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【结 构 式】 
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【分子编号】20323 【品名】2-(trimethylsilyl)-1-ethanol 【CA登记号】2916-68-9 |
【 分 子 式 】C5H14OSi 【 分 子 量 】118.25106 【元素组成】C 50.79% H 11.93% O 13.53% Si 23.75% |
合成路线1
该中间体在本合成路线中的序号：(XXXV)Protection of ethyl lactate (XXX) with tert-butyldimethylsilyl chloride in DMF in the presence of imidazole provides derivative (XXXI), which is then converted into dipeptide (XXXII) by first hydrolysis with LiOH in THF/H2O followed by coupling with L-proline methyl ester (X) by means of DCC, HOBt and NMM. Next, hydrolysis of the methyl ester of (XXXII) with LiOH in THF/H2O yields carboxylic acid (XXXIII). Esterification of Z-D-N-Me-Leu (XXXIV) with 2-(trimethylsilyl)ethanol (XXXV) by means of EDCI, DMAP and Et3N in DMF furnishes leucine derivative (XXXVI), whose Z protecting group is removed by hydrogenation over Pd/C in MeOH/AcOEt to afford secondary amine (XXXVII). Coupling of carboxylic acid (XXXIII) with amine (XXXVII) is then performed by means of BOPCl, Et3N. Treatment with tetrabutylammonium fluoride in DMF allows protecting group removal to provide carboxylic acid derivative (XXXVIII), which is then attached to macrocycle (XXIX) by means of BOP and NMM in CH2Cl2 to furnish the target didemnin.
| 【1】 Li, W.-R.; et al.; Total synthesis and structural investigations of didemnins A, B, and C. J Am Chem Soc 1990, 112, 21, 7659. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 29552 | methyl (2S)-2-pyrrolidinecarboxylate | 2133-40-6 | C6H11NO2 | 详情 | 详情 |
| (XXIX) | 50769 | ethyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoate | C11H24O3Si | 详情 | 详情 | |
| (XXX) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (XXXI) | 50769 | ethyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoate | C11H24O3Si | 详情 | 详情 | |
| (XXXII) | 50770 | methyl (2S)-1-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylate | C15H29NO4Si | 详情 | 详情 | |
| (XXXIII) | 50771 | (2S)-1-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylic acid | C14H27NO4Si | 详情 | 详情 | |
| (XXXIV) | 50772 | (2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid | C15H21NO4 | 详情 | 详情 | |
| (XXXV) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (XXXVI) | 50773 | 2-(trimethylsilyl)ethyl (2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoate | C20H33NO4Si | 详情 | 详情 | |
| (XXXVII) | 50774 | 2-(trimethylsilyl)ethyl (2R)-4-methyl-2-(methylamino)pentanoate | C12H27NO2Si | 详情 | 详情 | |
| (XXXVIII) | 37840 | (2R)-2-[([(2S)-1-[(2S)-2-hydroxypropanoyl]pyrrolidinyl]carbonyl)(methyl)amino]-4-methylpentanoic acid | C15H26N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)The phosphorylation of (XXVI) with POCl3 and 2-(trimethylsilyl)ethanol (XXVII) yields the phosphate ester (XXVIII), which is finally fully desilylated with HF and pyridine to afford the target fostriecin.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XXVII) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (XXVIII) | 55476 | (1R,3R,4Z,6Z,8E)-3,10-bis{[tert-butyl(diphenyl)silyl]oxy}-1-{(1R,2E)-1-{[tert-butyl(diphenyl)silyl]oxy}-1-methyl-3-[(2R)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-4,6,8-decatrienyl bis[2-(trimethylsilyl)ethyl] phosphate | C77H105O9PSi5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)The cyclization of acetoacetic ester (I) with crotonaldehyde (II) by means of Na and 2-(trimethylsilyl)ethanol (A) in ethyl ether gives the cyclohexenone carboxylic ester (III), which is hydroxylated by means of NaH, Tbdms-OTf and dimethyldioxirane (DMDO) in DMF, yielding the alpha-hydroxy compound (IV). The bromination of (IV) with NBS and AIBN, followed by treatment with Ag2CO3 in acetone/water, affords the diol (V), which is oxidized with DMP to the cyclohexenedione (VI). The cyclization of (VI) with benzocyclobutane (VII) in hot toluene provides the tricyclic dione (VIII), which is aromatized by means of CSA in pyridine/MeOH, furnishing the dihydroanthraquinone (IX). The Grignard condensation of (IX) with isoamylmagnesium bromide (X) in THF gives the adduct (XI), which is finally desilylated by means of TAS-F in THF.
