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【结 构 式】 
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【分子编号】42703 【品名】methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate 【CA登记号】 |
【 分 子 式 】C8H11F6O5P 【 分 子 量 】332.1365212 【元素组成】C 28.93% H 3.34% F 34.32% O 24.09% P 9.33% |
合成路线1
该中间体在本合成路线中的序号：(XX)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：(X)The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (Via) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi. The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).
| 【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 40817 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol | C11H24O3Si | 详情 | 详情 | |
| (VIb) | 40818 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone | C11H24O3Si | 详情 | 详情 | |
| (I) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 39221 | 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid | 73991-95-4 | C7H10O5 | 详情 | 详情 |
| (IV) | 40815 | (3S)-3-hydroxydihydro-2(3H)-furanone | 19444-84-9 | C4H6O3 | 详情 | 详情 |
| (V) | 40816 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone | C10H20O3Si | 详情 | 详情 | |
| (VII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (VIII) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (IX) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (X) | 42703 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate | C8H11F6O5P | 详情 | 详情 | |
| (XI) | 46134 | propyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate | C22H37NO3SSi | 详情 | 详情 | |
| (XII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIII) | 46136 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-iodo-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-5-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether | C19H32INOSSi | 详情 | 详情 | |
| (XIV) | 40825 | tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone | C17H30O3SSi | 详情 | 详情 | |
| (XV) | 46135 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-propanol | C10H24O2Si | 详情 | 详情 | |
| (XVI) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XVII) | 40827 | tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole | C30H57NO2SSi2 | 详情 | 详情 | |
| (XVIII) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XIX) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (VIa) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi . The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).
| 【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 40817 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol | C11H24O3Si | 详情 | 详情 | |
| (VIb) | 40818 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone | C11H24O3Si | 详情 | 详情 | |
| (I) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 39221 | 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid | 73991-95-4 | C7H10O5 | 详情 | 详情 |
| (IV) | 40815 | (3S)-3-hydroxydihydro-2(3H)-furanone | 19444-84-9 | C4H6O3 | 详情 | 详情 |
| (V) | 40816 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone | C10H20O3Si | 详情 | 详情 | |
| (VII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (VIII) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (IX) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (X) | 42703 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate | C8H11F6O5P | 详情 | 详情 | |
| (XI) | 46134 | propyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate | C22H37NO3SSi | 详情 | 详情 | |
| (XII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIII) | 46136 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-iodo-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-5-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether | C19H32INOSSi | 详情 | 详情 | |
| (XIV) | 40825 | tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone | C17H30O3SSi | 详情 | 详情 | |
| (XV) | 46135 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-propanol | C10H24O2Si | 详情 | 详情 | |
| (XVI) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XVII) | 40827 | tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole | C30H57NO2SSi2 | 详情 | 详情 | |
| (XVIII) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XIX) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 |