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【结 构 式】 
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【分子编号】11807 【品名】methyl (3S)-3,4-dihydroxybutanoate 【CA登记号】 |
【 分 子 式 】C5H10O4 【 分 子 量 】134.132 【元素组成】C 44.77% H 7.51% O 47.71% |
合成路线1
该中间体在本合成路线中的序号：(XXII)3) The esterification of L-malic acid (XX) with methanol and acetyl chloride gives the dimethyl ester (XXI), which is reduced with borane-dimethyl sulfide in THF yielding 3(S),4-dihydroxybutyric acid methyl ester (XXII). Partial protection of (XXII) with trityl chloride in pyridine affords 3(S)-hydroxy-4-(trityloxy) butyric acid methyl ester (XXIII), which is hydrolyzed with NaOH to the corresponding free acid (XXIV). The condensation of (XXIV) with succinic acid monoallyl ester, magnesium salt (XXV) by means of the carbonyl diimidazole (DCI) in THF gives 5(S)-hydroxy-3-oxo-6-(trityloxy)hexanoic acid allyl ester (XXVI), which is reduced with triethylborane and NaBH4 in THF and treated with H2O2 at -70 C to afford 3(R),5(S)-6-(trityloxy)hexanoic acid allyl ester (XXVII). The protection of the hydroxyl groups of (XXVII) with tert-butyldiphenylsilyl chloride and imidazole in DMF gives the fully protected ester (XXVIII), which is treated with trifluoroacetic acid in dichloromethane yielding erythro-3(R),5(S)-bis(tert-butyldiphenylsilyloxy)-6-hydroxyhexanoic acid allyl ester (XXIX). The oxidation of (XXIX) with pyridinium chlorochromate in dichloromethane affords the oxo-ester (XXX), which is condensed with phosphonate (X), as in method 2 above, to give ester (XXXI). The hydrolysis of (XXXI) with triphenylphosphine and palladium tetrakis triphenylphosphine as before yields the protected acid (XXXII), which is finally deprotected with tetrabutylammonium fluoride, also as before. [3(R),5(S)-erythro-isomer].
| 【1】 Kathawala, F. (Novartis AG); Analogs of mevalolactone and derivs. thereof, processes for their production, pharmaceutical compsns. containing them and their use as pharmaceuticals. JP 1991047167; US 4739073; WO 8402131 . |
| 【2】 Chen, K.-M.; Hardtmann, G.E.; Lee, G.T.; Linder, J.; Wattanasin, S. (Novartis AG; Novartis Deutschland GmbH); Preparation of olefinic cpds. EP 0244364 . |
| 【3】 Kapa, P.K. (Novartis AG); 6-Substituted-4-hydroxy-tetrahydropyran-2-ones. US 4571428 . |
| 【4】 Castaner, J.; Prous, J.; Fluvastatin Sodium. Drugs Fut 1991, 16, 9, 804. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 11795 | dimethyl [3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]methylphosphonate | C20H23FNO3P | 详情 | 详情 | |
| (XX) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (XXI) | 11806 | dimethyl (2S)-2-hydroxybutanedioate | 617-55-0 | C6H10O5 | 详情 | 详情 |
| (XXII) | 11807 | methyl (3S)-3,4-dihydroxybutanoate | C5H10O4 | 详情 | 详情 | |
| (XXIII) | 11808 | methyl (3R)-3-hydroxy-5,5,5-triphenylpentanoate | C24H24O3 | 详情 | 详情 | |
| (XXIV) | 11809 | (3R)-3-Hydroxy-5,5,5-triphenylpentanoic acid | C23H22O3 | 详情 | 详情 | |
| (XXV) | 11810 | magnesium di[3-(allyloxy)-3-oxopropanoate] | C12H14MgO8 | 详情 | 详情 | |
| (XXVI) | 11811 | allyl (5S)-5-hydroxy-3-oxo-6-(trityloxy)hexanoate | C28H28O5 | 详情 | 详情 | |
| (XXVII) | 11812 | allyl (3R,5S)-3,5-dihydroxy-6-(trityloxy)hexanoate | C28H30O5 | 详情 | 详情 | |
| (XXVIII) | 11813 | allyl (3R,5S)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-(trityloxy)hexanoate | C60H66O5Si2 | 详情 | 详情 | |