| 【1】 Danishefsky, S.J.; Allen, J.G.; The total synthesis of (±)-rishirilide B. J Am Chem Soc 2001, 123, 2, 351. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (I) | 45600 | 2-(trimethylsilyl)ethyl 3-oxobutanoate | C9H18O3Si | 详情 | 详情 | |
| (II) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (III) | 45601 | 2-(trimethylsilyl)ethyl 6-methyl-2-oxo-3-cyclohexene-1-carboxylate | 367-57-7 | C13H22O3Si | 详情 | 详情 |
| (IV) | 45602 | 2-(trimethylsilyl)ethyl (1R,6S)-1-hydroxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate | C13H22O4Si | 详情 | 详情 | |
| (V) | 45603 | 2-(trimethylsilyl)ethyl (1R,6S)-1,5-dihydroxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate | C13H22O5Si | 详情 | 详情 | |
| (VI) | 45604 | 2-(trimethylsilyl)ethyl (1R,6R)-1-hydroxy-6-methyl-2,5-dioxo-3-cyclohexene-1-carboxylate | C13H20O5Si | 详情 | 详情 | |
| (VII) | 45605 | (7R)-2,8-bis[[tert-butyl(dimethyl)silyl]oxy]bicyclo[4.2.0]octa-1,3,5-trien-7-yl tert-butyl(dimethyl)silyl ether; [((7R)-2,8-bis[[tert-butyl(dimethyl)silyl]oxy]bicyclo[4.2.0]octa-1,3,5-trien-7-yl)oxy](tert-butyl)dimethylsilane | C26H50O3Si3 | 详情 | 详情 | |
| (VIII) | 45606 | 2-(trimethylsilyl)ethyl (2R,3R,4aS,9R,9aR,10S)-8,9,10-tris[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-3-methyl-1,4-dioxo-1,2,3,4,4a,9,9a,10-octahydro-2-anthracenecarboxylate | C39H70O8Si4 | 详情 | 详情 | |
| (IX) | 45607 | 2-(trimethylsilyl)ethyl (2R,3R)-8-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-3-methyl-1,4-dioxo-1,2,3,4-tetrahydro-2-anthracenecarboxylate | C27H38O6Si2 | 详情 | 详情 | |
| (X) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (XI) | 45608 | 2-(trimethylsilyl)ethyl (1R,2R,3R)-8-[[tert-butyl(dimethyl)silyl]oxy]-1,2-dihydroxy-1-isopentyl-3-methyl-4-oxo-1,2,3,4-tetrahydro-2-anthracenecarboxylate | C32H50O6Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)A new synthesis of paclitaxel has been reported: The esterification of (2R,3S)-2,3-epoxy-3-phenylpropionic acid (I) with 2-(trimethylsilyl)ethanol (II) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene gives the expected ester (III), which is treated with LiBr in acetic acid to yield the (2R,3R)-3-bromo-2-hydroxy ester (IV). The reaction of (IV) with sodium azide in hot DMF affords the corresponding azido derivative (V), which is reduced with ammonium formate or H2 over Pd/C giving the (2R,3S)-3-amino-2-hydroxy ester (VI). The amidation of (VI) with benzyl chloroformate (VII) yields the corresponding benzyloxycarbonylamino compound (VIII), which is esterified with benzoyl chloride (IX) and triethylamine affording (2R,3S)-2-(benzoyloxy)-3-(benzyloxycarbonylamino)-3-phenylpropionic acid 2-(trimethylsilyl)ethyl ester (X). The condensation of the ester (X) with 7-O-(triethylsilyl)baccatin (XI) by means of 4-(1-pyrrolidinyl)-piperidine (4-PP) and dicyclohexylcarbodiimide (DCC) in hot toluene gives the mixed ester (XII). Finally, this compound is hydrogenated with ammonium formate and Pd/C to obtain a free amino group to which the benzoyl group of the a-position is transferred by a treatment with formic acid yielding pure paclitaxel.
