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【结 构 式】 
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【分子编号】39163 【品名】(methoxymethyl)(triphenyl)phosphonium chloride 【CA登记号】4009-98-7 |
【 分 子 式 】C20H20ClOP 【 分 子 量 】342.804662 【元素组成】C 70.07% H 5.88% Cl 10.34% O 4.67% P 9.04% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The (+)-isolimonene (I) was submitted to a regioselective hydroboration with dicyclohexylborane to give the alcohol (II), which was oxidized with CrO3 to the corresponding carboxylic acid (III). The iodolactonization of (III) by means of KI, I2 and NaHCO3 yielded a separable, diastereomeric mixture of iodolactones (IV) + (V). The suitable isomer (IV) was condensed with methyl vinyl ketone (VI) by means of tris(trimethylsilyl)silane and AIBN in refluxing toluene to afford the alkylated lactone (VII) as an inseparable diastereomeric mixture. The ketonic group of (VII) was treated with ethanedithiol (VIII) and BF3/Et2O in dichloromethane to provide a separable mixture of thioketal lactones (IX)+(X). The suitable isomer (X) was hydrolyzed with NaOH in refluxing methanol to give the hydroxyacid (XI), which was treated with diazomethane to yield the corresponding methyl ester (XII). The oxidation of the OH group of (XII) by means of PCC affords the ketoester (XIII), which is submitted to a Wittig condensation with methoxymethyltriphenylphosphonium chloride (XIV) by means of KHMDS in THF/HMPA to provide the methoxymethylene derivative (XV). The cleavage of the dithioketal group of (XV) by means of HgCl2 and CaCO3 in acetonitrile regenerates the keto group giving compound (XVI), which is finally transformed into the target (+)-artemisinin by photooxidation with O2 in methanol in the presence of Rose Bengal, followed by a treatment with 70 % HClO4.
| 【1】 Yadav, J.S.; et al.; Stereoselective total synthesis of (+)-artemisinin. Tetrahedron Lett 2003, 44, 2, 387. |
| 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) | 61739 | (1R)-(+)-trans-Isolimonene; (+)-p-Mentha-2,8-diene; (1R)-(+)-trans-Isolimonene with G.C. | 5113-87-1 | C10H16 | 详情 | 详情 |
| (II) | 61740 | (2S)-2-[(1R,4R)-4-methyl-2-cyclohexen-1-yl]-1-propanol | C10H18O | 详情 | 详情 | |
| (III) | 61741 | (2S)-2-[(1R,4R)-4-methyl-2-cyclohexen-1-yl]propanoic acid | C10H16O2 | 详情 | 详情 | |
| (IV) | 61742 | (3aS,6R,7R,7aR)-7-iodo-3,6-dimethylhexahydro-1-benzofuran-2(3H)-one | C10H15IO2 | 详情 | 详情 | |
| (V) | 61743 | (3S,3aS,6R,7R,7aR)-7-iodo-3,6-dimethylhexahydro-1-benzofuran-2(3H)-one | C10H15IO2 | 详情 | 详情 | |
| (VI) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (VII) | 61744 | (3aS,6R,7aS)-3,6-dimethyl-7-(3-oxobutyl)hexahydro-1-benzofuran-2(3H)-one | C14H22O3 | 详情 | 详情 | |
| (VIII) | 27313 | 1,2-ethanedithiol | 540-63-6 | C2H6S2 | 详情 | 详情 |
| (IX) | 61745 | (3aS,6R,7R,7aS)-3,6-dimethyl-7-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]hexahydro-1-benzofuran-2(3H)-one | C16H26O2S2 | 详情 | 详情 | |
| (X) | 61746 | (3aS,6R,7S,7aS)-3,6-dimethyl-7-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]hexahydro-1-benzofuran-2(3H)-one | C16H26O2S2 | 详情 | 详情 | |
| (XI) | 61747 | 2-{(1S,2S,3S,4R)-2-hydroxy-4-methyl-3-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]cyclohexyl}propanoic acid | C16H28O3S2 | 详情 | 详情 | |
| (XII) | 61748 | methyl 2-{(1S,2S,3S,4R)-2-hydroxy-4-methyl-3-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]cyclohexyl}propanoate | C17H30O3S2 | 详情 | 详情 | |
| (XIII) | 61749 | methyl 2-{(1S,3S,4R)-4-methyl-3-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]-2-oxocyclohexyl}propanoate | C17H28O3S2 | 详情 | 详情 | |
| (XIV) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XV) | 61750 | methyl 2-{(1S,3S,4R)-2-[(E)-methoxymethylidene]-4-methyl-3-[2-(2-methyl-1,3-dithiolan-2-yl)ethyl]cyclohexyl}propanoate | C19H32O3S2 | 详情 | 详情 | |
