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【结 构 式】 
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【药物名称】Altorhyrtin C, Spongistatin 2 【化学名称】(1S,3S,5R,9R,10R,11R,13R,14S,15R,17S,18R,19R,23Z,25R,27S,29S,31S,33S,36S,37S,38R,41S,43S,49S)-3,37-Diacetoxy-11-[4(S)-hydroxy-2-methylene-5(E),7-octadienyl]-10,14,15,17,27,43-hexahydroxy-31-methoxy-18,36,38,43,49-pentamethyl-39-methylene-8,12,45,46,47,48,50-heptaoxaheptacyclo[39.3.1.1(1,5).1(9,13).1(15,19).1(25,29).1(29,33)]pentacont-23-ene-7,35-dione 【CA登记号】 【 分 子 式 】C63H96O21 【 分 子 量 】1189.45497 |
【开发单位】Arizona State University (Originator) 【药理作用】Oncolytic Drugs, Antimitotic Drugs, Microtubule-Stabilizing Agents |
合成路线1
Tetrahydropyran intermediate (X). The asymmetric addition of Ipc2B-crotyl to 4-(Tbdps-O)-2-butenal (I) gives the chiral secondary alcohol (II), which is protected with benzyl bromide and NaH to yield the benzyl ether (III). The desilylation of (III) by means of TBAF affords the primary alcohol (IV), which is submitted to a Sharpless asymmetric epoxidation to provide the epoxide (V). Ring opening of (V) by means of Ti(iPrO)4 and benzoic acid gives the benzoate ester (VI), which is cyclized by means of Hg(OAc)2 to yield the tetrahydropyran derivative (VII). Hydrolysis of the benzoate group of (VII) by means of MeONa affords the trihydroxy compound (VIII), which is treated with acetone and Ts-OH to provide the acetonide (IX). Finally, oxidation of the hydroxymethyl group of (IX) by means of Swern oxidant yields the target tetrahydropyran-2-carbaldehyde intermediate (X).
| 【1】 Smith, A.B. III; Zhuang, L.; Brook, C.S.; Boldi, A.M.; McBriar, M.D.; Moser, W.H.; Murase, N.; Nakayama, K.; Verhoest, P.R.; Lin, Q.; Spongistatin synthetic studies. 1. Construction of a C(29-48) subtarget. Tetrahedron Lett 1997, 38, 50, 8667. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 60351 | 4-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-butenal | C20H24O2Si | 详情 | 详情 | |
| (II) | 64595 | (3S,4R,5E)-7-{[tert-butyl(diphenyl)silyl]oxy}-3-methyl-1,5-heptadien-4-ol | C24H32O2Si | 详情 | 详情 | |
| (III) | 64596 | benzyl (1R,2E)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(1S)-1-methyl-2-propenyl]-2-butenyl ether; {[(2E,4R,5S)-4-(benzyloxy)-5-methyl-2,6-heptadienyl]oxy}(tert-butyl)diphenylsilane | C31H38O2Si | 详情 | 详情 | |
| (IV) | 64597 | (2E,4R,5S)-4-(benzyloxy)-5-methyl-2,6-heptadien-1-ol | C15H20O2 | 详情 | 详情 | |
| (V) | 54598 | tert-butyl (1S,2R)-1-(sec-butyl)-2-methoxy-4-pentenyl(methyl)carbamate | C16H31NO3 | 详情 | 详情 | |
| (VI) | 64599 | (1R,2R,3S)-2-(benzyloxy)-1-[(1R)-1,2-dihydroxyethyl]-3-methyl-4-pentenyl benzoate | C22H26O5 | 详情 | 详情 | |
| (VII) | 64600 | (2R,3S,4R,5R)-2-[(acetyloxy)methyl]-4-(benzyloxy)-6-(hydroxymethyl)-5-methyltetrahydro-2H-pyran-3-yl benzoate | C24H28O7 | 详情 | 详情 | |
| (VIII) | 64601 | (2R,3S,4R,5R)-4-(benzyloxy)-2,6-bis(hydroxymethyl)-5-methyltetrahydro-2H-pyran-3-ol | C15H22O5 | 详情 | 详情 | |
| (IX) | 64602 | [(4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]methanol | C18H26O5 | 详情 | 详情 | |
| (X) | 64603 | (4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxine-6-carbaldehyde | C18H24O5 | 详情 | 详情 |
合成路线2
