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【结 构 式】 
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【分子编号】42754 【品名】(1-iodoethylidene)(triphenyl)phosphorane 【CA登记号】 |
【 分 子 式 】C20H18IP 【 分 子 量 】416.241152 【元素组成】C 57.71% H 4.36% I 30.49% P 7.44% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The intermediate (IV) has been obtained as follows: The condensation of silylated propionic aldehyde (I) with the mesylated acetylene (II) by means of Pd(PPh3)4 and Et2Zn in THF gives the hexanol (III), which is protected with chloromethyl (methyl)ether by means of DIEA and Bu4NI, yielding the desired acetylenic intermediate (IV) (1) The intermediate (XXII) has been obtained as follows: The desilylation of hexanol (III) with TBAF gives the acetylenic diol (V), which is protected with p-methoxy-benzaldehyde diethyl acetal (VI) catalyzed by CSA, affording the cyclic ketal (VII). The homologation of (VI) with formaldehyde and BuLi yields the propargyl alcohol (VIII), which is treated with Ac2O to provide the acetate (IX) (1). The partial hydrogenation of the triple bond of (IX) with Red-Al gives the allyl alcohol (X), which is asymmetrically epoxidated by the Sharpless method, yielding the epoxide (XI). The reduction of (XI) with Red-Al affords the chiral diol (XII), which is monoesterified with pivaloyl chloride and TEA to provide the pivalate (XIII). The silylation of (XIII) with Tbdms-OTf and lutidine furnishes the silylated pivalate (XIV), which is hydrolyzed with K2CO3 in methanol to give the primary alcohol (XV). The Swern oxidation of (XV) gives the aldehyde (XVI) (2), which is condensed with the intermediate acetylenic derivative (IV) by means of BuLi and LiBr in THF, yielding the adduct (XVII). The partial reduction of the triple bond of (XVII) with H2 over Pd/Pb/CaCO3 gives compound (XVIII) with a cis double bond. The protection of the OH group of (XVIII) as the methoxymethyl ether, followed by desilylation with HF in pyridine, yields the primary alcohol (XIX), which is oxidized with DMP to the corresponding aldehyde (XX). Finally, this compound is condensed with the iodophosphorane (XXI) to afford the target intermediate, the iodo compound (XXII).
| 【1】 Marsshall, J.A.; et al.; Synthesis of discodermolide subunits by SE2' addition of nonracemic allenylstannanes to aldehydes. J Org Chem 1998, 63, 3, 817. |
| 【2】 Marshall, J.A.; Hohns, B.A.; Total synthesis of (+)-discodermolide. J Org Chem 1998, 63, 22, 7885. |
| 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) | 42735 | (2S)-2-methyl-3-[(triethylsilyl)oxy]propanal | C10H22O2Si | 详情 | 详情 | |
| (II) | 42736 | methyl(dimethylene)[[(1R)-1-methyl-2-propynyl]oxy]-lambda(6)-sulfane | C7H12OS | 详情 | 详情 | |
| (III) | 42737 | (2S,3S,4S)-2,4-dimethyl-1-[(triethylsilyl)oxy]-5-hexyn-3-ol | C14H28O2Si | 详情 | 详情 | |
| (IV) | 42738 | (2S,3S,4S)-3-(methoxymethoxy)-2,4-dimethyl-5-hexynyl triethylsilyl ether; (5S,6S)-9,9-diethyl-6-methyl-5-[(1S)-1-methyl-2-propynyl]-2,4,8-trioxa-9-silaundecane | C16H32O3Si | 详情 | 详情 | |
| (V) | 42739 | (2S,3S,4S)-2,4-dimethyl-5-hexyne-1,3-diol | C8H14O2 | 详情 | 详情 | |
| (VI) | 35670 | 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether | C12H18O3 | 详情 | 详情 | |
| (VII) | 42740 | methyl 4-[(2R,4S,5S)-5-methyl-4-[(1S)-1-methyl-2-propynyl]-1,3-dioxan-2-yl]phenyl ether; (2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-4-[(1S)-1-methyl-2-propynyl]-1,3-dioxane | C16H20O3 | 详情 | 详情 | |
| (VIII) | 42741 | (4S)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-pentyn-1-ol | C17H22O4 | 详情 | 详情 | |
| (IX) | 42742 | (4S)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-pentynyl acetate | C19H24O5 | 详情 | 详情 | |
| (X) | 42743 | (E,4S)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-penten-1-ol | C17H24O4 | 详情 | 详情 | |
| (XI) | 42744 | ((2R,3R)-3-[(1S)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]oxiranyl)methanol | C17H24O5 | 详情 | 详情 | |
| (XII) | 42745 | (3S,4S)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-1,3-pentanediol | C17H26O5 | 详情 | 详情 | |
| (XIII) | 42746 | (3S,4S)-3-hydroxy-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]pentyl pivalate | C22H34O6 | 详情 | 详情 | |
| (XIV) | 42747 | (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]pentyl pivalate | C28H48O6Si | 详情 | 详情 | |
| (XV) | 42748 | (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-1-pentanol | C23H40O5Si | 详情 | 详情 | |
| (XVI) | 42749 | (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]pentanal | C23H38O5Si | 详情 | 详情 | |
| (XVII) | 42750 | (5S,7S,10S,11S,12S)-15,15-diethyl-11-(methoxymethoxy)-5-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,10,12-hexamethyl-4,14-dioxa-3,15-disila-8-heptadecyn-7-ol | C39H70O8Si2 | 详情 | 详情 | |
| (XVIII) | 42751 | (5S,7S,8Z,10S,11S,12S)-15,15-diethyl-11-(methoxymethoxy)-5-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,10,12-hexamethyl-4,14-dioxa-3,15-disila-8-heptadecen-7-ol | C39H72O8Si2 | 详情 | 详情 | |
