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【结 构 式】 
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【分子编号】14965 【品名】methyl 3-hydroxy-2-methylpropanoate; METHYL (S)-(+)-3-HYDROXY-2-METHYLPROPIONATE 【CA登记号】80657-57-4 |
【 分 子 式 】C5H10O3 【 分 子 量 】118.1326 【元素组成】C 50.84% H 8.53% O 40.63% |
合成路线1
该中间体在本合成路线中的序号：(XI)A partial synthesis of rapamycin has been reported: The condensation of sulfone (I) with epoxide (II) by means of butyllithium followed by desulfonation with Na/Hg gives the partially protected diol (III), which is treated with methanesulfonyl chloride and NaH to afford the epoxide (IV). Ring opening of epoxide (IV) with LiI and BF3.Et2O followed by protection of the resulting alcohol with PMBOC(NH)CCl3 yields the primary iodo compound (V). The condensation of (V) with the fully protected dihydroxyaldehyde (VI) (see later) by means of butyllithium in THF/HMPT gives the fully protected trihydroxyketone (VII), which is hydrolyzed with camphorsulfonic acid (CSA) to the corresponding gemdiol and reprotected with pivaloyl chloride (the primary alcohol) and tert-butyldimethylsilyl trifluoromethanesulfonate (the secondary alcohol), yielding a new fully protected trihydroxyketone (VIII). Elimination of the pivaloyl group with DIBAL and the dithiane group with MeI/CaCO3 affords the hydroxyketone (IX), which is finally oxidized with oxalyl chloride to the ketoaldehyde (X), the C(27)-C(42) fragment [the C(12)-C(15) fragment with the C(12)-substituent based on the IUPAC nomenclature recommendations]. The fully protected dihydroxyaldehyde (VI) is obtained as follows: The reaction of methyl 3-hydroxy-2(R)-methylpropionate (XI) with BPSCl followed by reduction with LiBH4 to the corresponding alcohol and oxidation with oxalyl chloride gives the aldehyde (XII), which is protected with propane-1,3-dithiol and BF3.Et2O to afford the dithiane compound (XIII). Elimination of the silyl group with TBAF followed by esterification with tosyl chloride, reaction with NaI and, finally, with sodium phenylsulfinate gives the sulfone (XIV), which is condensed with the partially protected dihydroxyaldehyde (XV), oxidized with oxalyl chloride and desulfonated with Al/Hg to afford the dithianyl ketone (XVI). The reaction of (XVI) with lithium hexamethyldisilylazane gives the corresponding enolate, which is treated with dimethyllithium cuprate to yield the fully protected unsaturated dihydroxyaldehyde (VI).
| 【1】 Leahy, J.W.; Smith, A.B.; McCauley, J.A.; Condon, S.M.; Leazer, J.L.; Maleczka, R.E.; Rapamycin synthetic studies. 1. Construction of the C(27)-C(42) subunit. Tetrahedron Lett 1994, 35, 28, 4907. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 52385 | [4-(methyloxy)phenyl]methyl 2,2,2-trichloroethanimidoate | C10H10Cl3NO2 | 详情 | 详情 | ||
| (I) | 14955 | triisopropyl([(1R,2R,4R)-2-methoxy-4-[(phenylsulfonyl)methyl]cyclohexyl]oxy)silane; [(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]methyl phenyl sulfone | C23H40O4SSi | 详情 | 详情 | |
| (II) | 14956 | tert-butyl[[(2R,3R)-3-methyloxiranyl]methoxy]diphenylsilane; tert-butyl(diphenyl)silyl [(2R,3R)-3-methyloxiranyl]methyl ether | C20H26O2Si | 详情 | 详情 | |
| (III) | 14957 | (2S,3R)-1-[[tert-butyl(diphenyl)silyl]oxy]-4-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-3-methyl-2-butanol | C37H62O4Si2 | 详情 | 详情 | |
| (IV) | 14958 | triisopropyl[((1R,2R,4S)-2-methoxy-4-[(2R)-2-[(2S)oxiranyl]propyl]cyclohexyl)oxy]silane; (1R,2R,4S)-2-methoxy-4-[(2R)-2-[(2S)oxiranyl]propyl]cyclohexyl triisopropylsilyl ether | C21H42O3Si | 详情 | 详情 | |
| (V) | 14959 | [((1R,2R,4S)-4-[(2R,3R)-4-iodo-3-[(4-methoxybenzyl)oxy]-2-methylbutyl]-2-methoxycyclohexyl)oxy](triisopropyl)silane; (1R,2R,4S)-4-[(2R,3R)-4-iodo-3-[(4-methoxybenzyl)oxy]-2-methylbutyl]-2-methoxycyclohexyl triisopropylsilyl ether | C29H51IO4Si | 详情 | 详情 | |
| (VI) | 14960 | (4R)-4-[(E,3R)-3-(1,3-dithian-2-yl)-1-methyl-1-butenyl]-2,2-dimethyl-1,3-dioxolane | C14H24O2S2 | 详情 | 详情 | |
| (VII) | 14961 | (1R,2R,4S)-4-[(2R,3S)-4-(2-[(1R,2E)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methyl-2-butenyl]-1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methylbutyl]-2-[(triisopropylsilyl)oxy]cyclohexanol | C42H72O6S2Si | 详情 | 详情 | |
| (VIII) | 14962 | (2R,3E,5R)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-[2-((2S,3R)-2-[(4-methoxybenzyl)oxy]-4-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-3-methylbutyl)-1,3-dithian-2-yl]-3-methyl-3-hexenyl pivalate | C51H92O7S2Si2 | 详情 | 详情 | |