Bis-tetrahydropyran intermediate (XXIV). The asymmetric addition of Ipc2B-crotyl to 5-benzyloxypentanal (XI) gives the secondary alcohol (XII), which is protected with Boc2O and NaHMDS in THF yielding the carbamate (XIII). The reaction of (XIII) with IBr in toluene affords the iodinated cyclic carbonate (XIV), which is converted into the epoxide (XV) by reaction with K2CO3 in methanol/water. The reaction of the epoxide (XV) with 1,3-dithiane (XVI) by means of BuLi in THF/HMPA provides the dihydroxy compound (XVII), which is converted into the acetonide (XIX) by reaction with 2,2-dimethoxypropane (XVIII) and PPTS . The condensation of (XIX) with the tetrahydropyran-2-carbaldehyde intermediate (X) by means of BuLi in ethyl ether/HMPA gives the bis acetonide derivative (XX) (1), which is deprotected by means of CSA, cyclized by means of Hg(ClO4)2 and acylated with Piv-Cl and pyridine to yield the bis tetrahydropyranyl intermediate (XXI). The silylation of the OH group of (XXI) by means of Tbdms-OTf, followed by debenzylation by means of HCOONH4 and Pd/C affords the butanol derivative (XXII), which is successively silylated, first with Tbdps-Cl /imidazole and then with Tes-OTf and lutidine to provide the fully silylated compound (XXIII). Finally, the elimination of the pivaloyl group of (XXIII) by means of DIBAL in THF, followed by reaction with I2, PPh3 and imidazole in toluene gives the iodomethyl bis tetrahydropyran intermediate (XXIV) (2).
| 【2】 Smith, A.B. III; Lin, Q.; Doughty, V.A.; Zhuang, L.; McBriar, M.D.; Kerns, J.K.; Brook, C.S.; Murase, N.; Nakayama, K.; The spongistatins: Architecturally complex natural products - Part two: Synthesis of the C(29-51) subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew Chem. Int Ed 2001, 40, 1, 196. |
| 【1】 Smith, A.B. III; Zhuang, L.; Brook, C.S.; Boldi, A.M.; McBriar, M.D.; Moser, W.H.; Murase, N.; Nakayama, K.; Verhoest, P.R.; Lin, Q.; Spongistatin synthetic studies. 1. Construction of a C(29-48) subtarget. Tetrahedron Lett 1997, 38, 50, 8667. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 64603 | (4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxine-6-carbaldehyde | C18H24O5 | 详情 | 详情 | |
| (XI) | 64604 | 5-(benzyloxy)pentanal | C12H16O2 | 详情 | 详情 | |
| (XII) | 64605 | (3R,4R)-8-(benzyloxy)-3-methyl-1-octen-4-ol | C16H24O2 | 详情 | 详情 | |
| (XIII) | 64606 | (1R,2R)-1-[4-(benzyloxy)butyl]-2-methyl-3-butenyl tert-butyl carbonate | C21H32O4 | 详情 | 详情 | |
| (XIV) | 64607 | (4R,5R)-4-[4-(benzyloxy)butyl]-6-(iodomethyl)-5-methyl-1,3-dioxan-2-one | C17H23IO4 | 详情 | 详情 | |
| (XV) | 64608 | (1R)-5-(benzyloxy)-1-{(1R)-1-[(2S)oxiranyl]ethyl}pentyl methyl carbonate | C18H26O5 | 详情 | 详情 | |
| (XVI) | 42372 | 1,3-dithiane | 505-23-7 | C4H8S2 | 详情 | 详情 |
| (XVII) | 64609 | (2S,3S,4R)-8-(benzyloxy)-1-(1,3-dithian-2-yl)-3-methyl-2,4-octanediol | C20H32O3S2 | 详情 | 详情 | |
| (XVIII) | 64610 | 1,3-dimethoxy-2,2-dimethylpropane; 3-methoxy-2,2-dimethylpropyl methyl ether | C7H16O2 | 详情 | 详情 | |
| (XIX) | 64611 | (4R,5R,6S)-4-[4-(benzyloxy)butyl]-6-(1,3-dithian-2-ylmethyl)-2,2,5-trimethyl-1,3-dioxane; benzyl 4-[(4R,5R,6S)-6-(1,3-dithian-2-ylmethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]butyl ether | C23H36O3S2 | 详情 | 详情 | |
| (XX) | 64612 | (S)-[(4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl][2-({(4S,5R,6R)-6-[4-(benzyloxy)butyl]-2,2,5-trimethyl-1,3-dioxan-4-yl}methyl)-1,3-dithian-2-yl]methanol | C41H60O8S2 | 详情 | 详情 | |
| (XXI) | 64613 | {(2R,3S,4R,5R,6R)-4-(benzyloxy)-6-[(S)-{(2R,4S,5R,6R)-6-[4-(benzyloxy)butyl]-4-hydroxy-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl}(hydroxy)methyl]-3-hydroxy-5-methyltetrahydro-2H-pyran-2-yl}methyl pivalate | C38H56O10 | 详情 | 详情 | |
| (XXII) | 64614 | {(2R,3S,4R,5R,6R)-6-[(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-hydroxybutyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl](hydroxy)methyl]-3,4-dihydroxy-5-methyltetrahydro-2H-pyran-2-yl}methyl 2,2-dimethylpropanoate | C30H58O10Si | 详情 | 详情 | |
| (XXIII) | 64615 | {(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl 2,2-dimethylpropanoate | C64H118O10Si5 | 详情 | 详情 | |
