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【结 构 式】 
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【分子编号】54783 【品名】(4S,7R,8S,9S,16S)-4,8-dihydroxy-13-(hydroxymethyl)-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione 【CA登记号】 |
【 分 子 式 】C27H41NO6S 【 分 子 量 】507.69168 【元素组成】C 63.88% H 8.14% N 2.76% O 18.91% S 6.32% |
合成路线1
该中间体在本合成路线中的序号：(XXVI)The condensation of aldehyde (XVIII) with the chiral 3-heptanone derivative (XIX) by means of LDA in THF gives the heptadecadien-7-ol derivative (XX), which is silylated with Tbdms-OTf to yield the fully silylated compound (XXI). The selective desilylation of the primary OH group with HF and pyridine in THF affords the heptadecadien-1-ol derivative (XXII), which is submitted to a Swern oxidation followed by a treatment with NaClO2 to provide the carboxylic acid (XXIII). The selective desilylation of the 15-hydroxyl of (XXII) by means of TBAF in THF gives the hydroxyacid (XXIV), which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to yield the macrolactone (XXV). The fully deprotection of (XXV) with HF and pyridine affords the hydroxymethyl macrolactone (XXVI), which is epoxidated with Ti(O-iPr)4, diethyl-L-tartrate and tBu-OOH to provide the epoxidated precursor (XXVII). Finally, this compound is treated with diethylaminosulfurtrifluoride (DAST) in dichloromethane to furnish the target fluorinated epothilone.
| 【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】 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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XIX) | 40830 | (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C21H46O3Si2 | 详情 | 详情 | |
| (XX) | 54777 | (7S,10R,11S,12S,16E,19S)-7-{[tert-butyl(dimethyl)silyl]oxy}-11-hydroxy-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one | C64H101NO6SSi3 | 详情 | 详情 | |
| (XXI) | 54778 | (7S,10R,11S,12S,16E,19S)-7,11-bis{[tert-butyl(dimethyl)silyl]oxy}-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one | C70H115NO6SSi4 | 详情 | 详情 | |
| (XXII) | 54779 | (5S,8R,9S,10S,14E,17S)-9-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,19,19,20,20-dodecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-14-[(trityloxy)methyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one | C64H101NO6SSi3 | 详情 | 详情 | |
| (XXIII) | 54780 | (3S,6R,7S,8S,12E,15S,16E)-3,7,15-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12-[(trityloxy)methyl]-12,16-heptadecadienoic acid | C64H99NO7SSi3 | 详情 | 详情 | |
| (XXIV) | 54781 | (3S,6R,7S,8S,12E,15S,16E)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12-[(trityloxy)methyl]-12,16-heptadecadienoic acid | C58H85NO7SSi2 | 详情 | 详情 | |
| (XXV) | 54782 | (4S,7R,8S,9S,16S)-4,8-bis{[tert-butyl(dimethyl)silyl]oxy}-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-[(trityloxy)methyl]oxa-13-cyclohexadecene-2,6-dione | C58H83NO6SSi2 | 详情 | 详情 | |
| (XXVI) | 54783 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-13-(hydroxymethyl)-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C27H41NO6S | 详情 | 详情 | |
| (XXVII) | 54784 | (1R,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-16-(hydroxymethyl)-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione | C27H41NO7S | 详情 | 详情 |