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【结 构 式】 
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【分子编号】42632 【品名】(2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal 【CA登记号】 |
【 分 子 式 】C18H24O3 【 分 子 量 】288.38676 【元素组成】C 74.97% H 8.39% O 16.64% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The intermediate (XXI) has been obtained as follows: The condensation of the chiral benzylated hydroxypentanone (XII) with the chiral aldehyde (XIII) by means of DCHBCl gives the chiral hydroxyheptanone (XIV), which is protected at the OH group with p-methoxybenzyl trichloroacetimidate (Pmb-Tca), yielding the expected benzyl ether (XV). The reduction of the CO group of (XV) by means of LiAlH4, with simultaneous debenzylation affords the alpha-diol (XVI), which is oxidized with NaIO4 to provide the aldehyde (XVII). The condensation of (XVII) with the allyl compound (XVIII) by means of CrCl2 and KH in THF gives the octadiene compound (XIX), which is desilylated with camphorsulfonic acid (CSA) to yield the unsaturated alcohol (XX). Finally, this alcohol is oxidized with DMP to the desired intermediate aldehyde (XXI).
| 【1】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935. |
| 【2】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 42623 | (1S)-1-methyl-2-oxobutyl benzoate | C12H14O3 | 详情 | 详情 | |
| (XIII) | 42624 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropanal | C10H22O2Si | 详情 | 详情 | |
| (XIV) | 42625 | (1S,3R,4R,5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-1,3,5-trimethyl-2-oxohexyl benzoate | C22H36O5Si | 详情 | 详情 | |
| (XV) | 42626 | (1S,3R,4R,5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-1,3,5-trimethyl-2-oxohexyl benzoate | C30H44O6Si | 详情 | 详情 | |
| (XVI) | 42627 | (2S,4S,5R,6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-2,3-heptanediol | C23H42O5Si | 详情 | 详情 | |
| (XVII) | 42628 | (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal | C21H36O4Si | 详情 | 详情 | |
| (XVIII) | 42629 | (1-bromo-2-propenyl)(trimethyl)silane | 94397-40-7 | C6H13BrSi | 详情 | 详情 |
| (XIX) | 42630 | tert-butyl([(2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl ether | C24H40O3Si | 详情 | 详情 | |
| (XX) | 42631 | (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadien-1-ol | C18H26O3 | 详情 | 详情 | |
| (XXI) | 42632 | (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal | C18H24O3 | 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 target compound has been obtained as follows: The condensation of ester intermediate (XI) with aldehyde intermediate (XXI) by means of lithium 2,2,6,6-tetramethylpiperidide (Li-TMP) gives the addition compound (XXXI), which is reduced at the ester group with LiAlH4, yielding the carbinol (XXXII). The reduction of this carbinol by sulfonation with mesitylenesulfonyl chloride, followed by reduction with LiAlH4, affords the corresponding methyl derivative (XXXIII), which is silylated at the secondary OH group with TBDMS-Otf, providing the fully protected compound (XXXIV). Elimination of the Pmb protecting groups of (XXXIV) with DDQ yields the diol (XXXV), which is selectively oxidized at the primary OH group to the corresponding aldehyde (XXXVI) by means of TEMPO. The Wittig condensation of (XXXVI) with phosphonate (XXXVII) by means of K2CO3 and 18-C-6 affords the octadecatetraenoic ester (XXXVIII), which is treated with trichloroacetyl isocyanate and K2CO3 to provide the carbamate (XXXIX). The reduction of the ester group of (XXXIX) by means of DIBAL gives the primary alcohol (XL), which is finally oxidized with DMP to the expected intermediate aldehyde (XLI).
