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【结 构 式】 
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【分子编号】42656 【品名】(2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal 【CA登记号】 |
【 分 子 式 】C12H16O3 【 分 子 量 】208.25724 【元素组成】C 69.21% H 7.74% O 23.05% |
合成路线1
该中间体在本合成路线中的序号：(IV)The intermediate (XV) has been obtained as follows: The reaction of methyl 3-hydroxy-2(S)-methylpropionate (I) with 4-methoxybenzyl trichloroacetimidate gives methyl 3-(4-methoxybenzyloxy)-2(S)-methylpropionate (II), which is reduced with LiAlH4, yielding the primary alcohol (III). The Swern oxidation of (III) affords the aldehyde (IV), which is condensed with the chiral imidazolidinone (V) to provide the adduct (VI). The transamidation of (VI) with N,O-dimethylhydroxylamine by means of Me3Al gives the methoxyamide (VII), which is debenzylated with DDQ to yield the diol (VIII). The reaction of (VIII) with 4-methoxybenzaldehyde diethylacetal (IX) and CSA affords the cyclic ketal (X), which is condensed with the propionyloxazolidinone (XI) by means of dibutylboron triflate to furnish the adduct (XII). The silylation of the OH group of (XII) with Tbdms-OTf gives the silyl ether (XIII), which is reduced at the amide group with LiBH4 to yield the primary alcohol (XIV). Finally, this compound is treated with I2 and PPH3 to afford the intermediate iodo derivative (XV).
| 【1】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823. |
| 【2】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (III) | 42655 | (2R)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-propanol | C12H18O3 | 详情 | 详情 | |
| (IV) | 42656 | (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal | C12H16O3 | 详情 | 详情 | |
| (V) | 42657 | (4R,5S)-3-[(Z)-1-butoxy-1-propenyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C17H23NO3 | 详情 | 详情 | |
| (VI) | 42658 | (4R,5S)-3-[(2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C25H31NO6 | 详情 | 详情 | |
| (VII) | 42659 | (2R,3S,4S)-3-hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide | C17H27NO5 | 详情 | 详情 | |
| (VIII) | 42660 | (2R,3S,4S)-3,5-dihydroxy-N-methoxy-N,2,4-trimethylpentanamide | C9H19NO4 | 详情 | 详情 | |
| (IX) | 35670 | 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether | C12H18O3 | 详情 | 详情 | |
| (X) | 42661 | (2R)-N-methoxy-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-N-methylpropanamide | C17H25NO5 | 详情 | 详情 | |
| (XI) | 10968 | (4R)-3-Acetyl-4-benzyl-1,3-oxazolidin-2-one; (R)-(-)-3-Acetyl-4-benzyl-2-oxazolidinone | 184363-65-3 | C12H13NO3 | 详情 | 详情 |
| (XII) | 42662 | (4R)-4-benzyl-3-[(2R,3S,4S)-3-hydroxy-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C28H35NO7 | 详情 | 详情 | |
| (XIII) | 42663 | (4R)-4-benzyl-3-[(2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C34H49NO7Si | 详情 | 详情 | |
| (XIV) | 42664 | (2S,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-1-pentanol | C24H42O5Si | 详情 | 详情 | |
| (XV) | 42665 | tert-butyl(dimethyl)silyl (1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl ether; tert-butyl[((1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl)oxy]dimethylsilane | C24H41IO4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)The condensation of the known ketone (XVII) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).
| 【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 【3】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 46148 | [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide | C38H49BrNOPSSi | 详情 | 详情 | |
| (XVII) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVIII) | 42656 | (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal | C12H16O3 | 详情 | 详情 | |
| (XIX) | 46149 | (2S,3S,4R,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6,6-tetramethyl-9-decen-5-one | C28H48O5Si | 详情 | 详情 | |
| (XX) | 46150 | (5S,8R,9S)-5-allyl-9-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-4,10-dioxa-3,11-disilatridecan-7-one | C34H62O5Si2 | 详情 | 详情 | |
| (XXI) | 46151 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanal | C33H60O6Si2 | 详情 | 详情 | |
| (XXII) | 46152 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoic acid | C33H60O7Si2 | 详情 | 详情 | |
| (XXIII) | 46153 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoate | C34H62O7Si2 | 详情 | 详情 | |
| (XXIV) | 46154 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate | C26H54O6Si2 | 详情 | 详情 | |
| (XXV) | 46155 | methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate | C26H52O6Si2 | 详情 | 详情 | |
| (XXVI) | 46156 | methyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate | C46H85NO6SSi3 | 详情 | 详情 | |
| (XXVII) | 46157 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C45H83NO6SSi3 | 详情 | 详情 | |
| (XXVIII) | 46158 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)The condensation of the known ketone (XVII) (2) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).
| 【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 【3】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 46148 | [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide | C38H49BrNOPSSi | 详情 | 详情 | |
| (XVII) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVIII) | 42656 | (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal | C12H16O3 | 详情 | 详情 | |
| (XIX) | 46149 | (2S,3S,4R,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6,6-tetramethyl-9-decen-5-one | C28H48O5Si | 详情 | 详情 | |
| (XX) | 46150 | (5S,8R,9S)-5-allyl-9-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-4,10-dioxa-3,11-disilatridecan-7-one | C34H62O5Si2 | 详情 | 详情 | |
| (XXI) | 46151 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanal | C33H60O6Si2 | 详情 | 详情 | |
| (XXII) | 46152 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoic acid | C33H60O7Si2 | 详情 | 详情 | |
| (XXIII) | 46153 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoate | C34H62O7Si2 | 详情 | 详情 | |
| (XXIV) | 46154 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate | C26H54O6Si2 | 详情 | 详情 | |
| (XXV) | 46155 | methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate | C26H52O6Si2 | 详情 | 详情 | |
| (XXVI) | 46156 | methyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate | C46H85NO6SSi3 | 详情 | 详情 | |
| (XXVII) | 46157 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C45H83NO6SSi3 | 详情 | 详情 | |
| (XXVIII) | 46158 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 |