| (XVI) | 10239 | methyl 2-[(1S,3S,4R)-2-[(Z)-methoxymethylidene]-4-methyl-3-(3-oxobutyl)cyclohexyl]propanoate | C17H28O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(F)The reduction of ethylene ketal (XXI) with LiAlH4 produces the hydroxymethyl compound (XXII), which by selective tosylation with tosyl chloride yields the tosyloxymethyl compound (XXIII). The cyclization of (XXIII) with NaH in DMF affords the epoxy methane derivative (XXIV), which is deprotected by treatment with piruvic acid (D) in THF to give 2-(3-hydroxy-1-octen-1-yl)-3,5-epoxymethanocyclopentane-1-carboxaldehyde (XXV). The selective protection of the hydroxyl group of (XXV) with ethyl vinyl ether (E) affords the 1-ethoxyethoxy compound (XXVI), which is submitted to homologation in the aldehyde group by treatment with methoxymethylene-triphenylphosphorane (F) and butyllithium in THF, followed by hydrolysis of the non-isolated enol ether with mercuric acetate - water to give the acetaldehyde homolog (XXVII). The Wittig reaction of (XXVII) with 4-carboxybutyltriphenylphosphonium chloride (G) and NaH in DMSO yields 9,11-dideoxy-11alpha,9alpha-epoxymethano-15-(1-ethoxyethoxy)-PGE2 (XXVIII), which is finally deprotected by treatment with acetic acid in THF-water.
| 【1】 Trost, B.M.; et al.; An enantioconvergent approach to prostanoids. J Chem Soc Chem Commun 1978, 10, 436-438. |
| 【2】 Castaner, J.; Owen, R.T.; U-46619. Drugs Fut 1980, 5, 9, 453. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (D) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (F) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (G) | 39165 | (3-carboxypropyl)(triphenyl)phosphonium chloride | C22H22ClO2P | 详情 | 详情 | |
| (XXI) | 39157 | (1R,2R,3R,4S)-3-(1,3-dioxolan-2-yl)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-(methoxycarbonyl)cyclopentyl [1,1'-biphenyl]-4-carboxylate | C35H46O8 | 详情 | 详情 | |
| (XXII) | 39158 | (1R,2R,3S,4S)-3-(1,3-dioxolan-2-yl)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-(hydroxymethyl)cyclopentanol | C21H38O6 | 详情 | 详情 | |
| (XXIII) | 39159 | [(1S,2S,3R,4R)-2-(1,3-dioxolan-2-yl)-3-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-hydroxycyclopentyl]methyl 4-methylbenzenesulfonate | C28H44O8S | 详情 | 详情 | |
| (XXIV) | 39160 | (1S,2E)-3-[(1S,4R,5S,6R)-5-(1,3-dioxolan-2-yl)-2-oxabicyclo[2.2.1]hept-6-yl]-1-pentyl-2-propenyl 1-ethoxyethyl ether; (1S,4R,5S,6R)-5-(1,3-dioxolan-2-yl)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]heptane | C21H36O5 | 详情 | 详情 | |
| (XXV) | 39161 | (1S,4R,5S,6R)-6-[(E,3S)-3-hydroxy-1-octenyl]-2-oxabicyclo[2.2.1]heptane-5-carbaldehyde | C15H24O3 | 详情 | 详情 | |
| (XXVI) | 39162 | (1S,4R,5S,6R)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]heptane-5-carbaldehyde | C19H32O4 | 详情 | 详情 | |
| (XXVII) | 39164 | 2-[(1S,4R,5S,6S)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]acetaldehyde | C20H34O4 | 详情 | 详情 | |
| (XXVIII) | 39166 | (Z)-7-[(1S,4R,5S,6S)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid | C25H42O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXII)The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of KOtBu in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of TsOH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 【2】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 44545 | tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C40H58O3S2Si2 | 详情 | 详情 | |
| (XXIIIa) | 44546 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether | C40H58O3S2Si2 | 详情 | 详情 | |
| (IX) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 | |
| (X) | 44533 | (2S)-3-(benzyloxy)-2-methylpropanal | C11H14O2 | 详情 | 详情 | |
| (XI) | 44534 | (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane | C10H20O2Si | 详情 | 详情 | |
| (XII) | 44535 | (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one | C17H22O3 | 详情 | 详情 | |
| (XIII) | 44536 | (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol | C17H24O3 | 详情 | 详情 | |
| (XIV) | 44537 | (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol | C18H26O3 | 详情 | 详情 | |
| (XV) | 44538 | (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | C19H29IO4 | 详情 | 详情 | |
| (XVI) | 44539 | (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol | C19H30O4 | 详情 | 详情 | |
