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【结 构 式】 
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【分子编号】55468 【品名】2-(triphenylphosphoranylidene)acetaldehyde 【CA登记号】 |
【 分 子 式 】C20H17OP 【 分 子 量 】304.328142 【元素组成】C 78.93% H 5.63% O 5.26% P 10.18% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)The enantioselective condensation of 3-(trimethylsilyl)propynal (V) with allylmagnesium bromide (VI) by means of (+)-Ipc2B-OMe as chiral catalyst gives hex-5-en-1-yn-3(R)-ol (VII), which is silylated with Tbdps-Cl and imidazole to yield the silyl ether (VIII). The oxidation of the terminal double bond of (VII) by means of OsO4 and NaIO4 affords the aldehyde (IX), which is submitted to a Wittig condensation with the phosphorane (X) in benzene to provide the unsaturated ester (XI). The enantioselective dihydroxylation of the double bond of (XI) with AD-mix-beta in tert-butanol/water gives the dihydroxyester (XII), which is protected with 2-methoxypropene (XIII) and PPTS to yield the isopropylidene ketal (XIV). The bromination of the triple bond of (XIV), followed by selective hydrogenation, affords the cis-bromovinyl compound (XV), whose ester group is reduced with LiAlH4 in THF to provide the primary alcohol (XVI). The oxidation of (XVI) with (COCl)2 and TEA in DMSO gives the carbaldehyde (XVII), which is submitted to a Wittig condensation with the phosphorane (XVIII) in hot dichloromethane to yield the diunsaturated aldehyde (XIX). The enantioselective condensation of aldehyde (XIX) with allylmagnesium bromide catalyzed by (+)Ipc2-B-OMe affords the chiral alcohol (XX), which is esterified with acryloyl chloride (XXI) and DIEA in dichloromethane to provide the ester (XXII). Compound (XXII) is submitted to a ring-closing metathesis catalyzed by a Rh catalyst (Grubbs's catalyst), yielding the dihydropyran derivative (XXIII), which is submitted to cleavage of the acetonide group by means of Montmorillonite K 10 to afford the diol (XXIV). The condensation of the bromovinyl group of (XXIV) with the intermediate boronic ester (IV) by means of Pd(PPh3)4 and Ag2O gives compound (XXV) with the complete backbone of the target fostriecin. The selective monosilylation of (XXV) with Tbdps-OTf gives the intermediate (XXVI).
| 【1】 Falck, J.R.; Reddy, Y.K.; Asymmetric total synthesis of (+)-fostriecin. Org Lett 2002, 4, 6, 969. |
| 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) | 55458 | tert-butyl(diphenyl){[(2E,4Z)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-pentadienyl]oxy}silane; tert-butyl(diphenyl)silyl (2E,4Z)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-pentadienyl ether | C27H37BO3Si | 详情 | 详情 | |
| (V) | 20043 | 3-(trimethylsilyl)-2-propynal | C6H10OSi | 详情 | 详情 | |
| (VI) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (VII) | 55459 | (3R)-5-hexen-1-yn-3-ol | C6H8O | 详情 | 详情 | |
| (VIII) | 55460 | tert-butyl(diphenyl)silyl (1R)-1-ethynyl-3-butenyl ether; tert-butyl{[(1R)-1-ethynyl-3-butenyl]oxy}diphenylsilane | C22H26OSi | 详情 | 详情 | |
| (IX) | 55461 | (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-4-pentynal | C21H24O2Si | 详情 | 详情 | |
| (X) | 37071 | ethyl 2-(triphenylphosphoranylidene)propanoate | 5717-37-3 | C23H23O2P | 详情 | 详情 |
| (XI) | 55462 | ethyl (E,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-2-methyl-2-hepten-6-ynoate | C26H32O3Si | 详情 | 详情 | |
