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【结 构 式】 
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【分子编号】39940 【品名】2-(triphenylphosphoranylidene)propanal 【CA登记号】 |
【 分 子 式 】C21H19OP 【 分 子 量 】318.355022 【元素组成】C 79.23% H 6.02% O 5.03% P 9.73% |
合成路线1
该中间体在本合成路线中的序号：(XI)The metal-ammonia reduction of 4,6-dimethoxy-m-xylene (I) gives 1,5-dimethyl-2,4-dimethoxy-1,4-cyclohexadiene (II), which by treatment with potassium tert-butoxide in DMSO is converted into the conjugated diene (III). The Dies-Alder reaction of (III) with dimethyl acetylenedicarboxylate (A), and subsequent elimination of the bridge affords dimethyl 3-methyl-4,6-dimethoxyphthalate (IV), which is selectively monodemethylated with BCl3 yielding the o-hydroxyphthalic ester (V). The hydrolysis and anhydrization of (V) gives 3-hydroxy-5-methoxy-6-methylphthalic anhydride (VI), which is reduced with Zn and HCl in acetic acid affording 4-methyl-5-methoxy-7-hydroxyphthalide (VII). The reaction of (VII) with allyl bromide (B) by means of K2CO3 in ether gives the allylic ether (VIII), which undergoes thermal rearrangement into 4-methyl-5-methoxy-7-hydroxy-6-allyl-phthalide (IX). The ozonolysis of (IX) affords the aldehyde (X), which by a Wittig condensation with 1-formylethylydenetriphenylphosphorane (XI) is converted into the new aldehyde (XII). A new Wittig reaction of (XII) with the phosphorane (XIII) gives the ethyl ester (XIV), which is finally hydrolyzed and partially reduced with diimide.
| 【1】 Castaner, J.; Hillier, K.; Mycophenolic acid. Drugs Fut 1978, 3, 8, 594. |
| 【2】 Wright, J.J.; Birch, A.J.; A total synthesis of mycophenolic acid. J Chem Soc 1969, 14, 788-789. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (A) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (I) | 39930 | 1,5-dimethoxy-2,4-dimethylbenzene; 5-methoxy-2,4-dimethylphenyl methyl ether | C10H14O2 | 详情 | 详情 | |
| (II) | 39931 | 1,5-dimethoxy-2,4-dimethyl-1,4-cyclohexadiene; 5-methoxy-2,4-dimethyl-1,4-cyclohexadien-1-yl methyl ether | C10H16O2 | 详情 | 详情 | |
| (III) | 39932 | 3-methoxy-4,6-dimethyl-1,3-cyclohexadien-1-yl methyl ether; 2,4-dimethoxy-1,5-dimethyl-1,3-cyclohexadiene | C10H16O2 | 详情 | 详情 | |
| (IV) | 39933 | dimethyl 4,6-dimethoxy-3-methylphthalate | C13H16O6 | 详情 | 详情 | |
| (V) | 39934 | dimethyl 6-hydroxy-4-methoxy-3-methylphthalate | C12H14O6 | 详情 | 详情 | |
| (VI) | 39935 | 7-hydroxy-5-methoxy-4-methyl-2-benzofuran-1,3-dione | C10H8O5 | 详情 | 详情 | |
| (VII) | 39936 | 7-hydroxy-5-methoxy-4-methyl-2-benzofuran-1(3H)-one | C10H10O4 | 详情 | 详情 | |
| (VIII) | 39937 | 7-(allyloxy)-5-methoxy-4-methyl-2-benzofuran-1(3H)-one | C13H14O4 | 详情 | 详情 | |
| (IX) | 39938 | 6-allyl-7-hydroxy-5-methoxy-4-methyl-2-benzofuran-1(3H)-one | C13H14O4 | 详情 | 详情 | |
| (X) | 39939 | 2-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde | C12H12O5 | 详情 | 详情 | |
| (XI) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XII) | 39941 | (E)-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-methyl-2-butenal | C15H16O5 | 详情 | 详情 | |
| (XIII) | 39942 | ethyl 2-(triethylphosphoranylidene)acetate | C10H21O2P | 详情 | 详情 | |
| (XIV) | 39943 | ethyl (2E,4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methyl-2,4-hexadienoate | C19H22O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVIII)The oxidation of (XXV) with DMP in dichloromethane gives the aldehyde (XXVII), which is condensed with phosphorane (XXVIII) in refluxing toluene to yield aldehyde (XXIX). The reduction of (XXIX) with Zn(BH4)2 in ethyl ether affords alcohol (XXX), which is condensed with 2-sulfanylbenzothiazole (XXXI) by means of Bu3P and TMAD in benzene providing the thioether (XXXII). The oxidation of (XXXII) with Mo7O24(NH4)6 and H2O2 in ethanol gives the sulfone (XXXIII), which is condensed with the aldehyde (XXXIV) by means of LHMDS in THF to yield intermediate (XXXV). The selective monodesilylation of (XXXV) with PPTS in chloroform/methanol, followed by oxidation with DMP, affords the aldehyde (XXXVI).