| 【1】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377. |
| 【2】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 42622 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C34H52O5Si | 详情 | 详情 | |
| (XXI) | 42632 | (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal | C18H24O3 | 详情 | 详情 | |
| (XXXI) | 42641 | 2,6-dimethylphenyl (2S,3S,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienoate | C52H76O8Si | 详情 | 详情 | |
| (XXXII) | 42642 | (2R,3R,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadiene-1,3-diol | C44H70O7Si | 详情 | 详情 | |
| (XXXIII) | 42643 | (3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-14-[[tert-butyl(dimethyl)silyl]oxy]-6,16-bis[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-1,3,11-hexadecatrien-8-ol | C44H70O6Si | 详情 | 详情 | |
| (XXXIV) | 42644 | (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S,4Z)-2-[(4-methoxybenzyl)oxy]-1,3-dimethyl-4,6-heptadienyl]-5-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disila-7-pentadecene; (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl 4-methoxybenzyl ether | n/a | C50H84O6Si2 | 详情 | 详情 |
| (XXXV) | 42645 | (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol | n/a | C34H68O4Si2 | 详情 | 详情 |
| (XXXVI) | 42646 | (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal | n/a | C34H66O4Si2 | 详情 | 详情 |
| (XXXVII) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (XXXVIII) | 42647 | methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate | n/a | C37H70O5Si2 | 详情 | 详情 |
| (XXXIX) | 42648 | methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate | n/a | C38H71NO6Si2 | 详情 | 详情 |
| (XL) | 42649 | (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-tridecadienyl carbamate | C37H71NO5Si2 | 详情 | 详情 | |
| (XLI) | 42650 | (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tridecadienyl carbamate | C37H69NO5Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XLI)The intermediate (XLIII) has been obtained in two related ways: 1) The protection of (2S,3S,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (I) with p-methoxybenzyl bromide and NaH gives the benzyl ether (XXXIV) which is ozonolyzed with O3, yielding the aldehyde (XXXV), which is condensed with the phosphonium salt (XXXVI) by means of KHMDS to afford the iodovinyl derivative (XXXVII). The homologation of (XXXVII) with vinylzinc bromide (XXXVIII) provides the octadiene derivative (XXXIX), which is desilylated with TFA, furnishing the primary alcohol (XL). The oxidation of (XL) with DMP gives the aldehyde (XLI), which is treated with CH3-MgBr, yielding the secondary alcohol (XLII). Finally, this alcohol is oxidized with DMP to the target intermediate ketone (XLIII). 2) The protection of (2S,3R,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (XVII) with p-methoxybenzyl bromide and NaH gives the benzyl ether (XLIV), which is ozonolyzed with O3, yielding the aldehyde (XLV). The reaction of (XLV) with CH3-MgBr affords the secondary alcohol (XLVI), which is desilylated with TFA.
| 【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) | 42608 | [(1R,3S,4S)-4-aminospiro[2.2]pent-1-yl]methanol | C6H11NO | 详情 | 详情 | |
| (XXXIV) | 42717 | tert-butyl([(2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl ether | n/a | C22H38O3Si | 详情 | 详情 |
| (XXXV) | 42628 | (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal | C21H36O4Si | 详情 | 详情 | |
| (XXXVI) | 42718 | (iodomethyl)(triphenyl)phosphonium iodide | n/a | C19H17I2P | 详情 | 详情 |
| (XXXVII) | 42719 | tert-butyl([(2S,3S,4S,5Z)-6-iodo-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S,5Z)-6-iodo-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl ether | n/a | C22H37IO3Si | 详情 | 详情 |
| (XXXVIII) | 42720 | bromo(vinyl)zinc | n/a | C2H3BrZn | 详情 | 详情 |
| (XXXIX) | 42630 | tert-butyl([(2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl ether | C24H40O3Si | 详情 | 详情 | |
| (XL) | 42631 | (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadien-1-ol | C18H26O3 | 详情 | 详情 | |
| (XLI) | 42632 | (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal | C18H24O3 | 详情 | 详情 | |
| (XLII) | 42721 | (3S,4S,5S,6Z)-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-6,8-nonadien-2-ol | C19H28O3 | 详情 | 详情 | |
| (XLIII) | 42722 | (3R,4S,5S,6Z)-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-6,8-nonadien-2-one | C19H26O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXV)Chiral octadienoic aldehyde intermediate (XXV): The reaction of the silylated allyl bromide (XX) with CrCl2 in THF gives the Cr derivative (XXI), which is condensed with the chiral pentanoic aldehyde intermediate (XIX) to yield the secondary alcohol (XXII). Elimination of the Tms group of (XXII) by means of KH in THF affords the desired (Z)-diene (XXIII), which is desilylated by means of CSA in methanol/dichloromethane to provide the primary alcohol (XXIV). Finally this compound is oxidized by means of DMP in dichloromethane to furnish the target, chiral octadienoic aldehyde intermediate (XXV).