| (XVII) | 44540 | benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane | C37H44O4Si | 详情 | 详情 | |
| (XVIII) | 44541 | (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol | C39H48O3S2Si | 详情 | 详情 | |
| (XIX) | 44542 | (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether | C45H62O3S2Si2 | 详情 | 详情 | |
| (XX) | 44543 | (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol | C38H56O3S2Si2 | 详情 | 详情 | |
| (XXI) | 44544 | (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal | C38H54O3S2Si2 | 详情 | 详情 | |
| (XXII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXIV) | 44547 | (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal | C39H56O3S2Si2 | 详情 | 详情 | |
| (XXV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XXVI) | 44548 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether | C40H58O2S2Si2 | 详情 | 详情 | |
| (XXVII) | 44549 | tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C39H58O4Si2 | 详情 | 详情 | |
| (XXVIII) | 44550 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C52H75NO6SSi2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXVII)Synthesis of the thiazole intermediate (XXXIII): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with phosphonium salt (XXVII), LHMDS, Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX), which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI). The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII), which is acylated with Ac2O, TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 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) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XXIII) | 44520 | (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile | C9H10N2OS | 详情 | 详情 | |
| (XXIV) | 44521 | ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C11H15NO3S | 详情 | 详情 | |
| (XXV) | 44522 | ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C17H29NO3SSi | 详情 | 详情 | |
| (XXVI) | 44523 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal | C15H25NO2SSi | 详情 | 详情 | |
| (XXVII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXVIII) | 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 | |
| (XXIX) | 46122 | ethyl(triphenyl)phosphonium iodide | C20H20IP | 详情 | 详情 | |
| (XXX) | 46123 | tert-butyl(dimethyl)silyl (1S,3E)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole | C18H31NOSSi | 详情 | 详情 | |
| (XXXI) | 26246 | tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole | C18H30INOSSi | 详情 | 详情 | |
| (XXXII) | 46124 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol | C12H16INOS | 详情 | 详情 | |
| (XXXIII) | 46125 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate | C14H18INO2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXII)The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane to furnish the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 44545 | tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C40H58O3S2Si2 | 详情 | 详情 | |
| (XXIIIb) | 44546 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether | C40H58O3S2Si2 | 详情 | 详情 | |
| (IX) | 46125 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate | C14H18INO2S | 详情 | 详情 | |
| (X) | 44533 | (2S)-3-(benzyloxy)-2-methylpropanal | C11H14O2 | 详情 | 详情 | |
| (XI) | 44534 | (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane | C10H20O2Si | 详情 | 详情 | |
| (XII) | 44535 | (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one | C17H22O3 | 详情 | 详情 | |
| (XIII) | 44536 | (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol | C17H24O3 | 详情 | 详情 | |
| (XIV) | 44537 | (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol | C18H26O3 | 详情 | 详情 | |
| (XV) | 44538 | (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | C19H29IO4 | 详情 | 详情 | |
| (XVI) | 44539 | (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol | C19H30O4 | 详情 | 详情 | |
| (XVII) | 44540 | benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane | C37H44O4Si | 详情 | 详情 | |
| (XVIII) | 44541 | (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol | C39H48O3S2Si | 详情 | 详情 | |
