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【结 构 式】 
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【分子编号】32448 【品名】[(3R,4S,5S,6S)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol 【CA登记号】 |
【 分 子 式 】C24H46O3Sn 【 分 子 量 】501.33744 【元素组成】C 57.5% H 9.25% O 9.57% Sn 23.68% |
合成路线1
该中间体在本合成路线中的序号：(XXXVI)The reaction of 5-iodo-4-methyl-3-(tert-butydimethylsilyloxy)-4-pentenal (XXVI) with methyl iodide and CrCl2 in dioxane/THF gives the diiodohexenal (XXVII), which is desilylated with TBAF in THF yielding the secondary alcohol (XXVIII). The esterification of (XXVIII) with protected perhydropyridazinecarboxylic acid (XXIX) by means of EDC and DIEA in dichloromethane affords the carboxylic ester (XXX), which is deprotected with TFA in dichloromethane to give the unprotected ester (XXXI). The condensation of (XXXI) with carboxylic acid (XXXII) by means of 1-hydroxy-7-azabenzotriazole (HOAt) and EDC in dichloromethane yields the protected amide (XXXIII), which is deprotected with TFA affording (XXXIV) with a free amino group. The condensation of (XXXIV) with the acid (XXXV) (obtained by oxidation of carbinol (XXXVI) with tetrapropylammonium perruthenate (TPAP)) by means of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and DIEA in DMF provides the amide (XXXVII), which is cyclized by means of triphenylarsine and Pd dibenzylideneacetone complex yielding the cyclic intermediate (XXXVIII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of sanglifehrin A. Angew Chem. Int Ed Engl 1999, 38, 16, 2447. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVI) | 32438 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-methyl-4-pentenal | C12H23IO2Si | 详情 | 详情 | |
| (XXVII) | 32439 | tert-butyl([(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl ether | C13H24I2OSi | 详情 | 详情 | |
| (XXVIII) | 32440 | (1E,3S,5E)-1,6-diiodo-2-methyl-1,5-hexadien-3-ol | C7H10I2O | 详情 | 详情 | |
| (XXIX) | 32441 | (3S)-1,2-bis(tert-butoxycarbonyl)hexahydro-3-pyridazinecarboxylic acid | C15H26N2O6 | 详情 | 详情 | |
| (XXX) | 32442 | 1,2-di(tert-butyl) 3-[(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl] (3S)tetrahydro-1,2,3-pyridazinetricarboxylate | C22H34I2N2O6 | 详情 | 详情 | |
| (XXXI) | 32443 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)hexahydro-3-pyridazinecarboxylate | C12H18I2N2O2 | 详情 | 详情 | |
| (XXXII) | 32444 | (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (XXXIII) | 32445 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C31H44I2N4O7 | 详情 | 详情 | |
| (XXXIV) | 32446 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C26H36I2N4O5 | 详情 | 详情 | |
| (XXXV) | 32447 | (3R,4S,5R,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]nonane-6-carboxylic acid | C24H44O4Sn | 详情 | 详情 | |
| (XXXVI) | 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 | |
| (XXXVII) | 32449 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[([(3R,4S,5R,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]carbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate; (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[([(3R,4S,5R,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]carbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C50H78I2N4O8Sn | 详情 | 详情 | |
| (XXXVIII) | 32450 | (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone; (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone | C38H51IN4O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(LX)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 |