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【结 构 式】 
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【分子编号】42622 【品名】2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate 【CA登记号】 |
【 分 子 式 】C34H52O5Si 【 分 子 量 】568.86938 【元素组成】C 71.79% H 9.21% O 14.06% Si 4.94% |
合成路线1
该中间体在本合成路线中的序号：(XI)The intermediate (XI) has been obtained as follows: The condensation of the chiral ketone (I) with unsaturated aldehyde (II) by means of chlorodicyclohexylborane (DCHBCl) gives the chiral heptenone (III), which is esterified with propanal and SmI3, yielding the ester (IV). The ketalization of (IV) with 2-(phenylselanyl)acetaldehyde diethyl acetal (V) by means of pyridinium p-toluenesulfonate (PPTS) affords the cyclic ketal (VI), which is oxidized with NaIO4 and condensed with the silylated enol ether (VII), providing the lactone (VIII). Methanolysis of the lactone (VII) with MeONa and silylation of the hydroxyester gives methyl ester (IX), which is hydrolyzed with KOH and reesterified with 2,6-dimethylphenol (X) and DCC, yielding the desired intermediate, the aryl ester (XI).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 42614 | (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone | C14H20O3 | 详情 | 详情 | |
| (II) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (III) | 42615 | (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one | C18H26O4 | 详情 | 详情 | |
| (IV) | 42616 | (1R)-1-[(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl]-2-methyl-2-propenyl propionate | C21H32O5 | 详情 | 详情 | |
| (V) | 42617 | 1-[(2,2-diethoxyethyl)selanyl]benzene; 1-ethoxy-2-(phenylselanyl)ethyl ethyl ether | C12H18O2Se | 详情 | 详情 | |
| (VI) | 42618 | (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether | C26H34O4Se | 详情 | 详情 | |
| (VII) | 42619 | tert-butyl[(1-methoxyvinyl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl 1-methoxyvinyl ether | C9H20O2Si | 详情 | 详情 | |
| (VIII) | 42620 | (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one | C20H28O4 | 详情 | 详情 | |
| (IX) | 42621 | methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C27H46O5Si | 详情 | 详情 | |
| (X) | 37388 | 2,6-dimethylphenol | 576-26-1 | C8H10O | 详情 | 详情 |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XI)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：(XXXVIII)Synthesis of the target (+)-Discodermolide: The reaction of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with p-methoxybenzyl trichloroacetimidate gives the benzyl ether (XXVI), which is condensed with ethylmagnesium bromide in THF to yield the chiral ketone (XXVII). The reaction of (XXVII) with 2-methylpropenal (XXVIII) by means of (c-Hex)2B-Cl and TEA in ethyl ether affords the chiral hydroxyketone (XXIX), which is reduced with SmI2 and propanal to provide the beta-diol monoester (XXX). The methanolysis of (XXX) by means of K2CO3 furnishes the diol (XXXI), which can also be obtained directly by reduction of (XXIX) with Me4NBH(OAc)3 in acetonitrile/AcOH. The reaction of (XXXI) with the diethylacetal (XXXII) and PPTS in refluxing toluene gives the phenylselenoacetal (XXXIII), which is oxidized with NaIO4 and treated with DBU to achieve a Claisen rearrangement and yield the eight member lactone (XXXIV). The hydrolysis of (XXXIV) with KOH in refluxing aqueous methanol affords the hydroxyacid (XXXV), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP in dichloromethane to provide the phenyl ester (XXXVII). The reaction of (XXXVII) with Tbdms-OTf and lutidine gives the silylated ester (XXXVIII). Alternatively, the methanolysis of the lactone (XXXIV) with NaOMe in methanol gives the hydroxyester (XXXIX), which is treated with Tbdms-OTf as before to yield the silylated ester (XL). The hydrolysis of the ester (XL) with KOH in refluxing aqueous methanol affords the silylated hydroxyacid (XLI), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP to provide the already reported phenyl ester (XXXVIII).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (XXVI) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (XXVII) | 42614 | (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone | C14H20O3 | 详情 | 详情 | |
| (XXVIII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (XXIX) | 42615 | (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one | C18H26O4 | 详情 | 详情 | |
| (XXX) | 62842 | (1R)-1-{(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl}-2-methyl-2-propenyl butyrate | C22H34O5 | 详情 | 详情 | |
| (XXXI) | 62843 | (3R,4R,5S,6S)-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-1-heptene-3,5-diol | C18H28O4 | 详情 | 详情 | |
| (XXXII) | 62844 | 1-[(2,2-dipropoxyethyl)selanyl]benzene; 2-(phenylselanyl)-1-propoxyethyl propyl ether | C14H22O2Se | 详情 | 详情 | |
| (XXXIII) | 42618 | (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether | C26H34O4Se | 详情 | 详情 | |
| (XXXIV) | 42620 | (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one | C20H28O4 | 详情 | 详情 | |
| (XXXV) | 62845 | (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid | C20H30O5 | 详情 | 详情 | |
| (XXXVI) | 37388 | 2,6-dimethylphenol | 576-26-1 | C8H10O | 详情 | 详情 |
| (XXXVII) | 62847 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C28H38O5 | 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 | |
| (XXXIX) | 62846 | methyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C21H32O5 | 详情 | 详情 | |
| (XL) | 42621 | methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C27H46O5Si | 详情 | 详情 | |
| (XLI) | 62848 | (Z,6S,7R,8S)-7-{[tert-butyl(dimethyl)silyl]oxy}-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid | C26H44O5Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXVIII)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 |