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【结 构 式】 
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【分子编号】42700 【品名】2-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]acetaldehyde 【CA登记号】 |
【 分 子 式 】C21H34O3SSi 【 分 子 量 】394.65066 【元素组成】C 63.91% H 8.68% O 12.16% S 8.13% Si 7.12% |
合成路线1
该中间体在本合成路线中的序号：(XVI)The intermediate (XVI) has been obtained as follows: The ozonolysis of (2S,3S,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (I) with O3 in DMSO gives the aldehyde (II), which is condensed with phosphorane (III) to yield the chiral heptenoic acid methyl ester (IV). The reaction of (IV) with benzaldehyde (V) by means of KHMDS affords the cyclic ketal (VI), which is desilylated with HF to provide the carbinol (VII). The oxidation of (VII) in methanol gives the dimethylacetal (VIII), which is treated with CSA in methanol to yield the tetrahydropyranylacetic acid methyl ester (IX). The silylation of the OH group of (IX) with Tbdms-OTf affords the silyl ether (X), which is hydrolyzed with LiOH to the corresponding free acetic acid (XI). The condensation of (XI) with N,O-dimethylhydroxylamine (XII) by means of DCC and HOBT provides the methoxyamide (XIII), which is treated with phenylsulfanyltrimethylsilane (XIV), ZnI2 and tetrabutylammonium iodide to give the phenylsulfanyl derivative (XV). Finally, the methoxyamide group of (XV) is reduced with LiAlH4 to afford the target acetaldehyde derivative (XVI).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 42688 | (2S,3S,4S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexen-3-ol | C14H30O2Si | 详情 | 详情 | |
| (II) | 42689 | (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,4-dimethylpentanal | C13H28O3Si | 详情 | 详情 | |
| (III) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (IV) | 42690 | methyl (E,4S,5S,6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,6-dimethyl-2-heptenoate | C16H32O4Si | 详情 | 详情 | |
| (V) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VI) | 42691 | methyl 2-[(4S,5R,6R)-6-((1S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylethyl)-5-methyl-2-phenyl-1,3-dioxan-4-yl]acetate | C23H38O5Si | 详情 | 详情 | |
| (VII) | 42692 | methyl 2-[(4S,5R,6R)-6-[(1S)-2-hydroxy-1-methylethyl]-5-methyl-2-phenyl-1,3-dioxan-4-yl]acetate | C17H24O5 | 详情 | 详情 | |
| (VIII) | 42693 | methyl 2-[(4S,5R,6S)-6-[(1R)-2,2-dimethoxy-1-methylethyl]-5-methyl-2-phenyl-1,3-dioxan-4-yl]acetate | C19H28O6 | 详情 | 详情 | |
| (IX) | 42694 | methyl 2-[(2S,3R,4S,5R)-4-hydroxy-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl]acetate | C11H20O5 | 详情 | 详情 | |
| (X) | 42695 | methyl 2-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl)acetate | C17H34O5Si | 详情 | 详情 | |
| (XI) | 42696 | 2-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl)acetic acid | C16H32O5Si | 详情 | 详情 | |
| (XII) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (XIII) | 42697 | 2-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl)-N-methoxy-N-methylacetamide | C18H37NO5Si | 详情 | 详情 | |
| (XIV) | 42698 | trimethyl(phenylsulfanyl)silane; phenyl trimethylsilyl sulfide | 4551-15-9 | C9H14SSi | 详情 | 详情 |
| (XV) | 42699 | 2-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-N-methoxy-N-methylacetamide | C23H39NO4SSi | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XVI)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 |