| (IX) | 14963 | (2R,3S,6R,7E,9R)-9-[[tert-butyl(dimethyl)silyl]oxy]-10-hydroxy-3-[(4-methoxybenzyl)oxy]-1-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,6,8-trimethyl-7-decen-5-one | C43H78O7Si2 | 详情 | 详情 | |
| (X) | 14964 | (2R,3E,5R,8S,9R)-1-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-9-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4,8-trimethyl-5-oxo-3-decenoic 1,1-dimethylpropionic anhydride | C48H84O9Si2 | 详情 | 详情 | |
| (XI) | 14965 | methyl 3-hydroxy-2-methylpropanoate; METHYL (S)-(+)-3-HYDROXY-2-METHYLPROPIONATE | 80657-57-4 | C5H10O3 | 详情 | 详情 |
| (XII) | 14966 | (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methylpropanal | C20H26O2Si | 详情 | 详情 | |
| (XIII) | 14967 | tert-butyl[[(2R)-2-(1,3-dithian-2-yl)propyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (2R)-2-(1,3-dithian-2-yl)propyl ether | C23H32OS2Si | 详情 | 详情 | |
| (XIV) | 14968 | (2R)-2-(1,3-dithian-2-yl)propyl phenyl sulfone; 2-[(1R)-1-methyl-2-(phenylsulfonyl)ethyl]-1,3-dithiane | C13H18O2S3 | 详情 | 详情 | |
| (XV) | 14969 | (4S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 22323-80-4 | C6H10O3 | 详情 | 详情 |
| (XVI) | 14970 | (3R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-(1,3-dithian-2-yl)-1-butanone | C13H22O3S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)The chiral sulfone intermediate (XIV) has been obtained as follows: The silylation of 3-hydroxy-2(R)-methylpropionic acid methyl ester (XXVII) as usual gives the silylated ester (XXVIII), which is reduced to the chiral propanol (XXIX). The reaction of (XXIX) with TsCl and pyridine yields the tosylate (XXX), which is condensed with methyl phenyl sulfone (XXXI) by means of n-BuLi in THF to afford the chiral sulfone (XXXII). Desilylation of (XXXII) with TBAF in THF provides the 4-hydroxy-3-methylbutylsulfone (XXXIII), which is finally resilylated with TBDMS-Cl and imidazole to furnish the target intermediate (XIV).
| 【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 40825 | tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone | C17H30O3SSi | 详情 | 详情 | |
| (XXVII) | 14965 | methyl 3-hydroxy-2-methylpropanoate; METHYL (S)-(+)-3-HYDROXY-2-METHYLPROPIONATE | 80657-57-4 | C5H10O3 | 详情 | 详情 |
| (XXVIII) | 40838 | methyl (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methylpropanoate | C21H28O3Si | 详情 | 详情 | |
| (XXIX) | 40839 | (2S)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methyl-1-propanol | C20H28O2Si | 详情 | 详情 | |
| (XXX) | 40840 | (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methylpropyl 4-methylbenzenesulfonate | C27H34O4SSi | 详情 | 详情 | |
| (XXXI) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XXXII) | 40841 | (3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methylbutyl phenyl sulfone; tert-butyl[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]diphenylsilane | C27H34O3SSi | 详情 | 详情 | |
| (XXXIII) | 40842 | (2S)-2-methyl-4-(phenylsulfonyl)-1-butanol | C11H16O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXI)The preparation of the C7-C12 building block (II) (segment B) is performed as follows. Protection of methyl 3-hydroxy-2(R)-methylpropionate by means of dihydropyran and p-toluenesulfonic acid in CH2Cl2 gives the tetrahydropyranyl ether (XXII), which is then reduced with LiAlH4 in Et2O to yield alcohol (XXIII) and derivatized to tosylate (XXIV) under the usual conditions. Reaction of 3-methyl-3-buten-1-ol (XXV) with N-bromosuccinimide and triphenylphosphine in CH2Cl2 affords the butenyl bromide (XXVI) which, after conversion to the corresponding Grignard reagent, is coupled with tosylate (XXIV) in the presence of catalytic Li2CuCl4 leading to adduct (XXVII). Then, dihydroxylation of olefin (XXVII) and subsequent oxidative cleavage employing OsO4 and NaIO4 gives the desired ketone (II) (2). Scheme 3.
| 【2】 Klar, U., Buchmann, B., Schwede, W., Skuballa, W., Hoffmann, J., Lichtner, R.B. Total synthesis and antitumor activity of ZK-EPO: The first fully synthetic epothilone in clinical development. Angew Chem Int Ed Engl 2006, 45(47): 7942-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 65645 | C13H25O3 | 详情 | 详情 | ||
| (XXI) | 14965 | methyl 3-hydroxy-2-methylpropanoate; METHYL (S)-(+)-3-HYDROXY-2-METHYLPROPIONATE | 80657-57-4 | C5H10O3 | 详情 | 详情 |
| (XXII) | 65662 | C10H19O4 | 详情 | 详情 | ||
| (XXIII) | 65663 | C9H18O3 | 详情 | 详情 | ||
| (XXIV) | 65664 | C10H20O5S | 详情 | 详情 | ||
| (XXV) | 47474 | 3-methyl-3-buten-1-ol | 763-32-6 | C5H10O | 详情 | 详情 |
| (XXVI) | 65665 | 4-Bromo-2-methyl-1-butene; 1-Bromo-3-methyl-3-butene; 2-Methyl-4-bromo-1-butene; 3-Methyl-3-butenyl bromide | 20038-12-4 | C5H9Br | 详情 | 详情 |
| (XXVII) | 65666 | C14H26O2 | 详情 | 详情 |