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【结 构 式】 
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【分子编号】61720 【品名】(E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-methoxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenal 【CA登记号】 |
【 分 子 式 】C27H40O5Si 【 分 子 量 】472.6971 【元素组成】C 68.61% H 8.53% O 16.92% Si 5.94% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The condensation of aldehyde (I) with boronate (II) in toluene gives the chiral alcohol (III), which is treated with Tbdms-OTf and TEA to yield the silyl ether (IV). The hydroxylation of the terminal double bond of (IV) by means of 9-BBN in refluxing THF affords the primary alcohol (V), which is oxidized by means of the Swern oxidant to provide the aldehyde (VI). The homologation of (VI) with methyltriphenylphosphonium iodide (VII) and NaHMDS gives the unsaturated compound (VIII), which is deprotected at the ketonide group by means of TFA in dichloromethane to afford the diol (IX). The dehydration of (IX) by means of tosylimidazole (X) and NaH in THF provides the epoxide (XI), which is condensed with the Grignard reagent (XIII) (obtained by reaction of the tributyltin derivative (XII) with MgBr2) to give the secondary alcohol (XIV). The reaction of 2-allyl-6-methoxybenzamide (XV) with I2 in THF/water gives the lactone (XVI), which is treated with Zn and AcOH to yield 2-allyl-6-methoxybenzoic acid (XVII). The esterification of acid (XVII) with alcohol (XIV) by means of DEAD and PPH3 affords the corresponding ester (XVIII), which is submitted to a ring closing metathesis reaction by means of a Ru catalyst to provide the macrolactone (XIX). The cleavage of the Pmb protecting group of (XIX) by means of DDQ gives the primary alcohol (XX), which is oxidized to the aldehyde (XXI) by means of DMP oxidant.
| 【1】 Smith, A.B.; Zheng, J.Y.; Total synthesis of (-)-salicylihalamide A and related congeners. Tetrahedron 2002, 58, 33, 6455. |
| 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) | 61703 | 2-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]acetaldehyde | C9H16O3 | 详情 | 详情 | |
| (II) | 61704 | diisopropyl (4S,5S)-2-[(E)-2-butenyl]-1,3,2-dioxaborolane-4,5-dicarboxylate | C14H23BO6 | 详情 | 详情 | |
| (III) | 61705 | (2R,3S)-1-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methyl-4-penten-2-ol | C13H24O3 | 详情 | 详情 | |
| (IV) | 61706 | tert-butyl(dimethyl)silyl (1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-3-butenyl ether; tert-butyl[((1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-3-butenyl)oxy]dimethylsilane | C19H38O3Si | 详情 | 详情 | |
| (V) | 61707 | (3S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methyl-1-pentanol | C19H40O4Si | 详情 | 详情 | |
| (VI) | 61708 | (3S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methylpentanal | C19H38O4Si | 详情 | 详情 | |
| (VII) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (VIII) | 61709 | tert-butyl(dimethyl)silyl (1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-4-pentenyl ether; tert-butyl[((1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-4-pentenyl)oxy]dimethylsilane | C20H40O3Si | 详情 | 详情 | |
| (IX) | 61710 | (2S,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-7-octene-1,2-diol | C15H32O3Si | 详情 | 详情 | |
| (X) | 47846 | 1-[(4-methylphenyl)sulfonyl]-1H-imidazole | 2232-08-8 | C10H10N2O2S | 详情 | 详情 |
| (XI) | 61711 | tert-butyl(dimethyl)({(1R,2S)-2-methyl-1-[(2S)oxiranylmethyl]-4-pentenyl}oxy)silane; tert-butyl(dimethyl)silyl (1R,2S)-2-methyl-1-[(2S)oxiranylmethyl]-4-pentenyl ether | C15H30O2Si | 详情 | 详情 | |
| (XII) | 61712 | tributyl{(E)-3-[(4-methoxybenzyl)oxy]-1-propenyl}stannane; 4-methoxybenzyl (E)-3-(tributylstannyl)-2-propenyl ether | C23H40O2Sn | 详情 | 详情 | |
| (XIII) | 61713 | bromo{(E)-3-[(4-methoxybenzyl)oxy]-1-propenyl}magnesium | C11H13BrMgO2 | 详情 | 详情 | |
| (XIV) | 61716 | (2E,5R,7R,8S)-7-{[tert-butyl(dimethyl)silyl]oxy}-1-[(4-methoxybenzyl)oxy]-8-methyl-2,10-undecadien-5-ol | C26H44O4Si | 详情 | 详情 | |
| (XV) | 61714 | 2-allyl-6-methoxy-N,N-dipropylbenzamide | C17H25NO2 | 详情 | 详情 | |
| (XVI) | 61715 | 3-(iodomethyl)-8-methoxy-3,4-dihydro-1H-isochromen-1-one | C11H11IO3 | 详情 | 详情 | |
| (XVII) | 47491 | 2-allyl-6-methoxybenzoic acid | C11H12O3 | 详情 | 详情 | |
| (XVIII) | 61717 | (1S,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-{(E)-4-[(4-methoxybenzyl)oxy]-2-butenyl}-4-methyl-6-heptenyl 2-allyl-6-methoxybenzoate | C37H54O6Si | 详情 | 详情 | |
| (XIX) | 61718 | (3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-methoxy-3-{(E)-4-[(4-methoxybenzyl)oxy]-2-butenyl}-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one | C35H50O6Si | 详情 | 详情 | |
| (XX) | 61719 | (3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-[(E)-4-hydroxy-2-butenyl]-14-methoxy-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one | C27H42O5Si | 详情 | 详情 | |
| (XXI) | 61720 | (E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-methoxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenal | C27H40O5Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)The demethylation of (XXI) by means of BBr3 gives the hydroxyaldehyde (XXII), which is oxidized to the corresponding carboxylic acid (XXIII) by means of NaClO2. The protection of the phenolic OH group of (XXIII) by means of Tbdms-OTf and TEA yields the silyl ether (XXIV), which is submitted to a Curtius rearrangement by means of isobutyl chloroformate, NaN3 and 2-(trimethylsilyl)ethanol, affording the carbamate (XXV). The acylation of carbamate (XXV) with heptadienoyl chloride (XXVI) and NaHMDS provides the advanced intermediate (XXVII), which is finally deprotected by successive treatments with TBAF and with HF/pyridine to provide the target Salicylhalamide A.
| 【1】 Smith, A.B.; Zheng, J.Y.; Total synthesis of (-)-salicylihalamide A and related congeners. Tetrahedron 2002, 58, 33, 6455. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 56950 | (E)-4-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoic acid | C32H52O6Si2 | 详情 | 详情 | |
| (XXI) | 61720 | (E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-methoxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenal | C27H40O5Si | 详情 | 详情 | |
| (XXII) | 61721 | (E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenal | C26H38O5Si | 详情 | 详情 | |
| (XXIII) | 61722 | (E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoic acid | C26H38O6Si | 详情 | 详情 | |
| (XXV) | 61723 | 2-(trimethylsilyl)ethyl (E)-3-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenylcarbamate | C37H65NO6Si3 | 详情 | 详情 | |
| (XXVI) | 61725 | (2Z,4Z)-2,4-heptadienoyl chloride | C7H9ClO | 详情 | 详情 | |
| (XXVII) | 61724 | 2-(trimethylsilyl)ethyl (E)-3-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl[(2Z,4Z)-2,4-heptadienoyl]carbamate | C44H73NO7Si3 | 详情 | 详情 |