd,J=10.53Hz,1H,H20),5.18(brd,J=17.40Hz,1H,H20),5.77(m,1H,H4)；13C NMR(CDCl3)δ(ppm)-5.4(TBS CH3),-4.7(TBS CH3),4.5(TE5 CH2),6.5(TES CH3),15.5(CH3 18),17.9(TBS C(CH3)3),22.5(CH319),25.7(TBS C(CH3)3),26.3(CH3 16),29.8(CH3 17),29.8(C5),30.4(C6),39.6(C14),41.3(C15),44.5(C9),45.0(C8),58.1(C3),66.5(C10),68.2(C13),83.0(C1),91.7(C7),115.7(C20),137.0(C11),137.6(C4’),145.5(C12),175.0(C4),202.4(C2)；IR(CCl4)υ3500,3000,1780,1720,1100cm-1；MS(CI)607(M+1,10),589(56),475(100),457(61)；
1,2-二羟基-反式-内酯13,-78℃氮气下，向搅拌着的1.23M Red-Al(4.6mmol,5.6mmol)的THF溶液中快速加入顺式-羟基酮12(P10=TES,P13=TBS),(342mg,0.563mmol)的THF(25ml)溶液。1.5小时后，直接向其中滴加入25ml15％NaOH溶液，室温下剧烈搅拌3小时，然后倾入100mlH2O中，用乙醚(100ml×2)提取。合并有机层，用100ml水，100ml盐水洗涤，无水Na2SO4干燥，减压浓缩得0.35g灰黄色固体。此物经硅胶层析，以10％乙醚的己烷溶液，后以25％乙酸乙酯的己烷溶液洗脱，得290mg反式-二醇13，其为无色针状物，14.5mg(4.2％)反式一羟基酮，以及20mg顺式-二醇和未知副产物的混合物。室温氮气下向此含顺式二醇的混合物THF(1ml)溶液中加入0.5ml30％NaOH溶液。2.5小时后，将其倾入30mlH2O中，用30ml乙醚提取。有机层用30mlH2O30,ml盐水洗涤，无水Na2SO4干燥，减压浓缩，得0.028黄色固体，其再经硅胶层析纯化，以5％乙酸乙酯的己烷溶液洗脱，又得12mg(总产量：302mg,88％)反式-二醇13(P10=TES,P13=TBS)。
元素分析：C33H60O6Si2
理论值：C,65.08；H,9.92
实侧值：C,65.08；H:9.9813(P10=TES,P13=TBS):mp127-128℃,1H NMR(500MHz,CDCl3)δ0.09(s,3H,TBSCH3),0.11(s,3H,TBS CH3),0.60(q,J=8.1Hz,6H,TES CH2),0.87(s,9H,TBS t-Bu),0.96(t,J=8.1Hz,9H,TES CH3)1.13(s,3H,CH3 17),1.23(s,3H,CH3 16),1.31(s,3H,CH3 19),1.42(dd,J=3.7,12.8Hz,1H,H9β),1.46(ddd,J=4.8,8.8,11.4Hz,1H,H6),1.74(dddd,J=3.3,7.3,9.9,12.4Hz,1H,H6),1.99(d,J=1.5Hz,3H,CH3 18),2.10(m,1H,H5),2.21(dd,J=3.7,5.4Hz,1H,H14α),2.26(m,3H,H5,H9α,H14β),2.92(d,J=7.7Hz,1H,H3),3.84(dd,J=2.2,7.7Hz,1H,H2),3.85(s,1H,OH1),3.97(dd,J=2.9,11.4Hz,1H,H7),4.47(dd,J=3.7,11.4Hz,2H,H13,H10),5.01(dd,J=1.8,12.2Hz,1H,H20),5.07(dd,J=1.7,17.0Hz,1H,H20),5.78(dddd,J=7.3,7.3,10.1,16.5Hz,1H,H4),6.87(d,J=2.9Hz,1H,OH2),13C NMR(CDCl3)δ(ppm)-5.31,-4.59,4.79,6.55,16.60,17.68,21.24,24.70,25.62,28.50,29.52,30.05,40.20,40.41,44.18,45.18,45.60,66.62,69.25,71.32,88.91,116.09,136.96,138.63,139.93,180.10,IR(CHCl3)υ3050,1730,1460,1350cm-1,MS(EI)608(M,13),590(26),267(100),
碳酸酯14,-78℃氮气下，向搅拌着的二醇13(P10=TES,P13=TBS),(1.00g,1.64mmol)的CH2Cl2(58ml)和吡啶(5.8ml)的溶液中滴加入8.2ml2M碳酰氯(16.4mmol)的甲苯溶液，升温至-23℃，搅拌30分钟，向其中加入50ml饱和NaHCO3水溶液，升温至室温10分钟后，用200ml10％乙酸乙酯的己烷溶液提取。有机层用100ml10％CuSO4水溶液，200ml×2饱和NaHCO3水溶液及盐水洗涤，无水Na2SO4干燥，减压浓缩，得1.1g灰黄色固体。此物经3英寸硅胶垫过滤，以15％乙酸乙酯的己烷溶液洗脱，得1.045g(100％)碳酸酯14((P10=TES,P13=TBS)，其为白色固体。
元素分析：C34H58O7Si2
理论值：C,64.31；H,9.21
实侧值：C,64.41；H:9.2214(P10=TES,P13=TBS):mp146-147℃,1H NMR(500MHz,CDCl3)δ0.11(s,3H,TBSCH3),0.12(s,3H,TBS CH3),0.61(q,J=7.8Hz,6H,TES CH2),0.88(s,9H,TBS t-Bu),0.96(t,J=7.8Hz,9H TES CH3),1.20(s,3H,CH3 17),1.30(s,3H,CH3 16),1.32(s,3H,CH3 19),1.40(ddd,J=2.7,4.5,9.2Hz,1H,H6),1.44(d,J=3.7,13.3Hz,1H,H9β),1.71(dddd,J=2.7,6.9,9.6,12.8Hz,1H,H6),2.11(ddd,J=7.8,15.3,15.3Hz,1H,H5),2.29(dd,J=3.2,15.6Hz,1H,H14α),2.31(m,2H,H5,H9α),2.59(dd,J=9.2,15.6Hz,1H,H14β),2.99(d,J=7.3Hz,1H,H3α),4.02(dd,J=2.7,11.4Hz,1H,H7β),4.38(dd,J=3.7,11.0Hz,1H,H10β),4.47(d,J=7.3Hz,1H,H2β),4.57(dd,J=2.1,9.2Hz,1H,H13β),5.02(dd,J=1.4,10.1Hz,1H,H20),5.06(dd,J=1.4,16.9Hz,1H,H20),5.77(dddd,J=6.9,6.9,10.1,17.0Hz,1H,H4),13C NMR(CDCl3)δ(ppm)-5.37,-4.60,4.75,6.51,17.02,17.60,21.24,24.64,25.55,27.36,29.50,30.11,37.56,39.96,42.89,43.75,45.39,66.54,68.29,87.37,90.05,116.15.136.54,136.94,144.93,153.32,169.89,IR(CHCl3)υ3070,1800cm-1.MS(EI)634(M,12),577(100),
酮酯15,-78℃氮气下，向搅拌着的内酯14(P10=TES,P13=TBS)(1.05g,1.65mmol)的甲醇(70ml)溶液中加入饱和臭氧的CH2Cl2(50ml,40ml，然后是8ml溶液，直至径TLC检查无起始物存在为止。-78℃下顺序加入三乙胺(4.8ml)及三甲基亚磷酸酯(3.1ml)。搅拌3分钟后，升温至0℃，搅拌2小时，将溶液倾入250ml饱和NaHCO3水溶液，然后用CH2CL2(200ml×3)提取，合并有机层，用150ml饱和NaHCO3溶液洗涤，无水Na2SO4干燥，减压浓缩，得1.10g醛，其为无色油状物。此物用于进一步纯化。
0℃下，于2分钟内向搅拌着的醛(1.10g)于叔丁醇(30.8ml)，丙酮(10.3ml)和8ml1.25M(10mmol)的KH2PO4溶液中加入11.3ml1M(11.3mmol)的KMnO4溶液。反应混合物于0℃下搅拌30分钟，倾入200ml10％Na2S2O3溶液中，用乙酸乙酯(200ml×3)提取3次。合并有机层，用50m水洗涤，无水Na2SO4干燥，减压蒸馏。于室温下向搅拌着的油状残渣的醚溶液中加入CH2N2(20ml)的醚溶液。减压浓缩，得1.15g无色油状物。此物经2英寸硅胶垫过滤，以40％乙酸乙酯己烷溶液洗涤，减压浓缩，得1.01g,(91％)的内酸酯15(P10=TES,P13=TBS)。
元素分析：C34H58O9Si2
理论值：C,67.22；H,8.77
实侧值：C,61.30；H:8.7915(P10=TES,P13=TBS,R=Me):1H NMR(500MHz,CDCl3)δ0.12(s,3H,TBS CH3),0.12(s,3H,TBS CH3),0.60(q,J=8.1Hz,6H,TES CH2),0.88(s,9H,TBS t-Bu),0.96(t,J=8.1Hz,9H,TES CH3),1.21(s,3H,CH3),1.30(s,3H,CH3),1.33(s,3H,CH3),1.51(dd,J=3.7,13.2Hz,1H,H9β),1.53(m,1H,H6),2.06(d,J=1.1Hz,3H,CH3 18),2.07(ddd,J=2.9,7.7,21.6Hz,1H,H6),2.29(dd,J=3.7,15.8Hz,1H,H14α),2.31(dd,J=13.2,13.2Hz,1H,H9α),2.46(ddd,J=7.7,16.8,24.5Hz,1H,H5),2.53(ddd,J=5.5,7.7,16.8Hz,1H,H5),2.60(dd,J=9.2,15.8Hz,1H,H14β),2.99(d,J=7.3Hz,1H,H3α),3.68(s,3H,CO2Me),4.09(dd,J=2.6,12.1Hz,1H,H7β),4.39(dd,J=3.7,11.0Hz,1H,H10β),4.47(d,J=7.3Hz,1H,H2β),4.59(dd,J=1.8,9.2Hz,1H,H13β)；
烯醇酯16,-78℃下，向搅拌着的内酯酯15(P10=TES,P13=TBS,R=Me)(1.01g,1.51mmol)的THF(24.5ml)溶液中慢慢沿瓶壁于3分钟内加入19.4ml0.2MLDA(3.88mmol)的THF溶液。搅拌35分钟后，快速加入10ml33％乙酸的THF溶液。5分钟后，将混合物倾入150ml饱和NaHCO3水溶液中，用CHCL3(200ml×3)提取，合并的有机层经无水Na2SO4干燥，减压浓缩，得1.02g稀醇酯16粗品(P10=TES,P13=TBS,R=Me)，其为无色油状物。大约3％未反应的内酯酯15依然存在，但此物无须进行纯化即可使用。16(P10=TES,P13=TBS,R=Me):1H NMR(300MHz,CDCl3)δ0.09(s,3H,TBS CH3),0.10(s,3H,TBS CH3),0.61(q,6H,TES CH2),0.87(s,9H,TBS t-Bu),0.96(t,J=8.0Hz,TES CH3),1.08(s,3H,CH3),1.21(s,3H,CH3),1.33(S,3H,CH3),1.61(d,J=4.3Hz,1H,OH-7),1.89(dd,J=4.3,13.9Hz,1H,H9α),1.95(dd,J=11.2,11.2Hz,1H,H9β),2.01(d,J=1.1Hz,3H,CH3 18),2.22(ddd,J=2.7,10.7,15.5Hz,1H,H6β),2.45(dd,J=4.8,15.5Hz,1H,H6α),2.54(dd,J=9.1,15.0Hz,1H,H14β),2.86(dd,J=3.7,15.0Hz,1H,H14α),3.07(s,1H,H3α),3.40(ddd,J=4.8,4.8,9.6Hz,1H,H7α),3.75(s,3H,CO2Me),4.39(dd,J=4.3,11.2Hz,1H,H10β),4.60(d,J=4.3,11.2Hz,1H,H2β),4.67(dd,J=2.1,9.1Hz,1H,H13β),12.24(s,1H,OH4).
烯醇酯17,0℃氮气下，向搅拌的烯醇酯16粗品(P10=TES,P13=TBS,R=Me)(1.02g)的THF(13ml)和2-甲氧丙烷(13ml)的溶液中加入0.48ml0.1M对甲苯磺酸(0.048mmol)的THF溶液。混合物于0℃下搅拌10分钟，加三乙胺(0.66ml)。减压浓缩，硅胶层析纯化，以7.5％乙酸乙酯的己烷溶液增至30％乙酸乙酯的己烷作洗脱液，得938mg烯醇酯17(P7=TES,P10=TES,P13=TBS,R=Me),(84％，从15起始计)及30mg(3％)回收的内酯酯15。17(P7=MOP,P10=TES,P13=TBS,R=Me):mp 95-97℃,1H NMR(300MHz,CDCl3)δ0.08(s,3H,TBS CH3),0.10(s,3H,TBS CH3),0.59(q,J=7.7Hz,6H,TES CH3),0.87(s,9H,TBS t-Bu),0.95(t,J=7.7Hz,9H,TES CH3),1.10(s,3H,CH3),1.19(s,3H,CH3),1.30(s,3H,CH3),1.34(s,3H,MOP CH3),1.37(s,3H,MOP CH3),1.84(m,2H,H9α,H9β),1.98(s,3H,CH3 18),2.17(ddd,J=2.8,10.4,15.9Hz,1H,H6β),2.52,(dd,J=9.3,15.4Hz,1H,H14β),2.63(dd,J=4.4,15.9Hz,1H,H6α),2.88(dd,J=3.8,15.4Hz,1H,H14α),3.06(s,1H,H3α),3.26(s,3H,MOP OMe),3.37(dd,J=4.4,10.4Hz,1H,H7α),3.72(s,3H,CO2Me),4.36(dd,J=6.0,9.3Hz.1H,H10β),4.57(d,J=2.2Hz,1H,H2β),1.67(dd,J=2.8,9.3Hz,1H,H13β),12.24(s,1H,OH4).
烯醇酯17(P7=TES),0℃下，向烯醇酯16(P10=TES,P13=TBS,R=Me)(9mg,0.0137mmole)和DMAP(3.5mg,0.0286mmole)的吡啶溶液(0.6ml)中加入三乙基甲硅烷基氯化物(0.025ml,0.14mmol)。混合物于室温搅拌16小时，用乙酸乙酯稀释(10ml)，倾入饱和NaHCO3水溶液(20ml)中，用20％乙酸乙酯/己烷(20ml×3)提取。合并有机层，无水Na2SO4干燥，过滤，浓缩，得25mg粗品17。柱层析(10％乙酸乙酯/己烷)后得10mg(95％)烯醇酯17纯品(P7=P10=TES,P13=TBS,R=Me)。17(P7=P10=TES,P13=TBS,R=Me):1H NMR(300MHz,CDCl3)δ0.08(s,3H,TBSCH3),0.10(s,3H,TBS CH3),0.59(q,J=8.1Hz,12H,TES CH2,),0.87(s,9H,TBS t-Bu),0.95(t,J=7.7Hz,18H,TES CH3),1.05(s,3H,CH3),1.19(s,3H,CH3),1.30(s,3H,CH3),1.84(m,2H,H9α,H9β),1.98(s,3H,CH3 18),2.17(ddd,J=2.8,10.4,15.9Hz,1H,H6β),2.31(dd,J=4.4,15.9Hz,1H,H6α),2.52,(dd,J=9.3,15.4Hz,1H,H14β),2.85(dd,J=3.8,15.4Hz,1H,H14α),3.03(brs,1H,H3α),3.34(dd,J=5.0,10.4Hz,1H,H7α),3.75(s,3H,CO2Me OMe),4.36(dd,J=5.0,10.4Hz,1H,H10β),4.58(d,J=2.7Hz,1H,H2β),4.66(brd,J=11.0Hz,1H,H13β),12.22(s,1H,OH4).