| (XIX) | 44542 | (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether | C45H62O3S2Si2 | 详情 | 详情 | |
| (XX) | 44543 | (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol | C38H56O3S2Si2 | 详情 | 详情 | |
| (XXI) | 44544 | (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal | C38H54O3S2Si2 | 详情 | 详情 | |
| (XXII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXIV) | 44547 | (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal | C39H56O3S2Si2 | 详情 | 详情 | |
| (XXV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XXVI) | 44548 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether | C40H58O2S2Si2 | 详情 | 详情 | |
| (XXVII) | 44549 | tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C39H58O4Si2 | 详情 | 详情 | |
| (XXVIII) | 46127 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C53H77NO6SSi2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXVII)Synthesis of the thiazole intermediate (XXXIII): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with phosphonium salt (XXVII), LHMDS, Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX), which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI). The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII), which is acylated with Ac2O, TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 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) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XXIII) | 44520 | (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile | C9H10N2OS | 详情 | 详情 | |
| (XXIV) | 44521 | ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C11H15NO3S | 详情 | 详情 | |
| (XXV) | 44522 | ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate | C17H29NO3SSi | 详情 | 详情 | |
| (XXVI) | 44523 | (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal | C15H25NO2SSi | 详情 | 详情 | |
| (XXVII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXVIII) | 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 | |
| (XXIX) | 46122 | ethyl(triphenyl)phosphonium iodide | C20H20IP | 详情 | 详情 | |
| (XXX) | 46123 | tert-butyl(dimethyl)silyl (1S,3E)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole | C18H31NOSSi | 详情 | 详情 | |
| (XXXI) | 26246 | tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole | C18H30INOSSi | 详情 | 详情 | |
| (XXXII) | 46124 | (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol | C12H16INOS | 详情 | 详情 | |
| (XXXIII) | 46125 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate | C14H18INO2S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XXII)The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provides the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 44545 | tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C40H58O3S2Si2 | 详情 | 详情 | |
| (XXIIIb) | 44546 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether | C40H58O3S2Si2 | 详情 | 详情 | |
| (IX) | 46125 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate | C14H18INO2S | 详情 | 详情 | |
| (X) | 44533 | (2S)-3-(benzyloxy)-2-methylpropanal | C11H14O2 | 详情 | 详情 | |
| (XI) | 44534 | (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane | C10H20O2Si | 详情 | 详情 | |
| (XII) | 44535 | (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one | C17H22O3 | 详情 | 详情 | |
| (XIII) | 44536 | (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol | C17H24O3 | 详情 | 详情 | |
| (XIV) | 44537 | (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol | C18H26O3 | 详情 | 详情 | |
| (XV) | 44538 | (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | C19H29IO4 | 详情 | 详情 | |
| (XVI) | 44539 | (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol | C19H30O4 | 详情 | 详情 | |
| (XVII) | 44540 | benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane | C37H44O4Si | 详情 | 详情 | |
| (XVIII) | 44541 | (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol | C39H48O3S2Si | 详情 | 详情 | |
| (XIX) | 44542 | (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether | C45H62O3S2Si2 | 详情 | 详情 | |
| (XX) | 44543 | (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol | C38H56O3S2Si2 | 详情 | 详情 | |
