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【结 构 式】 
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【分子编号】23622 【品名】methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane 【CA登记号】3112-85-4 |
【 分 子 式 】C7H8O2S 【 分 子 量 】156.20532 【元素组成】C 53.82% H 5.16% O 20.49% S 20.53% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of 13C-labelled methyl phenyl sulfone (I) with 2-(tert-butyldimethylsilyloxy)acetic acid ethyl ester (II) by means of BuLi in THF gives the labelled propanone derivative (III), which is condensed with ethyl 2-bromoacetate (IV) by means of NaH in THF to yield the gamma-oxo ester (V). Desulfurization of (V) by means of Al/Hg in THF/water affords the silylated 5-hydroxy-4-oxopentanoic acid ethyl ester (VI), which is desilylated by means of AcOH in THF/water to provide the free hydroxyester (VII). The condensation of (VII) with phthalimide (VIII) by means of DEAD and PPh3 in toluene gives the phthalimido derivative (IX), which is finally treated with refluxing 6N HCl to provide the target labelled aminolevulinic acid.
| 【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217. |
| 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) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (I) | 61635 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda~6~-sulfane | C7H8O2S | 详情 | 详情 | |
| (II) | 61636 | ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}acetate | C10H22O3Si | 详情 | 详情 | |
| (III) | 61637 | 1-{[tert-butyl(dimethyl)silyl]oxy}-3-(phenylsulfonyl)acetone | C15H24O4SSi | 详情 | 详情 | |
| (III) | 64694 | 1-{[tert-butyl(dimethyl)silyl]oxy}-3-(phenylsulfonyl)acetone | C15H24O4SSi | 详情 | 详情 | |
| (IV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (V) | 61639 | ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-3-(phenylsulfonyl)pentanoate | C19H30O6SSi | 详情 | 详情 | |
| (V) | 64691 | ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-3-(phenylsulfonyl)pentanoate | C19H30O6SSi | 详情 | 详情 | |
| (VI) | 61640 | ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxopentanoate | C13H26O4Si | 详情 | 详情 | |
| (VI) | 64692 | ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxopentanoate | C13H26O4Si | 详情 | 详情 | |
| (VII) | 61641 | ethyl 5-hydroxy-4-oxopentanoate | C7H12O4 | 详情 | 详情 | |
| (VII) | 64693 | ethyl 5-hydroxy-4-oxopentanoate | C7H12O4 | 详情 | 详情 | |
| (VIII) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (IX) | 59167 | ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate | C15H15NO5 | 详情 | 详情 | |
| (IX) | 61642 | ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate | C15H15NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)Advanced intermediate phosphonium salt (XLI). The protection of (R)(+)-glycidol (XXV) with Pmb-Cl and NaH gives the benzyl ether (XXVI). Which is condensed with methyl phenyl sulfone (XXVII) by means of BuLi in THF/HMPA to yield the secondary alcohol (XXVIII). The reaction of (XXVIII) with Tbdms-OTf and lutidine affords the silyl ether (XXIX) (3), which is converted into the aldehyde (XXX) by debenzylation with DDQ, followed by oxidation with DMP. The condensation of (XXX) with phosphorane (XXXI) in refluxing benzene gives the unsaturated ester (XXXII), which is reduced with DIBAL in dichloromethane and protected with Ph-CH2Br and NaH to yield the benzyl ether (XXXIII). The condensation of sulfone (XXXIII) with the iodomethyl intermediate (XXIV) by means of BuLi in THF/HMPA affords the adduct (XXXIV), which is desulfurized by reaction with BuLi, diiodomethane and isopropylmagnesium chloride to provide the methylene compound (XXXV). The elimination of the benzyl protecting group of (XXXV) by means of LiDBB, followed by oxidation with DMP gives the carbaldehyde (XXXVI), which is condensed with CH2=PPh3 in THF to yield compound (XXXVII) (2).