| (XXIX) | 11804 | allyl (3R,5S)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-hydroxyhexanoate | C41H52O5Si2 | 详情 | 详情 | |
| (XXX) | 11815 | allyl (3R,5R)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-oxohexanoate | C41H50O5Si2 | 详情 | 详情 | |
| (XXXI) | 11797 | allyl (3R,5S,6E)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-6-heptenoate | C59H66FNO4Si2 | 详情 | 详情 | |
| (XXXII) | 11798 | (3R,5S,6E)-3,5-Bis[[tert-butyl(diphenyl)silyl]oxy]-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-6-heptenoic acid | C56H62FNO4Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The esterification of L-malic acid (VII) with methanol in acidic medium gives the dimethyl ester (VIII), which is chemoselectively reduced with BH3, Me2S and NaBH4 yielding the diol (IX). The reaction of (IX) with trimethyl orthoformate affords the cyclic orthoester (X), which is reduced with DIBAL to the aldehyde (XI). The methylation of (XI) with MeLi provides the isopropanol derivative (XII), which is submitted to a Swern oxidation to afford the corresponding ketone (XIII). The enolization of (XIII) with TBDMS-OTf and DIEA gives the silylated enol ether (XIV), which is finally cyclized to the target ketone (IV) by means of Lewis acids such as TiCl4, BF3.Et2O, SnCl4 or Et2AlCl, the best yields being obtained with the last mentioned reagent.
| 【1】 Leger, S.; et al.; Lewis acid-catalyzed intramolecular reaction between silyl enol ethers and ortho esters: an efficient approach to 1,6-anhydropyranoses. Synlett 1994, 25, 6, 829. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 38608 | 6,8-dioxabicyclo[3.2.1]octan-3-one | C6H8O3 | 详情 | 详情 | |
| (VII) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (VIII) | 11806 | dimethyl (2S)-2-hydroxybutanedioate | 617-55-0 | C6H10O5 | 详情 | 详情 |
| (IX) | 11807 | methyl (3S)-3,4-dihydroxybutanoate | C5H10O4 | 详情 | 详情 | |
| (X) | 38610 | methyl 2-[(4S)-2-methoxy-1,3-dioxolan-4-yl]acetate | C7H12O5 | 详情 | 详情 | |
| (XI) | 38611 | 2-[(4S)-2-methoxy-1,3-dioxolan-4-yl]acetaldehyde | C6H10O4 | 详情 | 详情 | |
| (XII) | 38612 | 1-[(4S)-2-methoxy-1,3-dioxolan-4-yl]-2-propanol | C7H14O4 | 详情 | 详情 | |
| (XIII) | 38613 | 1-[(4S)-2-methoxy-1,3-dioxolan-4-yl]acetone | C7H12O4 | 详情 | 详情 | |
| (XIV) | 38614 | tert-butyl(dimethyl)silyl 1-[[(4S)-2-methoxy-1,3-dioxolan-4-yl]methyl]vinyl ether; tert-butyl[(1-[[(4S)-2-methoxy-1,3-dioxolan-4-yl]methyl]vinyl)oxy]dimethylsilane | C13H26O4Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)The intermediate octadienal derivative (XXXI) has been obtained as follows: The selective monosilylation of 3(R),4-dihydroxybutyric acid methyl ester (XIV) by means of Tbdms-Cl and imidazole in dichloromethane gives the terminal silyl ether (XV), which is treated with PmbOC(=NH)CCl3 and TfOH in ethyl ether to yield the fully protected compound (XVI). The reduction of the ester group of (XVI) by means of LiAlH4 in THF affords the butanol derivative (XVII), which is subjected to Dess-Martin oxidation to furnish the corresponding aldehyde (XVIII). The condensation of (XVIII) with phosphonate (XIX) by means of DIEA and LiCl in acetonitrile provides the hexenoic ester (XX), which is reduced with DIBAL to the corresponding unsaturated alcohol (XXI). The reaction of (XXI) with Tbdps-Cl and imidazole gives the silyl ether (XXII), which is selectively monodesilylated