| (XXI) | 44544 | (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal | C38H54O3S2Si2 | 详情 | 详情 | |
| (XXII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXIV) | 44547 | (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal | C39H56O3S2Si2 | 详情 | 详情 | |
| (XXV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XXVI) | 44548 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether | C40H58O2S2Si2 | 详情 | 详情 | |
| (XXVII) | 44549 | tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C39H58O4Si2 | 详情 | 详情 | |
| (XXVIII) | 46127 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C53H77NO6SSi2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(LII)The previously referenced vinyl iodide intermediate (XXXIV) was obtained as follows: The reaction of L-mannonic acid gamma-lactone (XLVIII) with cyclohexanone (XLIX) by means of H2SO4 in toluene gave the bis-cyclohexylidene ketal (L), which was reduced with DIBAL in dichloromethane to yield the lactol (LI). The condensation of (LI) with the phosphonium chloride (LII) by means of t-Bu-OK in refluxing THF afforded the vinyl ether (LIII), which was hydroxylated with OsO4 and dihydroquinidine-4-chlorobenzoate as chiral ligand and acylated with acetic anhydride and pyridine to provide the diacetate (LIV). The condensation of (LIV) with the functionalized allyl silane (LV) by means of BF3/Et2O in acetonitrile gave the adduct (LVI), which was submitted to cyclization by means of Triton B(OMe) in THF/methyl acetate to yield the perhydropyrano[3,2-b]pyran derivative (LVII). The selective hydrolysis of the exocyclic cyclohexylidene ketal of (LVII) with hot AcOH/water afforded the diol (LVIII), which by oxidative cleavage with NaIO4 in THF afforded the aldehyde (LIX). The coupling of (LIX) with the silylated vinyl iodide (LX), catalyzed by NiCl2 and CrCl2 in DMSO, gave the silylated allyl alcohol (LXI), which was submitted to cleavage of the cyclohexylidene ketal by means of AcOH/TFA to yield the trihydroxy compound (LXII). The protection of the three OH groups of (LXII) with Tbdms-OTf and lutidine in dichloromethane afforded the tris-Tbdms protected vinyl silane (LXIII), which was finally iodinated with N-iodosuccinimide (NIS) in acetonitrile/chloroacetonitrile to provide the target vinyl iodide intermediate (XXXIV).
| 【1】 Kishi, Y.; Stamos, D.P.; Synthetic studies on halichondrins: A practical synthesis of the C.1-C.13 segment. Tetrahedron Lett 1996, 37, 48, 8643. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIV) | 48420 | methyl 2-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-((1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-iodo-2-propenyl)octahydropyrano[3,2-b]pyran-2-yl]acetate | C32H63IO7Si3 | 详情 | 详情 | |
| (XLVIII) | 25665 | (3R,4S,5S)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxydihydro-2(3H)-furanone | C6H10O6 | 详情 | 详情 | |
| (XLIX) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (L) | 52411 | C18H26O6 | 详情 | 详情 | ||
| (LI) | 52412 | C18H28O6 | 详情 | 详情 | ||
| (LII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (LIII) | 52413 | C20H32O6 | 详情 | 详情 | ||
| (LIV) | 52414 | C23H34O9 | 详情 | 详情 | ||
| (LV) | 52423 | methyl 3-(trimethylsilyl)-4-pentenoate | C9H18O2Si | 详情 | 详情 | |
| (LVI) | 52415 | C27H40O9 | 详情 | 详情 | ||
| (LVII) | 52416 | C25H38O8 | 详情 | 详情 | ||
| (LVIII) | 52417 | C19H30O8 | 详情 | 详情 | ||
| (LIX) | 52418 | C18H26O7 | 详情 | 详情 | ||
| (LX) | 52419 | (2-iodoethenyl)(trimethyl)silane | C5H11ISi | 详情 | 详情 | |
| (LXI) | 52420 | C23H38O7Si | 详情 | 详情 | ||
| (LXII) | 52421 | methyl 2-{(2R,4aS,6S,7S,8R,8aR)-7,8-dihydroxy-6-[(E)-1-hydroxy-3-(trimethylsilyl)-2-propenyl]octahydropyrano[3,2-b]pyran-2-yl}acetate | C17H30O7Si | 详情 | 详情 | |