酮18，室温氮气下，向搅拌着的烯醇酯17(P7=MOP,P10=TES,P13=TBS,R=Me),(963mg,1.3mmol)的DMF(30ml)溶液中加入固体苯硫氧化钾(250mg,1.69mmol)，然后加入苯硫酚(0.4ml,3,9mmol)。溶液于86℃下加热3.5小时，冷至室温，直接倾入250ml饱和NaHCO3水溶液中，用30％乙酸乙酯/己烷(150ml×3)提取。合并有机层，经2英寸硅胶垫过滤，减压浓缩，得1.29g粗产品，此物经径向层析纯化，以15％，后以20％，最张望以25％乙酸乙酯/己烷溶液洗脱，得763mg(86％)酮18((P7=MOP,P10=TES,P13=TBS)。18(P7=MOP,P10=TES,P13=TBS):1H NMR(300MHz,CDCl3)δ0.10(s,3H,TBSCH3),0.14(s,3H,TBS CH3),0.58(q,J=8.2Hz,6H,TES CH2),0.94(s,9H,TBS t-Bu),0.95(t,J=8.2Hz,9H,TES CH3),1.22(s,3H,CH3 19),1.30(s,3H,CH3 17),1.32(s,6H,MOP CH3),1.33(s,3H,CH3 16),1.80(m,1H,H5),1.81(dd,J=3.8,3.8Hz,1H,H9β),1.98(m,1H,H5),1.99(d,J=1.1Hz,3H,CH3 18),2.21(m,1H,H6β),2.29(dd,J=10.4.12.1Hz,1H,H9α),2.43(dd,J=9.3,15.4Hz,1H,H14α),2.53(m,1H,H6α),2.63(dd,J=5.0,15.4Hz,1H,H14β),2.70(d,J=5.0Hz,1H,H3),3.20(s,3H,MOP OMe),3.39(dd,J=6.1,10.4Hz,1H,H7),4.34(dd,J=3.9,10.4Hz,1H,H10),4.55(d,J=5.5Hz,1H,H2),4.73(dd,J=5.3,7.7Hz,1H,H13).
元素分析：C34H64O8Si2
理论值：C,63.49；H,9.47
实侧值：C,63.56；H:9.5518(P7=P10=TES,P13=TBS):1H NMR(300MHz,CDCl3)δ0.10(s,3H,TBS CH3),0.14(s,3H,TBS CH3),0.47-0.63(m,12H,TES CH2),0.90-0.99(m,27H,TBS t-Bu,TES CH3),1.22(s,3H,CH3),1.25(s,3H,CH3),1.33(s,3H,CH3),1.75(dt,J=11.6,1.6Hz,1H),1.85(d,J=3.3Hz,1H),1.90(t,J=3.9Hz,1H),1.97(t,J=8.1Hz,1H),2.00(s,3H,CH3),2.30(m,1H),2.39-2.60(m,3H),2.65(m,1H),3.35(dd,J=9.6,7.8Hz,1H,H7α),4.35(dd,J=10.8,3.3Hz,1H,H10β),4.57(d,J=5.1Hz,1H,H2β),4.72(m,1H,H13β).
酮18(P7=BOM)，室温氦气下，向搅拌着的酮18(P7=TES,P10=TES,P13=TBS),(293mg,0.43mmol)的THF(28.6ml)和甲醇(9.5ml)溶液中滴加入0.20ml0.1M PPTS的CH2CL2(0.02mmol)溶液。混合物搅拌3小时，倾入100ml饱和NaHCO3水溶液中，用乙酸乙酯(100ml×2)提取，合并有机层，用盐水洗涤，无水Na2SO4干燥，减压浓缩，得274mg羟基酮18(P7=H)，其为无色油状物，此物无须进一步纯化即可使用。18(P7=H,P10=TES,P13=TBS):mp75-77℃,1H NMR(500MHz,CDCl3)δ0.10(s,3H,TBS CH3),0.13(s,3H,TBS CH3),0.61(q,J=8.2Hz,6H,TES CH2),0.93(s,9H,TBSt-Bu),0.95(t,J=7.7Hz,9H,TES CH3),1.19(s,3H,CH3 19),1.22(s,3H,CH3 17),1.35(s,3H,CH3 16),1.84(dd,J=13.7,4.1Hz,1H,H9α),1.88(m,2H,H9β,OH7),1.92(m,1H,H6β),2.05(d,J=1.4Hz,3H,CH3 18),2.10(m,1H,H6α),2.36(dddd,J=1.4,4.1,9.9,14.4Hz,1H,H5α),2.47(dd,J=8.9,15.4Hz,1H,H14β),2.51(m,1H,H5β),2.54(dd,J=4.8,15.4Hz,1H,H14β),2.86(d,J=5.5Hz,1H,H3),3.59(ddd,J=4.5,6.2,11.3Hz,1H,H7),4.38(dd,J=4.1,9.1Hz,1H,H10),4.56(d,J=5.5Hz,1H,H2),4.69(ddd,J=1.4,4.8,9.3Hz 1H,H13),Anal.Calcd.for C32H56O7Si2x.5H2O:C,62.19；H,9.30.FoundC,62.16；H,9.22.
氮气下，向搅拌着的羟基酮18(P7=H)(179mg,0.29mmol)的CH2CL2(9.5ml)二异丙基胺(1.49ml,8.6mmol)以及碘化四丁基季铵盐(253mg,0.69mmol)中滴加苄氧甲基氯化物(0.42ml,2.86mmol)。反应混合物回流32小时，冷至室温，倾入100ml饱和NaHCO3水溶液中，用50％乙酸乙酯/己烷(100ml×2)提取，合并有机层，盐水洗涤，无水Na2SO4干燥，减压浓缩，得249mg羟基酮，为带黄色的油状物。此物经硅胶层析纯化，得196mg(92％)酮18(P7=BOM,P10=TES,P13=TBS)，为无色油状物。18(P7=BOM,P10=TES,P13=TBS):1H NMR(500MHz,CDCl3)δ0.10(s,3H,TBS CH3),0.13(s,3H,TBS CH3),0.59(q,J=7.7Hz,6H,TES CH2),0.94(s,9H,TBS t-Bu),0.94(t,J=7.7Hz,9H,TES CH3),1.22(s,3H,CH3 17),1.31(s,3H,CH3 19),1.33(s,3H,CH316),1.87(dd,J=12.1,3.8Hz,1H,H9α),1.98(d,J=1.4Hz,3H,CH3 18),1.99(m,2H,H6β,H9β),2.21(m,1H,H6α),2,34(dd,J=10.4,12.1Hz,1H,H5α),2.43(dd,J=9.3,15.4Hz,1H,H14α),2.55(ddd,J=5.5,11.0,13.7Hz,1H,H5β),2.62(dd,J=5.0,15.4Hz,1H,H14β),2.74(d,J=5.0Hz,1H,H3),3.38(dd,J=6.6,11Hz,1H,H7),4.38(dd,J=3.8,10.4Hz,1H,H10),4.56(d,J=5.0Hz,1H,H2),4.58(d,J=11.5Hz 1H,CH2Ph),4.64(d,J=11.5Hz 1H,CH2Ph),4.68(m,2H,H13,OCH2O),4.82(d,J=7.2Hz 1H,OCH2O),7.31(m,5H,Ph).
酮22a(P5=TMS)。-78℃氮气下，向剧烈搅拌，着的酮18(P7=SOM,P10=TES,P13=TBS)(315mg,0.42mmol)在THF(10.5ml)，三乙胺(0.88ml,6.3mmol)以及三甲基甲硅烷基氯化物(0.53ml,4.2mmol)的溶液中沿并瓶壁滴加1.35ml 0.5M LDA(0.68mmol)的THF溶液。25分钟后，加2ml饱和NaHCO3水溶液，用150ml己烷稀烯，用20ml饱和NaHCO3水溶液及盐水洗涤，无水Na2SO4干燥，减压浓缩。生成的油状物经硅藻土过滤，用己烷洗脱，滤液减压浓缩，得338mg(99％)TMS烯醇醚21a(P7=SOM,P10=TES,P13=TBS,P4=TMS)，其为无色油状物。室温氮气下，向剧烈搅拌下的TMS烯醇醚21a(P7=BOM,P10=TES,P13=TBS,P4=TMS)(224mg,0.274mmol)的己烷溶液(2.8ml)中滴加入14.9ml0.02M MCPBA(0.30mmol)的己烷溶液。5小时后，加入2ml饱和NaHCO3水溶液和2ml10％Na2S2O3水溶液。混合物用150ml乙酸乙酯稀释，依次用20ml饱和NaHCO3水溶液，20ml10％Na2SO4水溶液，20ml饱和NaHCO3水溶液及盐水洗涤，无水Na2SO4水溶液干燥，减压浓缩，得231mg粗品，为无色油状物，其无须纯化即可使用，或者，经硅胶闪柱层析纯化，得168mg(74％)22a(P7=BOM,P10=TES,P13=TBS,P5=TMS)同时带有15％21a和18的混合物其可循环利用。22a(P7=BOM,P10=TES,P13=TBS,P5=TMS):mp50.5-52℃,1H NMR(500MHz,CDCl3)δ0.10(s,3H,TBS CH3),0.13(s,9H,TMS CH3),0.14(s,3H,TBS CH3),0.59(q,J=8.2Hz,6H,TES CH2),0.94(s,9H,TBS t-Bu),0.94(t,J=8.2Hz,9H,TES CH3),1.24(s,3H,CH3 17),1.32(s,3H,CH3 19),1.33(s,3H,CH3 16),1.82(dd,J=11.3,13.7Hz,1H,H9α),1.95(d,J=1.4Hz,3H,CH3 18),1.98(dd,J=3.4,13.7Hz,1H,H9β),2.16(ddd,J=6.2,7.2,13.3Hz,1H,H6α),2.40(dt,J=11.4,13.3Hz,6β),2.43(dd,J=9.2,15.2Hz,1H,H14β),2.63(dd,J=5.5,15.2Hz,1H,H14α),2.74(d,J=5.5Hz,1H,H3α),3.40(dd,J=7.2,10.6Hz,1H,H7α),4.36(dd,J=3.4,11.3Hz,1H,H10β),4.40(dd,J=6.2,12.0Hz,1H,H5α),4.54(d,J=5,5Hz,1H,H2β),4.57(d,J=11.7Hz 1H,CH2Ph),4.64(d,J=11.7Hz 1H,CH2Ph),4.68(d,J=7.0Hz 1H,OCH2O),4.74(m,1H,H13),4.78(d,J=7.0Hz,1H,OCH2O),7.31(m,5H,Ph).
元素分析：C43H72O9Si2
理论值：C,63.19；H,8.88
实侧值：C,63.19；H:8.92
酮22a(P5=H)。0℃下，向剧烈搅拌下的22a粗品(P7=BOM,P10=TES,P13=TBS,P5=TMS)(231mg,0.274mmol)的己腈溶液(7ml)中滴加7ml 1∶10∶10(体积比)的48％HF水溶液∶吡啶∶乙腈的混合物。搅拌20分钟后，加入饱和NaHCO3水溶液，用150ml乙酸乙酯稀释，用30ml饱和NaHCO3水溶液及盐水洗涤，无水Na2SO4干燥，减压浓缩，得223mg醇粗品，其为无色油状物。此物经硅胶层析纯化，得155mg(74％)酮22a(P7=BOM,P10=TES,P13=TBS,P5=H),15mg(7％)5β-羟基酮及33mg(14％可回收物质)1∶1的TMS烯醇醚21a及酮18的混合物。22a(P7=BOM,P10=TES,P13=TBS,P5=H):1H NMR(500MHz,CDCl3)δ0.10(s,3H.TBS CH3),0.14(s,3H,TBS CH3),0.59(q,J=8.2Hz,6H,TES CH2),0.94(s,9H,TBSt-Bu),0.94(t,J=8.2Hz,9H,TES CH3),1.23(s,3H,CH3 19),1.32(s,3H,CH3 17),1.33(s,3H,CH3 16),1.83(dd,J=11.0,13.7Hz,1H,H6β),1.97(d,J=1.4Hz,3H,H18),2.01(dd,J=3.2,13.7Hz,1H,H9β),2.11(ddd,J=5.5,7.7,13.7Hz,1H,H6α),2.47(dd,J=8.7,15.4Hz,1H,H14β),2.57(m,2H,H14α,H9α),2.88(d,J=5.5Hz,1H,H3α),3,39(dd,J=7.7,11.0Hz,1H,H7α),3.41(d,J=3.3Hz,1H,OH-5),4.38(m,2H,H5β,H10),4.55(d,J=5.5Hz,1H,H2β),4.57(d,J=11.5Hz 1H,CH2Ph),4.62(d,J=11.5Hz 1H,CH2Ph),4.72(m,2H,H13β,OCH2O),4.80(d,J=7.1Hz 1H,OCH2O),7.31(m,5H,Ph).
酮22a(P5=TMS)来自酮22a(P5=H)0℃氮气下，向剧烈搅拌下的5-羟基-4-酮22a(P1=BOM,P10=TES,P13=TBS,P5=H)(51mg,0067mmol)的CH2Cl2(2,2ml)三乙胺(0.14ml,1.0mmol的溶液)中加入三甲基甲硅烷基氯化物(0.04ml,0.34mmol)。0.5小时后，用5ml饱和NaHCO3水溶液终止反应，150ml己烷提取，有机层用50ml饱和NaHCO3水溶液和盐水洗涤，无水Na2SO4干燥，减压浓缩，得56mg无色油状物。此物经硅胶过滤，滤液减压浓缩，得54mg(96％)酮22a((P7=BOM,P10=TES,P13=TBS,P5=TMS)。醇23a。-65℃氮气下，向搅拌着的酮22a(P7=BOM,P10=TES,p13=TBS,P5=TMS)(18.9mg,0.023mmol)的CH2Cl2(4ml的溶液)中滴加入0.073ml 3.1M MeMgBr的乙醚溶液(0.23mmol)，升温至-48℃，搅拌16.5小时，用0.13ml2.0M AcOH的THF(0.25mmol)溶液终止反应，然后将其倾入一个搅拌下的50ml饱和NaHCO3水溶液和50ml乙酸乙酯的混合物中。水相用50ml乙酸乙酯提取。合并的有机层用盐水洗涤，无水Na2SO4干燥，减压浓缩，得20.5mg无色油状物。此物经硅胶层析纯化，得18.4mg(95％)醇23a(P7=BOM,P10=TES,p13=TBS,P5=TMS)，其为无色油状物。23a(P7=BOM,P10=TES4 P13=TBS,P5=TMS):1H NMR(500MHz,CDCl3)δ0.09(s,9H,TMS),0.11(s,3H,TBS CH3),0.12(s,3H,TBS CH3),0.56(q,J=7.9Hz,6H,TESCH2),0.92(t,J=7.9Hz,9H,TES CH3),0.93(s,9H,TBS t-Bu),1.25(s,3H,CH3 17),1.28(s,3H,CH319),1.33(s,3H,CH3 20),1.34(s,3H,CH316),1.74(ddd,J=3.8,4.1,13.0Hz,1H,H6α),1.99(d,J=1.4Hz,3H.H18),2.01(dd,J=11.3,13.0Hz,1H,H9α),2.06(m,2H,H3,H9β),2.13(ddd,J=1.7,12.3,13.0Hz,1H,H6β),2.37(dd,J=5.5,15.0Hz,1H,H14α),2.54(dd,J=9.2,15.0Hz,1H,H14β),2.96(s,1H,OH-4),3.51(dd,J=1.7,4.1Hz,1H,H5),3.73(dd,J=3.8,12.3Hz,1H,H7α),4.32(dd,J=4.1,11.3Hz,1H,H10β),4.64(s,2H,CH2Ph),4.72(d,J=6.8Hz,1H,OCH2O),4.80(m,3H,H2,H13,OCH2O),7.31(m,5H,Ph).
