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【结 构 式】 
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【分子编号】42709 【品名】Diazomethylphoshonic acid dimethyl ester 【CA登记号】27491-70-9 |
【 分 子 式 】C3H7N2O3P 【 分 子 量 】150.074022 【元素组成】C 24.01% H 4.7% N 18.67% O 31.98% P 20.64% |
合成路线1
该中间体在本合成路线中的序号：(XXVI)The intermediate (XXXIII) has been obtained as follows: The silylation of the OH group of (2S,3R,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (XVII) with Tbdms-OTf gives the bis-silyl ether (XVIII), which is ozonolyzed with O3 to yield the aldehyde (XIX). The condensation of (XIX) with the phosphonate (XX) by means of KHMDS affords the methyl heptenoate (XXI), which is reduced with LiAlH4 to the carbinol (XXII). The esterification of (XXII) with pivaloyl chloride and pyridine affords the pivaloyl ester (XXIII), which is selectively desilylated with HF and pyridine to provide the primary alcohol (XXIV). The Swern oxidation of (XXIV) gives the aldehyde (XXV), which is condensed with the phosphonate (XXVI) to yield the terminal acetylene derivative (XXVII). Iodination of (XXVII) with I2 and morpholine affords the iodoacetylene (XXVIII), which is condensed with the already reported acetaldehyde intermediate (XVI) by means of NiCl2/CuCl2 to provide the acetylenic alcohol (XXIX). The reduction of the triple bond of (XXIX) with H2 over Pd/C gives the corresponding allyl alcohol derivative (XXX), which is silylated with Tbdms-OTf to the trisilylated compound (XXXI). Elimination of the pivaloyl protecting group of (XXXI) by means of DIBAL yields the primary alcohol (XXXII), which is treated first with MsCl and TEA and then with LiBr to furnish the target bromoderivative intermediate (XXXIII).
| 【1】 Hung, D.T.; et al.; Syntheses of discodermolides useful for investigating microtubule binding and stabilization. J Am Chem Soc 1996, 118, 45, 11054. |
| 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) | 42700 | 2-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]acetaldehyde | C21H34O3SSi | 详情 | 详情 | |
| (XVII) | 42701 | (2S,3R,4S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexen-3-ol | C14H30O2Si | 详情 | 详情 | |
| (XVIII) | 42381 | (5S,6R)-2,2,3,3,6,9,9,10,10-nonamethyl-5-[(1R)-1-methyl-2-propenyl]-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexenyl ether | C20H44O2Si2 | 详情 | 详情 | |
| (XIX) | 42702 | (2R,3S,4S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylpentanal | C19H42O3Si2 | 详情 | 详情 | |
| (XX) | 42703 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate | C8H11F6O5P | 详情 | 详情 | |
| (XXI) | 42704 | methyl (Z,4S,5R,6S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-2-heptenoate | C23H48O4Si2 | 详情 | 详情 | |
| (XXII) | 42705 | (Z,4S,5R,6S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-2-hepten-1-ol | C22H48O3Si2 | 详情 | 详情 | |
| (XXIII) | 42706 | (Z,4S,5R,6S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-2-heptenyl pivalate | C27H56O4Si2 | 详情 | 详情 | |
| (XXIV) | 42707 | (Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,6-trimethyl-2-heptenyl pivalate | C21H42O4Si | 详情 | 详情 | |
| (XXV) | 42708 | (Z,4S,5R,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-7-oxo-2-heptenyl pivalate | C21H40O4Si | 详情 | 详情 | |
| (XXVI) | 42709 | Diazomethylphoshonic acid dimethyl ester | 27491-70-9 | C3H7N2O3P | 详情 | 详情 |
| (XXVII) | 42710 | (Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-2-octen-7-ynyl pivalate | C22H40O3Si | 详情 | 详情 | |
| (XXVIII) | 42711 | (Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-8-iodo-2,4,6-trimethyl-2-octen-7-ynyl pivalate | C22H39IO3Si | 详情 | 详情 | |
| (XXIX) | 42712 | (Z,4S,5R,6S,9S)-5-[[tert-butyl(dimethyl)silyl]oxy]-10-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-9-hydroxy-2,4,6-trimethyl-2-decen-7-ynyl 2,2-dimethylpropanoate | C43H74O6SSi2 | 详情 | 详情 | |
| (XXX) | 42713 | (2Z,4S,5S,6S,7Z,9S)-5-[[tert-butyl(dimethyl)silyl]oxy]-10-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-9-hydroxy-2,4,6-trimethyl-2,7-decadienyl 2,2-dimethylpropanoate | C43H76O6SSi2 | 详情 | 详情 | |