| (XXIV) | 64616 | tert-butyl[((2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl ether | C59H109IO8Si5 | 详情 | 详情 |
合成路线3
Advanced intermediate phosphonium salt (XLI). The protection of (R)(+)-glycidol (XXV) with Pmb-Cl and NaH gives the benzyl ether (XXVI). Which is condensed with methyl phenyl sulfone (XXVII) by means of BuLi in THF/HMPA to yield the secondary alcohol (XXVIII). The reaction of (XXVIII) with Tbdms-OTf and lutidine affords the silyl ether (XXIX) (3), which is converted into the aldehyde (XXX) by debenzylation with DDQ, followed by oxidation with DMP. The condensation of (XXX) with phosphorane (XXXI) in refluxing benzene gives the unsaturated ester (XXXII), which is reduced with DIBAL in dichloromethane and protected with Ph-CH2Br and NaH to yield the benzyl ether (XXXIII). The condensation of sulfone (XXXIII) with the iodomethyl intermediate (XXIV) by means of BuLi in THF/HMPA affords the adduct (XXXIV), which is desulfurized by reaction with BuLi, diiodomethane and isopropylmagnesium chloride to provide the methylene compound (XXXV). The elimination of the benzyl protecting group of (XXXV) by means of LiDBB, followed by oxidation with DMP gives the carbaldehyde (XXXVI), which is condensed with CH2=PPh3 in THF to yield compound (XXXVII) (2).
| 【1】 Smith, A.B. III; Lin, Q.; Pettit, G.R.; Chapuis, G.R.; Chapuis, J.-C.; Schmidt, J.M.; Synthesis and in vitro cancer cell growth inhibitory activity of monocyclic model cpds. containing spongistatin triene side-chains. Bioorg Med Chem Lett 1998, 8, 6, 567. |
| 【2】 Smith, A.B. III; Lin, Q.; Doughty, V.A.; Zhuang, L.; McBriar, M.D.; Kerns, J.K.; Brook, C.S.; Murase, N.; Nakayama, K.; The spongistatins: Architecturally complex natural products - Part two: Synthesis of the C(29-51) subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew Chem. Int Ed 2001, 40, 1, 196. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 64616 | tert-butyl[((2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl ether | C59H109IO8Si5 | 详情 | 详情 | |
| (XXV) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (XXVI) | 63135 | 4-methoxybenzyl (2R)oxiranylmethyl ether; (2R)-2-{[(4-methoxybenzyl)oxy]methyl}oxirane | C11H14O3 | 详情 | 详情 | |
| (XXVII) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XXVIII) | 64617 | (2S)-1-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)-2-butanol | C18H22O5S | 详情 | 详情 | |
| (XXIX) | 64618 | (3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]butyl phenyl sulfone; tert-butyl{[(1S)-1-{[(4-methoxybenzyl)oxy]methyl}-3-(phenylsulfonyl)propyl]oxy}dimethylsilane | C24H36O5SSi | 详情 | 详情 | |
| (XXX) | 64619 | (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(phenylsulfonyl)butanal | C16H26O4SSi | 详情 | 详情 | |
| (XXXI) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XXXII) | 64620 | ethyl (E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(phenylsulfonyl)-2-hexenoate | C20H32O5SSi | 详情 | 详情 | |
| (XXXIII) | 64621 | (3S,4E)-6-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hexenyl phenyl sulfone; ({(1S,2E)-4-(benzyloxy)-1-[2-(phenylsulfonyl)ethyl]-2-butenyl}oxy)(tert-butyl)dimethylsilane | C25H36O4SSi | 详情 | 详情 | |
| (XXXIV) | 64622 | (3S,4E)-6-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-4-hexenyl phenyl sulfone; ({(1S,2E)-4-(benzyloxy)-1-[3-{(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}-2-(phenylsulfonyl)propyl]-2-butenyl}oxy)(tert-butyl)dimethylsilane | C84H144O12SSi6 | 详情 | 详情 | |
| (XXXV) | 64623 | ({(1S,2E)-4-(benzyloxy)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2-butenyl}oxy)(tert-butyl)dimethylsilane; benzyl (2E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2,6-heptadienyl ether | C79H140O10Si6 | 详情 | 详情 | |
