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【结 构 式】 
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【分子编号】46125 【品名】(1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate 【CA登记号】 |
【 分 子 式 】C14H18INO2S 【 分 子 量 】391.27293 【元素组成】C 42.98% H 4.64% I 32.43% N 3.58% O 8.18% S 8.2% |
合成路线1
该中间体在本合成路线中的序号：(XXXIII)Synthesis of the thiazole intermediate (XXXIII): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with phosphonium salt (XXVII), LHMDS, Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX), which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI). The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII), which is acylated with Ac2O, TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XXIII) | 44520 | (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile | C9H10N2OS | 详情 | 详情 | |
| (XXIV) | 44521 | ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C11H15NO3S | 详情 | 详情 | |
| (XXV) | 44522 | ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C17H29NO3SSi | 详情 | 详情 | |
| (XXVI) | 44523 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal | C15H25NO2SSi | 详情 | 详情 | |
| (XXVII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXVIII) | 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 | |
| (XXIX) | 46122 | ethyl(triphenyl)phosphonium iodide | C20H20IP | 详情 | 详情 | |
| (XXX) | 46123 | tert-butyl(dimethyl)silyl (1S,3E)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole | C18H31NOSSi | 详情 | 详情 | |
| (XXXI) | 26246 | tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole | C18H30INOSSi | 详情 | 详情 | |
| (XXXII) | 46124 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol | C12H16INOS | 详情 | 详情 | |
| (XXXIII) | 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2
该中间体在本合成路线中的序号：(XXXIII)Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIII) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXIV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXV). The macrolactonization of (XXXV) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVI), which is desilylated with HF and pyridine in THF, furnishing the dihydroxylactone (XXXVII). Finally, this compound is epoxidated by means of dimethyldioxirane (XXXVIII) in dichloromethane to give the target epothilone B.
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 44519 | phenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | C33H58O5Si2 | 详情 | 详情 | |
| (XXXIII) | 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 | |
| (XXXIV) | 46126 | phenyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[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 | C47H77NO7SSi2 | 详情 | 详情 | |
| (XXXV) | 40835 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-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 | |
| (XXXVI) | 40836 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C39H69NO5SSi2 | 详情 | 详情 | |
| (XXXVII) | 40837 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C27H41NO5S | 详情 | 详情 | |
| (XXXVIII) | 31501 | 3,3-dimethyl-1,2-dioxirane | C3H6O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)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4
该中间体在本合成路线中的序号：(IX)The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane to furnish the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).
| 【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 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 44545 | tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C40H58O3S2Si2 | 详情 | 详情 | |
| (XXIIIb) | 44546 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether | C40H58O3S2Si2 | 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 | |
| (X) | 44533 | (2S)-3-(benzyloxy)-2-methylpropanal | C11H14O2 | 详情 | 详情 | |
| (XI) | 44534 | (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane | C10H20O2Si | 详情 | 详情 | |
| (XII) | 44535 | (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one | C17H22O3 | 详情 | 详情 | |
| (XIII) | 44536 | (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol | C17H24O3 | 详情 | 详情 | |
| (XIV) | 44537 | (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol | C18H26O3 | 详情 | 详情 | |
| (XV) | 44538 | (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | C19H29IO4 | 详情 | 详情 | |
| (XVI) | 44539 | (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol | C19H30O4 | 详情 | 详情 | |
| (XVII) | 44540 | benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane | C37H44O4Si | 详情 | 详情 | |
| (XVIII) | 44541 | (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol | C39H48O3S2Si | 详情 | 详情 | |
| (XIX) | 44542 | (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether | C45H62O3S2Si2 | 详情 | 详情 | |
| (XX) | 44543 | (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol | C38H56O3S2Si2 | 详情 | 详情 | |
| (XXI) | 44544 | (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal | C38H54O3S2Si2 | 详情 | 详情 | |
| (XXII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXIV) | 44547 | (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal | C39H56O3S2Si2 | 详情 | 详情 | |
| (XXV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XXVI) | 44548 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether | C40H58O2S2Si2 | 详情 | 详情 | |
