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【结 构 式】 
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【分子编号】57935 【品名】(2S,4S)-2,4-pentanediol 【CA登记号】 |
【 分 子 式 】C5H12O2 【 分 子 量 】104.14908 【元素组成】C 57.66% H 11.61% O 30.72% |
合成路线1
该中间体在本合成路线中的序号：(XXXIII)The synthesis of the phosphonate intermediate (XXXVII) has been performed as follows: The reaction of the 2-hexynoic ester (XVIII) with Tbdps-Cl gives the silyl ether (XIX), which is reduced with DIBAL to yield the propargyl alcohol (XX). The protection of (XX) by reaction with dihydropyran affords the tetrahydropyranyl ether (XXI), which is selectively deprotected by means of DDQ to provide the acetylenic alcohol (XXII). The oxidation of (XXII) by means of SO3/pyridine, and NaClO2, followed by methylation with diazomethane gives the acetylenic ester (XXIII), which is condensed with phosphonate (XXIV) by means of BuLi to yield the chiral phosphonate (XXV). The condensation of (XXV) with 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XXVI) affords the ketonic adduct (XXVII), which is reduced with NaBH4 and CeCl3 to provide the secondary alcohol (XXVIII). The reaction of (XXVIII) with Mom-Cl gives the corresponding Mom-ether (XXIX), whose tetrahydropyranyl group is hydrolyzed by means of HCl to yield the primary alcohol (XXX). The selective monoreduction of the acetylenic triple bond of (XXX) by means of Red-Al affords the octadienyl alcohol (XXXI), which is oxidized with DMP to the expected aldehyde (XXXII). The reaction of (XXXII) with (R,R)-pentane-2,4-diol (XXXIII) affords the propylene ketal (XXXIV), which is desilylated by means of TBAF to provide the secondary alcohol (XXXV). The condensation of (XXXV) with the phosphonoacetic acid (XXXVI) furnishes the corresponding ester (XXXVII).
| 【1】 Ahmed, A.; Hoegenauer, E.K.; Enev, V.S.; Hanbauer, M.; Kaehlig, H.; Ohler, E.; Mulzer, J.; Total synthesis of the microtubule stabilizing antitumor agent laulimalide and some nonnatural analogues: The power of Sharpless' asymmetric epoxidation. J. Org. Chem. 2003, 68, 8, 3026. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 61141 | propyl (5S)-5-hydroxy-6-[(4-methoxybenzyl)oxy]-2-hexynoate | C17H22O5 | 详情 | 详情 | |
| (XIX) | 61142 | propyl (5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-2-hexynoate | C33H40O5Si | 详情 | 详情 | |
| (XX) | 61143 | (5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-2-hexyn-1-ol | C30H36O4Si | 详情 | 详情 | |
| (XXI) | 61144 | tert-butyl{[(1S)-1-{[(4-methoxybenzyl)oxy]methyl}-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentynyl]oxy}diphenylsilane; tert-butyl(diphenyl)silyl (1S)-1-{[(4-methoxybenzyl)oxy]methyl}-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentynyl ether | C35H44O5Si | 详情 | 详情 | |
| (XXII) | 61145 | (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexyn-1-ol | C27H36O4Si | 详情 | 详情 | |
| (XXIII) | 61146 | methyl (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexynoate | C28H36O5Si | 详情 | 详情 | |
| (XXIV) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (XXV) | 61147 | dimethyl (3S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-oxo-7-(tetrahydro-2H-pyran-2-yloxy)-5-heptynylphosphonate | C30H41O7PSi | 详情 | 详情 | |
| (XXVI) | 61148 | (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde | C7H10O2 | 详情 | 详情 | |
| (XXVII) | 61149 | (E,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-8-(tetrahydro-2H-pyran-2-yloxy)-1-octen-6-yn-3-one | C35H44O5Si | 详情 | 详情 | |
| (XXVIII) | 61150 | (E,3S,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-8-(tetrahydro-2H-pyran-2-yloxy)-1-octen-6-yn-3-ol | C35H46O5Si | 详情 | 详情 | |