| (LXIII) | 52422 | methyl 2-{(2R,4aS,6S,7R,8S,8aS)-7,8-bis{[tert-butyl(dimethyl)silyl]oxy}-6-[(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(trimethylsilyl)-2-propenyl]octahydropyrano[3,2-b]pyran-2-yl}acetate | C35H72O7Si4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(LV)The previously referenced vinyl iodide intermediate (XXXIV) was obtained as follows: The reaction of L-mannonic acid gamma-lactone (LI) with cyclohexanone (LII) by means of H2SO4 in toluene gave the bis-cyclohexylidene ketal (LIII), which was reduced with DIBAL in dichloromethane to yield the lactol (LIV). The condensation of (LIV) with the phosphonium chloride (LV) by means of t-Bu-OK in refluxing THF afforded the vinyl ether (LVI), which was hydroxylated with OsO4 and dihydroquinidine-4-chlorobenzoate as chiral ligand and acylated with acetic anhydride and pyridine to provide the diacetate (LVII). The condensation of (LVII) with the functionalized allyl silane (LVIII) by means of BF3/Et2O in acetonitrile gave the adduct (LIX), which was submitted to cyclization by means of Triton B(OMe) in THF/methyl acetate to yield the perhydropyrano[3,2-b]pyran derivative (LX). The selective hydrolysis of the exocyclic cyclohexylidene ketal of (LX) with hot HOAc/water afforded the diol (LXI), which by oxidative cleavage with NaIO4 in THF afforded the aldehyde (LXII). The coupling of (LXII) with the silylated vinyl iodide (LXIII), catalyzed by NiCl2 and CrCl2 in DMSO, gave the silylated allyl alcohol (LXIV), which was submitted to cleavage of the cyclohexylidene ketal by means of HOAc/TFA to yield the trihydroxy compound (LXV). The protection of the three OH groups of (LXV) with Tbdms-OTf and lutidine in dichloromethane afforded the tris-Tbdms protected vinyl silane (LXVI), which was finally iodinated with N-iodosuccinimide (NIS) in acetonitrile/chloroacetonitrile to provide the target vinyl iodide intermediate (XXXIV).
| 【1】 Kishi, Y.; Stamos, D.P.; Synthetic studies on halichondrins: A practical synthesis of the C.1-C.13 segment. Tetrahedron Lett 1996, 37, 48, 8643. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIV) | 48420 | methyl 2-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-((1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-iodo-2-propenyl)octahydropyrano[3,2-b]pyran-2-yl]acetate | C32H63IO7Si3 | 详情 | 详情 | |
| (LI) | 25665 | (3R,4S,5S)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxydihydro-2(3H)-furanone | C6H10O6 | 详情 | 详情 | |
| (LII) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (LIII) | 52411 | C18H26O6 | 详情 | 详情 | ||
| (LIV) | 52412 | C18H28O6 | 详情 | 详情 | ||
| (LV) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (LVI) | 52413 | C20H32O6 | 详情 | 详情 | ||
| (LVII) | 52414 | C23H34O9 | 详情 | 详情 | ||
| (LVIII) | 52415 | C27H40O9 | 详情 | 详情 | ||
| (LIX) | 52423 | methyl 3-(trimethylsilyl)-4-pentenoate | C9H18O2Si | 详情 | 详情 | |
| (LX) | 52416 | C25H38O8 | 详情 | 详情 | ||
| (LXI) | 52417 | C19H30O8 | 详情 | 详情 | ||
| (LXII) | 52418 | C18H26O7 | 详情 | 详情 | ||
| (LXIII) | 52419 | (2-iodoethenyl)(trimethyl)silane | C5H11ISi | 详情 | 详情 | |
| (LXIV) | 52420 | C23H38O7Si | 详情 | 详情 | ||
| (LXV) | 52421 | methyl 2-{(2R,4aS,6S,7S,8R,8aR)-7,8-dihydroxy-6-[(E)-1-hydroxy-3-(trimethylsilyl)-2-propenyl]octahydropyrano[3,2-b]pyran-2-yl}acetate | C17H30O7Si | 详情 | 详情 | |
| (LXVI) | 52422 | methyl 2-{(2R,4aS,6S,7R,8S,8aS)-7,8-bis{[tert-butyl(dimethyl)silyl]oxy}-6-[(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(trimethylsilyl)-2-propenyl]octahydropyrano[3,2-b]pyran-2-yl}acetate | C35H72O7Si4 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IV)The reaction of cyclohexanone (I) with acrylonitrile (II) by means of pyrrolidine gives 3-(2-oxocyclohexyl)propionitrile (III), which is condensed with methoxymethyltriphenylphosphonium chloride (IV) in THF to yield the methoxymethylene derivative (V). The condensation of propionitrile (V) with 4-bromostyrene (VI) by means of n-BuLi ethyl ether affords the styryl ketone (VII), which is cyclized by means of triphenyl phosphite and O3 (or air, methylene blue and light) to provide trioxane (VIII) as a diastereomeric mixture that is separated by column chromatography. Finally, the vinyl group of the desired diastereomer (VIII) is oxidized with KMnO4 in acetone to afford the target compound.