| (XII) | 55463 | ethyl (2S,3R,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydroxy-2-methyl-6-heptynoate | C26H34O5Si | 详情 | 详情 | |
| (XIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XIV) | 55464 | ethyl (4S,5R)-5-((2R)-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butynyl)-2,2,4-trimethyl-1,3-dioxolane-4-carboxylate | C29H38O5Si | 详情 | 详情 | |
| (XV) | 55465 | ethyl (4S,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolane-4-carboxylate | C29H39BrO5Si | 详情 | 详情 | |
| (XVI) | 55466 | [(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methanol | C27H37BrO4Si | 详情 | 详情 | |
| (XVII) | 55467 | (4S,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde | C27H35BrO4Si | 详情 | 详情 | |
| (XVIII) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (XIX) | 55469 | (E)-3-[(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-propenal | C29H37BrO4Si | 详情 | 详情 | |
| (XX) | 55470 | (1E,3R)-1-[(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]-1,5-hexadien-3-ol | C32H43BrO4Si | 详情 | 详情 | |
| (XXI) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XXII) | 55471 | (1R)-1-{(E)-2-[(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]ethenyl}-3-butenyl acrylate | C35H45BrO5Si | 详情 | 详情 | |
| (XXIII) | 55472 | (6R)-6-{(E)-2-[(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]ethenyl}-5,6-dihydro-2H-pyran-2-one | C33H41BrO5Si | 详情 | 详情 | |
| (XXIV) | 55473 | (6R)-6-((1E,3R,4R,6R,7Z)-8-bromo-6-{[tert-butyl(diphenyl)silyl]oxy}-3,4-dihydroxy-3-methyl-1,7-octadienyl)-5,6-dihydro-2H-pyran-2-one | C30H37BrO5Si | 详情 | 详情 | |
| (XXV) | 55474 | (6R)-6-((1E,3R,4R,6R,7Z,9Z,11E)-6,13-bis{[tert-butyl(diphenyl)silyl]oxy}-3,4-dihydroxy-3-methyl-1,7,9,11-tridecatetraenyl)-5,6-dihydro-2H-pyran-2-one | C51H62O6Si2 | 详情 | 详情 | |
| (XXVI) | 55475 | (6R)-6-((1E,3R,4R,6R,7Z,9Z,11E)-3,6,13-tris{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxy-3-methyl-1,7,9,11-tridecatetraenyl)-5,6-dihydro-2H-pyran-2-one | C67H80O6Si3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Free radical bromination of 3-tolunitrile gives 3-cyanobenzyl bromide, which is oxidized with hexamine/acetic acid to 3-cyanobenzaldehyde. A Knoevenagel reaction with malonic acid then gives 3-cyanocinnamic acid, which is reduced to the alcohol via the acid chloride. The tetrazole ring is formed by reaction of the alcohol with sodium azide and triethylamine hydrogen chloride in dimethyl acetamide. This tetrazole group is then protected using trityl chloride and triethylamine in dichloromethane. The key chiral epoxidation is conducted using tert-butyl hydroperoxide and catalytic quantities of diisopropyl L-tartrate and titanium (IV) isopropoxide. A Swern oxidation then gives the aldehyde, which is homolagated to the trans-alpha,beta-unsaturated aldehyde using the formyl methylene ylid. This aldehyde is then reacted at -100 C with the ylid formed from n-decylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF. A base catalyzed Sn2 reaction between the diene epoxide and methyl 3-thiopropionate in methanol gives the protected analogue of LY-170680. Finally, the protecting groups are removed using acid ion exchange resin followed by base hydrolysis in methanol/water. After chromatography LY-170680 is crystallized from acetone/hexane.