| 【1】 Shimizu, T.; et al.; Total synthesis of reveromycin A. Org Lett 2000, 2, 14, 2153. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 42472 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-8-(2-hydroxyethyl)-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C32H48O9 | 详情 | 详情 | |
| (XXVII) | 42474 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-9-methyl-8-(2-oxoethyl)-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C32H46O9 | 详情 | 详情 | |
| (XXVIII) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XXIX) | 42475 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-9-methyl-8-[(E)-3-methyl-4-oxo-2-butenyl]-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C35H50O9 | 详情 | 详情 | |
| (XXX) | 42476 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-8-[(E)-4-hydroxy-3-methyl-2-butenyl]-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C35H52O9 | 详情 | 详情 | |
| (XXXI) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (XXXII) | 42477 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-8-[(E)-4-(1,3-benzothiazol-2-ylsulfanyl)-3-methyl-2-butenyl]-3-butyl-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C42H55NO8S2 | 详情 | 详情 | |
| (XXXIII) | 42478 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-8-[(E)-4-(1,3-benzothiazol-2-ylsulfonyl)-3-methyl-2-butenyl]-3-butyl-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C42H55NO10S2 | 详情 | 详情 | |
| (XXXIV) | 42479 | (2R,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-[(triethylsilyl)oxy]butanal | C17H38O3Si2 | 详情 | 详情 | |
| (XXXV) | 42480 | 1-allyl 4-((2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-8-[(2E,4E,6S,7S)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-[(triethylsilyl)oxy]-2,4-octadienyl]-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl) succinate | C52H88O10Si2 | 详情 | 详情 | |
| (XXXVI) | 42481 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-8-((2E,4E,6S,7R)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-oxo-2,4-octadienyl)-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C46H72O10Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is desilylated by means of TFA in dichloromethane, yielding the dihydroxymacrolactone (XVI). Finally, the double bond of (XVI) is epoxidized by means of dimethyldioxirane (DMDO) or MCPBA in chloroform.
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VIII) | 44453 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C23H44O5Si | 详情 | 详情 | |
| (IX) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (X) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (XI) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XIII) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XIV) | 44457 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C34H57NO5SSi | 详情 | 详情 | |
| (XV) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 | |
| (XVI) | 44447 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C26H39NO5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VII) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (VIII) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (IX) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (X) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (XIII) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XIV) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (XV) | 44458 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C16H28INOSSi | 详情 | 详情 | |
| (XVI) | 44459 | [(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide | C34H43INOPSSi | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to give the desired thiazole intermediate (IX).