| 【1】 Gao, Y.; Zepp, C.M. (Sepracor Inc.); Taxol process and cpds.. US 5760251 . |
| 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) | 20322 | (2R,3S)-3-phenyl-2-oxiranecarboxylic acid | C9H8O3 | 详情 | 详情 | |
| (II) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (III) | 20324 | 2-(trimethylsilyl)ethyl (2R,3S)-3-phenyl-2-oxiranecarboxylate | C14H20O3Si | 详情 | 详情 | |
| (IV) | 20325 | 2-(trimethylsilyl)ethyl (2S,3S)-3-bromo-2-hydroxy-3-phenylpropanoate | C14H21BrO3Si | 详情 | 详情 | |
| (V) | 20326 | 2-(trimethylsilyl)ethyl (2R,3S)-3-azido-2-hydroxy-3-phenylpropanoate | C14H21N3O3Si | 详情 | 详情 | |
| (VI) | 20327 | 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoate | C14H23NO3Si | 详情 | 详情 | |
| (VII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VIII) | 20329 | 2-(trimethylsilyl)ethyl (2R,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-3-phenylpropanoate | C22H29NO5Si | 详情 | 详情 | |
| (IX) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (X) | 20331 | (1R,2S)-2-[[(benzyloxy)carbonyl]amino]-2-phenyl-1-[[2-(trimethylsilyl)ethoxy]carbonyl]ethyl benzoate | C29H33NO6Si | 详情 | 详情 | |
| (XI) | 20332 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C37H52O11Si | 详情 | 详情 | |
| (XII) | 20333 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[((2R,3S)-2-(benzoyloxy)-3-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C61H71NO16Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(A)The Curtius degradation of carboxylic acid (XIV) with Ph2PON3 and 2-(trimethylsilyl)ethanol (A) gives the carbamate (XV), which is acylated with 2-(benzyloxy)acetyl chloride (XVI) and LiHMDS in THF, yielding the imide (XVII). The condensation of (XVII) with aldehyde (XVIII) by means of TiCl4 and DIEA in dichloromethane affords the expected adduct (XIX), which is oxidized with TFAA and DMSO in dichloromethane/DIEA, providing the beta-ketoimide (XX) as a diastereomeric mixture at the benzyloxy group. The cyclization of (XX) by means of CSA in methanol, followed by separation of the diastereomeric mixture, furnished the hydroxy tetrahydropyran derivative (XXI), which is submitted to a Swern oxidation to give the trahydropyranone (XXII). The reaction of (XXII) with diiodomethane, TiCl4 and Zn yields the exo-methylene compound (XXIII), which is desilylated with TBAF in DMF to afford intermediate (XXIV). Finally, this compound is submitted to a reductive cleavage of the benzyloxy and cyclic carbonate groups with Na/NH3 in THF/ethyl ether to furnish the target compound.
| 【1】 Roush, W.R.; Pfeifer, L.A.; Total synthesis of mycalamide A and 7-epi-mycalamide A. Org Lett 2000, 2, 6, 859. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (XIV) | 43443 | (4S,4aR,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxine-4-carboxylic acid | C15H22O9 | 详情 | 详情 | |
| (XV) | 43444 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-ylcarbamate | C20H35NO9Si | 详情 | 详情 | |
| (XVI) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (XVII) | 43445 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[2-(benzyloxy)acetyl]carbamate | C29H43NO11Si | 详情 | 详情 | |
| (XVIII) | 43446 | (3R,4S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methylhexanal | C19H42O3Si2 | 详情 | 详情 | |
| (XIX) | 43447 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl((2R,5R,6S,7R)-2-(benzyloxy)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-6-methyloctanoyl)carbamate | C48H85NO14Si3 | 详情 | 详情 | |
| (XX) | 43448 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl((5R,6S,7R)-2-(benzyloxy)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-3-oxooctanoyl)carbamate | C48H83NO14Si3 | 详情 | 详情 | |
| (XXI) | 43449 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,4R,5R,6R)-4-hydroxy-2-methoxy-5,6-dimethyltetrahydro-2H-pyran-2-yl]ethanoyl]ca | C37H57NO14Si | 详情 | 详情 | |
| (XXII) | 43450 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,5S,6R)-2-methoxy-5,6-dimethyl-4-oxotetrahydro-2H-pyran-2-yl]ethanoyl]carbamate | C37H55NO14Si | 详情 | 详情 | |
| (XXIII) | 43451 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,5R,6R)-2-methoxy-5,6-dimethyl-4-methylenetetrahydro-2H-pyran-2-yl]ethanoyl]car | C38H57NO13Si | 详情 | 详情 | |
| (XXIV) | 43452 | (2S)-N-((4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl)-2-(benzyloxy)-2-[(2R,5R,6R)-2-methoxy-5,6-dimethyl-4-methylenetetrahydro-2H-pyran-2-yl]ethanamide | C32H45NO11 | 详情 | 详情 |