| (XXXVI) | 64624 | (2E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2,6-heptadienal | C72H132O10Si6 | 详情 | 详情 | |
| (XXXVII) | 64625 | tert-butyl({(1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl}oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl ether | C73H134O9Si6 | 详情 | 详情 |
合成路线4
The selective monodesilylation of (XXXVII) by means of NaOH gives the butanol derivative (XXXVIII),which is treated with TsCl, TEA and DMAP to yield the tosylate (XXXIX). The reaction of (XXXIX) with LiI and lutidine, followed by silylation of the remaining OH groups with Tms-OTf and lutidine affords the silylated iodobutyl derivative (XL), which is finally treated with triphenylphosphine and Li2CO3 in acetonitrile/benzene to provide the desired advanced intermediate phosphonium salt (XLI).
| 【1】 Smith, A.B. III; Lin, Q.; Doughty, V.A.; Zhuang, L.; McBriar, M.D.; Kerns, J.K.; Brook, C.S.; Murase, N.; Nakayama, K.; The spongistatins: Architecturally complex natural products - Part two: Synthesis of the C(29-51) subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew Chem. Int Ed 2001, 40, 1, 196. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVII) | 64625 | tert-butyl({(1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl}oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl ether | C73H134O9Si6 | 详情 | 详情 | |
| (XXXVIII) | 64626 | (2R,3S,4R,5R,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-hydroxybutyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-2-((4S,5E)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylene-5,7-octadienyl)-5-methyltetrahydro-2H-pyran-3,4-diol | C45H88O9Si3 | 详情 | 详情 | |
| (XXXIX) | 64627 | 4-((2R,3S,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{(S)-[(2R,3R,4R,5S,6R)-6-((4S,5E)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylene-5,7-octadienyl)-4,5-dihydroxy-3-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-6-methoxy-3-methyltetrahydro-2H-pyran-2-yl)butyl 4-methylbenzenesulfonate | C52H94O11SSi3 | 详情 | 详情 | |
| (XL) | 64628 | tert-butyl({(1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-iodobutyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl}oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-iodobutyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl ether | C51H103IO8Si5 | 详情 | 详情 | |
| (XLI) | 64629 | [4-((2R,3S,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{(S)-{(2R,3S,4R,5R,6R)-6-((4S,5E)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylene-5,7-octadienyl)-3-methyl-4,5-bis[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-6-methoxy-3-methyltetrahydro-2H-pyran-2-yl)butyl](triphenyl)phosphonium iodide | C69H118IO8PSi5 | 详情 | 详情 |
合成路线5
Iodomethyl tetrahydropyran intermediate (XLVII): The condensation between epoxides (XLII), (XLIV) and silylated 1,3-dithiane (XLIII) gives the dihydroxy compound (XLV), which is treated first with 2,2-dimethoxypropane (XVIII) to create an acetonide group, and then with Hg(ClO4)2 to promote cyclization to yield the tetrahydropyran derivative (XLVI). Finally, the TsO group of (XLVI) is treated with lithium iodide in methanol to afford the desired iodomethyl tetrahydropyran intermediate (XLVII)
| 【1】 Smith, A.B.; et al.; The spongistatins: Architecturally complex natural products - Part one: A formal synthesis of (+)-spongistatin 1 by construction of an advanced ABCD fragment. Angew Chem. Int Ed 2001, 40, 1, 191. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XLII) | 64630 | tert-butyl(diphenyl)silyl (3S)-4-[(2S)oxiranyl]-3-[(triethylsilyl)oxy]butyl ether; (7S)-9,9-diethyl-2,2-dimethyl-7-[(2S)oxiranylmethyl]-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane | C28H44O3Si2 | 详情 | 详情 | |
