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【结 构 式】 
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【分子编号】30295 【品名】tetradecanoyl chloride 【CA登记号】112-64-1 |
【 分 子 式 】C14H27ClO 【 分 子 量 】246.82048 【元素组成】C 68.13% H 11.03% Cl 14.36% O 6.48% |
合成路线1
该中间体在本合成路线中的序号：(XVII)The cyclization of 2(R)-bromobutane-1,4-diol (VIII) by means of NaH in THF, followed by acylation with Ts-Cl gives the chiral epoxide (IX), which is treated with NaI in hot acetone to yield the iodo-epoxide (X). The enantiocontrolled condensation of (X) with the commercial imine (XI) by means of Cs-OH catalyzed by a chiral phase transfer catalyst affords the epoxy iminoester (XII). The reaction of the epoxy group of (XII) with N-methylbenzylamine in methanol provides the expected amino-alcohol (XIII), which is treated with citric acid to hydrolyze the imino group to give amine (XIV). Elimination of the benzyl protecting group of (XIV) by means of H2 over Pd/C yields the diamino ester (XV), which is cyclized to the hydroxy-caprolactam (XVI) by reaction with Na-OMe in methanol at 80 C in a sealed tube. The reaction of the OH group of (XVI) with tetradecanoyl chloride (XVII) by means of TFA affords the corresponding ester (XVIII). The condensation of the amino group of (XVIII) with the intermediate phenyl thioester (VII) in refluxing dioxane provides the corresponding amide (XIX), which is finally deprotected by a first treatment with DDQ in water/methanol/dichloromethane, followed by desilylation with PPTS in hot methanol/dichloromethane to yield the target bengamide B.
| 【1】 Boeckman, R.K.; Clark, T.J.; Shook, B.C.; A practical enantioselective total synthesis of the bengamides B, E, and Z. Org Lett 2002, 4, 12, 2109. |
| 【2】 Boeckman, R.K.; et al.; The development of a convergent and efficient enantioselective synthesis of the bengamides via a common polyol intermediate. Helv Chim Acta 2002, 85, 12, 4532. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 57116 | S-phenyl (2R,3S,4R,5R,6E)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methoxy-8-methyl-4-(2-naphthyloxy)-6-nonenethioate | C33H44O5SSi | 详情 | 详情 | |
| (VIII) | 57126 | (2R)-2-bromo-1,4-butanediol | C4H9BrO2 | 详情 | 详情 | |
| (IX) | 57117 | 2-[(2S)oxiranyl]ethyl 4-methylbenzenesulfonate | C11H14O4S | 详情 | 详情 | |
| (X) | 57118 | (2S)-2-(2-iodoethyl)oxirane | C4H7IO | 详情 | 详情 | |
| (XI) | 57119 | tert-butyl 2-[(diphenylmethylene)amino]acetate | C19H21NO2 | 详情 | 详情 | |
| (XII) | 57120 | tert-butyl (2S)-2-[(diphenylmethylene)amino]-4-[(2S)oxiranyl]butanoate | C23H27NO3 | 详情 | 详情 | |
| (XIII) | 57121 | tert-butyl (2S,5S)-6-[benzyl(methyl)amino]-2-[(diphenylmethylene)amino]-5-hydroxyhexanoate | C31H38N2O3 | 详情 | 详情 | |
| (XIV) | 57122 | tert-butyl (2S,5S)-2-amino-6-[benzyl(methyl)amino]-5-hydroxyhexanoate | C18H30N2O3 | 详情 | 详情 | |
| (XV) | 57123 | tert-butyl (2S,5S)-2-amino-5-hydroxy-6-(methylamino)hexanoate | C11H24N2O3 | 详情 | 详情 | |
| (XVI) | 57124 | (3S,6S)-3-amino-6-hydroxy-1-methyl-2-azepanone | C7H14N2O2 | 详情 | 详情 | |
| (XVII) | 30295 | tetradecanoyl chloride | 112-64-1 | C14H27ClO | 详情 | 详情 |
| (XVIII) | 47783 | (3S,6S)-6-amino-1-methyl-7-oxoazepanyl myristate | C21H40N2O3 | 详情 | 详情 | |
| (XIX) | 57125 | (3S,6S)-6-{[(2R,3S,4R,5R,6E)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methoxy-8-methyl-4-(2-naphthyloxy)-6-nonenoyl]amino}-1-methyl-7-oxoazepanyl myristate | C48H78N2O8Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)Ketone (XVI) was treated with phenylselanyl chloride and LHMDS yielding the selenium derivative (XVII). Enone (XVIII) was then produced by oxidative elimination of the selenide (XVII). Reduction of the unsaturated ketone (XVIII) with NaBH4 in the presence of CeCl3 gave the 3-beta-allylic alcohol (XIX). This was acylated with myristoyl chloride (XX) to afford ester (XXI). Finally, acid deprotection of the silyl ether and the p-methoxyphenyl acetal of (XXI) furnished the title compound.
