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【结 构 式】

【药物名称】WB-2663B, FR-901464

【化学名称】4(S)-Acetoxy-N-[(2R,3R,5S,6S)-6-[5-[(3R,4R,5R,7S)-4,7-dihydroxy-7-methyl-1,6-dioxaspiro[2.5]octan-5-yl]-3-methyl-2(E),4(E)-pentadienyl]-2,5-dimethyltetrahydropyran-3-yl]-2(Z)-pentenamide

【CA登记号】146478-72-0

【 分 子 式 】C27H41NO8

【 分 子 量 】507.62972

【开发单位】Fujisawa (Originator), National Institutes of Health (Originator)

【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, Oncolytic Drugs

合成路线1

Synthesis of the unsaturated acid precursor (V) is carried out as follows. Desilylation of 4-(trimethylsilyl)-3-butyn-2-ol (I) with tetrabutylammonium fluoride affords (II). The lithium acetylide generated from alkyne (II) is then carboxylated by CO2 to furnish the pentynoic acid derivative (III). Subsequent acetylation of the alcohol hydroxyl group of (III) leads to acetate ester (IV). Then, Lindlar hydrogenation of the triple bond gives rise to the cis alkene (V).

1 Thompson, C.F.; Jamison, T.F; Jacobsen, E.N.; Total synthesis of FR901464. Convergent assembly of chiral componenents prepared by asymmetric catalysis. J Am Chem Soc 2000, 122, 45, 10482.
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) 62000 (2S)-4-(trimethylsilyl)-3-butyn-2-ol C7H14OSi 详情 详情
(II) 13488 (2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol 2914-69-4 C4H6O 详情 详情
(III) 62111 (4S)-4-hydroxy-2-pentynoic acid C5H6O3 详情 详情
(IV) 62112 (4S)-4-(acetyloxy)-2-pentynoic acid C7H8O4 详情 详情
(V) 62113 (Z,4S)-4-(acetyloxy)-2-pentenoic acid C7H10O4 详情 详情

合成路线2

Hetero Diels-Alder reaction between diene (VI) and aldehyde (VII) in the presence of chiral chromium complex furnishes the optically active dihydropyran compound (VIII). Subsequent oxidation of the silyl enol ether moiety of (VIII) with m CPBA under Rubottom conditions affords the alpha-hydroxy ketone (IX). Reduction of ketone (IX) is accomplished via the tosyl hydrazone (X), which is then reduced to (XI) employing NaBH3CN. Desilylation of (XI) with tetrabutylammonium fluoride gives the terminal acetylene (XII), which is further isomerized to the thermodynamically more stable internal alkyne (XIII) in the presence of potassium tert-butoxide in DMSO. Treatment of (XIII) with Schwartz's reagent, followed by quenching of the vinylzirconium intermediate with I2 leads to the vinyl iodide (XIV). After conversion of alcohol (XIV) into the chloromethanesulfonate (XV), displacement with LiN3 provides azide (XVI).