| 【1】 Smith, A.B. III; Lin, Q.; Pettit, G.R.; Chapuis, G.R.; Chapuis, J.-C.; Schmidt, J.M.; Synthesis and in vitro cancer cell growth inhibitory activity of monocyclic model cpds. containing spongistatin triene side-chains. Bioorg Med Chem Lett 1998, 8, 6, 567. |
| 【2】 Smith, A.B. III; Lin, Q.; Doughty, V.A.; Zhuang, L.; McBriar, M.D.; Kerns, J.K.; Brook, C.S.; Murase, N.; Nakayama, K.; The spongistatins: Architecturally complex natural products - Part two: Synthesis of the C(29-51) subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew Chem. Int Ed 2001, 40, 1, 196. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 64616 | tert-butyl[((2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl ether | C59H109IO8Si5 | 详情 | 详情 | |
| (XXV) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (XXVI) | 63135 | 4-methoxybenzyl (2R)oxiranylmethyl ether; (2R)-2-{[(4-methoxybenzyl)oxy]methyl}oxirane | C11H14O3 | 详情 | 详情 | |
| (XXVII) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XXVIII) | 64617 | (2S)-1-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)-2-butanol | C18H22O5S | 详情 | 详情 | |
| (XXIX) | 64618 | (3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]butyl phenyl sulfone; tert-butyl{[(1S)-1-{[(4-methoxybenzyl)oxy]methyl}-3-(phenylsulfonyl)propyl]oxy}dimethylsilane | C24H36O5SSi | 详情 | 详情 | |
| (XXX) | 64619 | (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(phenylsulfonyl)butanal | C16H26O4SSi | 详情 | 详情 | |
| (XXXI) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XXXII) | 64620 | ethyl (E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(phenylsulfonyl)-2-hexenoate | C20H32O5SSi | 详情 | 详情 | |
| (XXXIII) | 64621 | (3S,4E)-6-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hexenyl phenyl sulfone; ({(1S,2E)-4-(benzyloxy)-1-[2-(phenylsulfonyl)ethyl]-2-butenyl}oxy)(tert-butyl)dimethylsilane | C25H36O4SSi | 详情 | 详情 | |
| (XXXIV) | 64622 | (3S,4E)-6-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-4-hexenyl phenyl sulfone; ({(1S,2E)-4-(benzyloxy)-1-[3-{(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}-2-(phenylsulfonyl)propyl]-2-butenyl}oxy)(tert-butyl)dimethylsilane | C84H144O12SSi6 | 详情 | 详情 | |
| (XXXV) | 64623 | ({(1S,2E)-4-(benzyloxy)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2-butenyl}oxy)(tert-butyl)dimethylsilane; benzyl (2E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2,6-heptadienyl ether | C79H140O10Si6 | 详情 | 详情 | |
| (XXXVI) | 64624 | (2E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2,6-heptadienal | C72H132O10Si6 | 详情 | 详情 | |
| (XXXVII) | 64625 | tert-butyl({(1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl}oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl ether | C73H134O9Si6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXXI)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4
该中间体在本合成路线中的序号：(XVI)The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (Via) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi. The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).
| 【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 40817 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol | C11H24O3Si | 详情 | 详情 | |
| (VIb) | 40818 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone | C11H24O3Si | 详情 | 详情 | |
| (I) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 39221 | 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid | 73991-95-4 | C7H10O5 | 详情 | 详情 |
| (IV) | 40815 | (3S)-3-hydroxydihydro-2(3H)-furanone | 19444-84-9 | C4H6O3 | 详情 | 详情 |
| (V) | 40816 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone | C10H20O3Si | 详情 | 详情 | |
| (VII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (VIII) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (IX) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (X) | 42703 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate | C8H11F6O5P | 详情 | 详情 | |
| (XI) | 46134 | propyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate | C22H37NO3SSi | 详情 | 详情 | |
| (XII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIII) | 46136 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-iodo-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-5-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether | C19H32INOSSi | 详情 | 详情 | |
| (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 | |
| (XV) | 46135 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-propanol | C10H24O2Si | 详情 | 详情 | |
| (XVI) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XVII) | 40827 | tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole | C30H57NO2SSi2 | 详情 | 详情 | |
| (XVIII) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XIX) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVI)The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (VIa) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi . The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).
| 【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 40817 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol | C11H24O3Si | 详情 | 详情 | |
| (VIb) | 40818 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone | C11H24O3Si | 详情 | 详情 | |
| (I) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 39221 | 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid | 73991-95-4 | C7H10O5 | 详情 | 详情 |
| (IV) | 40815 | (3S)-3-hydroxydihydro-2(3H)-furanone | 19444-84-9 | C4H6O3 | 详情 | 详情 |
| (V) | 40816 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone | C10H20O3Si | 详情 | 详情 | |
| (VII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (VIII) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (IX) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (X) | 42703 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate | C8H11F6O5P | 详情 | 详情 | |
| (XI) | 46134 | propyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate | C22H37NO3SSi | 详情 | 详情 | |
| (XII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIII) | 46136 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-iodo-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-5-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether | C19H32INOSSi | 详情 | 详情 | |
| (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 | |
| (XV) | 46135 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-propanol | C10H24O2Si | 详情 | 详情 | |
| (XVI) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XVII) | 40827 | tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole | C30H57NO2SSi2 | 详情 | 详情 | |
| (XVIII) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XIX) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)N-Boc-Homophenylalanine (I) was coupled to N,O-dimethyl hydroxylamine using DCC, and the resulting N-methoxy amide (II) was reduced to aldehyde (III) with LiAlH4. Sulfonyl phosphonate (VI), (prepared from methyl phenyl sulfone (IV) and diethyl chlorophosphate (V)), was then condensed with aldehyde (III) in the presence of NaH to provide the vinylogous sulfone (VII). Subsequent acid deprotection of the Boc group of (VII) yielded amine (VIII). This was finally coupled with mixed anhydride (X), (obtained from morpholinocarbonyl-phenylalanine (IX) and isobutyl chloroformate in the presence of N-methylmorpholine), to furnish the target amide.