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 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) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (II) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (III) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (IV) | 40599 | Allyltributyltin; Tributyl-2-propenylstannane | 24850-33-7 | C15H32Sn | 详情 | 详情 |
| (V) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VI) | 44530 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H17NO2S | 详情 | 详情 | |
| (VII) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (VIII) | 44532 | (iodomethylene)(triphenyl)phosphorane | C19H16IP | 详情 | 详情 | |
| (IX) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/CH3CN to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in MeOH. Finally this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (II) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (III) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (IV) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (V) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VII) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (VIII) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (IX) | 46110 | methyl 2-(triphenylphosphoranylidene)-4-pentenoate | C24H23O2P | 详情 | 详情 | |
| (X) | 46113 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5,8-nonatrienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,6-heptadienyl ether | C21H35NOSSi | 详情 | 详情 | |
| (XI) | 46114 | (4Z,7S,8E)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-9-(2-methyl-1,3-thiazol-4-yl)-4,8-nonadien-1-ol | C21H37NO2SSi | 详情 | 详情 | |
| (XII) | 46115 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-9-iodo-2,6-dimethyl-1,5-nonadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-7-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-heptenyl ether | C21H36INOSSi | 详情 | 详情 | |
| (XIII) | 46116 | (2R)-N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine | C29H51N3O2SSi | 详情 | 详情 | |
| (XIV) | 46117 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile | C24H40N2OSSi | 详情 | 详情 | |
| (XV) | 44460 | N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine | C8H16N2O | 详情 | 详情 | |
| (XVI) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XVII) | 46119 | tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | C51H99NO6SSi4 | 详情 | 详情 | |
| (XVIII) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VII) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (VIII) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (IX) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (X) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (XIII) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XIV) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (XV) | 44458 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C16H28INOSSi | 详情 | 详情 | |
| (XVI) | 44459 | [(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide | C34H43INOPSSi | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) and catalyzed by (S)-(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX).
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 【2】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 . |
| 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) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (II) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (III) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (IV) | 40599 | Allyltributyltin; Tributyl-2-propenylstannane | 24850-33-7 | C15H32Sn | 详情 | 详情 |
| (V) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VI) | 44530 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H17NO2S | 详情 | 详情 | |
| (VII) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (VIII) | 42754 | (1-iodoethylidene)(triphenyl)phosphorane | C20H18IP | 详情 | 详情 | |
| (IX) | 46125 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate | C14H18INO2S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/acetonitrile to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in methanol. Finally, this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (II) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (III) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (IV) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (V) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VII) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (VIII) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (IX) | 46110 | methyl 2-(triphenylphosphoranylidene)-4-pentenoate | C24H23O2P | 详情 | 详情 | |
| (X) | 46113 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5,8-nonatrienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,6-heptadienyl ether | C21H35NOSSi | 详情 | 详情 | |
| (XI) | 46114 | (4Z,7S,8E)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-9-(2-methyl-1,3-thiazol-4-yl)-4,8-nonadien-1-ol | C21H37NO2SSi | 详情 | 详情 | |
| (XII) | 46115 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-9-iodo-2,6-dimethyl-1,5-nonadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-7-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-heptenyl ether | C21H36INOSSi | 详情 | 详情 | |
| (XIII) | 46116 | (2R)-N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine | C29H51N3O2SSi | 详情 | 详情 | |
| (XIV) | 46117 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile | C24H40N2OSSi | 详情 | 详情 | |
| (XV) | 44460 | N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine | C8H16N2O | 详情 | 详情 | |
| (XVI) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XVII) | 46119 | tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | C51H99NO6SSi4 | 详情 | 详情 | |