| (XLIII) | 64631 | tert-butyl(1,3-dithian-2-yl)dimethylsilane | C10H22S2Si | 详情 | 详情 | |
| (XLIV) | 64632 | (4R)-2,2-dimethyl-4-{[(2S)-2-methyloxiranyl]methyl}-1,3-dioxolane | C9H16O3 | 详情 | 详情 | |
| (XLV) | 64633 | (2R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[2-((2S,4S)-6-{[tert-butyl(diphenyl)silyl]oxy}-2,4-dihydroxyhexyl)-1,3-dithian-2-yl]-2,4-dimethylpentyl 4-methylbenzenesulfonate | C46H72O7S3Si2 | 详情 | 详情 | |
| (XLVI) | 64634 | ((2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate | C46H70O9SSi2 | 详情 | 详情 | |
| (XLVII) | 64635 | tert-butyl(dimethyl)silyl (2R,4S,6R)-2-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-(iodomethyl)-2-methoxy-4-methyltetrahydro-2H-pyran-4-yl ether; tert-butyl[2-((4S,6S)-6-{[(2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(iodomethyl)-2-methoxy-4-methyltetrahydro-2H-pyran-2-yl]methyl}-2,2-dimethyl-1,3-dioxan-4-yl)ethoxy]diphenylsilane | C39H63IO6Si2 | 详情 | 详情 |
合成路线6
Dithiane intermediate (LII). The ozonolysis of the allylic diol (XLVIII) with O3 and PPh3 in dichloromethane/methanol gives the aldehyde (XLIX), which is condensed with propane-1,3-dithiol (L) by means of BF3/OEt2 in dichloromethane to yield the dihydroxylated 1,3-dithiane derivative (LI). Finally, this compound is protected with 3,4-Dmp-CHO (A) and PPTS to afford the desired dithiane intermediate (LII).
| 【1】 Smith, A.B.; et al.; The spongistatins: Architecturally complex natural products - Part one: A formal synthesis of (+)-spongistatin 1 by construction of an advanced ABCD fragment. Angew Chem. Int Ed 2001, 40, 1, 191. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 46036 | 3,4-dimethylbenzaldehyde | 5973-71-7 | C9H10O | 详情 | 详情 |
| (XVIII) | 64636 | (2R,3R,4R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-hexen-3-ol | C14H30O2Si | 详情 | 详情 | |
| (XLIX) | 64637 | (2S,3S,4R)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2,4-dimethylpentanal | C13H28O3Si | 详情 | 详情 | |
| (L) | 29729 | 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide | 109-80-8 | C3H8S2 | 详情 | 详情 |
| (LI) | 64638 | (2R,3S,4S)-4-(1,3-dithian-2-yl)-2-methyl-1,3-pentanediol | C10H20O2S2 | 详情 | 详情 | |
| (LII) | 64639 | (4S,5R)-2-(3,4-dimethylphenyl)-4-[(1S)-1-(1,3-dithian-2-yl)ethyl]-5-methyl-1,3-dioxane | C19H28O2S2 | 详情 | 详情 |
合成路线7
Spiranic phenylsulfone intermediate (LXIII). The cyclization of the dithiane derivative (LIII) by means of HCL and Hg(ClO4)2/CaCO3 in acetonitrile/water gives a mixture of the desired spiroketal compound (LV) along with its isomer (LIV) that can be converted to (LV) by treatment with HClO4. The reaction of (LV) with Piv-Cl and TEA, followed by silylation with Tbdms-Cl and imidazole allows the selective silylation of the secondary OH group yielding (LVI). The cleavage of the Piv group of (LVI) by means of DIBAL in dichloromethane, followed by treatment with I2, PPh3 and imidazole in benzene affords the iodomethyl compound (LVII). The condensation of (LVII) with the dithiane intermediate (LII) by means of BuLi in THF/HMPA provides compound (LVIII), which is treated with Hg(ClO4)2 and CaCO3 and reduced with NaBH4 to cleave the dithiane auxiliary and yield alcohol (LIX). The protection of the OH group of (LIX) with Bom-Cl and DIEA affords compound (LX), which is reduced with DIBAL to cleave the cyclic ketal group and provide the primary alcohol (LXI). The reaction of (LXI) with I2, PPh3 and imidazole in benzene/acetonitrile gives the iodo derivative (LXII), which is finally treated with sodium phenylsulfinate in hot DMF to yield the desired spiranic phenylsulfone derivative (LXIII).
