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【结 构 式】 
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【分子编号】44531 【品名】(1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate 【CA登记号】 |
【 分 子 式 】C12H15NO3S 【 分 子 量 】253.32204 【元素组成】C 56.9% H 5.97% N 5.53% O 18.95% S 12.66% |
合成路线1
该中间体在本合成路线中的序号：(VII)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2
该中间体在本合成路线中的序号：(X)The omega iodoalkyl thiazole intermediate (XII) is obtained as follows: The cyclization of 2-hydroxypropionaldehyde dimethyl acetal (I) with acetaldehyde (II) by means of warm Dowex (H+) and catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) gives the chiral tetrahydrofuran derivative (III), which is acylated with Ac-Cl and pyridine to yield the acetoxy compound (IV). The reaction of (IV) with BF3/Et2O, propane-1,3-dithiol (V) and TiCl4 affords the protected dithiane (VI), which is oxidized with oxalyl chloride in DMSO to provide the ketone (VII). The Wittig condensation of (VII) with phosphine oxide (VIII) by means of BuLi in THF provides the protected alkyl thiazole (IX), which is treated with HgClO4 to cleave the dithiane ring and yield carbaldehyde (X). Finally, this aldehyde is coupled with iodomethylenephosphorane (XI) by means of NaHMDS in THF/HMPA to afford the target omega iodoalkyl thiazole intermediate (XII).
| 【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404. |
| 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) | 54261 | 1,1-dimethoxy-2-propanol | 42919-42-6 | C5H12O3 | 详情 | 详情 |
| (II) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
| (III) | 54262 | (4S,5R)-5-methyltetrahydro-2,4-furandiol | C5H10O3 | 详情 | 详情 | |
| (IV) | 54263 | (2R,3S)-5-hydroxy-2-methyltetrahydro-3-furanyl acetate | n/a | C7H12O4 | 详情 | 详情 |
| (V) | 29729 | 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide | 109-80-8 | C3H8S2 | 详情 | 详情 |
| (VI) | 54264 | (1S,2R)-1-(1,3-dithian-2-ylmethyl)-2-hydroxypropyl acetate | n/a | C10H18O3S2 | 详情 | 详情 |
| (VII) | 54265 | (1S)-1-(1,3-dithian-2-ylmethyl)-2-oxopropyl acetate | C10H16O3S2 | 详情 | 详情 | |
| (VIII) | 47000 | (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole | C17H16NOPS | 详情 | 详情 | |
| (IX) | 54266 | (1S,2E)-1-(1,3-dithian-2-ylmethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl acetate | C15H21NO2S3 | 详情 | 详情 | |
| (X) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (XI) | 44532 | (iodomethylene)(triphenyl)phosphorane | C19H16IP | 详情 | 详情 | |
| (XII) | 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3
该中间体在本合成路线中的序号：(VII)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：(VII)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5
该中间体在本合成路线中的序号：(VII)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：(X)The omega iodoalkyl thiazole intermediate (XII) is obtained as follows: The cyclization of 2-hydroxypropionaldehyde dimethyl acetal (I) with acetaldehyde (II) by means of warm Dowex (H+) and catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) gives the chiral tetrahydrofuran derivative (III), which is acylated with Ac-Cl and pyridine to yield the acetoxy compound (IV). The reaction of (IV) with BF3/Et2O, propane-1,3-dithiol (V) and TiCl4 affords the protected dithiane (VI), which is oxidized with oxalyl chloride in DMSO to provide the ketone (VII). The Wittig condensation of (VII) with phosphine oxide (VIII) by means of BuLi in THF provides the protected alkyl thiazole (IX), which is treated with HgClO4 to cleave the dithiane ring and yield carbaldehyde (X). Finally, this aldehyde is coupled with iodomethylenephosphorane (XI) by means of NaHMDS in THF/HMPA to afford the target omega iodoalkyl thiazole intermediate (XII).
| 【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404. |
| 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) | 54261 | 1,1-dimethoxy-2-propanol | 42919-42-6 | C5H12O3 | 详情 | 详情 |
| (II) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
| (III) | 54262 | (4S,5R)-5-methyltetrahydro-2,4-furandiol | C5H10O3 | 详情 | 详情 | |
| (IV) | 54263 | (2R,3S)-5-hydroxy-2-methyltetrahydro-3-furanyl acetate | n/a | C7H12O4 | 详情 | 详情 |
| (V) | 29729 | 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide | 109-80-8 | C3H8S2 | 详情 | 详情 |
| (VI) | 54264 | (1S,2R)-1-(1,3-dithian-2-ylmethyl)-2-hydroxypropyl acetate | n/a | C10H18O3S2 | 详情 | 详情 |
| (VII) | 54265 | (1S)-1-(1,3-dithian-2-ylmethyl)-2-oxopropyl acetate | C10H16O3S2 | 详情 | 详情 | |
| (VIII) | 47000 | (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole | C17H16NOPS | 详情 | 详情 | |
| (IX) | 54266 | (1S,2E)-1-(1,3-dithian-2-ylmethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl acetate | C15H21NO2S3 | 详情 | 详情 | |
| (X) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (XI) | 44532 | (iodomethylene)(triphenyl)phosphorane | C19H16IP | 详情 | 详情 | |
| (XII) | 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 |