元素分析：C44H76O9Si2
理论值：C,63.42；H,9.19
实侧值：C,63.40；H:9.15
羟基链烯24a。向回流着的醇23a(P7=BOM,P10=TES,P13=TBS,P5=TMS)(46.7mg,0.055mmol)的甲苯(1.1ml)溶液中加入1.1ml 0.1M Burgess试剂的甲苯溶液(0.11mmol)。混合物回流20分钟，然后冷却至室温，乙酸乙酯稀释，用饱和NaHCO3水溶液，盐水洗涤，无水Na2SO4干燥并过滤，减压浓缩滤液，得46mg粗品链烯。此物无需纯化即可使用。
0℃下，向搅拌下的此粗品链烯(46mg,0.055mmol)的乙腈(2.5ml)，溶液中加入2.5ml,1∶10∶10(体积比)的48％HF水溶液∶吡啶∶乙腈的混合物。此混合物于0℃下搅拌20分钟，用饱和NaHCO3溶液终止反应，乙酸乙酯提取两次，合并有机层，用盐水洗涤，无水Na2SO4干燥，过滤，滤液真空下浓缩，得48小时无色油状物，其经硅胶层析纯化，得25.9g(62％)羟基链烯24a(P7=SOM,P10=TES,P13=TBS,R=H)，以及2.1ml未反应的醇23a(4％)。24a(P7=BOM,P10=TES,P13=TBS,R=H):mp66-68℃1H NMR(500MHz,CDCl3)δ0.12(s,3H,TBS CH3),0.13(s,3H,TBS CH3),0.59(q,J=7.9Hz,6H,TES CH2),0.94(t,J=7.9Hz,9H,TES CH3),0.95(s,9H,TBS t-Bu),1.18(s,3H,CH3 19),1.23(s,3H,CH317),1.35(s,3H,CH3 16),1.73(d,1H,J=3.4Hz,OH5),1.83(dd,J=9.9,10.5Hz,1H,H9α),1.91(ddd,J=7.2,7.5,13.4Hz,1H,H6α),1.97(dd,J=3.8,9.9Hz,1H,H9β),2.03(d,J=1.4Hz,3H,18),2.14(ddd,J=9.6,9.6,13.4Hz,1H,H6β)2.35(dd,J=5.1,15.4Hz,1H,H14α),2.50(dd,J=9.6,15.4Hz,1H,H14β),3.03(d,J=5.8Hz,1H,H3α),3.44(dd,J=7.5,9.6,Hz,1H,H7α),4.38(m,2H,H10,H5),4.54(d,J=5.8Hz,1H,H2),4.58(d,J=11.6Hz,1H,CH2Ph),4.62(d,J=11.6Hz,1H,CH2Ph),4.73(d,J=7.0Hz,1H,OCH2O),4.75(m,1H,H13),4.79(d,J=7.0Hz,1H,OCH2O),5.00(s,1H,H20E),5.18(s,1H,H20Z),7.31(m,5H,Ph)
元素分析：C41H66O8Si2
理论值：C,65.47；H,8.98
实侧值：C,65.63；H:8.97
烯丙甲磺酸酯24aa,0℃下氮气下，向搅拌下的烯丙醇24a(P7=SOM,P10=TES,P13=TBS,R=H)(11.5mg,0.0154mmol)的吡啶(0.6ml)溶液中滴加入甲磺酰氯(0.02ml,0.258mmol)。45分钟后，加入饱和NaHCO3水溶液(0.05ml)。混合物搅拌10分仲，倾入20ml饱和NaHCO3水溶液保，用40％乙酸乙酯/己烷(20ml×3)提取。合并有机层，无水Na2SO4干燥，减压浓缩，得13mg,24aa(P7=SOM,P10=TES,P13=TBS,R=MS)，其为无色油状物，此物无须纯化即可使用。24aa(P7=BOM,P10=TES,P13=TBS,R=Ms):1H NMR(300MHz,CDCl3)；δ0.12(s,3H,TBS CH3),δ0.13(s,3H,TBS CH3),0.58(q,J=7.9Hz,6H,TES CH2),0.93(s,9H,TBS t-Bu),0,94(t,J=7.9Hz,9H,TES CH3),1.23(s,3H,CH3 17),1.22(s,3H,CH3 19),1.34(s,3H,CH3 16),1.80(br t,J=13Hz,1H,H9α),1.98(m,1H,H6),1.79(ddd,J=2.2,5.5,15.1Hz,1H,H14α),2.01(d,J=1.1Hz,1H,CH318),2.06(dd,J=3.3,13.7Hz,1H,H9β),2.01(br s,3H,CH3 18),2.22-2.32(m,3H,H14α,H6α,H6β),2.54(dd,J=9.9,15.4Hz,1H,H14β),3.02(s,3H,OSO2CH3),3.05(d,J=6.0Hz,1H,H3α),3.45(t,J=8.5Hz,1H,H7α),4.37(dd,J=3.6,11.0Hz,1H,H10β),4.57(d,J=6.0Hz,1H,H2β),4.59(q,2H,PhCH2O),4.69(d,J=7.1Hz,1H,OCH2O),4.74(m,1H,H13β),4.76(d,J=7.1Hz,1H,OCH2O),5.03(br t,J=8.5Hz,1H,H5β),5.09(brs,1H,H20),5.24(brs,1H,H20),7.35(m,5H,Ph).
三醇25a。0℃氮气下，向搅拌着的烯丙醇24a(P7=BOM,P10=TES,P13=TBS,R=H)(45mg,0.0606mmol)的吡啶(0.32ml)和乙醚(3.2ml)混合液中加入0.157M OSO4的THF溶液(0.42ml,0.066mmol)。12小时后，0℃下，加入NaHSO4(530mg)吡啶(0.3ml)，THF(2ml)以及水(3ml)。混合物于室温下剧烈搅拌14小时，倾入50ml饱和NaHCO3水溶液中，用乙酸乙酯提取(40ml×3)，合并有机层，经无水Na2O4干燥，减压浓缩，得60mg灰黄色油状物，其径柱层析(30％，乙酸乙酯/己烷)，得34.3mg(73％)三醇25a(P7=BOM,P10=TES,P13=TBS)。25a(P7=BOM,P10=TES,P13=TBS):1H NMR(500MHz,CDCl3)；δ0.11(s,6H,TBSCH3),0.60(ddd,J=9.0Hz,6H,TES CH2),0.79(s,3H,CH3 19),0.93(s,9H,TBS t-Bu),0.94(dd,J=9.0Hz,9H,TES CH3),1.22(s,3H,CH3 17),1.35(s,3H,CH3 16),1.64(dd,J=5.6,16.4Hz,1H,H9β),1.70(m,1H,H6β),2.22(dd,J=2.7,16.8Hz,1H,H9α),2.23(d,J=0.7Hz,3H,CH3 18),,2.36(dd,J=9.2,15.0Hz,1H,H14β),2.45(m,1H,H6α),2.96(s,1H,OH5),3.21(dd,6.9,15.0Hz,1H,H14α),3.42(d,J=5.0Hz,1H,H3α),3.53(m,1H,H20),3.38(s,1H,OH4),3.70(t,J=3.0Hz,1H,H5β),4.04(br d,J=11Hz,1H,H20),4.06(dd,J=11.5,5.0Hz,1H,H7α),4.48(d,J=5.0Hz,1H,H2β),4.49(d,J=12.0Hz,1H,PhCH2O),4.53(br s,1H,H10β),4.71(m,1H,H13β),4.72(d,J=12.0Hz,1H,PhCH2O),4.85(d,J=6.8Hz,1H,OCH2O),4.98(d,J=6.8Hz,1H,OCH2O),7.34(m,5H,
元素分析：C41H68O10Si2
理论值：C,63.36；H,8.82
实侧值：C,63.19；H:8.75
二醇甲碘酸酯26a，室温氮气下，向搅拌下的烯丙甲磺酸酯24aa(P7=BOM,P10=TES,P13=TBS.R=Ms(5mg,0.0064mmol)的吡啶(0.4ml)和THF(0.4ml)的混合物中加入0.157M O3O4的THF(0.06ml)溶液，7小时后，加入NaHSO3(150mg)和水(0.2ml)，混合物剧烈搅拌14小时，倾入20ml饱和NaHCO3水溶液中，用乙酸乙酯(20ml×3)提取。合并有机层，无水Na2SO4干燥，减压浓缩，得6mg灰黄色的油状物，此油状物经柱层析(40％乙酸乙酯/己烷)纯化，得2.7mg(50％)二醇甲磺酸酯26a(P7=BOM,P10=TES,P13=TBS,R=Ms)。26a(P7=BOM,P10=TES,P13=TBS,R=Ms):1H NMR(500MHz,CDCl3)δ0.14(s,6H,TBS CH3),0.58(ddd,J=8.0Hz,6H,TES CH2),0.89(s,3H,CH3 19),0.93(s,9H,TBSt-Bu),0.94(dd,J=8.0Hz,9H,TES CH3),1.31(s,3H,CH3 17),1.37(s,3H,CH3 16),1.76(dd,J=5.5,15.1,1Hz,H9β),1.95(m,1H,H6β),2.23(d,J=0.7Hz,3H,CH3 18),2.25(dd,J=4.8,15.1Hz,1H,H9α),2.39(dd,J=9.2,15.1Hz,1H,H14β),2.45(m,1H,H6α),2.89(dd,6.8,15.1Hz,1H,H14α),3.05(d,J=3.4Hz,1H,H3α),3.06(s,3H,OSO2CH3),3.35(s,1H,OH4),3.52(m,1H,H20),3.92(dd,J=4.5,11.6Hz,1H,H7α),4.13(dd,J=1.0,11.3Hz,1H,H20),4.46(br d,J=4.5Hz,1H,H10),4.52(d,J=3.4Hz,1H,H2),4.54(d,J=12.0Hz,1H,PhCH2O),4.70(d,J=12.0Hz,1H,PhCH2O),4.83(d,J=6.9Hz,1H,OCH2O),4.84(m,1H,H5β),4.92(m,1H,H13β),4.93(d,J=6.9Hz,1H,OCH2O),7.34(m,5H,Ph).
二醇甲苯磺酸酯26aa。-78℃氮气下，向搅拌的三醇25a(P7=BOM,P10=TES,P13=TBS)(37mg,0.0476mmol)的CH2Cl2(0.4ml)溶液中加入三乙胺(0.25ml)，然后再加入三甲基氯硅烷(0.075ml)。溶液于-78℃下搅拌1小时，倾入20ml饱和NaHCO3水溶液中，用CHCl3(30ml×3)提取，合并有机层，无水Na2SO4干燥，减压浓缩，得38.2mg无色油状物。将此油溶于THF(0.5ml)中，冷却至-78℃，向其中加入0.2MLDA(0.9ml,0.18mmol)的THF溶液，20分钟后，于-78℃下加入对甲苯磺酰氯(35mg,0.183mmole)。-35℃下搅拌3小时后，加入MeOH(0.2ml)和二乙胺10.3ml)。此溶液于-35℃下搅拌30分钟，倾入30ml饱和NaH-CO3水溶液中，用CHCl3(40ml×3)提取。合并有机层，无水Na2SO4干燥，减压浓缩，得58mg无色油状物。将此油状物溶于乙腈(3.6ml)和吡啶(3.6ml)中，0℃下加入48％HF(0.36ml)，水溶液于0℃下搅拌15分钟。将其倾入30ml饱和NaHCO3水溶液中，用氯仿(40ml×3)提取，合并有机层，无水Na2SO4干燥，减压浓缩，得56mg二醇甲苯磺酸酯26aa，往柱层析(40％乙酸乙酯/己烷)后得34mg(80％)二醇甲苯磺酸酯26aa(P7=BOM,P10=TES,P13=TBS,R=Ts)。26aa(P7=BOM,P10=TES,P13=TBS,R=Ts).1H NMR(300MHz,CDCl3)；δ0.18(s,6H,TBS CH3),0.58(d,J=12.5Hz,6H,TES CH2),0.82(s,3H,CH3 19),0.94(dd,J=13.0Hz,9H,TES CH3),0.97(s,9H,TBS t-Bu),1.28(s,3H,CH3 17),1.34(s,3H,CH3 16),1.67(dd,J=16.5,4.4Hz,1H,H9β),1.80(m,1H,H6β),2.13(dd,J=16.5,4.4Hz,1H,H9α),2.18(m,1H,H6α),2.24(s,3H,CH3 18),2.33(s,3H,CH3Ph),2.42(dd,J=14.8,9.3Hz,1H,H14β),2.90(m,1H,H14α),2.93(br s,1H,OH4),3.08(br d,J=3.3Hz,1H,H3α),3.38(br t,J=11.0Hz,1H,H7α),3.87(m,1H,H20),4.09(br d,J=9.9Hz,1H,H20),4.52(d,J=3.3Hz,1H,H2β),4.45(br d,J=4.4Hz,1H,H10β),4.46(d,J=12,1Hz,1H,PhCH2O),4.59(d,J=12.1Hz,1H,PhCH2O),4.66(br t,J=3.8Hz,1H,H5β),4.75(d,J=7.1Hz,1H,OCH2O),4.83(d,J=7.1Hz,1H,OCH2O),4.89(br dd,J=7.7,6.6Hz,1H,H13β),7.14(d,J=8.2Hz,2H,SO2Ph),7.34(m,5H,OCH2Ph),7.75(d,J=8.2Hz,2H,SO2Ph).