1 Thompson, C.F.; Jamison, T.F; Jacobsen, E.N.; Total synthesis of FR901464. Convergent assembly of chiral componenents prepared by asymmetric catalysis. J Am Chem Soc 2000, 122, 45, 10482.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 62114 triethyl({(E)-1-[(Z)ethylidene]-2-butenyl}oxy)silane; (E)-1-[(Z)ethylidene]-2-butenyl triethylsilyl ether C12H24OSi 详情 详情
(VII) 62115 5-(trimethylsilyl)-4-pentynal C8H14OSi 详情 详情
(VIII) 62116 (2S,3R,6R)-3,6-dimethyl-2-[4-(trimethylsilyl)-3-butynyl]-3,6-dihydro-2H-pyran-4-yl triethylsilyl ether; (4-{(2S,3R,6R)-3,6-dimethyl-4-[(triethylsilyl)oxy]-3,6-dihydro-2H-pyran-2-yl}-1-butynyl)(trimethyl)silane C20H38O2Si2 详情 详情
(IX) 62117 (2R,3R,5R,6S)-3-hydroxy-2,5-dimethyl-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-4H-pyran-4-one C14H24O3Si 详情 详情
(X) 62118 N'-{(2R,3S,5S,6S)-3-hydroxy-2,5-dimethyl-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-4H-pyran-4-ylidene}-4-methylbenzenesulfonohydrazide C21H32N2O4SSi 详情 详情
(XI) 62119 (2R,3S,5S,6S)-2,5-dimethyl-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-2H-pyran-3-ol C14H26O2Si 详情 详情
(XII) 62120 (2R,3S,5S,6S)-6-(3-butynyl)-2,5-dimethyltetrahydro-2H-pyran-3-ol C11H18O2 详情 详情
(XIII) 62121 (2R,3S,5S,6S)-6-(2-butynyl)-2,5-dimethyltetrahydro-2H-pyran-3-ol C11H18O2 详情 详情
(XIV) 62122 (2R,3S,5S,6S)-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran-3-ol C11H19IO2 详情 详情
(XV) 62123 (2R,3S,5S,6S)-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran-3-yl chloromethanesulfonate C12H20ClIO4S 详情 详情
(XVI) 62124 (2R,3R,5S,6S)-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran-3-yl azide; (2R,3R,5S,6S)-3-azido-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran C11H18IN3O 详情 详情

合成路线3

Enantioselective cycloaddition of dienyne (XVII) with aldehyde (XVIII) affords dihydropyran (XIX). Subsequent Rubottom oxidation of the silyl enol ether (XIX) gives a mixture of epimeric alpha-hydroxy ketones (XX), which is further equilibrated to the desired stereoisomer (XXI) in the presence of K2CO3 in MeOH. After protection of the hydroxyl group of (XXI) as the triisopropylsilyl ether (XXII), Wittig reaction with methylene triphenylphosphorane provides the exocyclic olefin (XXIII). Replacement of the silylated primary hydroxyl of (XXIII) with a iodide group to yield (XXIV) is accomplished by treatment with I2 and PPh3. Removal of the remaining silyl group of (XXIV) with tetrabutylammonium fluoride and acetic acid yields the allylic alcohol (XXV), which can be diastereoselectively epoxidized with t butyl hydroperoxide and vanadyl acetylacetonate, producing (XXVI) as a single isomer. Reprotection of (XXVI) with triisopropylsilyl triflate affords the corresponding silyl ether (XXVII). Hydrozirconation of acetylene (XXVII), followed by Negishi coupling with the vinyl iodide (XVI) furnishes the diene system (XXVIII). Subsequent azido group reduction in (XXVIII) with trimethylphosphine in moist THF provides amine (XXIX).