| (XIX) | 42752 | (2S,3S,4S,5Z,7S,9S,10R)-9-[[tert-butyl(dimethyl)silyl]oxy]-3,7-bis(methoxymethoxy)-10-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2,4-dimethyl-5-undecen-1-ol | C35H62O9Si | 详情 | 详情 | |
| (XX) | 42753 | (2R,3S,4S,5Z,7S,9S,10R)-9-[[tert-butyl(dimethyl)silyl]oxy]-3,7-bis(methoxymethoxy)-10-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2,4-dimethyl-5-undecenal | C35H60O9Si | 详情 | 详情 | |
| (XXI) | 42754 | (1-iodoethylidene)(triphenyl)phosphorane | C20H18IP | 详情 | 详情 | |
| (XXII) | 42755 | (5S,6S,7Z,9S,11S)-5-[(1S,2Z)-3-iodo-1-methyl-2-butenyl]-9-(methoxymethoxy)-11-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,13,13,14,14-pentamethyl-2,4,12-trioxa-13-sila-7-pentadecene; tert-butyl(dimethyl)silyl (1S,3S,4Z,6S,7S,8S,9Z)-10-iodo-3,7-bis(methoxymethoxy)-1-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,8-dimethyl-4,9-undecadienyl ether | C37H63IO8Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) and catalyzed by (S)-(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (II) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (III) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (IV) | 40599 | Allyltributyltin; Tributyl-2-propenylstannane | 24850-33-7 | C15H32Sn | 详情 | 详情 |
| (V) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VI) | 44530 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H17NO2S | 详情 | 详情 | |
| (VII) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (VIII) | 42754 | (1-iodoethylidene)(triphenyl)phosphorane | C20H18IP | 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 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX)
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (II) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (III) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (IV) | 40599 | Allyltributyltin; Tributyl-2-propenylstannane | 24850-33-7 | C15H32Sn | 详情 | 详情 |
| (V) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VI) | 44530 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H17NO2S | 详情 | 详情 | |
| (VII) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (VIII) | 42754 | (1-iodoethylidene)(triphenyl)phosphorane | C20H18IP | 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 |
合成路线4
该中间体在本合成路线中的序号：(IX)The intermediate iodovinyl compound (XI) has been obtained as follows: The reaction of 2-(hydroxymethyl)thiazole-4-carboxylic acid ethyl ester (I) with Troc-Cl and pyridine in dichloromethane gives the protected compound (II), which is reduced with DIBAL in the same solvent to yield the carbaldehyde (III). The condensation of aldehyde (III) with phosphorane (IV) in refluxing benzene affords the unsaturated aldehyde (V), which is asymmetrically allylated by means of (+)-diisopinocampheyl(allyl)borane in pentane to provide the chiral secondary alcohol (VI). The reaction of (VI) with Tbdms-Cl and lutidine in dichloromethane gives the silyl ether (VII), which is oxidized at the terminal double bond by means of OsO4 and Pb(OAc)4 to yield the aldehyde (VIII). The condensation of (VIII) with phosphorane (IX) and LiOH in THF affords the iodovinyl compound (X), which is finally treated with Troc-Cl and pyridine to provide the desired iodovinyl intermediate (XI).
| 【1】 Zhang, X.-G.; Chappell, M.D.; Lee, C.B.; Kuduk, S.D.; Danishefsky, S.J.; Chou, T.-C.; Wang, Z.-G.; Stachel, S.J.; Total synthesis and antitumor activity of 12,13-dexoxyepothilone F: An unexpected solvolysis problem at C15, mediated by remote substitution at C21. J Org Chem 2000, 65, 20, 6525. |
| 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) | 49350 | ethyl 2-(hydroxymethyl)-1,3-thiazole-4-carboxylate | C7H9NO3S | 详情 | 详情 | |
| (II) | 49351 | ethyl 2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazole-4-carboxylate | C10H10Cl3NO5S | 详情 | 详情 | |
| (III) | 49352 | (4-formyl-1,3-thiazol-2-yl)methyl 2,2,2-trichloroethyl carbonate | C8H6Cl3NO4S | 详情 | 详情 | |
| (IV) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (V) | 49353 | [4-[(E)-2-methyl-3-oxo-1-propenyl]-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C11H10Cl3NO4S | 详情 | 详情 | |
| (VI) | 49354 | [4-[(1E,3S)-3-hydroxy-2-methyl-1,5-hexadienyl]-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C14H16Cl3NO4S | 详情 | 详情 | |
| (VII) | 49355 | [4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C20H30Cl3NO4SSi | 详情 | 详情 | |
| (VIII) | 49356 | [4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-5-oxo-1-pentenyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C19H28Cl3NO5SSi | 详情 | 详情 | |
| (IX) | 42754 | (1-iodoethylidene)(triphenyl)phosphorane | C20H18IP | 详情 | 详情 | |
| (X) | 49357 | [4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-1,3-thiazol-2-yl]methanol | C18H30INO2SSi | 详情 | 详情 | |
| (XI) | 49358 | [4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C21H31Cl3INO4SSi | 详情 | 详情 |