螺[4,4]二氧己烷27a(来自二醇甲磺酸酯26a)。室温氮气下，向搅拌下的二醇甲磺酸酯26a(P7=BOM,P10=TES,P13=TBS,R=MS)(2.7mg)的甲苯溶液(0.4ml)中加入二异丙基乙基胺(0.008ml)。溶液回流3.5小时，冷却至室温，倾入20ml饱和NaH-CO3水溶液中，用乙酸乙酯(20ml×3)提取，并有机层，无水Na2SO4干燥，减压浓缩，得3mg灰黄色油状物，此油经柱层析(30％乙酸乙酯/己烷)纯化得1mg(42％)螺[4,4]二氧己烷27a。27a(P7=BOM,P10=TES,P13=TBS):1H NMR(500MHz,CDCl3)；δ0.10(s,6H,TBSCH3),0.59(dd,J=8.0Hz,6H,TES CH2),0.92(s,9H,TBS t-Bu),0.94(dd,J=8.0Hz,9H,TES CH3),1.20(s,3H,CH3 17),1.26(s,3H,CH3 19),1.32(s,3H,CH3 16),1.93(dd,J=11.3,13.4Hz,1H,H9α),1.98(d,J=1.4Hz,3H,CH3 18),2.06(dd,J=6.0,18.6Hz,1H,H6β),2.11(dd,J=4.5,13.4Hz,1H,H9β),2.14(d,J=5.5Hz,1H,H3α),2.41(dd,J=9.2,15.1Hz,1H,H14β),2.43(m,1H,H6α),2.54(s,1H,OH4),2.76(dd,J=5.2,15.1Hz,H14α),3.21(dd,J=3.4,13.0Hz,1H,H7α),4.36(d,J=8.6Hz,1H,H20α),4.37(dd,J=4.1,11.3Hz,1H,H10β),4.40(br d,J=8.2Hz,1H,H5α),4.60(d,J=5.5Hz,1H,H2β),4.61(d,J=12.6Hz,1H,PhCH2O),4.67(m,1H,H13β),4.69(d,J=12.6Hz,1H,PhCH2O),4.75(d,J=7.5Hz,1H,OCH2O),4.86(d,J=7.5Hz,1H,OCH2O),4.91(dd,J=0.7,8.6Hz,1H,H20β),7.34(m,5H,Ph).
元素分析：C41H66O9Si2
理论值：C,64.87；H,8.76
实侧值：C,64.61；H:8.78
螺[4,4]二氧己烷27a(来自二醇甲苯磺酸酯26aa。室温氮气下向搅拌下的二醇甲苯磺酸酯26aa(P7=BOM,P10=TES,P13=TBS,R=Ts)(33mg,0.0354mmol)的甲苯(3.3ml)溶液中加入DBU(0.11ml,0.73mmole)。溶液于80℃下加热10分钟，40分钟内使之升温至110℃，于此温度下保持30分钟，再冷却至室温。溶液经短硅胶填充柱过滤，以30％乙酸乙酯/己烷作洗脱液，滤液浓缩，得25mg粗品27a，其经柱层析纯化(30％乙酸乙酯/己烷)得21mg(78％)螺[4,4]二氧己烷27a(P7=BOM,P10=TES,P13=TBS)。螺[4,4]二氧己烷29，室温氮气下，向搅拌下的螺[4,4]二氧己烷27a(P7=BOM,P10=TES,P13=TBS)(21mg,0.0276mmole)和二甲基氨基吡啶(3.4mg,0.027mmole)的吡啶溶液(110μl,1.37mmole)中加入乙酸酐(26μl,0.276mmole)。溶液搅拌25小时，用乙酸乙酯稀释，倾入20ml饱和NaHCO3水溶液中，用乙酸乙酯(20ml×3)提取。合并有机层，Na2SO4干燥，减压浓缩，得26mg灰黄色油状物，其经柱层析(25％乙酸乙酯/乙烷)纯化，得16mg(72％)螺[4,4]二氧己烷29(P7=BOM,P10=TES,P13=TBS)。29(P7=BOM,P10=TES,P13=TBS):1H NMR(500MHz,CDCl3)；δ0.10(s,3H,TBSCH3),0.12(s,3H,TBS CH3),0.56(q,6H,TES CH2),0.92(t,9H,TES CH3),0.94(s,9H,TBS t-Bu),1.35(s,3H,CH3 16),1.30(s,3H,CH3 17),1.29(s,3H,CH3 19),1.96(br t,J=13.0Hz,1H,H9α),1.98(d,J=1.4Hz,3H,CH3 18),2.02(dd,J=7.5,13.0,1H,H9β),2.07(dt,J=8.0,13.0Hz,1H,H6β),2.13(s,3H,OAc),2.24(dd,J=3.4,15.0Hz,1H,H14α),240(dd,J=8.6,15.0Hz,1H,H14β),2.51(ddd,J=4.1,9.2,15.0Hz,1H,H6α),2.63(d,J=6.5Hz,1H,H3α),3.69(dd,J=4.1,13.0Hz,H7α),4.35(dd,J=3.4,11.3Hz,1H,H10β),4.64(m,4H,PhCH2O,H2β,H5α),4.75(d,J=7.2Hz,1H,OCH2O),4.76(br d,J=9.2Hz,1H,H20),4.83(d,J=7.2Hz,1H,OCH2O),4.85(br d,J=9.2Hz,1H,H20),4.88(br t,J=8.2Hz,1H,H13β),7.35(m,5H,Ph).
苯甲酸酯30。-78℃氮气下，向搅拌下的螺[4,4]二氧己烷29(P7=BOM,P10=TES,P13=TBS)(6mg,0.0075mmol)的THF(0.5ml)溶液中加入0.3M苯基锂的乙醚溶液(44μl,0.013mmol)。此溶液于-78℃下搅拌15分钟，用10％乙酸/THF溶液终止反应。用乙酸乙酯稀释，倾入20ml饱和NaHCO3水溶液中，用乙酸乙酯(20ml×3)提取。合并有机层，无水Na2SO4干燥，减压浓缩，得8mg灰黄色油状物，此油状物经柱层析(25％乙酸乙酯/己烷)，得6.2mg(94％苯甲酯酯30(P7=BOM,P13=TBS,R=TES)。30(P7=BOM,P13=TBS,R=TES):1H NMR(500MHz,CDCl3)；δ0.09(s,3H,TBS CH3),0.14(s,3H,TBS CH3),0.60(ddd,6H,TES CH2),0.94(s,9H,TBS t-Bu),0.96(t,6H,TESCH3),1.23(s,3H,CH3 17),1.38(s,3H,CH3 19),1.46(s,3H,CH3 16),1.69(s,1H,OH1),1.97(ddd,J=14.5,10.0,3.1Hz,1H,H6β),2.05(dd,J=16.1,5.1Hz,1H,H9β),2.09(dd,J=15.1,6.2Hz,1H,H14β),2.13(s,3H,CH3 18),2.22(dd,J=15.1,8.2Hz,1H,H14α),2.23(dd,J=15.0,8.5Hz,1H,H9β),2.24(s,1H,OAc4),2.38(dd,J=16.1,4.1Hz,1H,H9α),2.67(m,1H,H6α),3.40(d,J=6.2Hz,1H,H3α),3.99(dd,J=10.1,6.8Hz,1H,H7α),4.20(d,J=8.2Hz,1H,H20β),4.29(d,J=8.2Hz,1H,H20α),4.49(d,J=12.0Hz,1H,PhCH2O),4.63(br t,1H,H10β),4.74(d,J=12.0Hz,1H,PhCH2O),4.92(d,J=6.9Hz,1H,OCH2O),4.91-4.95(m,2H,H13β& H5α),5.01(d,J=6.9Hz,1H,OCH2O),5.66(d,J=6.2Hz,1H,H2β),7.28(m,1H,PhCH2),7.35(m,4H,PhCH2),7.48(m,2H,PhCOO-m),7.59(m,1H,PhCOO-p),8.11(m,2H,PhCOO-o).
醇31，向苯甲酸酯30(P7=BOM,P13=TBS,R=TES)(6.2mg,0.007mmol)的2mlTHF溶液中加入0.1ml0.1MTBAF的THF溶液。混合物于25氮气下搅拌2小时。混合物用10ml乙酸乙酯稀释，倾入10ml饱和NaHCO3水溶液中，有机相用10ml饱和NaHCO3水溶液洗涤，无水Na2SO4干燥，减压浓缩，得4.5mg(93％)醇31(P2=BOM,P13=TBS,R=H)。31(P7=BOM,P13=TBS.R=H):mp213-216℃1H NMR(500MHz,CDCl3)；δ0.10(s,3H,TBS CH3),0.15(s,3H,TBS CH3),0.94(s,9H,TBS t-Bu),1.26(s,3H,CH3 17),1.39(s,3H,CH3 19),1.45(s,3H,CH3 16),1.68(s,1H,OH1),1.89(ddd,J=14.5,10.0,2.5Hz,1H,H6β),2.10(dd,J=15.0,9.0Hz,1H,H14β),2.15(dd,J=15.0,8.0Hz,1H,H14α),2.18(s,3H,CH3 18),2.23(dd,J=15.0,8.5Hz,1H,H9β),2.26(s,1H,OAc4),2.40(dd,J=15.0,3.5Hz,1H,H9α),2.68(m,1H,H6α),2.90(br s,1H,OH10),3.54(d,J=6.0Hz,1H,H3α),4.16(d,J=8.0Hz,1H,H20β),4.23(dd,J=10.0,7.0Hz,1H,H7α),4.30(d,J=8.0Hz,1H,H20α),4.68(dd,J=15Hz,2H,PhCH2O),4.78(m,1H,H10β),4.87(d,J=6.5Hz,1H,OCH2O),4.95(t,J=2.0Hz,1H,H20α),4.92(d,J=7.0Hz,1H,OCH2O),4.93(brd,J=2.0Hz,1H,H13β),4.96(br d,J=6.5Hz,1H,H5α),4.97(d,J=6.5Hz,1H,OCH2O),5.68(d,J=6.0Hz,1H,H2β),7.28(m,1H,PhCH2O),7.35(m,4H,PhCH2O),7.40(m,2H,PhCOO-m),7.59(m,1H,PhCOO-p),8.13(m,2H,PhCOO-o)
元素分析：C43H60O10Si×0.5H2O
理论值：C,66.72；H,7.94
实侧值：C,66.75；H:7.96
醇31经醇30a.0℃下向搅拌着的螺[4,4]二氧己烷29(P7=BOM,P10=TES,P13=TBS)(16mg,0.02mmole)的2腈(0.33ml)溶液中加入4％HF-吡啶复合物的乙腈(0.8ml)溶液。混合物于0℃下搅拌11小时，乙酸酯稀样，倾入20ml饱和NaHCO3水溶液中，CHCl3(30ml×3)提取。合并有机层，无水Na2SO4干燥，减压浓缩，得13.5mg(0.0196mmole)30a，其为油状物，将此油状物溶于THF(1ml)中，冷却至-78℃,-78℃下向其中加入0.285M苯基锂的THE(0.144ml,2.1eg)溶液。10分钟后，将溶液倾入20ml饱和NaHCO3水溶液中，CHCl3(30ml×3)提取。合并有机层，无水Na2SO4干燥，减压浓缩，得16mg灰黄色油状物，其经结晶得12.7mg(85％)苯甲酸酯31(P7=BOM,P13=TBS,R=H)酮32，室温下，向苯甲酸酯31(P7=BOM,P13=TBS,R=H)(18mg,0.235mmole)和4-甲基吗啉N-氧化物(18mg,0.154m-mole)的CH2Cl2(2.6ml)溶液中加入过钌酸四丙基铵(6mg,0.017mmole)。溶液于室温下搅拌15分钟，经硅胶过滤(30％乙酸乙酯/己烷)。滤液减压浓缩，得酮苯甲酸酯32(P7=BOM,P13=TBS)(18mg,100％)。32(P7=MOP,P13=TBS):1H NMR(300MHz,CDCl3)δ0.12(s,3H,TBS CH3),0.16(s,3H,TBS CH3),0.94(s,9H,TBS t-Bu),1.25(s,3H,CH3),1.42(s,3H,CH3),1.44(s,6H,MOP CH3),1.49(s,3H,CH3),1.75(s,1H,OH1),1.76(m,1H,H6),1.83(s,3H,CH3 18),2.21(dd,J=7,15Hz,1H,H14),2.25(s,3H,OAc),2.29(dd,J=8,15Hz,1H,H14),2.61(d,J=16Hz,1H,H9),2.74(ddd,J=8,9,17Hz,1H,H6),3.19(s,3H,MOP OCH3),3.20(d,J=6Hz,1H,H3α),3.32(d,J=16Hz,1H,H9),3.78(dd,J=8,10Hz,1H,H7),4.15(d,J=8Hz,1H,H20),4.34(d,J=8Hz,1H,H20),4.89(d,J=9Hz,1H,H5),5.04(m,1H,H13),5.90(d,J=6Hz,1H,H2),7.50(m,2H,PhCOO-m),7.62(m,1H,PhCOO-p),8.24(m,2H,PhCOO-o).32(P7=TES,P13=TBS):1H NMR(300MHz,CDCl3)δ0,12(s,3H,TBS CH3),0.16(s,3H,TBS CH3),0.65(q,J=8Hz,3H,TES CH3),0.66(q,J=8Hz,3H,TES CH3),0.94(s,9H,TBS t-Bu),1.00(t,J=8Hz,3H,TES CH2),1.24(s,3H,CH3),1.38(s,3H,CH3),1.49(s,3H,CH3),1.75(s,1H,OH1),1.80(m,1H,H6),1.81(s,3H,CH3 18),2.20(dd,J=9,15Hz,1H,H14),2.26(s,3H,OAc CH3),2.29(dd.J=8,15Hz,1H,H14),2.48(ddd,J=8,9,17Hz,1H,H6),2.58(d,J=17Hz,1H,H9),3.15(d,J=6Hz,1H,H3α),3.36(d,J=17Hz,1H,H9),3.79(dd,J=7,9Hz,1H,H7),4.14(d,J=8Hz 1H,H20),4.33(d,J=8Hz,1H,H20),4.90(d,J=9Hz,1H,H5),5.04(m,1H,H13),5.90(d,J=6Hz,1H,H2),7.49(m,2H,PhCOO-m),7.61(m,1H,PhCOO-p),8.13(m,2H,PhCOO-o).3.2(P7=BOM,P13=TBS):1H NMR(500MHz,CDCl3)；δ0.16(s,3H,TBS CH3),0.18(s,3H,TBS CH3),0.94(s,9H,TBS t-Bu),1.26(s,3H,CH3 17),1.47(s,3H,CH3 19),1.52(s,3H,CH3 16),1.76(s,1H,OH1),1.83(d,3H,J=0.5Hz,CH3 18),1.89(ddd,J=15.0,9.5,1.5Hz,1H,H6β),2.21(dd,J=15.0,9.0Hz,1H,H14β),2.26(s,1H,OAc 4),2.29(dd,J=15,0,8.0Hz,1H,H14α),2.72(m,1H,H6α),2.75(d,J=16Hz,1H,H9α),3.18(d,J=6.5Hz,1H,H3α),3.26(d,J=16.5Hz,H9α),3.65(dd,J=9.0,7.5Hz,1H,H7α),4.15(d,J=7.5Hz,1H,H20β),4.34(d,J=7.5Hz,1H,H20α),4.61(d,J=12.0Hz,1H,PhCH2O),4.72(d,J=12.0Hz,1H,PhCH2O),4.81(d,J=7.0Hz,1H,OCH2O),4.92(d,J=7.0Hz,1H,OCH2O),4.93(br d,J=6.5Hz,1H,H5α),5.05(br t,J=6.5Hz,1H,H13β),5.91(d,J=6.0Hz,1H,H2β),7.28(m,1H,PhCH2O),7.35(m,4H,PhCH2O),7.50(m,2H,PhCOO-m),7.62(m,1H,PhCOO-p),8.13(m,2H,PhCOO-o)