1 Thompson, C.F.; Jamison, T.F; Jacobsen, E.N.; Total synthesis of FR901464. Convergent assembly of chiral componenents prepared by asymmetric catalysis. J Am Chem Soc 2000, 122, 45, 10482.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 62124 (2R,3R,5S,6S)-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran-3-yl azide; (2R,3R,5S,6S)-3-azido-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran C11H18IN3O 详情 详情
(XVII) 62125 triethyl{[(E)-1-methylene-2-penten-4-ynyl]oxy}silane; (E)-1-methylene-2-penten-4-ynyl triethylsilyl ether C12H20OSi 详情 详情
(XVIII) 61170 2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde;tert-butyldimethylsilyloxy acetaldehyde 102191-92-4 C8H18O2Si 详情 详情
(XIX) 62126 tert-butyl(dimethyl)silyl {(2R,6S)-6-ethynyl-4-[(triethylsilyl)oxy]-3,6-dihydro-2H-pyran-2-yl}methyl ether; tert-butyl({(2R,6S)-6-ethynyl-4-[(triethylsilyl)oxy]-3,6-dihydro-2H-pyran-2-yl}methoxy)dimethylsilane C20H38O3Si2 详情 详情
(XX) 62127 (2R,6R)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynyl-3-hydroxytetrahydro-4H-pyran-4-one C14H24O4Si 详情 详情
(XXI) 62128 (2R,3R,6R)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynyl-3-hydroxytetrahydro-4H-pyran-4-one C14H24O4Si 详情 详情
(XXII) 62129 (2R,3R,6R)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynyl-3-[(triisopropylsilyl)oxy]tetrahydro-4H-pyran-4-one C23H44O4Si2 详情 详情
(XXIII) 62130 tert-butyl(dimethyl)silyl {(2R,5S,6R)-6-ethynyl-4-methylene-5-[(triisopropylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl ether; tert-butyl({(2R,5S,6R)-6-ethynyl-4-methylene-5-[(triisopropylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methoxy)dimethylsilane C24H46O3Si2 详情 详情
(XXIV) 62131 (2R,3S,6R)-2-ethynyl-6-(iodomethyl)-4-methylenetetrahydro-2H-pyran-3-yl triisopropylsilyl ether; {[(2R,3S,6R)-2-ethynyl-6-(iodomethyl)-4-methylenetetrahydro-2H-pyran-3-yl]oxy}(triisopropyl)silane C18H31IO2Si 详情 详情
(XXV) 62132 (2R,3S,6R)-2-ethynyl-6-(iodomethyl)-4-methylenetetrahydro-2H-pyran-3-ol C9H11IO2 详情 详情
(XXVI) 62133 (3R,4R,5R,7R)-5-ethynyl-7-(iodomethyl)-1,6-dioxaspiro[2.5]octan-4-ol C9H11IO3 详情 详情
(XXVII) 62134 (3R,4R,5R,7R)-5-ethynyl-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl triethylsilyl ether; triethyl{[(3R,4R,5R,7R)-5-ethynyl-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl]oxy}silane C15H25IO3Si 详情 详情
(XXVIII) 62135 (3R,4R,5R,7R)-5-{(1E,3E)-5-[(2S,3S,5R,6R)-5-azido-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methyl-1,3-pentadienyl}-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl triethylsilyl ether; {[(3R,4R,5R,7R)-5-{(1E,3E)-5-[(2S,3S,5R,6R)-5-azido-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methyl-1,3-pentadienyl}-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl]oxy}(triethyl)silane C26H44IN3O4Si 详情 详情
(XXIX) 62136 (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-amine; (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-ylamine C26H46INO4Si 详情 详情

合成路线4

Acylation of amine (XXIX) with the unsaturated acid (V) in the presence of HBTU gives amide (XXX). Dehydroiodination of (XXX) by means of DBU in DMF leads to the exocyclic enol ether (XXXI). The O-silyl group of (XXXI) is then removed with tetrabutylammonium fluoride and acetic acid, to yield alcohol (XXXII). Finally, acid-catalyzed hydration of the cyclic enol ether (XXXII) in aqueous THF gives rise to the target hemiketal compound.

1 Thompson, C.F.; Jamison, T.F; Jacobsen, E.N.; Total synthesis of FR901464. Convergent assembly of chiral componenents prepared by asymmetric catalysis. J Am Chem Soc 2000, 122, 45, 10482.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 62113 (Z,4S)-4-(acetyloxy)-2-pentenoic acid C7H10O4 详情 详情
(XXIX) 62136 (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-amine; (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-ylamine C26H46INO4Si 详情 详情
(XXX) 62137 (1S,2Z)-4-{[(2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-yl]amino}-1-methyl-4-oxo-2-butenyl acetate C33H54INO7Si 详情 详情
(XXXI) 62138 (1S,2Z)-4-{[(2R,3R,5S,6S)-2,5-dimethyl-6-((2E,4E)-3-methyl-5-{(3R,4R,5R)-7-methylene-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-2,4-pentadienyl)tetrahydro-2H-pyran-3-yl]amino}-1-methyl-4-oxo-2-butenyl acetate C33H53NO7Si 详情 详情
(XXXII) 62139 (1S,2Z)-4-[((2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7-methylene-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadienyl}-2,5-dimethyltetrahydro-2H-pyran-3-yl)amino]-1-methyl-4-oxo-2-butenyl acetate C27H39NO7 详情 详情