by means of TsOH in ethanol to yield the alcohol (XXIII). The Swern oxidation of (XXIII) affords the corresponding aldehyde (XXIV), which is methylated with MeMgCl to provide the secondary alcohol (XXV). The Swern oxidation of (XXXV) yields the methyl ketone (XXVI), which is condensed with the intermediate 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XIII) by means of (cHex)2BCl and TEA, followed by a treatment with MsCl and TEA to afford the octadienone (XXVII). The reduction of (XXVII) by means of Zn(BH4)2 in ethyl ether provides the octadienol (XXVIII), which is silylated with Tbdms-OTf and lutidine to give the silyl ether (XXIX). The selective monodeprotection of (XXIX) by means of TBAF in AcOH yields the octadienol (XXX), which is oxidized with DMP to afford the intermediate octadienal derivative (XXXI)
| 【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 61148 | (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde | C7H10O2 | 详情 | 详情 | |
| (XIV) | 11807 | methyl (3S)-3,4-dihydroxybutanoate | C5H10O4 | 详情 | 详情 | |
| (XV) | 61174 | methyl (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxybutanoate | C11H24O4Si | 详情 | 详情 | |
| (XVI) | 61175 | methyl (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]butanoate | C19H32O5Si | 详情 | 详情 | |
| (XVII) | 61176 | (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-1-butanol | C18H32O4Si | 详情 | 详情 | |
| (XVIII) | 61177 | (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]butanal | C18H30O4Si | 详情 | 详情 | |
| (XX) | 61178 | methyl (E,5R)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexenoate | C21H34O5Si | 详情 | 详情 | |
| (XXI) | 61179 | (E,5R)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexen-1-ol | C20H34O4Si | 详情 | 详情 | |
| (XXII) | 61180 | (E,9R)-9-[(4-methoxybenzyl)oxy]-2,2,12,12,13,13-hexamethyl-3,3-diphenyl-4,11-dioxa-3,12-disila-6-tetradecene; tert-butyl(dimethyl)silyl (2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-4-hexenyl ether | C36H52O4Si2 | 详情 | 详情 | |
| (XXIII) | 61181 | (2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-4-hexen-1-ol | C30H38O4Si | 详情 | 详情 | |
| (XXIV) | 61182 | (2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-4-hexenal | C30H36O4Si | 详情 | 详情 | |
| (XXV) | 61183 | (3R,5E)-7-{[tert-butyl(diphenyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-5-hepten-2-ol | C31H40O4Si | 详情 | 详情 | |
| (XXVI) | 61184 | (3R,5E)-7-{[tert-butyl(diphenyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-5-hepten-2-one | C31H38O4Si | 详情 | 详情 | |
| (XXVII) | 61185 | (1E,4R,6E)-8-{[tert-butyl(diphenyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6-octadien-3-one | C38H46O5Si | 详情 | 详情 | |
| (XXVIII) | 61186 | (1E,3S,4R,6E)-8-{[tert-butyl(diphenyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6-octadien-3-ol | C38H48O5Si | 详情 | 详情 | |
| (XXIX) | 61187 | (E,9R,10S)-9-[(4-methoxybenzyl)oxy]-2,2,12,12,13,13-hexamethyl-10-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-3,3-diphenyl-4,11-dioxa-3,12-disila-6-tetradecene; tert-butyl(dimethyl)silyl (1S,2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-4-hexenyl ether | C44H62O5Si2 | 详情 | 详情 | |
| (XXX) | 61188 | (2E,5R,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadien-1-ol | C28H44O5Si | 详情 | 详情 | |
| (XXXI) | 61189 | (2E,5R,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal | C28H42O5Si | 详情 | 详情 |