| 【1】 Winkler, J.D.; Lewin, N.E.; Blumberg, P.M.; Harrison, S.; Kim, S.; Synthesis and biological evaluation of highly functionalized analogues of ingenol. J Am Chem Soc 1999, 121, 2, 296. |
| 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) | 30290 | (1S,5S,7R,9R,12R)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadec-10-ene-4,17-dione | C39H44O6Si | 详情 | 详情 | |
| (XVII) | 30291 | (1S,5S,7R,9R,12R)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-3-(phenylselanyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadec-10-ene-4,17-dione | C45H48O6SeSi | 详情 | 详情 | |
| (XVIII) | 30292 | (1S,5S,7R,9R,12R)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-diene-4,17-dione | C39H42O6Si | 详情 | 详情 | |
| (XIX) | 30293 | (1S,4S,5R,7R,9R,12R)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-hydroxy-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-dien-17-one | C39H44O6Si | 详情 | 详情 | |
| (XX) | 30295 | tetradecanoyl chloride | 112-64-1 | C14H27ClO | 详情 | 详情 |
| (XXI) | 30294 | (1S,4S,5S,7R,9R,12R)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-17-oxo-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-dien-4-yl myristate | C53H70O7Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The condensation of palmitoyl chloride (IV) with diazomethane produced diazoketone (V). This was then treated with HBr to yield bromoketone (VI).
| 【1】 Gandour, R.D.; et al.; (+)-Hemipalmitoylcarnitinium strongly inhibits carnitine palmitoyltransfease-I in intact mitochondria. J Med Chem 1993, 36, 2, 237. |
合成路线4
该中间体在本合成路线中的序号：The primary hydroxyl of (XXI) is protected as the silyl ether (XXII) by means of t-butyldimethylsilyl chloride and DMAP. Subsequent phosphorylation of the remaining secondary hydroxyl group with diphenylphosphoryl chloride gives phosphate ester (XXIII). Removal of the p-methoxybenzyl protecting group of (XXIII) is accomplished by oxidative cleavage with DDQ, yielding alcohol (XXIV), which is acylated by myristoyl chloride, to produce ester (XXV). Desilylation of (XXV) under acidic conditions affords alcohol (XXVI), which is converted to methyl ether (XXVII) using trimethyloxonium fluoborate as the alkylating reagent. Iridium-catalyzed deallylation of the allyl glucoside (XXVII) furnishes the cyclic glucosamine (XXVIII).