羟基酮33。-78℃下，向32(P7=BOM,P13=TBS)(16.2mg,0,0.2mmol)的THF(1.3ml)溶液中加入4当量的0.24M叔丁醇钾的THF(0.33ml,0.08mmol)溶液，溶液于-20℃下加热40分钟，然后升温至0℃，再置于0℃的苯亚硒酸酐(57mg,0.16mmol)的THF(1.3ml)悬浮液中。反应混合物于0℃下搅拌40分钟，然后用20ml乙酸乙酸稀释，倾入50ml饱和NaHCO3水溶液中，有机层依次用50ml饱和Na2S2O3水溶液和50ml饱和NaHCO3水溶液洗涤，用Na2SO4水溶液干燥，过滤蒸发得18.8mg羟基酮，其为油状。-78℃下，向羟基酮(18.8mg)粗品的THF(1.3ml)溶液中加入0.33ml,0.24M叔丁醇钾(0.08mmol)溶液，混合物搅拌20分钟，于-78℃下加入0.25ml 0.8M ACOH/THF溶液并搅拌5分钟。混合物用20ml酸乙酯稀释，倾入50ml饱和NaHCO3水溶液中，有机层经Na2SO4干燥，过滤，蒸发，得18.6mg黄色固体，其经硅胶塞过滤(2％乙酸乙酯/己烷～30％乙酸乙酯/己烷)，得15.9mg 33(P7=BOM,P13=TBS,(96％)。33(P7=MOP,P13=TBS):1H NMR(300MHz,CDCl3)δ0.13(s,3H,TBS CH3),0.15(s3H,TBS CH3),0.95(s,9H,TBSt-Bu),1.00(s,3H,CH3 16),1.09(s,3H,CH3 17),123(s,3H,MOP CH3),1.37(s,3H,MOPCH3),1.58(s,1H OH1),1.79(s,3H,CH3 19)1.90(dddJ=2.6,8.8,13.7Hz,1H,H6β),2.04(s,3H,CH3 18)2.13(dd,J=8.8,15.5Hz 1HH14β),2.22(dd,J=8.8,15.5Hz,1H,H14α),2.29(s,3H,OAc)2.79(ddd,6.3,9.9,14.8Hz,1H,H6α),3.17(s,3H,MOP OCH3),3.90(d,J=7.1Hz,1H H3α)4.16(d,J=8.2Hz,1H,H20α),4.25(d,J=2.2Hz,1H OH4),4.32(d,J=8.8Hz,1H,H20β)4.41(d,J=6.6,11.0Hz,1H,H7α),4.94(dd,J=22,9.9Hz,1H,H5α)5.03(ddd,J=1.1,8.2,8.8Hz,1H,H13β),5.20(d,J=6.2Hz,1H,H10α)5.60(d,J=72Hz,1H,H2β),7.48(t,J=7.7Hz,2H,PhCOO-m),7.61(t,J=7.7Hz,1H,PhCOO-p),8.10(d,J=7.1Hz,2H33(P7=BOM,P13=TBS):m.p.:234-236℃.1H NMR(500MHz,CDCl3)δ0.13(s,3H,TBS CH3),0.15(s,3H TBS CH3),0.95(s,9H TBS t-Bu),1.11(s,3H,CH3 16)1.18(s3H,CH3 17),1.59(s,1H,OH1),1.82(s,3H,CH3 18),1.89(ddd,J=2.4,42.4,14.4Hz,1HH6β),197(d,J=2.0Hz,3H,CH3 18),2.14(dd,J=8.6,15.4Hz,1H,H14β),2.21(dd,J=8.9,15.4Hz,1H,H14α),2.29(s,3H,Ac),270(ddd,J=6.5,9.6,1.44Hz,1H,H6α)3.93(d,J=6.9Hz,1H,H3α),4.17(d,J=8.6Hz,1H,H20β),4.28(d,J=2.4Hz,1H,OH10β)4.31(dd,J=6.5,12.4Hz,1H,H7α),4.32(d,J=8.6Hz,1H,H20α),4.45(d,J=12.2Hz,1H,PhCH2O),4.60(d,J=12.2Hz,1H,PhCH2O),4.60(d,J=7.3Hz,1H,OCH2O),4.73(d,J=7.3Hz,1H,OCH2O),4.97(dd,J=2.1,9.6Hz,1H,H5α),5.01(ddd,J=2.0,8.6,8.9Hz,1H,H13β),5.35(d,J=2.4Hz,1H,H10α),5.64(d,J=6.9Hz,1H,H2β),7.3(m,5HPhCH2),7.49(tt,J=1.7,7.9Hz,2H,PhCOO-m)7.61(tt,J=1.7,7.6Hz,1H,PhCOO-p)8.10(dd,j=12.79HzPhCOO.o).
乙酸酯34，室温下向33(P7=BOM,P13=TBS)(15.9mg,0.02mmol)和DMAP(1.2mg,0.01mmol)的吡啶(0.1ml)溶液中加入乙酸酐(38μl,0.4mmol)，搅拌反应19小时。混合物用20ml乙酸乙酯稀释，倾入50ml饱和NaHCO3水溶液中，有机层用Na2SO4干燥，过滤蒸发得18.1mg粗产品。此物经硅胶塞过滤，以20％乙酸乙酯/己烷洗脱，得16.8mg34(P7=BOM,P13=TBS)(100％产率)。34(P7=BOM,P13=TBS):1H NMR(500MHz,CDCl3)δ0.14(s,3H,TBS Me),0.16(s,3H,TBS Me),0.95(s,9H,TBS t-Bu),1.17(s,3H,CH3 17),1.18(s,3H,CH3 16),1.63(s,1H,OH1),1.76(s,3H,CH3 19),1.99(ddd,J=21,10.6,14.7Hz,1H,H6β),2.04(d,J=1.0Hz,3H,CH3 18),2.17(dd,J=8.6,15.1Hz,1H,H14β),2.19(s,3H,AcO10),2.24(dd,J=8.6,15.1Hz,1H,H14α),2.28(s,3H,AcO4),2.88(ddd,J=6.5,9.8,14.7Hz,1H,H6α),3.87(d,J=7.0Hz,1H,H3α),4.15(d,J=8.2Hz.1H,H20β),4.24(dd,J=6.5,10.6 Hz,1H,H7α),4.31(d,J=8.2Hz,1H,H20α),4.44(d,J=12.0Hz,1H,PhCH2O),4.68(d,J=12.0Hz,1H,PhCH2O),4.85(s,2H,OCH2O),4.95(dd,J=2.1,9.8Hz,1H,H5α),5.65(d,J=7.0Hz,1H,H2β),6.39(s,1H,H10α),7.30(m,5H,PhCH2),7.49(tt,J=1.4,8.2Hz,2H,PhCOO-m),7.61(tt,J=1.4,7.2Hz,1H,PhCOO-p),8.05(dd,J=1.2,8.2Hz,1H,PhCOO-o),IR(CHCl3)υ3600,3050,2975,2880,1750,1730,1460,1379,1250,1100,1020,860cm-1.34(P7=P13=TES):1H NMR(300MHz,CDCl3)δ0.57(q,J=7.7Hz,6H,TES CH2),0.67(q,J=7.7Hz,TES CH2),0.92(t,J=7.7Hz,9H,TES CH3),1.01(t,J=7.7Hz,9H,TESCH3),1.11(s,3H,CH3 17),1.19(s,3H,CH3 19),1.61(s,1H,OH1),1.67(s,3H,CH3 16),1.86(ddd,J=2.2,10.4,14.3Hz.1H,H6β),2.11(d,J=11Hz,3H,CH3 18),2.12(m,1H,H14β),2.17(s,3H,OAc10),2.23(dd,J=7.6,14.9Hz,1H.H14α),2.28(s,3H,OAc4),2.51(ddd,J=6.9,9.6,14.3Hz,1H,H6α),3.82(d,J=7.2Hz,1H,H3α),4.14(d,J=8.3Hz,1H,H20β),4.30(d,J=8.3Hz,1H,H20α),4.48(dd,J=6.6,10.4Hz,1H,H7α),4.92(dd,J=7.7,8.8Hz,1H,H5α),4.96(d,J=8.2Hz,1H,H13β),5.63(d,J=6.6Hz,1H,H2α),6.47(s,1H,H10α),7.47(t,J=7.1Hz,2H,PhCOO-m),7.60(t,J=7.1Hz,PhCOO-p),8.10(d,J=7.1Hz,PhCOO-o).
二醇35，室温氮气下，向34(P7=BOM,P13=TBS)(16.3mg、0.0199mmol)的THF(0.5ml)溶液中加入三(二乙氨基)锍二氟三甲基硅酸酯(TASF)(37mg,0.134mmole)。溶液搅拌40分钟，用乙酸乙酯稀释，倾入20ml饱和NaHCO3水溶液中，用CHCl3(30ml×3)提取，合并有机相，无水Na2SO4干燥，减压浓缩，得16mg灰黄色油状物，其经硅胶垫过滤，以70％乙酸乙酯/己烷作洗脱液，滤液浓缩得13.5mg(94％)7-BOMBⅢ(35)。35(P7=BOM)mp.224-225℃,1H NMR(500MHz,CDCl3),δ1.08(s,3H,CH3 17),1.18(s,3H,CH3 16),1.61(s,1H,OH1),1.77(s,3H,CH3 19),1.99(ddd,J=2,10.5,14.5Hz,1H,H6β),2.02(d,J=5Hz,1H,OH13),2.10(d,J=1.5Hz,3H,CH3 18),2.20(s,3H,AcO),2.28(s,3H,AcO),2.27-2.29(m,2H,H14),2.89(ddd,J=7,10,16.5Hz,1H,H6α),3.94(d,J=7Hz,1H,H3),4.16(dd,J=1,8.5Hz,1H,H20β),4.24(dd,J=6.5,10.5Hz,1H,H7),4.31(d,J=8Hz,1H,H20α),4.45(d,J=12.0Hz,1H,OCH2Ph),4.67(d,J=12.0Hz,1H,OCH2Ph),4.84(d,J=5Hz,1H,OCH2O),4.86(d,J=5Hz,1H,OCH2O),4.87(m,1H,H13β),4.95(dd,J=2.0,9.5Hz,1H,H5α),5.63(d,J=7Hz,1H,H2β),6.40(s,1H,H10α),7.30(m,5H,PhCH2),7.48(m,2H,PhCOO-m),7.61(m,1H,PhCOO-p),8.10(2H,m,PhCOO-o),13C NMR(CDCl3)δ(ppm)10.3,14.9,20.0,20.7,22.4,26.6,35.3,38.4,42.7,47.2,57.4,67.8,69.9,74.6,75.8,76.4,78.7,80.3,80.3,80.9,84.4,96.7,127.7,127.9,128.5,128.8,129.6,130.3,132.4,133.8,138.0,144.4,167.3,169.8,171.0,203.0IR(CHCl3)υ1720,1460cm-1
元素分析：C39H46O12
理论值：C,66.28；H,6.56
实侧值：C,66.09；H:6.59
7-BOM-紫杉醇、-45℃下，向7-BOM浆果赤霉素Ⅲ(35)(13.2mg,0.018mmol)的0.25mlTHF溶液中滴加21μl1.03M双(三甲基甲硅烷基)酰胺锂的THF溶液。-45℃下12时后，向混合物中滴加入(S)-顺式-1-苄氧基-3-三乙基甲硅烷氧基-4-氮杂环丁-2-酮(15mg、0.039mmol)的0.25mlTHF溶液，将其加热至0℃，保温1小时，然后加入0.2ml10％AcOH的THF溶液。使混合物在饱和NaHCO3水溶液和60％乙酸乙酯/己烷中进行分配，有机层蒸发得一残渣，其经硅胶过滤纯化，得20.2mg(2′R,3′S)-2′-三乙基甲硅烷基-7-BOM紫杉醇粗品。
0℃下，向20.2mg(0.018mmol)的(2′R,3′S)-2′-三乙基甲硅烷基-7-BOM紫杉醇的0.8ml乙腈和0.3ml吡啶溶液中加入0.10ml48％HF水溶液。混合物于0℃下搅拌1小时，使之在饱和NaHCO3水溶液和乙酸乙酯之间分配。蒸除乙酸乙酯，得17.7mg物质，其经闪柱层析，得15.4mg(86％)7-BOM-紫杉醇。7-BOM-Taxol:m.p169-172℃,1H NMR(CDCl3,300MHz)δ8.11(d,J=7.1Hz,2H,benzoate ortho),7.76(d,J=7.1Hz,1H,benzamide ortho),7.61-7.26(m,11H,aromatic),7.06(d,J=8.8Hz,1H,NH),6.33(s,1H,H10),6.17(dd,J=8.8,8.8Hz,1H,H13),5.79(dd,J=8.8,2.2Hz,1H,H3’),5.67(d,J=6.6Hz,1H,H2b),4.91(d,J=8.8Hz,1H,H5),4.87-4.77(m,3H,H2’,OCH2Ph),4.67(d,J=12Hz,OCH2O)4.43(d,J=12Hz,OCH2O),4.30(d,J=8.2Hz,1H,H20a),4.19(d,J=8.2Hz,1H,H20b),4.15(m,1H,H7),3.70(d,J=6.6Hz,1H,H3),3.61(d,J=2.5Hz,1H,2’OH),2.85(m,1H,H6a),2.35(s,3H,4Ac),2.20(m,2H,H14),2.19(s,3H,10Ac),2.05(m,1H,H6b),1.78(br s,6H,Me18,Me19),1.72(s,1H,1OH),1.19(brs,6H,Me16,Me17).
元素分析：C55H59O15×0.5H2O
理论值：C,67.20；H,6.15
实侧值：C,67.08；H:6.16
紫杉醇，室温下，向10％Pd/C(50mg)的乙醇(0.6ml)(用氢气饱和)悬浮液中加入7-BOM-紫杉醇(14.4mg,0.0148mmol)的乙醇(0.2ml×4)溶液。反应混合物在氢气下回流45分钟，经硅胶过滤，以乙酸乙酯洗脱。减压蒸除溶剂，得11.9mg紫杉醇(94％)，其中为无色针状物，其与标准的紫杉醇样品比较具有一样的光谱。Taxol:mp.210-212℃,1H NMR(500MHz,CDCl3)δ11.5(s,3H,CH3 16),1.24(s,3H,CH3 17),1.68(s,3H,CH3 19),1.75(s,1H,OH1),1.79(s,3H,CH3 18),1.90(ddd,J=14.6,11.0,2.3Hz,1H,H6β),2.26(s,3H,AcO10),2.33(dd,J=15.4,8.9Hz,1H,H14β),2.38(dd,J=15.4,8.9Hz,1H,H14α),2.41(s,3H,AcO4),2.46(d,J=4.1Hz,1H,OH7),2.57(ddd,J=10.0,14.6,6.5Hz,1H,H6α),3.54(d,J=5.0Hz,1H,OH2’),3.82(d,J=6.9Hz,1H,H3α),4.22(d,J=8.5Hz,1H,H20α),4.32(d,J=8.5Hz,1H,H20β),4.42(ddd,J=11.0,6.5,4.1Hz,1H,H7α),4.81(dd,J=5.0,2.5Hz,1H,H2’),4.96(dd,J=10.0,2.3Hz,1H,H5α),5.69(d,J=6.9Hz,1H,H2β),5.81(dd,J=8.7,2.5Hz,1H,H3’),6.25(dd,J=8.9,8.9Hz,1H,H13β),6.29(s,1H,H10α),6.98(d,J=8.7Hz,1H,NH),7.37(m,1H,PhCON-p),7.46(m,9H,Ph3’,PhCOO2’-m,PhCON-m),7.62(m,1H,PhCOO-p),7.76(br d,J=8.7Hz,1H,PhCON-o),8.16(br d,J=7.3Hz,1H,PhCOO-o).IR(CHCl3)υ1730,1650cm-1.