| (XXIX) | 61151 | (5S,6S)-9,9-dimethyl-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-8,8-diphenyl-6-[4-(tetrahydro-2H-pyran-2-yloxy)-2-butynyl]-2,4,7-trioxa-8-siladecane; tert-butyl(diphenyl)silyl (1S)-1-{(1S,2E)-1-(methoxymethoxy)-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentynyl ether | C37H50O6Si | 详情 | 详情 | |
| (XXX) | 61152 | (5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-7-octen-2-yn-1-ol | C32H42O5Si | 详情 | 详情 | |
| (XXXI) | 61153 | (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadien-1-ol | C32H44O5Si | 详情 | 详情 | |
| (XXXII) | 61154 | (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal | C32H42O5Si | 详情 | 详情 | |
| (XXXIII) | 57935 | (2S,4S)-2,4-pentanediol | C5H12O2 | 详情 | 详情 | |
| (XXXIV) | 61155 | tert-butyl(diphenyl)silyl (1S,2S,3E)-1-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-3-butenyl ether; (5S,6S)-6-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-9,9-dimethyl-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-8,8-diphenyl-2,4,7-trioxa-8-siladecane | C37H52O6Si | 详情 | 详情 | |
| (XXXV) | 61156 | (1E,3S,4S,6E)-7-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-3-(methoxymethoxy)-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6-heptadien-4-ol | C21H34O6 | 详情 | 详情 | |
| (XXXVI) | 61157 | 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetic acid | C6H7F6O5P | 详情 | 详情 | |
| (XXXVII) | 61158 | (1S,2S,3E)-1-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-3-butenyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | C27H39F6O10P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The synthesis of the 1,3-dioxane intermediate (XIII) has been performed as follows: The reaction of 2(S)-hydroxycyclopentanone (I) with Tbdps-Cl and imidazole in DMF gives the silyl ether (II), which is condensed with the phosphonate (III) by means of BuLi in THF to yield the new phosphonate (IV) after silylation with Tes-Cl and LDA. The Horner-Wadsworth-Emmons olefination of carbaldehyde (V) with phosphonate (IV) by means of LiCl and TEA in THF affords the silylated ketone (VI), which is reduced with NaBH4/CeCl3 and protected with Mom-Cl and DIEA to provide the dihydropyran derivative (VII). The cleavage of the Tes protecting group by means of TsOH, followed by oxidation of the resulting alcohol with SO3/pyridine in DMSO/dichloromethane gives the aldehyde (VIII). A new olefination reaction of aldehyde (VIII) with phosphorane (IX) by means of NaH in THF yields the methoxyamide (X), which is reduced with DIBAL in THF to afford the unsaturated aldehyde (XI). Finally, this aldehyde is treated with (2R,4R)-pentanediol (XII) and montmorillonite K-10 in hot toluene to provide the target 1,3-dioxane intermediate (XIII).
| 【1】 Mulzer, J.; Hanbauer, M.; Total synthesis of the antitumor agent (-)-laulimalide. Tetrahedron Lett 2002, 43, 18, 3381. |
| 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) | 61198 | (2S)-2-hydroxycyclopentanone | C5H8O2 | 详情 | 详情 | |
| (II) | 61199 | (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}cyclopentanone | C21H26O2Si | 详情 | 详情 | |
| (III) | 61200 | dipropyl methylphosphonate | C7H17O3P | 详情 | 详情 | |
| (IV) | 61201 | dipropyl (3S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-oxo-5-[(triethylsilyl)oxy]pentylphosphonate | C33H55O6PSi2 | 详情 | 详情 | |
| (V) | 61148 | (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde | C7H10O2 | 详情 | 详情 | |
| (VI) | 61202 | (E,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-[(triethylsilyl)oxy]-1-hexen-3-one | C34H50O4Si2 | 详情 | 详情 | |