| (XVIII) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IX)The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF to provide the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VII) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (VIII) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (IX) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (X) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (XIII) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XIV) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (XV) | 44458 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C16H28INOSSi | 详情 | 详情 | |
| (XVI) | 44459 | [(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide | C34H43INOPSSi | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX)
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 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) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (II) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (III) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (IV) | 40599 | Allyltributyltin; Tributyl-2-propenylstannane | 24850-33-7 | C15H32Sn | 详情 | 详情 |
| (V) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VI) | 44530 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H17NO2S | 详情 | 详情 | |
| (VII) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (VIII) | 42754 | (1-iodoethylidene)(triphenyl)phosphorane | C20H18IP | 详情 | 详情 | |
| (IX) | 46125 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate | C14H18INO2S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XIV)The cyclization of tetrahydropyran (I) with 2-butylacrolein (II) by means of K2CO3 at 110 C gives the spirodipyran (III), which is epoxidated with dimethyldioxirane in dichloromethane yielding the epoxide (IV). The rearrangement of (IV) by means of camphorsulfonic acid (CSA) affording the carbaldehyde (V), which is condensed with lithium trimethylsilylacetylene (VI) affording carbinol (VII) with incorrect stereochemistry. The oxidation of (VII) with DMP in dichloromethane providing the ketone (VIII), which is reduced with L-Selectride to the carbinol (IX) with the correct stereochemistry. The treatment of (IX) with K2CO3 in MeOH eliminates the trimethylsilyl group giving the acetylene (X), which is silylated at the OH group with TBDMS-OTf and lutidine in dichloromethane yielding (XI). The selective desilylation of (XI) with HF·pyr in THF affords the primary alcohol (XII), which is oxidated with DMP in dichloromethane affording the aldehyde (VIII). The Wittig condensation of (XIII) with phosphorane (XIV) in hot chlorobenzene furnishes the aldehyde (XV).
| 【1】 Guzzupe, A.N.; et al.; Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B. J Org Chem 2001, 66, 7, 2382. |
| 【2】 Cuzzupe, A.N.; et al.; Total synthesis of (-)-reveromycin B. Org Lett 2000, 2, 2, 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 |
|---|---|---|---|---|---|---|
| (I) | 41537 | tert-butyl(dimethyl)[2-[(2R,3S)-3-methyl-6-methylenetetrahydro-2H-pyran-2-yl]ethoxy]silane; tert-butyl(dimethyl)silyl 2-[(2R,3S)-3-methyl-6-methylenetetrahydro-2H-pyran-2-yl]ethyl ether | C15H30O2Si | 详情 | 详情 | |
| (II) | 41538 | (Z)-2-butyl-2-butenal | C8H14O | 详情 | 详情 | |
| (III) | 41539 | tert-butyl(dimethyl)silyl 2-[(2R,3S,6S)-9-butyl-3-methyl-1,7-dioxaspiro[5.5]undec-8-en-2-yl]ethyl ether; tert-butyl[2-[(2R,3S,6S)-9-butyl-3-methyl-1,7-dioxaspiro[5.5]undec-8-en-2-yl]ethoxy]dimethylsilane | C22H42O3Si | 详情 | 详情 | |
| (IV) | 41540 | C22H42O4Si | 详情 | 详情 | ||
| (V) | 41541 | (2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]decane-2-carbaldehyde | n/a | C22H42O4Si | 详情 | 详情 |
| (VI) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (VII) | 41542 | (1R)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-ol | n/a | C27H52O4Si2 | 详情 | 详情 |
| (VIII) | 41543 | 1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-one | n/a | C27H50O4Si2 | 详情 | 详情 |
| (IX) | 41544 | (1S)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-ol | n/a | C27H52O4Si2 | 详情 | 详情 |
| (X) | 41545 | (1S)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-2-propyn-1-ol | n/a | C24H44O4Si | 详情 | 详情 |
| (XI) | 41546 | (1S)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-2-propynyl tert-butyl(dimethyl)silyl ether; tert-butyl([(1S)-1-[(2R,5S,7R,8S)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-2-propynyl]oxy)dimethylsilane | n/a | C30H58O4Si2 | 详情 | 详情 |
| (XII) | 41547 | 2-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-1-ethanol | n/a | C24H44O4Si | 详情 | 详情 |
| (XIII) | 41548 | 2-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]acetaldehyde | n/a | C24H42O4Si | 详情 | 详情 |
| (XIV) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XV) | 41549 | (E)-4-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-2-methyl-2-butenal | n/a | C27H46O4Si | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(IV)The intermediate iodovinyl compound (XI) has been obtained as follows: The reaction of 2-(hydroxymethyl)thiazole-4-carboxylic acid ethyl ester (I) with Troc-Cl and pyridine in dichloromethane gives the protected compound (II), which is reduced with DIBAL in the same solvent to yield the carbaldehyde (III). The condensation of aldehyde (III) with phosphorane (IV) in refluxing benzene affords the unsaturated aldehyde (V), which is asymmetrically allylated by means of (+)-diisopinocampheyl(allyl)borane in pentane to provide the chiral secondary alcohol (VI). The reaction of (VI) with Tbdms-Cl and lutidine in dichloromethane gives the silyl ether (VII), which is oxidized at the terminal double bond by means of OsO4 and Pb(OAc)4 to yield the aldehyde (VIII). The condensation of (VIII) with phosphorane (IX) and LiOH in THF affords the iodovinyl compound (X), which is finally treated with Troc-Cl and pyridine to provide the desired iodovinyl intermediate (XI).