10-去乙酰基浆果赤霉素Ⅲ(36),0℃下向酮33(P7=MOP,P13=TES)(2.2mg,0.003mmol)的吡啶(30μl,0.36mmol)及乙腈(20μl)溶液中加入48％HF(12μl,0.32mmol)水溶液。此溶液升温至室温，搅拌36小时，用2ml乙酸乙酯稀释之，倾入含30ml饱和NaHCO3水溶液和20ml乙酸乙酯的分液漏斗中。水层用20ml乙酸乙酸提取2次，合并有机层，Na2SO4干燥，过滤，浓缩，得2.7mg黄色油状物。此物经硅胶柱层析纯化，以50％乙酸乙酯/己烷、再用乙酸乙酯洗脱，得1.5mg36，其与标准的10-DAB样品显示一致的光谱特性。
浆果赤霉素Ⅲ(37)。0℃向酮34(P7=MOP)(2.1mg,0.003mmol)的吡啶(30μl,0.36mmol)和乙脯(20μl)溶液中加入488％HF(12μl,0.32mmol)水溶液。此溶液升至室温后，搅拌36小时，混合物用2ml乙酸乙酯稀释，将其倾入含30ml饱和Na2CO3水溶液和20nl乙酸乙酯的分液漏斗中，水层用20ml乙酸乙酯提取2次，合并有机层，Na2SO4干燥，过滤，浓缩，得2.7mg黄色油状物，此物经硅胶柱层析纯化，以乙酸乙酯/己烷混合物洗脱，得1.7mg37，其与标准浆果赤霉素Ⅲ样品显示一致的光谱特性。
反庆路线A′羟基酮19。-78℃氮气下，向剧烈搅拌下的酮18(P7=MOP)(181mg,0.265mmol)的THF(2.2ml)溶液中沿瓶壁滴加入2.13ml0.2M LDA(0.426mmol)的TPHP溶液。10分钟后，沿瓶壁滴加116mg(s)一樟脑磺酰基氧杂氮丙啶(116mg,0.36mmol)的1.5mlTHF溶液。反应混合冷至-40℃，搅拌1小时，加入2ml饱和NaHCO3水溶液，混合物用50ml30％乙酸乙酯/己烷稀释，20ml饱和NaHCO3水溶液及盐水洗涤，无水Na2SO4干燥，减压浓缩。生成的油状物经硅胶过滤，以30％乙酸乙酯/己烷洗脱，浓缩得210mg无色油状物。此物经径向层析纯化，以25％乙酸乙酯/己烷洗脱，得150mg(81％)5β-羟基酮19，其为白色固体，15mg(8％)起始酮18以及10mg(5％)相应的5α-羟基酮。19(P7=MOP):1H NMR(500MHz,CDCl3)δ0.08(s,3H,TBS CH3),0.12(s,3H,TBS CH3),0.62(q,J=8.2Hz,6H,TES CH2),0.90(s,9H,TBSt-Bu),0.96(t,J=8.2Hz,9H,TESCH3),1.05(s,3H,CH3 19),1.19(s,3H,CH3 17),1.33(s,3H,CH3 16),1.35(s,3H,MOPCH3),1.43(s,3H,MOP CH3),1.67(dd,J=5.0,14.7Hz,1H,H9β),1.87(m,1H,H6β),2.12(dd,J=4.1,15.1Hz,1H,H14α),2.14(d,J=1.4Hz,3H,CH3 18),2.23(dd,J=7.3,14.7Hz,1H,H9α),2.55(dd,J=9.2,15.1Hz,1H,H14β),2.76(ddd,J=3.7,7.3,13.7Hz,1H,H6α),3.22(s,3H,MOP OCH3),3.24(d,J=4.1Hz,1H,OH5),3.28(d,J=6.0Hz,1H,H3α),3.83(dd,J=3.7,92Hz,1H,H7α),4.06(ddd,J=4.1,7.3,7.3Hz,1H,H5α),4.46(dd,J=5.0,7.3Hz,1H,H10β),4.53(d,J=6.0Hz,1H,H2β),4.63(dd,J=2.8,9.2Hz,1H,H13β).酮20,0℃氮气下，向剧烈搅拌下的5-羟基-4-酮19(P7=MOP)(420mg,0.602mmol)的CH2Cl(20ml)和三乙胺(1.18ml,8.5mmol)溶液中加入三甲基甲硅烷基氯纯物(0.40ml,3.3mmol)。0.5小时后，用5ml饱和NaHCO3水溶液终止反应，用50mlCHCl3提取，有机层经盐水洗涤，无水Na2SO4干燥，减压浓缩，得453mg(98％)酮20，其为无色油状物，此物无须纯化即可使用。20(P7=MOP):1H NMR(500MHz,CDCl3)δ0.11(s,6H,TBS CH3),0.12(s,9H,TMSCH3),0.59(q,J=7.8Hz,6H,TES CH2),0.94(s,9H,TBS t-Bu),0.96(t,J=7.8Hz,9H,TES CH3),1.23(s,3H,CH3 17),1.32(s,3H,CH3 19),1.33(s,3H,MOP CH3),1.35(s,3H,CH3 16),1.37(s,3H,MOP CH3),1.86(m,3H,H6β,H9α,H9β),2.05(d,J=1.4Hz,3H,CH3 18),2.43(d,J=3.7Hz,1H,H14β),2.45(d,J=4.6Hz,1H,H14α),2.59(ddd,J=6.0,8.2,14.2Hz,1H,H6α),2.84(d,J=6.0Hz,1H,H3α),3.21(s,3H,MOP OMe),3.51(dd,J=6.0,11.0Hz,1H,H7α),3.94(dd,J=4.1,8.2Hz,1H,H5α),4.38(dd,J=5.0,8.7Hz,1H,H10β),4.54(d,J=6.0Hz,1H,H2β),4.74(dd,J=6.4,6.4Hz,1H,H13β).二醇21。-78℃氮气下，向搅拌下的酮20(P7=MOP)(453mg,0.588mmol)的THF(23ml)溶液中滴加入1.95ml3MMe MgBr的乙醚溶液(5.85mmol)。混合物搅拌5.5小时，倾入100ml饱和NaH-CO3水溶液中，用CHCl3(100ml×3)提取。合并有机层，无水Na2SO4干燥，减压浓缩，得453mg羟基三甲基甲硅烷基醚，其为无色油状物。此物无须纯化即可使用。
0℃下，向搅拌下的三甲基甲硅烷基醚(453mg)的吡啶(8ml)和乙腈(8ml)溶液中加0.8ml48％HF水溶液。搅拌20分钟后，将生成的混合物倾入100ml饱和NaHCO3水溶液中，(50ml×3氯仿提取，合并有机层，无水Na2SO4干燥，减压浓缩，得422mg二醇21。此物无须纯化即可使用。21(P7=MOP):1H NMR(300MHz,CDCl3)δ0.08(s,3H,TBS CH3),0.10(s,3H,TBS CH3),0.56(q,J=7.7Hz,6H,TES CH2),0.90(s,9H,TBS t-Bu),0.93(t,J=7.7Hz,9H,TESCH3),1.16(s,3H,CH3 17),1.25(s,3H,CH3 16),1.29(s,3H,CH3 19),1.31(s,3H,CH320),1.38(s,3H,MOP CH3),1.46(s,3H,MOP CH3),1.81(d,J=3.8Hz,1H,H3α),1.86(d,J=9.9Hz,1H,H9β),1.90(dd,J=6.1,8.3Hz,1H,H9α),1.96(s,3H,CH3 18),2.12(ddd,J=3.3,3.3,10.4Hz,1H,H6α),2.30(m,1H,H6β),2.42(dd,J=3.9,15.4Hz,1H,H14α),2.61(dd,J=9.3,15.4Hz,1H,H14β),2.81(s,1H,OH4),3.04(m,1H,OH5),3.40(dd,J=3.9,15.8Hz,1H,H7α),4.28(dd,J=6.6,8.2Hz,1H,H10β),4.62(dd,J=1.6,7.8Hz,1H,H13β),4.66(d,J=3.8,1H,H2β).乙酸酯22。室温氮气下，向搅拌着的二醇21(P7=MOP)(470mg,0.66mmol)的吡啶(12ml)溶液中加入乙酸酐(4.5ml)。11小时后，混合物用50mlCHCl3稀释，倾入50ml饱和NaHCO3水溶液中，水相用CHCl3提取，合并提取物，用盐水洗涤，Na2SO4干燥并过滤，滤液减压浓缩，得470mg(94％，从20起始计)粗产品，其经1HNMR及TCL分析表明为乙酸酯22纯品。22(P5=Ac,P7=MOP):1H NMR(500MHz,CDCl3)δ0.10(s,3H,TBS CH3),0.13(s,3H,TBS CH3),0.59(q,J=7.8Hz,6H,TES CH2),0.94(s,9H,TBS t-Bu),0.95(t,J=7.8Hz,9H,TES CH3),1.18(s,3H,CH3 17),1.30(s,3H,CH3 16),132(s,3H,CH3 19),1.33(s,6H,CH320,MOP CH3),1.41(s,3H,MOP CH3),1.91(d,J=3.4Hz,1H,H3α),1.94(m,2H,H9,H9),2.00(d,J=1.5Hz,3H,CH3 18),2.06(ddd,J=3.9,3.9,11.7Hz,1H,H6α),2.10(s,3H,OAc),2.14(dd,J=11.7,23.9Hz,1H,H6β),2.38(dd,J=3.9,15.1Hz,1H,H14α),2.63(dd,J=9.3,15.1Hz,1H,H14β),2.78(d,J=1.5Hz,1H,OH4),3.20(s,3H,OMe CH3),3.38(dd,J=3.9,11.7Hz,1H,H7α),4.30(dd,J=4.9,10.3Hz,1H,H10β),4.50(ddd,J=1.5,3.9,12.2Hz,1H,H5α),4.64(dd,J=1.5,1.5Hz,1H,H13β),4.66(d,J=3.4Hz,1H,H2β).
链烯23。10℃氮气中，于3分钟内向搅拌下的醇22(P5=AC,P7=MOP)(26mg,0.034mmol)的CH2Cl2(1.48ml)和吡啶(0.37ml)溶液中加入SOCl2(0.037ml,5.1mmol)。混合物加热至室温搅拌2.3小时，用CHCl3稀释，倾入饱和NaHCO3水溶液中。水层用CHCl3提取，合并提取物，盐水洗涤，无水Na2SO4干燥并过滤，减压浓缩，得24mg粗产品，其经硅胶层析纯化得13mg(52％)4∶1的7-MOP-外内；环链烯以及6mg(27％)4∶1的7-羟基-外内；环链烯。23(P5=Ac,P7=MOP):1H NMR(500MHz,CDCl3)δ0.10(s,3H,TBS CH3),0.12(s,3H,TBS CH3),0.59(q,J=7.9,6H,TES CH2),0.93(s,9H,TBS t-Bu).0.96(t,J=7.9,9H,TESCH3),1.21(s,3H,CH3 17),1.30(s,3H,CH3 19),1.32(s,3H,MOP CH3),1.34(s,3H,MOPCH3),1.37(s,3H,CH3 16),1.72(m,2H,H6β,H9β),1.89(dd,J=3.8,13.4Hz,1H,H9β),2.03(d,J=1.37Hz,3H,CH3 18),2.05(s,3H,OAc CH3),2.33(dd,J=5.1,15.4Hz,1H,H14α),2.47(m,2H,H6α,H14β),3.06(d,J=5.8Hz,1H,H3α),3.20(s,3H,MOP OMe),3.38(dd,J=6.9,11.0Hz,1H,H7α),4.37(dd,J=3.8,11.0Hz,1H,H10β),4.53(d,J=5.8Hz,1H,H2β),4.74(m,1H,H13β),5.15(s,1H,H20E),5.21(d,J=1.37Hz,1H,H20Z).5.36(d,J=9.3Hz,1H,H5α).
二醇24,0℃氮气下，向搅拌着的4∶1外，内环链烯23(P5=AC,P7=MOP)(249mg,0.337mmol)的吡啶溶液中加入2.35ml0.157M(OSO4(0.368mmol)的THF溶液。1小时后，加入Na2SO4与6.2ml水，混合物于室温下搅拌1小时。然后用乙酸乙酯稀释，再倾入饱和NaHCO3水溶液中。水层用乙酸乙酯提取，合并提取物，盐水洗涤，无水Na2SO4干燥，减压浓缩，得281mg粗品，其经硅胶层析纯化，以50％乙酸乙酯/己烷洗脱，得190mg(73％)二醇24纯品及48mg(19％)乙酸烯醇酯。24(P5=Ac,P7=MOP):1H NMR(500MHz,CDCl3)δ0.10(s,3H,TBS CH3),0.11(s,3H,TBS CH3),0.60(dq,J=1.5,7.8Hz,6H,TES CH2),0.87(s,3H,CH3 19),0.93(s,9H,TBSt-Bu),0.95(t,J=7.8Hz,9H,TES CH3),1.20(s,3H,CH3 17),1.31(s,3H,CH3 16),1.33(s,3H,MOP CH3),1.47(s,3H,MOP CH3)1.54(dd,J=12.3,25.0Hz,1H,H6β),1.63(dd,J=5.5,15.1Hz,1H,H9β),2.05(s,3H,OAc),2.15(s,3H,CH3 18),2.26(m,2H,H9α,OH20)2.37(dd,J=9.2,14.7Hz,1H,H14β),2.46(ddd,J=4.8,4.8,13.4Hz,1H,H6α),2.69(d,J=4.5Hz,1H,H3α),3.18(s,3H,MOP CH3),3.28(dd,J=3.8,14.7Hz,1H,H14α),3.76(dd,J=4.0,11.6Hz,1H,H7α),3.84(m,2H,H20,H20),3.95(s,1H,OH4),4.42(dd,J=5.1,5.8Hz,1H,H10β),4.44(d,J=4.1Hz,1H,H2β),4.63(dd,J=4.1,12.3Hz,1H,H5α),4.67(dd,J=4.1,9.2Hz,1H,H13β).24(P7=BOM):1H NMR(300MHz,CDCl3)δ0.9(s,3H,TBS CH3),0.10(s,3H,TBS CH3),0.58(q,J=7.9Hz,2H,TES CH2),0.83(s,3H,CH3 19),0.92(s,9H,TBS t-Bu),0.93(t,J=7.9Hz,TES CH3),1.20(s,3H,CH3 17),1.33(s,3H,CH3 16),1.58(q,J=13.2Hz,1H,H6β),1.71(dd,J=10.4,5.5Hz,H9β),2.04(s,3H,OAc),2.17(br s,3H,CH3 18),2.20(dd,J=10.4,3.8Hz,1H,H9α),2.35(dd,J=14.8,9.1Hz,1H,H14β),2.43(dt,J=13.2,5.0Hz,1H,H6α),2.80(d,J=4.6Hz,1H,H3α),3.31(dd,J=4.4,14.8Hz,1H,H14α),3.71(dd,J=4.9,13.0Hz,1H,H7α),3.83(m,2H,H20),3.98(s,1H,OH1),4.46(d,J=4.8Hz,1H,H2β),4.48(m,1H,H10β),4.51(d,J=12.1Hz,1H,PhCH2O),4.64(dd,J=13.2,5.0Hz,1H,H5α),4.66(m,1H,H13β),4.70(d,J=12.1Hz,1H,PhCH2O),4.83(d,J=7.1Hz,1H,OCH2O),4.94(d,J=7.1Hz,1H,OCH2O),7.33(m,5H,Ph).