| 【1】 Wishart, G.; Baker, S.R.; Lucas, R.; Boot, J.R.; Sulukast. Drugs Fut 1991, 16, 5, 432. |
| 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) | 13243 | m-Tolunitrile; 3-Methylbenzonitrile | 620-22-4 | C8H7N | 详情 | 详情 |
| (II) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (III) | 13245 | 3-Formylbenzonitrile; 3-Cyanobenzaldehyde | 24964-64-5 | C8H5NO | 详情 | 详情 |
| (IV) | 13246 | (E)-3-(3-Cyanophenyl)-2-propenoic acid | C10H7NO2 | 详情 | 详情 | |
| (V) | 13247 | (E)-3-(3-Cyanophenyl)-2-propenoyl chloride | C10H6ClNO | 详情 | 详情 | |
| (VI) | 13248 | 3-[(E)-3-Hydroxy-1-propenyl]benzonitrile | C10H9NO | 详情 | 详情 | |
| (VII) | 13249 | (E)-3-[3-(1H-1,2,3,4-Tetraazol-5-yl)phenyl]-2-propen-1-ol | C10H10N4O | 详情 | 详情 | |
| (VIII) | 13250 | (E)-3-[3-(2-trityl-2H-1,2,3,4-Tetraazol-5-yl)phenyl]-2-propen-1-ol | C29H24N4O | 详情 | 详情 | |
| (IX) | 13251 | [(2S,3S)-3-[3-(2-trityl-2H-1,2,3,4-Tetraazol-5-yl)phenyl]oxiranyl]methanol | C29H24N4O2 | 详情 | 详情 | |
| (X) | 13252 | (2R,3S)-3-[3-(2-trityl-2H-1,2,3,4-Tetraazol-5-yl)phenyl]-2-oxiranecarbaldehyde | C29H22N4O2 | 详情 | 详情 | |
| (XI) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (XII) | 13253 | (E)-3-[(2S,3S)-3-[3-(2-trityl-2H-1,2,3,4-Tetraazol-5-yl)phenyl]oxiranyl]-2-propenal | C31H24N4O2 | 详情 | 详情 | |
| (XIII) | 13254 | 5-(3-[(2S,3S)-3-[(1E,3Z)-1,3-Tridecadienyl]oxiranyl]phenyl)-2-trityl-2H-1,2,3,4-tetraazole | C41H44N4O | 详情 | 详情 | |
| (XIV) | 13255 | methyl 3-[((1R,2E,4Z)-1-[(S)-hydroxy[3-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)phenyl]methyl]-2,4-tetradecadienyl)sulfanyl]propanoate | C45H52N4O3S | 详情 | 详情 | |
| (XV) | 13256 | methyl 3-[((1R,2E,4Z)-1-[(S)-hydroxy[3-(1H-1,2,3,4-tetraazol-5-yl)phenyl]methyl]-2,4-tetradecadienyl)sulfanyl]propanoate | C26H38N4O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The lithium derivative of 4-picoline (I) was acylated with ethyl 4-fluorobenzoate (II) to afford ketone (III). Condensation of (III) with dimethylformamide dimethylacetal provided enaminone (IV) which was subsequently cyclized with hydroxylamine to give the diaryl isoxazole (V). Isoxazole ring opening in (V) under basic conditions led to keto nitrile (VI). Chlorination of (VI) by means of POCl3, followed by reaction with hydrazine, furnished the amino pyrazole (VII). The diazonium salt (VIII) prepared from amino pyrazole (VII) was then added to the phosphorane aldehyde (IX) to generate the pyrazolotriazine (X). Hydrogenation of the triazine ring of (X) employing NaBH3CN produced the tetrahydro pyrazolotriazine (XI). This was finally acylated by phenylglyoxylic acid (XII) to yield the target alpha-oxo amide.