| 【1】 Zhang, X.-G.; Chappell, M.D.; Lee, C.B.; Kuduk, S.D.; Danishefsky, S.J.; Chou, T.-C.; Wang, Z.-G.; Stachel, S.J.; Total synthesis and antitumor activity of 12,13-dexoxyepothilone F: An unexpected solvolysis problem at C15, mediated by remote substitution at C21. J Org Chem 2000, 65, 20, 6525. |
| 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) | 49350 | ethyl 2-(hydroxymethyl)-1,3-thiazole-4-carboxylate | C7H9NO3S | 详情 | 详情 | |
| (II) | 49351 | ethyl 2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazole-4-carboxylate | C10H10Cl3NO5S | 详情 | 详情 | |
| (III) | 49352 | (4-formyl-1,3-thiazol-2-yl)methyl 2,2,2-trichloroethyl carbonate | C8H6Cl3NO4S | 详情 | 详情 | |
| (IV) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (V) | 49353 | [4-[(E)-2-methyl-3-oxo-1-propenyl]-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C11H10Cl3NO4S | 详情 | 详情 | |
| (VI) | 49354 | [4-[(1E,3S)-3-hydroxy-2-methyl-1,5-hexadienyl]-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C14H16Cl3NO4S | 详情 | 详情 | |
| (VII) | 49355 | [4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C20H30Cl3NO4SSi | 详情 | 详情 | |
| (VIII) | 49356 | [4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-5-oxo-1-pentenyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C19H28Cl3NO5SSi | 详情 | 详情 | |
| (IX) | 42754 | (1-iodoethylidene)(triphenyl)phosphorane | C20H18IP | 详情 | 详情 | |
| (X) | 49357 | [4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-1,3-thiazol-2-yl]methanol | C18H30INO2SSi | 详情 | 详情 | |
| (XI) | 49358 | [4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C21H31Cl3INO4SSi | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(III)The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (I) with DIBAL in dichloromethane gives the corresponding carbaldehyde (II), which is condensed with phosphorane (III) in refluxing benzene to yield the propionaldehyde (IV). The diastereocontrolled condensation of (IV) with (+)-allyl-di(isopinocampheyl)borane (V) in ethyl ether affords the chiral homoallyl alcohol (VI), which is silylated with Tbdms-Cl and imidazole to provide the silyl ether (VII).The oxidation of the terminal double bond of (VII) by means of OsO4, NaIO4 and 4-methylmorpholine N-oxide gives the 4-pentenal derivative (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the methyl heptadienoate (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is protected with trityl chloride and DMAP to provide the trityl ether (XII). The Hydroxylation of the terminal double bond of (XII) with 8-BBN and H2O2 gives the primary alcohol (XIII), which is treated with I2 and PPh3 to yield the iodo compound (XIV). The condensation of (XIV) with the hydrazone (XV) by means of LDA affords the chiral undecadienylhydrazone (XVI), which is treated with monoperoxyphthalic magnesium salt (MMPP) to provide the undecadienenitrile (XVII). The reduction of (XVII) with DIBAL in toluene gives the corresponding aldehyde (XVIII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy. Tetrahedron 1998, 54, 25, 7127. |
| 【2】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 【3】 He, Y.; Yang, Z.; Nicolaou, C.K.; Ninkovic, S.; Pastor, J.; Roschangar, F.; Sarabia, F.; Vallberg, H.; Vourloumis, D.; Winssinger, N.; King, N.P.; Finlay, M.R.V. (Novartis AG; Scripps Research Institute); Epothilone analogs. JP 2001504856; WO 9825929 . |
| 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) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (II) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (III) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (IV) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (VI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VII) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (VIII) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (IX) | 46110 | methyl 2-(triphenylphosphoranylidene)-4-pentenoate | C24H23O2P | 详情 | 详情 | |