| 【1】 Smith, A.B.; et al.; The spongistatins: Architecturally complex natural products - Part one: A formal synthesis of (+)-spongistatin 1 by construction of an advanced ABCD fragment. Angew Chem. Int Ed 2001, 40, 1, 191. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LII) | 64639 | (4S,5R)-2-(3,4-dimethylphenyl)-4-[(1S)-1-(1,3-dithian-2-yl)ethyl]-5-methyl-1,3-dioxane | C19H28O2S2 | 详情 | 详情 | |
| (LIII) | 64640 | (5R,7S)-5-[(benzyloxy)methyl]-7-[(2-{(2S)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-methoxypropyl}-1,3-dithian-2-yl)methyl]-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (2R,4S)-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(2-{(2S)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-methoxypropyl}-1,3-dithian-2-yl)pentyl ether | C37H68O6S2Si2 | 详情 | 详情 | |
| (LIV) | 64641 | (2R,4S,6R,8S,10S)-2-[(benzyloxy)methyl]-8-(hydroxymethyl)-10-methoxy-1,7-dioxaspiro[5.5]undecan-4-ol | C19H28O6 | 详情 | 详情 | |
| (LV) | 64642 | (2R,4S,6S,8S,10S)-2-[(benzyloxy)methyl]-8-(hydroxymethyl)-10-methoxy-1,7-dioxaspiro[5.5]undecan-4-ol | C19H28O6 | 详情 | 详情 | |
| (LVI) | 64643 | ((2S,4S,6S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)methyl pivalate | C30H50O7Si | 详情 | 详情 | |
| (LVII) | 64644 | benzyl [(2R,4S,6S,8S,10S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-(iodomethyl)-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl]methyl ether; {[(2R,4S,6S,8S,10S)-2-[(benzyloxy)methyl]-8-(iodomethyl)-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl]oxy}(tert-butyl)dimethylsilane | C25H41IO5Si | 详情 | 详情 | |
| (LVIII) | 64645 | benzyl {(2R,4S,6R,8S,10S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-[(2-{(1S)-1-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl}-1,3-dithian-2-yl)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl}methyl ether; ({(2R,4S,6R,8S,10S)-2-[(benzyloxy)methyl]-8-[(2-{(1S)-1-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl}-1,3-dithian-2-yl)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane | C44H68O7S2Si | 详情 | 详情 | |
| (LIX) | 64646 | (2R,3R)-1-((2R,4S,6R,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-3-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]-2-butanol | C41H64O8Si | 详情 | 详情 | |
| (LX) | 64647 | ({(2R,4S,6R,8S,10S)-8-{(2R,3R)-2-[(benzyloxy)methoxy]-3-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]butyl}-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane; benzyl ((2R,4S,6R,8S,10S)-8-{(2R,3R)-2-[(benzyloxy)methoxy]-3-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]butyl}-4-{[tert-butyl(dimethyl)silyl]oxy}-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)methyl ether | C49H72O9Si | 详情 | 详情 | |
| (LXI) | 64648 | (2R,3S,4S,5R)-5-[(benzyloxy)methoxy]-6-((2S,4S,6R,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-3-[(2,4-dimethoxybenzyl)oxy]-2,4-dimethyl-1-hexanol | C49H74O11Si | 详情 | 详情 | |
| (LXII) | 64649 | ({(2R,4S,6R,8S,10S)-8-{(2R,3S,4R,5S)-2-[(benzyloxy)methoxy]-4-[(2,4-dimethoxybenzyl)oxy]-6-iodo-3,5-dimethylhexyl}-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane; benzyl ((2R,4S,6R,8S,10S)-8-{(2R,3S,4R,5S)-2-[(benzyloxy)methoxy]-4-[(2,4-dimethoxybenzyl)oxy]-6-iodo-3,5-dimethylhexyl}-4-{[tert-butyl(dimethyl)silyl]oxy}-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)methyl ether | C49H73IO10Si | 详情 | 详情 | |
| (LXIII) | 64650 | (2S,3R,4S,5R)-5-[(benzyloxy)methoxy]-6-((2S,4S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-3-[(2,4-dimethoxybenzyl)oxy]-2,4-dimethylhexyl phenyl sulfone; ({(2R,4S,8S,10S)-8-[(2R,3S,4R,5S)-2-[(benzyloxy)methoxy]-4-[(2,4-dimethoxybenzyl)oxy]-3,5-dimethyl-6-(phenylsulfonyl)hexyl]-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane | C55H78O12SSi | 详情 | 详情 |
合成路线8
Assembly of the target compound. The condensation of the iodomethyl tetrahydropyran intermediate (XLVII) with the spiranic phenylsulfone derivative (LXIII) by means of BuLi in toluene gives the adduct (LXIV), which is desulfurized by methylenation with CH2I2 and i-PrMgCl in THF/HMPA to yield (LXV). The reaction of (LXV) with TBAF, followed by selective resilylation with Tbdms-Cl and imidazole and cleavage of the acetonide group with concomitant spiroketalization by means of HClO4 affords the bis spiroketal compound (LXVI). The cleavage of the benzyl ether group of (LXVI) by means of DDQ, followed by selective acetylation of the secondary OH group provides acetate (LXVII), which is silylated with Tes-OTf and lutidine, and selectively deprotected by means of HF and pyridine to give the primary alcohol (LXVIII). The oxidation of (LXVIII) with DMP and NaClO2, followed by silylation with Tips-Cl and TEA yields the silyl ester (LXIX).