| 【1】 Parker, M.H.; Krasavin, M.; Posner, G.H.; Paik, I.-H.; Jeon, H.B.; Shapiro, T.A.; Antimalarial simplified 3-aryltrioxanes: Synthesis and preclinical efficacy/toxicity testing in rodents. J Med Chem 2001, 44, 19, 3054. |
| 【2】 Posner, G.H.; Shapiro, T.A.; Parker, M.H.; Krasavin, M. (Johns Hopkins University); Water-soluble trioxanes as potent and safe antimalarial agents. US 6136847; WO 0059501 . |
| 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) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 49235 | 2-(beta-Cyanoethyl)cyclohexanone | C9H13NO | 详情 | 详情 | |
| (IV) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (V) | 49236 | 3-[2-[(Z)-methoxymethylidene]cyclohexyl]propanenitrile | C11H17NO | 详情 | 详情 | |
| (VI) | 49237 | 4-Bromostyrene; p-Bromostyrene | 2039-82-9 | C8H7Br | 详情 | 详情 |
| (VII) | 49238 | 3-[2-[(Z)-methoxymethylidene]cyclohexyl]-1-(4-vinylphenyl)-1-propanone | C19H24O2 | 详情 | 详情 | |
| (VIII) | 49239 | (1S,6R,9S,12R)-12-methoxy-6-methyl-9-(4-vinylphenyl)-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridecane; methyl (1S,6R,9S,12R)-6-methyl-9-(4-vinylphenyl)-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridec-12-yl ether | C20H26O4 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XXII)The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provides the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 44545 | tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C40H58O3S2Si2 | 详情 | 详情 | |
| (XXIIIb) | 44546 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether | C40H58O3S2Si2 | 详情 | 详情 | |
| (IX) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 | |
| (X) | 44533 | (2S)-3-(benzyloxy)-2-methylpropanal | C11H14O2 | 详情 | 详情 | |
| (XI) | 44534 | (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane | C10H20O2Si | 详情 | 详情 | |
| (XII) | 44535 | (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one | C17H22O3 | 详情 | 详情 | |
| (XIII) | 44536 | (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol | C17H24O3 | 详情 | 详情 | |
| (XIV) | 44537 | (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol | C18H26O3 | 详情 | 详情 | |
| (XV) | 44538 | (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | C19H29IO4 | 详情 | 详情 | |
| (XVI) | 44539 | (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol | C19H30O4 | 详情 | 详情 | |
| (XVII) | 44540 | benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane | C37H44O4Si | 详情 | 详情 | |
| (XVIII) | 44541 | (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol | C39H48O3S2Si | 详情 | 详情 | |
| (XIX) | 44542 | (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether | C45H62O3S2Si2 | 详情 | 详情 | |
| (XX) | 44543 | (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol | C38H56O3S2Si2 | 详情 | 详情 | |
| (XXI) | 44544 | (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal | C38H54O3S2Si2 | 详情 | 详情 | |
| (XXII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (XXIV) | 44547 | (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal | C39H56O3S2Si2 | 详情 | 详情 | |
| (XXV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XXVI) | 44548 | (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether | C40H58O2S2Si2 | 详情 | 详情 | |
| (XXVII) | 44549 | tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C39H58O4Si2 | 详情 | 详情 | |
| (XXVIII) | 44550 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C52H75NO6SSi2 | 详情 | 详情 |