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【结 构 式】 
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【分子编号】44525 【品名】(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate 【CA登记号】 |
【 分 子 式 】C22H37NO4SSi2 【 分 子 量 】467.77712 【元素组成】C 56.49% H 7.97% N 2.99% O 13.68% S 6.85% Si 12.01% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)Synthesis of the thiazole intermediate (XXXIV): 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 lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with HF and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in CH2Cl2 to yield the target thiazole intermediate (XXXIV).
| 【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 |
|---|---|---|---|---|---|---|
| (A) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (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) | 44524 | (4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol | C20H35NO2SSi2 | 详情 | 详情 | |
| (XXVIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XXIX) | 44525 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate | C22H37NO4SSi2 | 详情 | 详情 | |
| (XXX) | 44526 | 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether | C20H35NOSSi2 | 详情 | 详情 | |
| (XXXI) | 44527 | tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole | C20H37NOSSi2 | 详情 | 详情 | |
| (XXXII) | 44491 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H28INOSSi | 详情 | 详情 | |
| (XXXIII) | 44492 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H14INOS | 详情 | 详情 | |
| (XXXIV) | 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：(XXIX)Synthesis of the thiazole intermediate (XXXIV): 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 lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with FH and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in dichloromethane to yield the target thiazole intermediate (XXXIV).
| 【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 |
|---|---|---|---|---|---|---|
| (A) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (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) | 44524 | (4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol | C20H35NO2SSi2 | 详情 | 详情 | |
| (XXVIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XXIX) | 44525 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate | C22H37NO4SSi2 | 详情 | 详情 | |
| (XXX) | 44526 | 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether | C20H35NOSSi2 | 详情 | 详情 | |
| (XXXI) | 44527 | tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole | C20H37NOSSi2 | 详情 | 详情 | |
| (XXXII) | 44491 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H28INOSSi | 详情 | 详情 | |
| (XXXIII) | 44492 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H14INOS | 详情 | 详情 | |
| (XXXIV) | 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 |