| 【1】 Smith, A.B.; et al.; The spongistatins: Architecturally complex natural products - Part one: A formal synthesis of (+)-spongistatin 1 by construction of an advanced ABCD fragment. Angew Chem. Int Ed 2001, 40, 1, 191. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLVII) | 64635 | tert-butyl(dimethyl)silyl (2R,4S,6R)-2-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-(iodomethyl)-2-methoxy-4-methyltetrahydro-2H-pyran-4-yl ether; tert-butyl[2-((4S,6S)-6-{[(2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(iodomethyl)-2-methoxy-4-methyltetrahydro-2H-pyran-2-yl]methyl}-2,2-dimethyl-1,3-dioxan-4-yl)ethoxy]diphenylsilane | C39H63IO6Si2 | 详情 | 详情 | |
| (LXIII) | 64650 | (2S,3R,4S,5R)-5-[(benzyloxy)methoxy]-6-((2S,4S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-3-[(2,4-dimethoxybenzyl)oxy]-2,4-dimethylhexyl phenyl sulfone; ({(2R,4S,8S,10S)-8-[(2R,3S,4R,5S)-2-[(benzyloxy)methoxy]-4-[(2,4-dimethoxybenzyl)oxy]-3,5-dimethyl-6-(phenylsulfonyl)hexyl]-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane | C55H78O12SSi | 详情 | 详情 | |
| (LXIV) | 64651 | (2S,3R,4S,5R)-5-[(benzyloxy)methoxy]-6-((2S,4S,6R,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1-[((2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)methyl]-3-[(2,4-dimethoxybenzyl)oxy]-2,4-dimethylhexyl phenyl sulfone; ({(2R,4S,6R,8S,10S)-8-[(2R,3S,4R,5S)-2-[(benzyloxy)methoxy]-7-((2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)-4-[(2,4-dimethoxybenzyl)oxy]-3,5-dimethyl-6-(phenylsulfonyl)heptyl]-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane | C94H140O18SSi3 | 详情 | 详情 | |
| (LXV) | 64652 | ({(2R,4S,8S,10S)-8-{(2R,3S,4S,5R)-2-[(benzyloxy)methoxy]-6-[((2S,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)methyl]-4-[(2,4-dimethoxybenzyl)oxy]-3,5-dimethyl-6-heptenyl}-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane; benzyl ((2R,4S,8S,10S)-8-{(2R,3S,4S,5R)-2-[(benzyloxy)methoxy]-6-[((2S,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)methyl]-4-[(2,4-dimethoxybenzyl)oxy]-3,5-dimethyl-6-heptenyl}-4-{[tert-butyl(dimethyl)silyl]oxy}-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)methyl ether | C89H136O16Si3 | 详情 | 详情 | |
| (LXVI) | 64653 | (2S,4S,6R,8S,10S)-2-(2-{(1R,2S,3S,4R)-4-[(benzyloxy)methoxy]-5-((2S,4S,6S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-2-[(2,4-dimethoxybenzyl)oxy]-1,3-dimethylpentyl}-2-propenyl)-10-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-methyl-1-oxaspiro[5.5]undecane-4,8-diol | C70H112O14Si2 | 详情 | 详情 | |
| (LXVII) | 64654 | (2S,4S,6R,8S,10S)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,6S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-10-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-hydroxy-4-methyl-1-oxaspiro[5.5]undec-8-yl acetate | C65H106O14Si2 | 详情 | 详情 | |
| (LXVIII) | 64655 | (2S,4S,6R,8S,10S)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,6S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-10-(2-hydroxyethyl)-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl acetate | C65H106O14Si2 | 详情 | 详情 | |
| (LXIX) | 64656 | triisopropylsilyl 2-{(2S,4S,6R,8S,10S)-10-(acetyloxy)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl}acetate | C74H124O15Si3 | 详情 | 详情 |
合成路线9
The cleavage of the Bom and benzyl protecting groups of (LXIX) by means of 1-methyl-1,4-cyclohexadiene and Pd(OH)2/C in ethanol, followed by oxidation with DMP gives the ketonic carbaldehyde compound (LXX) (4), which is condensed with the advanced intermediate phosphonium salt (XLI) by means of NaHMDS in toluene to yield the adduct (LXXI). The selective deprotection of the Tms silyl ester groups of (LXXI) with KF in methanol affords the dihydroxyacid (LXXII), which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride, DIEA and DMAP in toluene to provide the macrolactone (LXXIII). The fully desilylation of (LXXIII) by means of HF in acetonitrile/water gives rise to a 1:3 mixture of spongistatin 2 and its epimer (LXXIV) with the unnatural configuration being predominant. Perchloric acid mediated epimerization of (LXXIV) in the presence of calcium perchlorate leads to a 3.9-2.3:1 mixture (with the natural configuration being predominant), along with some degradation products (2).