| (XXXI) | 42714 | (2Z,4S,5S,6S,7Z,9S)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-10-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-2,4,6-trimethyl-2,7-decadienyl 2,2-dimethylpropanoate | n/a | C49H90O6SSi3 | 详情 | 详情 |
| (XXXII) | 42715 | (2Z,4S,5S,6S,7Z,9S)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-10-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-2,4,6-trimethyl-2,7-decadien-1-ol | n/a | C44H82O5SSi3 | 详情 | 详情 |
| (XXXIII) | 42716 | (5S,6Z,8S,9S)-9-[(1S,2Z)-4-bromo-1,3-dimethyl-2-butenyl]-5-[[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]methyl]-2,2,3,3,8,11,11,12,12-nonamethyl-4,10-dioxa-3,11-disila-6-tridecene; (2S,3S,4S,5R,6S)-2-((2S,3Z,5S,6S,7S,8Z)-10-bromo-2,6-bis[[tert-butyl(dimethyl)silyl]oxy]-5,7,9-trimethyl-3,8-decadienyl)-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-4-yl tert-butyl(dimethyl)silyl ether | n/a | C44H81BrO4SSi3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X). Selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the precursor (XI), which is finally epoxidated with dimethyldioxirane (XII) in dichloromethane to furnish the target epothilone B.
| 【1】 White, J.D.; et al.; Improved synthesis of epothilone B employing alkylation of an alkyne for assembly of subunits. Org Lett 1999, 1, 9, 1431. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 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) | 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 | |
| (II) | 42709 | Diazomethylphoshonic acid dimethyl ester | 27491-70-9 | C3H7N2O3P | 详情 | 详情 |
| (III) | 46161 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-9-decynoate | C27H52O5Si2 | 详情 | 详情 | |
| (IV) | 46147 | 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether | C19H32BrNOSSi | 详情 | 详情 | |
| (V) | 46162 | methyl (3S,6R,7S,8S,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-12,16-heptadecadien-9-ynoate | C46H83NO6SSi3 | 详情 | 详情 | |
| (VI) | 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 | |
| (VII) | 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 | |
| (VIII) | 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 | |
| (IX) | 46159 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione | C39H67NO5SSi2 | 详情 | 详情 | |
| (X) | 46160 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione | C27H39NO5S | 详情 | 详情 | |
| (XI) | 40837 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C27H41NO5S | 详情 | 详情 | |
| (XII) | 31501 | 3,3-dimethyl-1,2-dioxirane | C3H6O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X) (1). Finally, the selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the target epothilone D.
| 【1】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 【2】 White, J.D.; et al.; Improved synthesis of epothilone B employing alkylation of an alkyne for assembly of subunits. Org Lett 1999, 1, 9, 1431. |
| 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) | 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 | |
| (II) | 42709 | Diazomethylphoshonic acid dimethyl ester | 27491-70-9 | C3H7N2O3P | 详情 | 详情 |
| (III) | 46161 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-9-decynoate | C27H52O5Si2 | 详情 | 详情 | |
| (IV) | 46147 | 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether | C19H32BrNOSSi | 详情 | 详情 | |
| (V) | 46162 | methyl (3S,6R,7S,8S,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-12,16-heptadecadien-9-ynoate | C46H83NO6SSi3 | 详情 | 详情 | |
| (VI) | 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 | |
| (VII) | 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 | |
| (VIII) | 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 | |
| (IX) | 46159 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione | C39H67NO5SSi2 | 详情 | 详情 | |
| (X) | 46160 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione | C27H39NO5S | 详情 | 详情 |