| 【1】 Kawai, Y.; Yamazaki, H.; Tanaka, H.; Oku, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolitriazines with interleukin-1 and tumour necrosis factor inhibitory activity. EP 0686156; JP 1996507056; WO 9419350 . |
| 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) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (II) | 22830 | ethyl 4-fluorobenzoate | 451-46-7 | C9H9FO2 | 详情 | 详情 |
| (III) | 45005 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C13H10FNO | 详情 | 详情 | |
| (IV) | 55996 | (Z)-3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridinyl)-2-propen-1-one | C16H15FN2O | 详情 | 详情 | |
| (V) | 55997 | 4-[5-(4-fluorophenyl)-4-isoxazolyl]pyridine | C14H9FN2O | 详情 | 详情 | |
| (VI) | 55998 | 3-(4-fluorophenyl)-3-oxo-2-(4-pyridinyl)propanenitrile | C14H9FN2O | 详情 | 详情 | |
| (VII) | 55999 | 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-ylamine; 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine | C14H11FN4 | 详情 | 详情 | |
| (VIII) | 56000 | 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-diazonium | C14H9FN5 | 详情 | 详情 | |
| (IX) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (X) | 56001 | 7-(4-fluorophenyl)-8-(4-pyridinyl)pyrazolo[5,1-c][1,2,4]triazine | C16H10FN5 | 详情 | 详情 | |
| (XI) | 56002 | 7-(4-fluorophenyl)-8-(4-pyridinyl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine | C16H14FN5 | 详情 | 详情 | |
| (XII) | 55589 | Benzoylformic acid; Phenylglyoxylic acid | 611-73-4 | C8H6O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)The reaction of benzyl alpha-D-mannopyranoside (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is treated with 2,2-dimethoxypropane (III) and CSA in dichloromethane to yield the acetonide (IV). The oxidation of the free OH group of (IV) with PCC in dichloromethane affords the ketone (V), which is reduced with NaBH4 to provide benzyl 6-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-alpha-D-talopyranoside (VI) with inverted configuration at C4. The reaction of (VI) with Tf2O and pyridine gives the triflate (VII), which is treated with NaN3 in DMF to yield the 4-azido derivative (VIII) with a new inversion of configuration at C4. The reaction of (VIII) with TBAF, followed by oxidation with PCC afforded the carbaldehyde (IX), which is condensed with the phosphorane (X) to provide the unsaturated azidoaldehyde (XI). The treatment of (XI) with H2 over Pd/C in methanol produces the reduction of the double bond, the reduction of the azide group to amine, and subsequent reductive cyclization of the resulting aminoaldehyde to give the perhydropyranopyridine derivative (XII). Further reductive debenzylation of (XII) with H2 over Pd/C in AcOH produces the formation of a lactol in equilibrium with the open chain aminoaldehyde (XIII), which undergoes a reductive amination to form the acetonide of swainsonine (XIV). Finally, this acetonide is decomposed by reaction with TFA to afford the target swainsonine.
| 【1】 Bashyal, B.P.; et al.; Synthesis of the alpha-mannosidase inhibitors swainsonine [(1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine and 1,4-dideoxy-1,4-imino-D-mannitol from mannose. Tetrahedron 1987, 43, 13, 3083. |
| 【2】 Fleet, G.W.J.; et al.; Enantiospecific synthesis of swainsonine (1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine, from D-mannose. Tetrahedron Lett 1984, 25, 17, 1853. |
| 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) | 62617 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol | C13H18O6 | 详情 | 详情 | |
| (II) | 62618 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)tetrahydro-2H-pyran-3,4,5-triol | C29H36O6Si | 详情 | 详情 | |
| (III) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 62619 | (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C32H40O6Si | 详情 | 详情 | |
| (V) | 62620 | (3aS,4S,6R,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one | C32H38O6Si | 详情 | 详情 | |
| (VI) | 62621 | (3aS,4S,6R,7S,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C32H40O6Si | 详情 | 详情 | |
| (VII) | 62622 | (3aS,4S,6R,7S,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trifluoromethanesulfonate | C33H39F3O8SSi | 详情 | 详情 | |
| (VIII) | 62623 | [(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methyl tert-butyl(diphenyl)silyl ether; {[(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methoxy}(tert-butyl)diphenylsilane | C32H39N3O5Si | 详情 | 详情 | |
| (IX) | 62624 | (3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-carbaldehyde | C16H19N3O5 | 详情 | 详情 | |
| (X) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (XI) | 62625 | (E)-3-[(3aS,4S,6R,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]-2-propenal | C18H21N3O5 | 详情 | 详情 | |
| (XII) | 62626 | (3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine | C18H25NO4 | 详情 | 详情 | |
| (XIII) | 62627 | (4S,5S)-5-[(2R,3R)-3-hydroxypiperidinyl]-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | C11H19NO4 | 详情 | 详情 | |
| (XIV) | 62616 | (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol | C11H19NO3 | 详情 | 详情 |