| 【2】 Smith, A.B. III; Lin, Q.; Doughty, V.A.; Zhuang, L.; McBriar, M.D.; Kerns, J.K.; Brook, C.S.; Murase, N.; Nakayama, K.; The spongistatins: Architecturally complex natural products - Part two: Synthesis of the C(29-51) subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew Chem. Int Ed 2001, 40, 1, 196. |
| 【1】 Smith, A.B.; et al.; The spongistatins: Architecturally complex natural products - Part one: A formal synthesis of (+)-spongistatin 1 by construction of an advanced ABCD fragment. Angew Chem. Int Ed 2001, 40, 1, 191. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLI) | 64629 | [4-((2R,3S,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{(S)-{(2R,3S,4R,5R,6R)-6-((4S,5E)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylene-5,7-octadienyl)-3-methyl-4,5-bis[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-6-methoxy-3-methyltetrahydro-2H-pyran-2-yl)butyl](triphenyl)phosphonium iodide | C69H118IO8PSi5 | 详情 | 详情 | |
| (LXIX) | 64656 | triisopropylsilyl 2-{(2S,4S,6R,8S,10S)-10-(acetyloxy)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl}acetate | C74H124O15Si3 | 详情 | 详情 | |
| (LXX) | 64657 | triisopropylsilyl 2-{(2S,4S,6R,8S,10S)-10-(acetyloxy)-2-{2-[(1R,2S,3S)-2-(acetyloxy)-5-((2S,4S,6R,8R,10S)-10-{[tert-butyl(dimethyl)silyl]oxy}-8-formyl-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethyl-4-oxopentyl]-2-propenyl}-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl}acetate | C59H106O14Si3 | 详情 | 详情 | |
| (LXXI) | 64658 | C110H208O21Si8 | 详情 | 详情 | ||
| (LXXII) | 64659 | C95H172O21Si5 | 详情 | 详情 | ||
| (LXXIII) | 64660 | (1R,3S,5S,6R,9R,10R,11R,13R,14S,15R,17S,18S,19R,25R,27S,29S,31S,33S,36S,37S,38R,41S,43S,49S)-3,37-bis(acetyloxy)-17,27-bis{[tert-butyl(dimethyl)silyl]oxy}-11-((4S,5E)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylene-5,7-octadienyl)-10-hydroxy-15,31-dimethoxy-18,36,38,43,49-pentamethyl-39-methylene-7,35-dioxo-14,43-bis[(triethylsilyl)oxy]-8,12,45,46,47,48-hexaoxaheptacyclo[39.3.1.1~1,5~.1~9,13~.1~15,19~.1~25,29~.1~29,33~] | C96H170O22Si5 | 详情 | 详情 | |
| (LXXIV) | 64661 | (1R,3S,5S,6R,9R,10R,11R,13R,14S,15R,17S,18R,19R,25R,27S,29S,31S,33S,36S,37S,38R,41S,43S,49S)-3,37-bis(acetyloxy)-10,14,17,27,43-pentahydroxy-11-[(4S,5E)-4-hydroxy-2-methylene-5,7-octadienyl]-15,31-dimethoxy-18,36,38,43,49-pentamethyl-39-methylene-7,35-dioxo-8,12,45,46,47,48-hexaoxaheptacyclo[39.3.1.1~1,5~.1~9,13~.1~15,19~.1~25,29~.1~29,33~] | C66H100O22 | 详情 | 详情 |