合成路线5

In a different synthetic strategy, the known Garner's aldehyde (I) is subjected to a Wittig reaction with phosphorane (II) to give the unsaturated ester (III), which is subsequently hydrogenated, producing (IV) as an inseparable mixture of diastereoisomers. Oxazolidine hydrolysis in (IV), followed by cyclization under acidic conditions leads to lactone (V). This is then converted to the thiolactone (VI) upon treatment with Lawesson's reagent in hot toluene. Condensation of thiolactone (VI) with the Wittig reagent (VII), followed by double bond isomerization in the presence of DBU furnishes the dihydropyran derivative (VIII). Stereoselective hydrogenation of the double bond of (VIII) with PtO2 gives rise to the desired all-cis isomer (IX). The methyl vester group of (IX) is then reduced to aldehyde (X) by means of DIBAL in cold toluene.

1 Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T.; A synthesis of FR901464. Tetrahedron Lett 2001, 42, 46, 8207.
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) 62140 tert-butyl (4S,5R)-4-formyl-2,2,5-trimethyl-1,3-oxazolidine-3-carboxylate C12H21NO4 详情 详情
(II) 37071 ethyl 2-(triphenylphosphoranylidene)propanoate 5717-37-3 C23H23O2P 详情 详情
(III) 62141 tert-butyl (4R,5R)-4-[(E)-3-ethoxy-2-methyl-3-oxo-1-propenyl]-2,2,5-trimethyl-1,3-oxazolidine-3-carboxylate C17H29NO5 详情 详情
(IV) 62142 tert-butyl (4R,5R)-4-(3-ethoxy-2-methyl-3-oxopropyl)-2,2,5-trimethyl-1,3-oxazolidine-3-carboxylate C17H31NO5 详情 详情
(V) 62143 tert-butyl (2R,3R)-2,5-dimethyl-6-oxotetrahydro-2H-pyran-3-ylcarbamate C12H21NO4 详情 详情
(VI) 62144 tert-butyl (2R,3R,5R)-2,5-dimethyl-6-thioxotetrahydro-2H-pyran-3-ylcarbamate C12H21NO3S 详情 详情
(VII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane;Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(VIII) 62145 methyl 2-{(2R,3R)-3-[(tert-butoxycarbonyl)amino]-2,5-dimethyl-3,4-dihydro-2H-pyran-6-yl}acetate C15H25NO5 详情 详情
(IX) 62146 methyl 2-{(2S,3S,5R,6R)-5-[(tert-butoxycarbonyl)amino]-3,6-dimethyltetrahydro-2H-pyran-2-yl}acetate C15H27NO5 详情 详情
(X) 62147 tert-butyl (2R,3R,5S,6S)-2,5-dimethyl-6-(2-oxoethyl)tetrahydro-2H-pyran-3-ylcarbamate C14H25NO4 详情 详情

合成路线6

Wittig reaction of aldehyde (X) with phosphorane (II) produces the unsaturated ester (XI), which is further reduced to the allylic alcohol (XII) with DIBAL in toluene. Treatment of (XII) with CBr4 and PPh3 leads to allyl bromide (XIII). This is then condensed with sodium p-toluenesulfinate (XIV), providing sulfone (XV). Subsequent acidic Boc group cleavage gives amine (XVI).