三醇25。-5℃氮气下，向搅拌下的乙酰氧基二醇24(P5=AC,P7=MOP)(26.5mg,0.035mmol)的无水甲醇(0.9ml)溶液中加入0.06ml0.166M(0.01mmol)甲醇钠甲醇溶液。2.5小时后，用10ml乙酸乙酯稀释反应混合物，然后倾入10ml饱和NaHCO3水溶液中，有机层用10ml饱和NaHCO3水溶液洗涤，无水Na2SO4干燥，减压浓缩，得25mg三醇25(100％)纯品。25(P7=MOP):1H NMR(500MHz,CDCl3)δ0.10(s,3H,TBS CH3),0.11(s,3H,TBS CH3),0.60(q,J=8.06Hz,6H,TESCH2),0.87(s,3H,CH3 19),0.94(s,9H,TBS t-Bu),0.95(t,J=8.1Hz,9H,TES CH3),1.19(s,3H,CH3 17),1.31(s,3H,CH3 16),1.33(s,3H,MOPCH3),1.47(s,3H,MOP CH3),1.59(dd,J=11.7,11.7HZ,1H,H6β),1.62(dd,J=5.5,16.1HZ,1H,H9β),2.11(d,J=0.7Hz,3H,CH3 18),2.24(dd,J=5.5,16.1Hz,1H,H9α),2.38(dd,J=9.5,15.0Hz,1H,H14β),2.45(ddd,J=4.4,4.4,13.6Hz,1H,H6α),2.60(d,J=4.4Hz,1H,H3α),3.21(s,3H,MOP OMe),3.25(dd,J=4.4,15.0Hz,1H,H14α),3.52(dd,J=4.4,12.8Hz,1H,H7α),3.72(dd,J=4.4,11.4Hz,1H,H5α),3.79(s,1H,OH4),3.86(d,J=11.0,1H,H20),3.93(d,J=11.4Hz,1H,H20),4.42(dd,J=5.1,5.1Hz,1H,H10β),4.45(d,J=4.4Hz,1H,H2β),4.66(dd,J=4.0,9.2Hz,1H,H13β).
对-甲氧亚苄基乙缩醛25b：向于CH2Cl2中搅拌的二醇24(P5=AC,P7=BOM)(6.5mg,0.0079mmol)和茴香醛二甲基缩醛(0.013ml,0.076mmol)中加入对-甲苯磺酸(0.002ml,0.1M的THF溶液，O.0002mmol)。生成的溶液于室温下搅拌15分钟，然后加入三乙胺(0.1ml)，继续搅拌10分钟。混合物用30％乙酸乙酯/己烷(15ml)溶液淋洗，然后水层用30％乙酸乙酯/己烷(2×5ml)提取。合并提取物，盐水洗涤，Na2SO4干燥并过滤。滤液减压浓缩，得12mg无色油状物，其经硅胶层析纯化，得6.9mg(96％)对-甲氧亚苄基乙缩醛25b，其为5∶1的非对映体的混合物。25b(P5=Ac,P7=BOM,major diasteromer):1H NMR(500MHz,CDCl3)δ-0.05(s,3H,TBSCH3),0.07(s,3H,TBS CH3),0.60(q,J=7.9Hz,2H,TES CH2),0.78(s,3H,CH3 19)0.82(s,9H,TBS t-Bu),0.95(t,J=7.9Hz,TES CH3),1.25(s,3H,CH3 17),1.37(s,3H,CH3 16),1.58(m,H6β),1.70(dd,J=16.8,5.8Hz,H9β),1.74(s,3H,OAc),2.26(s,3H,CH3 18),2.28(dd,J=16.8,1.4Hz,1H,H9α),2.38(dd,J=15.1,9.7Hz,1H,H14β),2.57(dt,J=5.1,9.9Hz,1H,H6α)3.10(dd,J=5.1,14.7Hz,1H,H14α),3.11(d,J=4.8Hz,1H,H3α),3.79(s,3H,OCH3),3.84(dd,J=5.0,11.5Hz,1H,H7α),4.15(d,J=8.2Hz,1H,H20),4.20(d,J=8.2Hz,1H,H20),4.48(d,J=12.0Hz,1H,OCH2Ph),4.55(d,J=4.8Hz,1H,H2β),4.57(m,1H,H10β),4.71(d,J=12.0Hz,1H,OCH2Ph),4.73(m,1H,H13β),4.78(dd,J=12.4,4.9Hz,1H,H5α),4.84(d,J=6.7Hz,1H,OCH2O),4.99(d,J=6.7Hz,1H,OCH2O),6.05(s,1H,acetal CH),6.80(d,J=7.5Hz,2H,p-MeOPh-o),7.27-7.36(m,
i 25b(P5=AC,P7=BOM，主要为非对映异构体)丙酮化合物26b。0℃下向搅拌着的对甲氧亚苄基乙缩醛25b(P5=AC,P7=BOM)(11.5mg,0.012mmol)的0.4ml甲苯溶液中加入二异丁基铝氢化物(0.082ml,2.0M的甲苯溶液，0.12mmol)。生成的溶液搅拌3.5小时，然后加入甲醇(0.1ml)。混合物用乙酸乙酯(5ml)稀释，与饱和酒石酸钾钠水溶液搅拌1.5小时。分出水相，用乙酸乙酯(2×10ml)提取，然后合并提取物，用盐水洗涤，Na2SO4干燥。过滤，滤液减压浓缩，得12mg粗品，其经硅胶层析(30％乙酸乙酯/己烷洗脱)纯化，得4.7mg甲酸乙缩醛混合物，1.1mg4-MPM-1,2,5,20-四醇以及5.2mg甲酸对-甲氧苄基醚混合物。
将甲酸乙缩醛混合物溶于甲醇中，加入3％NH4OH溶液，此浑浊物在室温下搅拌30分钟，然后冲洗入乙酸乙酯和饱和NaHCO3水溶液中，水相用乙酸乙酯提取(2×10ml)，合并提取物，盐水洗涤，Na2SO4干燥并过滤。减压浓缩滤液，得对-甲氧亚苄基乙缩醛混合物。将其溶于甲苯(0.4ml)中。冷却至0℃，加入二异丁基铝氢化物(0.02ml,2.0M甲苯溶液，0.08mmol)。生成的溶液搅拌3.5小时，加入甲醇(0.1ml)。混合物用乙酸乙酯(5ml)稀释，与饱和酒石酸钾钠水溶液搅拌1.5小时。分出水相，用乙酸乙酯(2×10ml)提取，合并提取物，盐水洗涤，Na2SO4干燥。过滤，滤液减压浓缩，得4.5mg粗品，其经硅胶层析纯比(30％乙酸乙酯/己烷洗脱)，得2.8mg4-MPM-1,2,5,20-四醇。
将甲酸对-甲氧苄基醚混合物溶于甲醇(0.1ml)中，加入3％NH4OH(0.1ml)，生成的混浊液于室温下搅拌30分钟，然后冲洗入乙酸乙酯和饱和NaHCO3水溶液中，水相用乙酸乙酯(2×10ml)提取，合并提取液，盐水洗液，Na2SO4干燥，过滤，减压浓缩，得4.8mg粗品，其经硅胶层析纯化，得3.2mg4-MPM-1,2,5,20-四醇，4-MPM-1,2,5,20-四醇的总产率为68％(从25b起始计)。4-MPM-1,2,5,20-tetraol·1H NMR(500MHz,CDCl3)δ0.13(s,3H,TBS CH3),0.06(s,3H,TBS CH3),0.60(q,J=8.0Hz,2H,TES CH2),0.89(s,9H,TBS t-Bu),0.95(t,J=8.0Hz,TES CH3),0.97(s,3H,CH3 19),1.22(s,3H,CH3 17),1.30(s,3H,CH3 16),1.83(dd,J=16.8,5.8Hz,H9α),1.91(q,J=12.4Hz,1H,H6β),2.12(m,2H,H9αand 14β),2.18(s,3H,CH3 18),2.55(m,2H,H14βand 6α),2.79(d,J=5.3Hz,1H,H3α),2.95(d,J=3.0Hz,1H,OH5),3.54(m,1H,OH20),3.66(dd,J=10.3,5.3Hz,1H,H2β),3.81(s,3H,OCH3),3.85(dd,J=5.2,11.6Hz,1H,H7α),3.91(dt,J=5.9,12.4,1H,H5α),4.18(s,1H,OH1),4.13(d,J=13Hz,1H,H20),4.20(dd,J=7.22,12.9Hz,1H,H20),4.47(d,J=11.8Hz,1H,OCH2Ph),4.58(m,1H,H10β),4.79(a,J=11.8Hz,1H,OCH2Ph),4.85(m,1H,H13β),4.87(d,J=6.8Hz,1H,OCH2O),5.0t(d,J=10.6Hz,1H,MPM CH2),5.10(d,J=6.8Hz,1H,OCH2O),5.11(d,J=10.6Hz,1H,MPM CH2),5.49(d,J=10.5Hz,1H,OH2),6.87(d,J=8.7Hz,2H),7.30(d,J=8.7Hz,2H,p-MeOPh-o),7.27-7.36(m,5H,p-MeOPh-m and PhCH2).
4-MPM-1,2,5 20-四醇
0℃下，向于0.2mlCH2Cl2和0.02ml2.2-二甲氧基丙烷中搅拌的4-MPM-1,2,5,20-四醇(2.0mg,0.0023mmol)中加入对-甲苯磺酸(0.002ml,0.1MTHF溶液，0.0002mmol)生成的溶液搅拌20分钟，加入三乙胺(0.1ml)，继续搅拌10分钟，将混合物冲洗入乙酸乙酸(10ml)和饱和NaHCO3水溶液中，水相用乙酸乙酯提取(2×5ml)。合并提取物，用盐水洗涤，Na2SO4干燥，过滤，滤液减压浓缩，得2.1mg粗品，其经硅胶层析纯化得1.1mg丙酮化合物26b26b(P520=C(CH3)2,P7=BOM):1H NMR(500MHz,CDCl3)δ-0.073(s,3H,TBS CH3),0.008(s,3H,TBS CH3),0.60(q,J=7.9Hz,6H,TES CH2),0.79(s,9H,TBS t-Bu),0.95(t,J=7.9Hz,9H,TES CH3),1.10(s,3H,CH3 19),1.25(s,3H,CH3 17),1.34(s,3H,CH3 16),1.41(s,3H,CH3 acetonide),1.46(s,3H,CH3 acetonide),1.88(dd,J=16.7,5.5Hz,H9β),2.08(dd,J=14.3,9.2Hz,1H,H14β),2.17(s,3H,CH3 18),2.21(dd,J=17.1,1.7Hz,1H,H9α),2.42(dd,J=14.3,7.2Hz,1H,H14α),2.61(d,J=5.1Hz,1H,H3α),2.62(m,1H,H6β),3.71(dd,J=11.3,5.1Hz,1H,H2β),3.75(dd,J=5.0,11.3Hz,1H,H7α),3.80(s,3H,OCH3),3.99(dd,J=12.0,6.2Hz,1H,H5α),4.01(d,J=14,2Hz,1H,H20),4.17(s,1H,OH1),4.44(d,J=14.2Hz,1H,H20),4.47(d,J=11.6Hz,1H,OCH2Ph),4.58(m,1H,H10β),4.80(d,J=11.6Hz,1H,OCH2Ph),4.84(d,J=11.3Hz,1H,OH2),4.85(m,1H,H13β),4.88(d,J=10.3Hz,1H,OCH2O),4.89(d,J=6.8Hz,1H,MPM CH2),5.00(d,J=10.3Hz,1H,OCH2Ph),5.10(d,J=6.8Hz,1H,MPM CH2),6.85(d,J=8.9Hz,2H,p-MeOPh-o),7.27(d,J=8.9Hz,2H,p-MeOPh-m),7.27-7.36(m,5H,PhCH2).
二醇碳酸酯27b:-78℃下，向于0.2mlCH2Cl2和0.02ml吡啶中搅拌的二醇26b(P520=C(CH3)2,P7=BOM)(1.1mg)中加入碳酰氯(0.010ml,2M甲苯液，0.02mmol)。生成的溶液于-78℃下搅拌10分钟，升温至0℃，保温3小时。此混合物用30％乙酸乙酯/己烷(5ml)稀释，倾入30％乙酸乙酯/己烷(10ml)和饱和NaHCO3水溶液中。水相用30％乙酸乙酯/己烷(2×5ml)提取，合并提取液，盐水洗涤，Na2SO4干燥，过滤，滤液减压浓缩，得1.3mg粗品，硅胶层析纯化，得0.9mg1,2-环碳酸酯纯品。
向于0.1mlTHF和0.05ml甲醇中搅拌的碳酸酯中加入甲苯磺酸酯吡啶翁盐(0.005ml,0.1M的CH2Cl2液)。混合物于室温下搅拌24小时，使之在饱和NaHCO3和乙酸乙酯之间进行分配，有机层用Na2SO4干燥，蒸发，得0.9mg二醇27b。27b(P7=BOM):1H NMR(500MHz,CDCl3)δ-0.24(s,3H,TBS CH3),-0.038(s,3H,TBSCH3),0.58(q,J=8.1Hz,6H,TES CH2),0.84(s,9H,TBS t-Bu),0.93(t,J=8.1Hz,9H,TESCH3),1.14(s,3H,CH3 19),1.19(s,3H,CH3 17),1.34(s,3H,CH3 16),1.88(brd,J=17Hz,H9β),2.00(br q,J=12Hz,1H,H6β),2.08(d,J=1.4Hz,3H,CH3 18),2.2(m,2H,H9αand 14β),2.35(br s,1H,H3α),2.39(dt,J=4.8,13Hz,H6α),2.74(brs,1H,20 OH),2.87(dd,J=15.1,5.1Hz,1H,H14α),3.71(dd,J=11.3,5.1Hz,1H,H2β),3.58(brs,2H,H7αand 20 OH),3.78(s,3H,OCH3),3.78(br m,1H,H5α),4.37(dd,J=13.0,5.8Hz,1H,H20),4.39(dd,J=4.8,5.8Hz,1H,H10β),4.47(m,2H,H20 and 2β),4.59(d,J=11.6Hz,1H,OCH2Ph),4.63(br m,1H,H13β),4.71(d,J=11.6Hz,1H,OCH2Ph),4.88(d,J=7.2Hz,1H,OCH2O),4.91(d,J=7.2Hz,1H,OCH2O),4.93(m,2H,MPM CH2),6.84(d,J=8.6Hz,2H,p-MeOPh-o),7.23(d,J=8.6Hz,2H,p-MeOPh-m),7.27-7.36(m,5H,PhCH2).