| (VII) | 61203 | (5S,6S)-6-{[tert-butyl(diphenyl)silyl]oxy}-10,10-diethyl-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-2,4,9-trioxa-10-siladodecane; tert-butyl(diphenyl)silyl (1S,2S,3E)-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1-{2-[(triethylsilyl)oxy]ethyl}-3-butenyl ether | C36H56O5Si2 | 详情 | 详情 | |
| (VIII) | 61204 | (3S,4S,5E)-3-{[tert-butyl(diphenyl)silyl]oxy}-4-(methoxymethoxy)-6-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-5-hexenal | C30H40O5Si | 详情 | 详情 | |
| (IX) | 61205 | dipropyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate | C10H22NO5P | 详情 | 详情 | |
| (X) | 61206 | (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-N-methoxy-6-(methoxymethoxy)-N-methyl-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienamide | C34H47NO6Si | 详情 | 详情 | |
| (XI) | 61154 | (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal | C32H42O5Si | 详情 | 详情 | |
| (XII) | 57935 | (2S,4S)-2,4-pentanediol | C5H12O2 | 详情 | 详情 | |
| (XIII) | 61155 | tert-butyl(diphenyl)silyl (1S,2S,3E)-1-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-3-butenyl ether; (5S,6S)-6-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-9,9-dimethyl-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-8,8-diphenyl-2,4,7-trioxa-8-siladecane | C37H52O6Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Aldehyde (II), prepared by ozonolysis of cyclohexene (I), was ketalized with (S,S)-2,4-pentanediol (III) to afford dioxane (IV). Titanium chloride-mediated coupling of acetal (IV) with the ketene acetal (V) afforded diastereoselectively adduct (VI), which was subsequently hydrolyzed to carboxylic acid (VII) by means of trifluoroacetic acid. Removal of the pentanediol moiety to furnish the (R)-alcohol (IX) was accomplished via Jones oxidation of the secondary alcohol (VII) to ketone (VIII), followed by beta-elimination in the presence of piperidinium acetate. Reduction of the free carboxyl group by borane-tetrahydrofuran complex gave diol (X), which was further converted to dimesylate (XI). Disulfide displacement of the mesylate groups provided (+)-lipoic acid isopropyl ester (XII), which was finally hydrolyzed to the title acid using K2CO3 in MeOH/H2O.
| 【1】 Elliott, J.D.; et al.; Asymmetric synthesis via acetal templates. 12. Highly diastereoselective coupling reactions with a ketene acetal. An efficient, asymmetric synthesis of R-(+)-alpha-lipoic acid. Tetrahedron Lett 1985, 26, 21, 2535. |
| 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) | 40446 | 1-cyclohexene | 110-83-8 | C6H10 | 详情 | 详情 |
| (II) | 57934 | isopropyl 6-oxohexanoate | C9H16O3 | 详情 | 详情 | |
| (III) | 57935 | (2S,4S)-2,4-pentanediol | C5H12O2 | 详情 | 详情 | |
| (IV) | 57936 | isopropyl 5-[(4S,6S)-4,6-dimethyl-1,3-dioxan-2-yl]pentanoate | C14H26O4 | 详情 | 详情 | |
| (V) | 57937 | {[1-(tert-butoxy)vinyl]oxy}(tert-butyl)dimethylsilane; 1-(tert-butoxy)vinyl tert-butyl(dimethyl)silyl ether | C12H26O2Si | 详情 | 详情 | |
| (VI) | 57938 | 1-[tert-butyl(dimethyl)silyl] 8-isopropyl (3S)-3-{[(1S,3S)-3-hydroxy-1-methylbutyl]oxy}octanedioate | C22H44O6Si | 详情 | 详情 | |
| (VII) | 57939 | (3S)-3-{[(1S,3S)-3-hydroxy-1-methylbutyl]oxy}-8-isopropoxy-8-oxooctanoic acid | C16H30O6 | 详情 | 详情 | |
| (VIII) | 57940 | (3S)-8-isopropoxy-3-{[(1S)-1-methyl-3-oxobutyl]oxy}-8-oxooctanoic acid | C16H28O6 | 详情 | 详情 | |
| (IX) | 57941 | (3S)-3-hydroxy-8-isopropoxy-8-oxooctanoic acid | C11H20O5 | 详情 | 详情 | |
| (X) | 57942 | isopropyl (6S)-6,8-dihydroxyoctanoate | C11H22O4 | 详情 | 详情 | |
| (XI) | 57943 | isopropyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate | C13H26O8S2 | 详情 | 详情 | |
| (XII) | 57944 | isopropyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate | C11H20O2S2 | 详情 | 详情 |