1 Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T.; A synthesis of FR901464. Tetrahedron Lett 2001, 42, 46, 8207.
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) 37071 ethyl 2-(triphenylphosphoranylidene)propanoate 5717-37-3 C23H23O2P 详情 详情
(X) 62147 tert-butyl (2R,3R,5S,6S)-2,5-dimethyl-6-(2-oxoethyl)tetrahydro-2H-pyran-3-ylcarbamate C14H25NO4 详情 详情
(XI) 62148 ethyl (E)-4-{(2S,3S,5R,6R)-5-[(tert-butoxycarbonyl)amino]-3,6-dimethyltetrahydro-2H-pyran-2-yl}-2-methyl-2-butenoate C19H33NO5 详情 详情
(XII) 62149 tert-butyl (2R,3R,5S,6S)-6-[(E)-4-hydroxy-3-methyl-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran-3-ylcarbamate C17H31NO4 详情 详情
(XIII) 62150 tert-butyl (2R,3R,5S,6S)-6-[(E)-4-bromo-3-methyl-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran-3-ylcarbamate C17H30BrNO3 详情 详情
(XIV) 62151 4-methylbenzenesulfinate C7H7O2S 详情 详情
(XV) 62152 tert-butyl (2R,3R,5S,6S)-2,5-dimethyl-6-{(E)-3-methyl-4-[(4-methylphenyl)sulfonyl]-2-butenyl}tetrahydro-2H-pyran-3-ylcarbamate C24H37NO5S 详情 详情
(XVI) 62153 (2R,3R,5S,6S)-2,5-dimethyl-6-{(E)-3-methyl-4-[(4-methylphenyl)sulfonyl]-2-butenyl}tetrahydro-2H-pyran-3-amine; (2R,3R,5S,6S)-2,5-dimethyl-6-{(E)-3-methyl-4-[(4-methylphenyl)sulfonyl]-2-butenyl}tetrahydro-2H-pyran-3-ylamine C19H29NO3S 详情 详情

合成路线7

Horner-Emmons condensation of aldehyde (XVII) with phosphonate (XVIII) gives rise to the Z-olefin (XIX). After ester group hydrolysis, the resultant carboxylic acid (XX) is coupled to amine (XVI) by using HBTU to produce amide (XXI).

1 Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T.; A synthesis of FR901464. Tetrahedron Lett 2001, 42, 46, 8207.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 62153 (2R,3R,5S,6S)-2,5-dimethyl-6-{(E)-3-methyl-4-[(4-methylphenyl)sulfonyl]-2-butenyl}tetrahydro-2H-pyran-3-amine; (2R,3R,5S,6S)-2,5-dimethyl-6-{(E)-3-methyl-4-[(4-methylphenyl)sulfonyl]-2-butenyl}tetrahydro-2H-pyran-3-ylamine C19H29NO3S 详情 详情
(XVII) 62154 (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}propanal C19H24O2Si 详情 详情
(XVIII) 62155 ethyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate C8H11F6O5P 详情 详情
(XIX) 62156 ethyl (Z,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-pentenoate C23H30O3Si 详情 详情
(XX) 62157 (Z,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-pentenoic acid C21H26O3Si 详情 详情
(XXI) 62158 (Z,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-N-((2R,3R,5S,6S)-2,5-dimethyl-6-{(E)-3-methyl-4-[(4-methylphenyl)sulfonyl]-2-butenyl}tetrahydro-2H-pyran-3-yl)-2-pentenamide C40H53NO5SSi 详情 详情

合成路线8

2-Deoxy-D-glucose (XXII) is protected as the cyclic acetal (XXIV) employing p methoxybenzaldehyde dimethyl acetal (XXIII) in the presence of TsOH. Subsequent oxidation of the anomeric hydroxyl group of (XXIV) with Br2 leads to lactone (XXV). After protection of the remaining 3-hydroxyl group of (XXV) as the silyl ether (XXVI), olefination with the Tebbe reagent provides the exocyclic vinyl ether (XXVII). Treatment of (XXVII) with PPTS and MeOH affords a separable mixture of epimeric methylketals (XXVIII). Desilylation of the desired isomer yields alcohol (XXIX), which is then oxidized to ketone (XXX) employing the Dess-Martin periodinane reagent.