| (X) | 46111 | methyl (2E,5S,6E)-2-allyl-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate | C22H35NO3SSi | 详情 | 详情 | |
| (XI) | 46112 | (2E,5S,6E)-2-allyl-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C21H35NO2SSi | 详情 | 详情 | |
| (XII) | 54771 | (2E,5S,6E)-2-allyl-5-{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienyl trityl ether; 4-{(1E,3S,5E)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-6-[(trityloxy)methyl]-1,5,8-nonatrienyl}-2-methyl-1,3-thiazole | C40H49NO2SSi | 详情 | 详情 | |
| (XIII) | 54772 | (4E,7S,8E)-7-{[tert-butyl(dimethyl)silyl]oxy}-8-methyl-9-(2-methyl-1,3-thiazol-4-yl)-4-[(trityloxy)methyl]-4,8-nonadien-1-ol | C40H51NO3SSi | 详情 | 详情 | |
| (XIV) | 54773 | tert-butyl(dimethyl)silyl (1S,3E)-7-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(trityloxy)methyl]-3-heptenyl ether; 4-{(1E,3S,5E)-3-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-2-methyl-6-[(trityloxy)methyl]-1,5-nonadienyl}-2-methyl-1,3-thiazole | C40H50INO2SSi | 详情 | 详情 | |
| (XV) | 44460 | N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine | C8H16N2O | 详情 | 详情 | |
| (XVI) | 54774 | (2R)-N-{(Z,2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-2-methoxy-1-pyrrolidinamine; N-{(Z,2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-N-[(2R)-2-methoxypyrrolidinyl]amine | C48H65N3O3SSi | 详情 | 详情 | |
| (XVII) | 54775 | (2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienenitrile | C43H54N2O2SSi | 详情 | 详情 | |
| (XVIII) | 54776 | (2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienal | C43H55NO3SSi | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(XI)The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is finally desilylated by means of TFA in dichloromethane, yielding the target epothilone C.
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VIII) | 44453 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C23H44O5Si | 详情 | 详情 | |
| (IX) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (X) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (XI) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XIII) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XIV) | 44457 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C34H57NO5SSi | 详情 | 详情 | |
| (XV) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(IX)The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VII) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (VIII) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (IX) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (X) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (XIII) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XIV) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (XV) | 44458 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C16H28INOSSi | 详情 | 详情 | |
| (XVI) | 44459 | [(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide | C34H43INOPSSi | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(II)Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to give the desired thiazole intermediate (IX).
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 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) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (II) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (III) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (IV) | 40599 | Allyltributyltin; Tributyl-2-propenylstannane | 24850-33-7 | C15H32Sn | 详情 | 详情 |
| (V) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VI) | 44530 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H17NO2S | 详情 | 详情 | |
| (VII) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (VIII) | 44532 | (iodomethylene)(triphenyl)phosphorane | C19H16IP | 详情 | 详情 | |
| (IX) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 |