| 【1】 Rasnick, D.; Klaus, J.L.; Palmer, J.T. (Khepri Pharmaceuticals Inc.); Irreversible cysteine protease inhibitors containi. WO 9523222 . |
| 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) | 23619 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-phenylbutyric acid | 100564-78-1 | C15H21NO4 | 详情 | 详情 |
| (II) | 23620 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-phenylpropylcarbamate | C17H26N2O4 | 详情 | 详情 | |
| (III) | 23621 | tert-butyl (1S)-1-formyl-3-phenylpropylcarbamate | C15H21NO3 | 详情 | 详情 | |
| (IV) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (V) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |
| (VI) | 23624 | diethyl (phenylsulfonyl)methylphosphonate | C11H17O5PS | 详情 | 详情 | |
| (VII) | 23625 | tert-butyl (1S,2E)-1-phenethyl-3-(phenylsulfonyl)-2-propenylcarbamate | C22H27NO4S | 详情 | 详情 | |
| (VIII) | 23626 | (1S,2E)-1-phenethyl-3-(phenylsulfonyl)-2-propenylamine; (E,3S)-5-phenyl-1-(phenylsulfonyl)-1-penten-3-amine | C17H19NO2S | 详情 | 详情 | |
| (IX) | 23627 | (2S)-2-[(4-morpholinylcarbonyl)amino]-3-phenylpropionic acid | C14H18N2O4 | 详情 | 详情 | |
| (X) | 23628 | N-(4-Morpholinylcarbonyl)-L-phenylalanine ethoxycarbonyl anhydride | C17H22N2O6 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The intermediate carbaldehyde (VI) and Weinreb amide (IX) have been obtained as follows. The reaction of tetrahydropyranyl glycidol (I) with methyl phenylsulfone (II) by means of BuLi in THF gives the secondary alcohol (III), which is protected with Pmb-Cl and NaH in DMF to yield the diether (IV). Selective cleavage of the THP group of (IV) by means of CSA in methanol affords the primary alcohol (V), which is oxidized with (COCl)2 and DMSO in dichloromethane to provide the aldehyde (VI). Further oxidation of (VI) by means of NaClO2 in t-butanol gives the carboxylic acid (VII), which is finally condensed with N,O-dimethylhydroxylamine (VIII) by means of iso-butyl chloroformate in dichloromethane to yield the intermediate Weinreb amide (IX).
| 【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973. |
| 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) | 63105 | 2-[(2R)oxiranyloxy]tetrahydro-2H-pyran; (2R)oxiranyl tetrahydro-2H-pyran-2-yl ether | C7H12O3 | 详情 | 详情 | |
| (II) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (III) | 63106 | (2S)-4-(phenylsulfonyl)-1-(tetrahydro-2H-pyran-2-yloxy)-2-butanol | C15H22O5S | 详情 | 详情 | |
| (IV) | 63107 | 2-{[(2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)butyl]oxy}tetrahydro-2H-pyran; (3S)-3-[(4-methoxybenzyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)butyl phenyl sulfone | C23H30O6S | 详情 | 详情 | |
| (V) | 63108 | (2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)-1-butanol | C18H22O5S | 详情 | 详情 | |
| (VI) | 63109 | (2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)butanal | C18H20O5S | 详情 | 详情 | |
| (VII) | 63110 | (2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)butanoic acid | C18H20O6S | 详情 | 详情 | |
| (VIII) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (IX) | 63111 | (2S)-N-methoxy-2-[(4-methoxybenzyl)oxy]-N-methyl-4-(phenylsulfonyl)butanamide | C20H25NO6S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Phosphonylation of the lithium anion of phenyl methyl sulfone (I) with diethyl chlorophosphate afforded the sulfonyl phosphonate (II). This was condensed with N-Boc-L-homophenylalaninal (III) under Wadsworth-Emmons conditions to furnish the vinyl sulfone (IV). After acidic Boc group cleavage, the resultant amine (V) was coupled with the N-carbamoyl phenylalanine (VI), via the corresponding mixed anhydride with isobutyl chloroformate, to afford the target amide.
| 【1】 Palmer, J.T.; Rasnick, D.; Klaus, J.L. (Celera Genomics); Irreversible cysteine protease inhibitors containing vinyl groups conjugated to electron withdrawing groups. US 6287840 . |
| 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) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (II) | 23624 | diethyl (phenylsulfonyl)methylphosphonate | C11H17O5PS | 详情 | 详情 | |
| (III) | 23621 | tert-butyl (1S)-1-formyl-3-phenylpropylcarbamate | C15H21NO3 | 详情 | 详情 | |
| (IV) | 23625 | tert-butyl (1S,2E)-1-phenethyl-3-(phenylsulfonyl)-2-propenylcarbamate | C22H27NO4S | 详情 | 详情 | |
| (V) | 23626 | (1S,2E)-1-phenethyl-3-(phenylsulfonyl)-2-propenylamine; (E,3S)-5-phenyl-1-(phenylsulfonyl)-1-penten-3-amine | C17H19NO2S | 详情 | 详情 | |
| (VI) | 56040 | (2S)-2-{[(4-methyl-1-piperazinyl)carbonyl]amino}-3-phenylpropanoic acid | C15H21N3O3 | 详情 | 详情 |