1 Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T.; A synthesis of FR901464. Tetrahedron Lett 2001, 42, 46, 8207.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 62159 (4R,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol C6H12O5 详情 详情
(XXIII) 26485 1-(dimethoxymethyl)-4-methoxybenzene 2186-92-7 C10H14O3 详情 详情
(XXIV) 62160 (4aR,8R,8aS)-2-(4-methoxyphenyl)hexahydropyrano[3,2-d][1,3]dioxine-6,8-diol C14H18O6 详情 详情
(XXV) 62161 (4aR,8R,8aS)-8-hydroxy-2-(4-methoxyphenyl)tetrahydropyrano[3,2-d][1,3]dioxin-6(4H)-one C14H16O6 详情 详情
(XXVI) 62162 (4aR,8R,8aR)-8-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methoxyphenyl)tetrahydropyrano[3,2-d][1,3]dioxin-6(4H)-one C20H30O6Si 详情 详情
(XXVII) 62163 {[(4aR,8R,8aR)-2-(4-methoxyphenyl)-6-methylenehexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}(tert-butyl)dimethylsilane; 4-((4aR,8R,8aR)-8-{[tert-butyl(dimethyl)silyl]oxy}-6-methylenehexahydropyrano[3,2-d][1,3]dioxin-2-yl)phenyl methyl ether C21H32O5Si 详情 详情
(XXVIII) 62164 4-((4aR,8R,8aR)-8-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-6-methylhexahydropyrano[3,2-d][1,3]dioxin-2-yl)phenyl methyl ether; {[(4aR,8R,8aR)-6-methoxy-2-(4-methoxyphenyl)-6-methylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}(tert-butyl)dimethylsilane C22H36O6Si 详情 详情
(XXIX) 62165 (4aR,6S,8R,8aS)-6-methoxy-2-(4-methoxyphenyl)-6-methylhexahydropyrano[3,2-d][1,3]dioxin-8-ol C16H22O6 详情 详情
(XXX) 62166 (4aR,6S,8aR)-6-methoxy-2-(4-methoxyphenyl)-6-methyltetrahydropyrano[3,2-d][1,3]dioxin-8(4H)-one C16H20O6 详情 详情

合成路线9

Tebbe methylenation of ketone (XXX) gives the exo-olefin (XXXI). The p methoxybenzylidene acetal moiety of (XXXI) is then reduced with DIBAL to generate the p-methoxybenzyl ether (XXXII). The free hydroxyl group of (XXXII) is then acylated with pivaloyl chloride, providing pivalate ester (XXXIII). Removal of the p-methoxybenzyl group of (XXXIII) by treatment with DDQ, followed by reprotection of the resultant alcohol (XXXIV) with t-butyldimethylsilyl triflate leads to silyl ether (XXXV). The pivalate ester group of (XXXV) is then cleaved by treatment with DIBAL to afford alcohol (XXXVI), which is oxidized to aldehyde (XXXVII) by using the Dess-Martin periodinane.

1 Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T.; A synthesis of FR901464. Tetrahedron Lett 2001, 42, 46, 8207.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXX) 62166 (4aR,6S,8aR)-6-methoxy-2-(4-methoxyphenyl)-6-methyltetrahydropyrano[3,2-d][1,3]dioxin-8(4H)-one C16H20O6 详情 详情
(XXXI) 62167 (4aR,6S,8aS)-6-methoxy-2-(4-methoxyphenyl)-6-methyl-8-methylenehexahydropyrano[3,2-d][1,3]dioxine; 4-[(4aR,6S,8aS)-6-methoxy-6-methyl-8-methylenehexahydropyrano[3,2-d][1,3]dioxin-2-yl]phenyl methyl ether C17H22O5 详情 详情
(XXXII) 62168 {(2R,3S,6S)-6-methoxy-3-[(4-methoxybenzyl)oxy]-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl}methanol C17H24O5 详情 详情
(XXXIII) 62169 {(2R,3S,6S)-6-methoxy-3-[(4-methoxybenzyl)oxy]-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl}methyl pivalate C22H32O6 详情 详情
(XXXIV) 62170 [(2R,3S,6S)-3-hydroxy-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl]methyl pivalate C14H24O5 详情 详情
(XXXV) 62171 ((2R,3S,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl)methyl pivalate C20H38O5Si 详情 详情
(XXXVI) 62172 ((2R,3S,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl)methanol C15H30O4Si 详情 详情
(XXXVII) 62173 (2S,3S,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-carbaldehyde C15H28O4Si 详情 详情

合成路线10

Condensation of sulfone (XXI) with aldehyde (XXXVII), followed by treatment with benzoyl chloride affords adduct (XXXVIII). Reductive elimination of sulfone (XXXVIIII) with sodium amalgam leads to the conjugated diene (XXXIX). Both O-silyl groups of (XXXIX) are removed by treatment with tetrabutylammonium fluoride, providing diol (XL). Then, esterification of (XL) with acetic anhydride and DMAP furnishes diacetate (XLI).