Claims (12)
1．在制备三环或四环紫杉烷中所采用的具有下列通式的中间体
其中
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31或与R2一同构成碳酸酯；
R3为氢，羟基，保护的羟基，或-OCOR32，或氧代；
R8为氢，烷基，链烯基，链炔基，芳基或杂芳基；
R9为氢，羟基，保护的羟基，氧代，或-OCOR33，或与R10一同构成碳酸酯；
R10为氢，羟基，保护的羟基，氧代，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35或MO-；
R29,R30,R31,R32,R33及R35为独立的氢，烷基，链烯基，链炔基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基或杂芳基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或为金属。
2．在制备三环或四环紫杉烷中所采用的具有下列通式的中间体其中
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31或与R1一同构成碳酸酯；
R3为氢，羟基，保护的羟基，-OCOR32，或氧代，或与R7b一同构成碳酸酯；
R7b为氢，烷基，氰基，羟基，保护的羟基，或-OCOR36，或与R3或R9一同构成碳酸酯；
R7c和R7d为独立的氢，烷基，链烯基，链炔基，芳基或杂芳基；
R9为氢，羟基，保护的羟基，氧代，或-OCOR33、或与R7b或R10一同构成碳酸酯；
R10为氢，烷基，保护的羟基，氧代，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35或MO-；
R29,R30,R31,R32,R33,R35和R36为独立的氢，烷基，链烯基，链炔基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基或杂芳基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或为金属。
3．在制备三环或四环紫杉烷中所采用的具有下列通式的中间体其中
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31或与R1一同构成碳酸酯；
R3为氢，羟基，保护的羟基，或-OCOR32；
R7b为氢，烷基，氰基，羟基，保护的羟基或-OCOR36；
R7c为氢，烷基，链烯基，链炔基，芳基或杂芳基；
R9为氢，羟基，保护的羟基，氧代，或-OCOR33，或与R10一同构成碳酸酯；
R10为氢，羟基，保护的羟基，氧代，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35或MO-；
R29,R30,R31,R32,R33和R35为独立的氧，烷基，链烯基，链炔基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基或杂芳基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或为金属。
4．在制备三环或四环紫杉烷中所采用的具有下列通式的中间体
其中R为C1-C8烷基
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31或与R1一同构成碳酸酯，或与R4a一同构成碳酸酯；
R4a为氢，烷基，羟基，保护的羟基，或-OCOR27，或与R2一同构成碳酸酯；
R7a为氢，卤素，羟基，保护的羟基，OR28，或-OCOR34，或与R9一同构成碳酸酯；
R9为氢，氧代，羟基，保护的羟基，-OR28，或-OCOR33，或与R7a或R10一同构成碳酸酯；
R10为氢，氧代，羟基，保护的羟基，-OR28，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35或MO-；
R28为功能基，其可增加紫杉烷衍生物的溶解度；
R29,R30,R31,R33,R34和R35为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或为金属。
5．在制备三环或四环紫杉烷中所采用的具有下列通式的中间体其中
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31或与R1或R4a一同构成碳酸酯；
R4a为氢，烷基，羟基，保护的羟基，或-OCOR27，与R4b一同构成氧代物，或与R2,R46或R5一同构成碳酸酯；
R4b为氢，烷基，链烯基，链炔基，芳基，杂芳基，或氰基，与R4a一同构成氧代物，与R4a或R5一同构成的碳酸酯，或与R5及其相连的遄原子一起形成螺[4,4]二氧己烷；
R5为氢，羟基，保护的羟基，-OCOR37，氧代，与R4a或4b一同构成碳酸酯，或与R4b及其相连接的碳原子一起形成螺[4,4]二氧己烷；
R7a为氢，卤素，羟基，保护的羟基，-OR28,OR28，或-OCOR34，或与R9一同构成碳酸酯；
R9为氢，氧代，羟基，保护的羟基，氧代，OR28，或-OCOR33。或与R7a或R10一同构成碳酸酯；
R10为氢，氧代，羟基，保护的羟基，-OR28，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，-OCOR35,MO-或
R28为功能基，其增加紫杉烷衍生物的溶解度；
R27,R29,R30,R31,R33,R34,R35和R37为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X1为-OX6,-SX7，或-NX8X9；
X2为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X3和X4为独立的氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X5为-COX10,-COOX10,COSX10,-COX8X10或-SO2X11；
X6为氢，烷基，链烯基，链炔基，芳基，杂芳基，羟基保护基或增加紫杉烷衍生物的溶解度的功能基；
X7为烷基，链烯基，链炔基，芳基，杂环芳基或巯基保护基；
X8为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
X9为氨基保护基；
X10为烷基，链烯基，链炔基，芳基，或杂芳基；
X11为为烷基，链烯基，链炔基，芳基，或杂芳基，-OX10，或-NX8X14；
X14为氢，烷基，链烯基，链炔基，芳基，或杂芳基；且
M包括铵或为金属。
6．合成三环或四环紫杉烷中间体的制备方法，其包括用BrMg(iPr)2和一种醛(或酮)与具下列结构通式的化合物反应，
随后，用光气和一种醇处理，形成具下列结构通式的化合物：
其中
R1为氢或保护的羟基；R2为氢或保护的羟基；
R3为氧代；
R7b为氢，烷基，氰基，羟基，保护的羟基或-OCOR36，或与R3或R9一同构成碳酸酯；
R7c和R7a为独立的氢，烷基，链烯基，链炔基，芳基或杂芳基；
R9为氢，保护的羟基，或氧代；
R10为-OP10；
R13为-OP13；且
P10和P13为羟基保护基。
7．合成三环或四环紫杉烷中间体的制备方法，其包括用四甲基哌啶锂与具下列结构通式的化合物反应，形成具下列结构通式的化合物：
其中
R1为氢或保护的羟基；
R7c为氢，烷基，链烯基，链炔基，芳基，或杂芳基；
R9为氢，保护的羟基，或氧代；且
P10及P13为羟基保护基。
8．合成三环或四环紫杉烷中间体的制备方法，其包括用四甲基哌啶锂和樟脑磺酰基氧杂氮丙啶与具下列结构通式的化合物反应，形成具下列结构通式的化合物：
其中
R9为氢，保护的羟基，或氧代；R7c为氢，烷基，链烯基，链炔基，芳基，或杂芳基；且P10和P13为羟基保护基。
9．合成三环或四环紫杉烷中间体的制备方法，其包括用氢化物还原剂，与具下列结构通式的化合物反应，形成具下列结构通式的化合物：
其中R9为氢，保护的羟基，或氧代；R7c为氢，烷基，链烯基，链炔基，芳基或杂芳基；且P10和P13为羟基保护基。
10．合成三环或四环紫杉烷中间体的制备方法，其包括用二异丙基酰胺锂与具下列结构通式的化合物反应，
形成具下列结构通式的化合物：
其中R为低级烷基，R1为氢，保护的羟基或R1和R2一同构成碳酸酯，R2为氢，保护的羟基或R1和R2一同构成碳酸酯，R9为氢，保护的羟基或氧代，且P10和P13为羟基保护基。
11．用于合成三环或四环紫杉烷中间体的制备方法，其包括用DBU与具下列结构通式的化合物反应，
形成具下列结构通式的化合物：
其中
R1为氢，羟基，保护的羟基或-OCOR30，或与R2一同构成碳酸酯；
R2为氢，羟基，保护的羟基，氧代，或-OCOR31，或与R1一同构成碳酸酯；
R4a为氢，烷基，羟基，或保护的羟基，或与R2一同构成碳酸酯；
R4b为羟基亚甲基；
R5为-OMs,-OTs或溴化物：
R7a为氢，保护的羟基，或-OCOR34，或与R9一同构成碳酸酯：
R9为氢，氧代，羟基，保护的羟基，或-OCOR33，-或与R7a或R10一同构成碳酸酯；
R10为氢，氧代，羟基，保护的羟基，或-OCOR29，或与R9一同构成碳酸酯；
R13为氢，羟基，保护的羟基，或-OCOR35；
R29,R33,R34和R35为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基。
12．合成三环或四环紫彬烷中间体的制备方法，其包括用KOt-Bu和(PhSeO)2O与具下列结构通式的化合物反应，形成具下列结构通式的化合物：
并且该反应产和受到外加的KOtBu，硅胶或其它酸或碱的影响，或加热使反应产物重排，成为具下列结构通式的化合物：其中
R1为氢，羟基，保护的羟基，或与R2一同构成碳酸酯；
R2为氢，保护的羟基或-OCOR31，或与R1或R4a一同构成碳酸酯；
R4a为氢，烷基，羟基，或保护的羟基，或-OCOR27，与R4b一同构成氧代物，或与R2,R4b，或R5一同构成碳酸酯；
R4b为氢，烷基，链烯基，链炔基，芳基，杂芳基，或氰基，与R4a一同构成氧代物，或与R4a或R5一同构成碳酸酯，或与R5及其相连接的碳原子一起形成螺[4,4]二氧己烷；
R5为氢，保护的羟基，-OCOR37，与R4a或R4b一同构成碳酸酯，或与R4b及其相连接的碳原子一起形成螺[4,4]二氧己烷；
R7a为氢，卤素，保护的羟基，或-oCOR34；
P13是羟基保护基；
R27,R30,R31,R34，和R37为独立的氢，烷基，链烯基，链炔基，烷氧基，芳氧基，-NX8X10,-SX10，单环芳基或单环杂芳基；
X8为氢，烷基，链烯基，链炔基，芳基，杂芳基，或杂原子取代的烷基，链烯基，链炔基，芳基或杂芳基，且
X10为烷基，链烯基，链炔基，芳基，杂芳基，或杂原子取代的烷基，链烯基，链炔基或杂芳基。
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| US095,161 | 1987-09-11 | ||
| US138229 | 1987-12-23 | ||
| US9516193A | 1993-07-20 | 1993-07-20 | |
| US095161 | 1993-07-20 | ||
| US13822993A | 1993-10-15 | 1993-10-15 | |
| US138,229 | 1993-10-15 | ||
| US08/189,058 US5405972A (en) | 1993-07-20 | 1994-01-27 | Synthetic process for the preparation of taxol and other tricyclic and tetracyclic taxanes |
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| JP (2) | JP3564135B2 (zh) |
| KR (3) | KR100325791B1 (zh) |
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| AT (2) | ATE238289T1 (zh) |
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| DE (2) | DE69432569T2 (zh) |
| DK (2) | DK0960881T3 (zh) |
| ES (2) | ES2149883T3 (zh) |
| GR (1) | GR3034343T3 (zh) |
| PT (2) | PT710223E (zh) |
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| FR2629818B1 (fr) * | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | Procede de preparation du taxol |
| FR2629819B1 (fr) * | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | Procede de preparation de derives de la baccatine iii et de la desacetyl-10 baccatine iii |
| USRE34277E (en) * | 1988-04-06 | 1993-06-08 | Centre National De La Recherche Scientifique | Process for preparing taxol |
| US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
| US5015744A (en) * | 1989-11-14 | 1991-05-14 | Florida State University | Method for preparation of taxol using an oxazinone |
| FR2662441B1 (fr) * | 1990-05-22 | 1992-10-23 | Rhone Poulenc Sante | Procede de preparation enantioselective de derives de la phenylisoserine. |
| FR2662440B1 (fr) * | 1990-05-22 | 1992-07-31 | Rhone Poulenc Sante | Procede de preparation stereoselective de derives de la phenylisoserine. |
| US5380916A (en) * | 1990-11-02 | 1995-01-10 | University Of Florida | Method for the isolation and purification of taxane derivatives |
| WO1993002064A1 (fr) * | 1991-07-16 | 1993-02-04 | Centre National De La Recherche Scientifique (Cnrs) | Nouveau derive de la 7-desacetoxy baccatine iv, sa preparation et son emploi |
| US5229526A (en) * | 1991-09-23 | 1993-07-20 | Florida State University | Metal alkoxides |
| US5416225A (en) * | 1992-03-30 | 1995-05-16 | Sloan-Kettering Institute For Cancer Research | Total synthesis of taxol |
| US5597931A (en) * | 1992-03-30 | 1997-01-28 | Sloan-Kettering Institute For Cancer Research | Total synthesis of taxol and analogues thereof |
| US5488116A (en) * | 1992-03-30 | 1996-01-30 | Sloan-Kettering Institute For Cancer Research | Total synthesis of taxol and analogues thereof |
| US5254703A (en) * | 1992-04-06 | 1993-10-19 | Florida State University | Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones |
| US5248796A (en) * | 1992-06-18 | 1993-09-28 | Bristol-Myers Squibb Company | Taxol derivatives |
| US5461169A (en) * | 1992-06-23 | 1995-10-24 | The Scripps Research Institute | Total synthesis of taxol and taxol analogs |
| US5481007A (en) * | 1992-06-23 | 1996-01-02 | The Scripps Research Institute | Taxoid synthesis |
| US5274137A (en) * | 1992-06-23 | 1993-12-28 | Nicolaou K C | Intermediates for preparation of taxols |
| ES2206465T3 (es) * | 1992-11-13 | 2004-05-16 | Florida State University | Taxanos sustituidos con butenilo y composiciones farmaceuticas. |
| US5508447A (en) * | 1994-05-24 | 1996-04-16 | Board Of Regents, The University Of Texas System | Short synthetic route to taxol and taxol derivatives |
-
1994
- 1994-01-27 US US08/189,058 patent/US5405972A/en not_active Expired - Fee Related
- 1994-07-20 JP JP50536795A patent/JP3564135B2/ja not_active Expired - Fee Related
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- 1994-07-20 SG SG9904909A patent/SG97813A1/en unknown
- 1994-07-20 SG SG1996006396A patent/SG44727A1/en unknown
- 1994-07-20 ES ES94923998T patent/ES2149883T3/es not_active Expired - Lifetime
- 1994-07-20 KR KR1019960700300A patent/KR100325791B1/ko not_active IP Right Cessation
- 1994-07-20 WO PCT/US1994/008350 patent/WO1995003265A1/en active Application Filing
- 1994-07-20 KR KR1020017011073A patent/KR100353666B1/ko not_active IP Right Cessation
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- 1994-07-20 EP EP94923998A patent/EP0710223B1/en not_active Expired - Lifetime
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- 1994-07-20 DK DK94923998T patent/DK0710223T3/da active
- 1994-07-20 CN CN94192841A patent/CN1046261C/zh not_active Expired - Fee Related
- 1994-07-20 AU AU74042/94A patent/AU687428B2/en not_active Ceased
- 1994-07-20 DE DE69424939T patent/DE69424939T2/de not_active Expired - Fee Related
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1995
- 1995-02-06 US US08/383,775 patent/US5637732A/en not_active Expired - Fee Related
- 1995-02-06 US US08/383,956 patent/US5618952A/en not_active Expired - Fee Related
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1996
- 1996-12-19 US US08/769,935 patent/US5760252A/en not_active Expired - Fee Related
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2000
- 2000-09-06 GR GR20000402031T patent/GR3034343T3/el not_active IP Right Cessation
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2003
- 2003-10-08 JP JP2003349652A patent/JP2004115526A/ja not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| JOURNAL OF AMERICAN CHEMICAL SOCIETY V116 NO4 1994.1.1 ROBERT HOLTON FIRST ZOTAL SYNTHESIS OF TAXOL 2.COMPLRTION OF THE CAND D RI * |
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