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【结 构 式】 
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【分子编号】35903 【品名】[(4S,6S)-3-ethynyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol 【CA登记号】 |
【 分 子 式 】C12H18O3 【 分 子 量 】210.27312 【元素组成】C 68.55% H 8.63% O 22.83% |
合成路线1
该中间体在本合成路线中的序号：(LIX)The silylation of hydroxyester (XLVIII) with Tips-Cl and imidazole in THF gives the fully protected compound (XLIX), which is reduced with DIBAL in dichloromethane to the carbinol (L).The epoxidation of the double bond of (L) with MCPBA in dichloromethane yields the epoxide (LI), which is condensed with the Grignard reagent (LII) by means of CuI in ethyl ether/THF affording the diol (LIII). Esterification of the primary OH group of (LIII) with pivaloyl chloride gives the ester (LIV), which is desilylated with TBAF in THF providing the diol (LV). The cyclic ketalization of (LV) catalyzed by PdCl2 and benzoquinone yields the cyclic ketal (LVI), which is debenzylated as usual affording the primary alcohol (LVII). The oxidation of (LVII) with TPAP and NMO in dichloromethane gives the aldehyde (LVIII), which is condensed with diazophosphonate (XXVII) by means of K2CO3 in methanol yielding the ethynyl derivative (LIX), with simultaneous hydrolysis of the pivaloyl ester. The reaction of (LIX) with tributyltin hydride and PdCl2 in dichloromethane affords the vinyl stannane derivative (LX). Finally, the hydroxymethyl group of (LX) is oxidized with TPAP, NMO and NaClO2 to the corresponding carboxylic group of the desired tributylstannane intermediate (XXXII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVII) | 35884 | diethyl 1-diazo-2-oxopropylphosphonate | C7H13N2O4P | 详情 | 详情 | |
| (XXXII) | 35904 | (4S,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]nonane-6-carboxylic acid | C24H44O4Sn | 详情 | 详情 | |
| (XLVIII) | 35892 | ethyl (E,4R,5R)-6-(benzyloxy)-5-hydroxy-4-methyl-2-hexenoate | C16H22O4 | 详情 | 详情 | |
| (XLIX) | 35893 | ethyl (E,4R,5R)-6-(benzyloxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-hexenoate | C25H42O4Si | 详情 | 详情 | |
| (L) | 35894 | (E,4R,5R)-6-(benzyloxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-hexen-1-ol | C23H40O3Si | 详情 | 详情 | |
| (LI) | 35895 | ((2S,3R)-3-[(1R,2R)-3-(benzyloxy)-1-methyl-2-[(triisopropylsilyl)oxy]propyl]oxiranyl)methanol | C23H40O4Si | 详情 | 详情 | |
| (LII) | 35896 | bromo(3-butenyl)magnesium | 7103-09-5 | C4H7BrMg | 详情 | 详情 |
| (LIII) | 35897 | (2S,3S,4R,5R)-6-(benzyloxy)-2-(3-butenyl)-4-methyl-5-[(triisopropylsilyl)oxy]-1,3-hexanediol | C27H48O4Si | 详情 | 详情 | |
| (LIV) | 35898 | (2S)-2-[(1S,2R,3R)-4-(benzyloxy)-1-hydroxy-2-methyl-3-[(triisopropylsilyl)oxy]butyl]-5-hexenyl pivalate | C32H56O5Si | 详情 | 详情 | |
| (LV) | 35899 | (2S)-2-[(1S,2R,3R)-4-(benzyloxy)-1,3-dihydroxy-2-methylbutyl]-5-hexenyl pivalate | C23H36O5 | 详情 | 详情 | |
| (LVI) | 35900 | [(4S,6S)-3-[(benzyloxy)methyl]-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate | C23H34O5 | 详情 | 详情 | |
| (LVII) | 35901 | [(4S,6S)-3-(hydroxymethyl)-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate | C16H28O5 | 详情 | 详情 | |
| (LVIII) | 35902 | [(4S,6S)-3-formyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate | C16H26O5 | 详情 | 详情 | |
| (LIX) | 35903 | [(4S,6S)-3-ethynyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol | C12H18O3 | 详情 | 详情 | |
| (LX) | 32448 | [(3R,4S,5S,6S)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol | C24H46O3Sn | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(LIX)The regiocontrolled condensation of the silylated propargyl aldehyde (LXI) with the chiral borane (LXII) gives the secondary alcohol (LXIII), which is silylated with TBDMS-OTf and lutidine in dichloromethane to the silyl ether (LXIV). The ozonolysis of the terminal double bond of (LXIV) with O3 in dichloromethane yields the aldehyde (LXV), which is condensed with the phosphonate (LXVI) by means of NaH in THF affording the unsaturated heptanoic ester (LXVII). The reduction of the ester group of (LXVII) with DIBAL in THF gives the alcohol (LXVIII), which is epoxidized with MCPBA as usual to the epoxide (LXIX). The condensation of (LXIX) with the Grignard reagent (LXX) in THF yields the diol (LXXI), which is selectively esterified with pivaloyl chloride affording the monopivalate (LXXII). The cyclic transketalization of (LXXII) catalyzed by HF in acetonitrile/water gives the cyclic ketal (LXXII), which is finally hydrolyzed by means of K2CO3 in methanol to provide the desired intermediate, the ethynyl derivative (LIX).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LIX) | 35903 | [(4S,6S)-3-ethynyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol | C12H18O3 | 详情 | 详情 | |
| (LXI) | 35905 | 3-(triethylsilyl)-2-propynal | C9H16OSi | 详情 | 详情 | |
| (LXIII) | 35906 | (3R,4R)-4-methyl-1-(triethylsilyl)-5-hexen-1-yn-3-ol | C13H24OSi | 详情 | 详情 | |
| (LXIV) | 35907 | ((3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-hexen-1-ynyl)(triethyl)silane; tert-butyl(dimethyl)silyl (1R,2R)-2-methyl-1-[2-(triethylsilyl)ethynyl]-3-butenyl ether | C19H38OSi2 | 详情 | 详情 | |
| (LXV) | 35908 | (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-5-(triethylsilyl)-4-pentynal | C18H36O2Si2 | 详情 | 详情 | |
| (LXVI) | 35909 | ethyl 3-(diethoxyphosphoryl)propanoate | 3699-67-0 | C9H19O5P | 详情 | 详情 |
| (LXVII) | 35910 | ethyl (E,4R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-7-(triethylsilyl)-2-hepten-6-ynoate | C22H42O3Si2 | 详情 | 详情 | |
| (LXVIII) | 35911 | (E,4R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-7-(triethylsilyl)-2-hepten-6-yn-1-ol | C20H40O2Si2 | 详情 | 详情 | |
| (LXIX) | 35912 | [3-[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(triethylsilyl)-3-butynyl]-2-oxiranyl]methanol | C20H40O3Si2 | 详情 | 详情 | |
| (LXX) | 35913 | bromo[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]magnesium | C6H11BrMgO2 | 详情 | 详情 | |
| (LXXI) | 35914 | (2S,3S,4R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-7-(triethylsilyl)-6-heptyne-1,3-diol | C26H52O5Si2 | 详情 | 详情 | |
| (LXXII) | 35915 | (2S,3S,4R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4-methyl-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-7-(triethylsilyl)-6-heptynyl pivalate | C31H60O6Si2 | 详情 | 详情 | |
| (LXXIII) | 35916 | [(4S,6S)-1,4-dimethyl-3-[2-(triethylsilyl)ethynyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate | C23H40O4Si | 详情 | 详情 |