1 Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T.; A synthesis of FR901464. Tetrahedron Lett 2001, 42, 46, 8207.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 62158 (Z,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-N-((2R,3R,5S,6S)-2,5-dimethyl-6-{(E)-3-methyl-4-[(4-methylphenyl)sulfonyl]-2-butenyl}tetrahydro-2H-pyran-3-yl)-2-pentenamide C40H53NO5SSi 详情 详情
(XXVII) 62173 (2S,3S,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-carbaldehyde C15H28O4Si 详情 详情
(XXXVIII) 62174 (1S,3E)-1-((2R,3S,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl)-5-{(2S,3S,5R,6R)-5-[((Z,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-pentenoyl)amino]-3,6-dimethyltetrahydro-2H-pyran-2-yl}-3-methyl-2-[(4-methylphenyl)sulfonyl]-3-pentenyl benzoate C62H85NO10SSi2 详情 详情
(XXXIX) 62175 (Z,4S)-N-{(2R,3R,5S,6S)-6-[(2E,4E)-5-((2R,3S,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl)-3-methyl-2,4-pentadienyl]-2,5-dimethyltetrahydro-2H-pyran-3-yl}-4-{[tert-butyl(diphenyl)silyl]oxy}-2-pentenam C48H73NO6Si2 详情 详情
(XL) 62176 (Z,4S)-4-hydroxy-N-((2R,3R,5S,6S)-6-{(2E,4E)-5-[(2R,3S,6S)-3-hydroxy-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl]-3-methyl-2,4-pentadienyl}-2,5-dimethyltetrahydro-2H-pyran-3-yl)-2-pentenamide C26H41NO6 详情 详情
(XLI) 62177 (1S,2Z)-4-[((2R,3R,5S,6S)-6-{(2E,4E)-5-[(2R,3S,6S)-3-(acetyloxy)-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl]-3-methyl-2,4-pentadienyl}-2,5-dimethyltetrahydro-2H-pyran-3-yl)amino]-1-methyl-4-oxo-2-butenyl acetate C30H45NO8 详情 详情

合成路线11

Treatment of diester (XLI) with LiOH produces a mixture of hydrolyzed products, from which the desired mono-acetylated compound (XLII) can be separated from its mono-acetyl regiosiomer and the fully hydrolyzed product. Epoxidation of the exocyclic olefin (XLII) with m-CPBA furnishes diastereoselectively epoxide (XLIII). Finally, deacetylation of the methyl ketal (XLIII) to the target hemiketal compound is achieved by treatment with an acidic cation-exchange resin in wet THF.

1 Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T.; A synthesis of FR901464. Tetrahedron Lett 2001, 42, 46, 8207.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLI) 62177 (1S,2Z)-4-[((2R,3R,5S,6S)-6-{(2E,4E)-5-[(2R,3S,6S)-3-(acetyloxy)-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl]-3-methyl-2,4-pentadienyl}-2,5-dimethyltetrahydro-2H-pyran-3-yl)amino]-1-methyl-4-oxo-2-butenyl acetate C30H45NO8 详情 详情
(XLII) 62178 (1S,2Z)-4-[((2R,3R,5S,6S)-6-{(2E,4E)-5-[(2R,3S,6S)-3-hydroxy-6-methoxy-6-methyl-4-methylenetetrahydro-2H-pyran-2-yl]-3-methyl-2,4-pentadienyl}-2,5-dimethyltetrahydro-2H-pyran-3-yl)amino]-1-methyl-4-oxo-2-butenyl acetate C28H43NO7 详情 详情
(XLIII) 62179 (1S,2Z)-4-[((2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-4-hydroxy-7-methoxy-7-methyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadienyl}-2,5-dimethyltetrahydro-2H-pyran-3-yl)amino]-1-methyl-4-oxo-2-butenyl acetate C28H43NO8 详情 详情
Extended Information