| 【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 42628 | (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal | C21H36O4Si | 详情 | 详情 | |
| (XX) | 42629 | (1-bromo-2-propenyl)(trimethyl)silane | 94397-40-7 | C6H13BrSi | 详情 | 详情 |
| (XXI) | 62840 | chloro[(E)-3-(trimethylsilyl)-2-propenyl]chromium | C6H13ClCrSi | 详情 | 详情 | |
| (XXII) | 62841 | (3R,4S,5S,6R,7S)-8-{[tert-butyl(dimethyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-5,7-dimethyl-3-(trimethylsilyl)-1-octen-4-ol | C27H50O4Si2 | 详情 | 详情 | |
| (XXIII) | 46630 | 2,4,4-trimethyl-5,6-dihydro-4H-1,3-oxazine | C7H13NO | 详情 | 详情 | |
| (XXIV) | 42631 | (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadien-1-ol | C18H26O3 | 详情 | 详情 | |
| (XXV) | 42632 | (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal | C18H24O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXV)The reaction of (XXXVIII) with Li-TMP and LiBr in THF gives the lithium enolate (XLII), which is condensed with the chiral octadienoic aldehyde intermediate (XXV) in THF to yield the aldol adduct (XLIII). The reduction of the phenyl ester group of (XLIII) by means of LiAlH4 in THF affords the diol (XLIV), which is submitted to a regioselective esterification with mesitylenesulfonyl chloride (XLV) to provide the sulfonate (XLVI). The deoxygenation of (XLVI) by means of LiAlH4 gives the desired alcohol (XLVII), which is protected with Tbdms-OTf and TEA to yield the fully protected compound (XLVIII). The selective deprotection of (XLVIII) by means of DDQ in dichloromethane affords the diol (XLIX), which is selectively oxidated at the primary OH group with TEMPO and PhI(OAc)2 to provide the aldehyde (L). The condensation of (L) with phosphonate (LI) by means of K2CO3 and 18-C-6 in toluene furnishes the chiral octadecatetraenoic ester (LII).
| 【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 42632 | (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal | C18H24O3 | 详情 | 详情 | |
| (XXXVIII) | 42622 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C34H52O5Si | 详情 | 详情 | |
| (XLII) | 62849 | C34H51LiO5Si | 详情 | 详情 | ||
| (XLIII) | 42641 | 2,6-dimethylphenyl (2S,3S,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienoate | C52H76O8Si | 详情 | 详情 | |
| (XLIV) | 42642 | (2R,3R,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadiene-1,3-diol | C44H70O7Si | 详情 | 详情 | |
| (XLV) | 41158 | 2,4,6-trimethylbenzenesulfonyl chloride | 773-64-8 | C9H11ClO2S | 详情 | 详情 |
| (XLVI) | 62850 | (2R,3R,4S,5S,6S,7Z)-2-{(Z,4S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl}-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienyl 2,4,6-trimethylbenzenesulfonate | C53H80O9SSi | 详情 | 详情 | |
| (XLVII) | 42643 | (3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-14-[[tert-butyl(dimethyl)silyl]oxy]-6,16-bis[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-1,3,11-hexadecatrien-8-ol | C44H70O6Si | 详情 | 详情 | |
| (XLVIII) | 42644 | (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S,4Z)-2-[(4-methoxybenzyl)oxy]-1,3-dimethyl-4,6-heptadienyl]-5-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disila-7-pentadecene; (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl 4-methoxybenzyl ether | n/a | C50H84O6Si2 | 详情 | 详情 |
| (XLIX) | 42645 | (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol | n/a | C34H68O4Si2 | 详情 | 详情 |
| (L) | 42646 | (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal | n/a | C34H66O4Si2 | 详情 | 详情 |
| (LI) | 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 |
| (LII) | 42647 | methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate | n/a | C37H70O5Si2 | 详情 | 详情 |