| (XXVII) | 44549 | tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C39H58O4Si2 | 详情 | 详情 | |
| (XXVIII) | 46127 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C53H77NO6SSi2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXXIII)Synthesis of the thiazole intermediate (XXXIII): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with phosphonium salt (XXVII), LHMDS, Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX), which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI). The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII), which is acylated with Ac2O, TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XXIII) | 44520 | (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile | C9H10N2OS | 详情 | 详情 | |
| (XXIV) | 44521 | ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C11H15NO3S | 详情 | 详情 | |
| (XXV) | 44522 | ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C17H29NO3SSi | 详情 | 详情 | |
| (XXVI) | 44523 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal | C15H25NO2SSi | 详情 | 详情 | |
| (XXVII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXVIII) | 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 | |
| (XXIX) | 46122 | ethyl(triphenyl)phosphonium iodide | C20H20IP | 详情 | 详情 | |
| (XXX) | 46123 | tert-butyl(dimethyl)silyl (1S,3E)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole | C18H31NOSSi | 详情 | 详情 | |
| (XXXI) | 26246 | tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole | C18H30INOSSi | 详情 | 详情 | |
| (XXXII) | 46124 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol | C12H16INOS | 详情 | 详情 | |
| (XXXIII) | 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6
该中间体在本合成路线中的序号：(XXXIII)Assembly of the target compound : The condensation of intermediates (XXI) and (XXXIII) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXIV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXV). The macrolactonization of (XXXV) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVI), which is finally desilylated with HF and pyridine in THF, furnishing the target epothilone D.
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 44519 | phenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | C33H58O5Si2 | 详情 | 详情 | |
| (XXXIII) | 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 | |
| (XXXIV) | 46126 | phenyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[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 | C47H77NO7SSi2 | 详情 | 详情 | |
| (XXXV) | 40835 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-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 | |
| (XXXVI) | 40836 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C39H69NO5SSi2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)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8
该中间体在本合成路线中的序号：(IX)The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provides the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).
| 【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 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 44545 | tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C40H58O3S2Si2 | 详情 | 详情 | |
| (XXIIIb) | 44546 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether | C40H58O3S2Si2 | 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 | |
| (X) | 44533 | (2S)-3-(benzyloxy)-2-methylpropanal | C11H14O2 | 详情 | 详情 | |
| (XI) | 44534 | (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane | C10H20O2Si | 详情 | 详情 | |
| (XII) | 44535 | (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one | C17H22O3 | 详情 | 详情 | |
| (XIII) | 44536 | (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol | C17H24O3 | 详情 | 详情 | |
| (XIV) | 44537 | (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol | C18H26O3 | 详情 | 详情 | |
| (XV) | 44538 | (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | C19H29IO4 | 详情 | 详情 | |
| (XVI) | 44539 | (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol | C19H30O4 | 详情 | 详情 | |
| (XVII) | 44540 | benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane | C37H44O4Si | 详情 | 详情 | |
| (XVIII) | 44541 | (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol | C39H48O3S2Si | 详情 | 详情 | |
| (XIX) | 44542 | (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether | C45H62O3S2Si2 | 详情 | 详情 | |
| (XX) | 44543 | (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol | C38H56O3S2Si2 | 详情 | 详情 | |
| (XXI) | 44544 | (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal | C38H54O3S2Si2 | 详情 | 详情 | |
| (XXII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXIV) | 44547 | (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal | C39H56O3S2Si2 | 详情 | 详情 | |
| (XXV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XXVI) | 44548 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether | C40H58O2S2Si2 | 详情 | 详情 | |
| (XXVII) | 44549 | tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C39H58O4Si2 | 详情 | 详情 | |
| (XXVIII) | 46127 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C53H77NO6SSi2 | 详情 | 详情 |