| 【1】 Nishijima, M.; Kurakata, S.-I.; Shiozaki, M.; Mochizuki, T.; Kanai, S.; Watanabe, Y.; Synthesis of lipid A type pyran carboxylic acids with ether chains and their biological activities. Carbohydr Res 2001, 333, 3, 203. |
| 【2】 Shiozaki, M.; Kurakata, S.; Kanai, S.; Kazama, Y. (Sankyo Co., Ltd.); Ether type lipid A1-carboxylic acid analogues. EP 1152007; JP 2000297096; US 2002161221; US 6511965; WO 0047595 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 30295 | tetradecanoyl chloride | 112-64-1 | C14H27ClO | 详情 | 详情 | |
| (XXI) | 57544 | 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-4-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-ylcarbamate | C40H58Cl3NO8 | 详情 | 详情 | |
| (XXII) | 57545 | 4-{2-[((1R)-1-{2-[((2S,3R,4R,5S,6R)-2-(allyloxy)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-hydroxy-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl)oxy]ethyl}-1,1'-biphenyl; 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-4-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-hydroxytetrahydro-2H-pyran-3-ylcarbamate | C46H72Cl3NO8Si | 详情 | 详情 | |
| (XXIII) | 57546 | 4-{2-[((1R)-1-{2-[((2S,3R,4R,5S,6R)-2-(allyloxy)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[(diphenoxyphosphoryl)oxy]-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl)oxy]ethyl}-1,1'-biphenyl; 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-4-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[(diphenoxyphosphoryl)oxy]tetrahydro-2H-pyran-3-ylcarbamate | C58H81Cl3NO11PSi | 详情 | 详情 | |
| (XXIV) | 57547 | 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[(diphenoxyphosphoryl)oxy]-4-{[(3R)-3-hydroxytetradecyl]oxy}tetrahydro-2H-pyran-3-ylcarbamate | C44H69Cl3NO11PSi | 详情 | 详情 | |
| (XXV) | 57548 | (1R)-1-{2-[((2S,3R,4R,5S,6R)-2-(allyloxy)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[(diphenoxyphosphoryl)oxy]-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl myristate | C58H95Cl3NO12PSi | 详情 | 详情 | |
| (XXVI) | 57549 | (1R)-1-{2-[((2S,3R,4R,5S,6R)-2-(allyloxy)-5-[(diphenoxyphosphoryl)oxy]-6-(hydroxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl myristate | C52H81Cl3NO12P | 详情 | 详情 | |
| (XXVII) | 57550 | 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-5-[(diphenoxyphosphoryl)oxy]-4-{[(3R)-3-(formyloxy)tetradecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-3-ylcarbamate | C40H57Cl3NO12P | 详情 | 详情 | |
| (XXVIII) | 57551 | (1R)-1-{2-[((2R,3S,4R,5R)-3-[(diphenoxyphosphoryl)oxy]-6-hydroxy-2-(methoxymethyl)-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl myristate | C50H79Cl3NO12P | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The acylation of phorbol (I) with tetradecanoyl chloride (II) in pyridine gives the triacyl phorbol (III), which is selective hydrolyzed with NaOMe in methanol at room temperature to yield the monoacyl phorbol (IV). The acylation of (IV) with acetic anhydride in pyridine at 8 C affords the diacetoxy tetradecanoyloxy phorbol (V). Finally, this compound is monodeacetylated by means of HClO4 in methanol at room temperature to provide the target mixed diacylphorbol.
| 【1】 Bresch, H.; et al.; Active components of croton oil. IX. Partial synthesis of the active components of croton oil. Z Naturforsch B - J Chem Sci 1968, 23, 4, 539. |
| 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) | 59382 | (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one | C20H28O6 | 详情 | 详情 | |
| (II) | 30295 | tetradecanoyl chloride | 112-64-1 | C14H27ClO | 详情 | 详情 |
| (III) | 59383 | [(1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b-dihydroxy-1,1,6,8-tetramethyl-5-oxo-9,9a-bis(tetradecanoyloxy)-1a,1b,4,4a,5,7a,7b,8,9,9a-decahydro-1H-cyclopropa[3,4]benzo[1,2-e]azulen-3-yl]methyl myristate | C62H106O9 | 详情 | 详情 | |
| (IV) | 59384 | (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9a-trihydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-5-oxo-1a,1b,4,4a,5,7a,7b,8,9,9a-decahydro-1H-cyclopropa[3,4]benzo[1,2-e]azulen-9-yl myristate | C34H54O7 | 详情 | 详情 | |
| (V) | 59385 | (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-9a-(acetyloxy)-3-[(acetyloxy)methyl]-4a,7b-dihydroxy-1,1,6,8-tetramethyl-5-oxo-1a,1b,4,4a,5,7a,7b,8,9,9a-decahydro-1H-cyclopropa[3,4]benzo[1,2-e]azulen-9-yl myristate | C38H58O9 | 详情 | 详情 |