|
【结 构 式】 
|
【药物名称】Bengamide B 【化学名称】Tetradecanoic acid 1-methyl-7-oxo-6(S)-[3(R),4(S),5(R)-trihydroxy-2(R)-methoxy-8-methyl-6(E)-nonenamido]hexahydro-1H-azepin-3(S)-yl ester 【CA登记号】104947-69-5 【 分 子 式 】C32H58N2O8 【 分 子 量 】598.82766 |
【开发单位】National Cancer Institute (Not Determined), Novartis (Not Determined) 【药理作用】Oncolytic Drugs |
合成路线1
The intermediate lactone (VII) was prepared as follows. Alpha-D-glucoheptonic gamma-lactone (I) was converted to the bis(acetonide) (II) by treatment with I2 in acetone. Methylation of the free hydroxyl group of (II) using Ag2O and methyl iodide provided the methyl ether (III). Selective removal of 1,2-acetonide of (III) in the presence of the 1,3-acetonide was accomplished by treatment of (III) with acetic acid. The resulting vicinal diol (IV) was then subjected to oxidative cleavage with NaIO4 to produce aldehyde (V). This was then olefinated with the low-valent organochromium species generated in situ from 1,1-diiodoisobutane (VI) and CrCl2 to produce the E-olefin (VII) as the major isomer, which was isolated using preparative HPLC.
| 【1】 Kinder, F.R. Jr.; et al.; Total synthesis of bengamides B and E. J Org Chem 2001, 66, 6, 2118. |
| 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) | 47767 | (3R,4S,5S)-3,4-dihydroxy-5-[(1R,2R)-1,2,3-trihydroxypropyl]dihydro-2(3H)-furanone | C7H12O7 | 详情 | 详情 | |
| (II) | 47768 | (4R,4aS,7R,7aS)-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-hydroxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one | C13H20O7 | 详情 | 详情 | |
| (III) | 47769 | (4R,4aS,7R,7aS)-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-methoxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one | C14H22O7 | 详情 | 详情 | |
| (IV) | 47770 | (4R,4aR,7R,7aS)-4-[(1R)-1,2-dihydroxyethyl]-7-methoxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one | C11H18O7 | 详情 | 详情 | |
| (V) | 47771 | (4S,4aS,7R,7aS)-7-methoxy-2,2-dimethyl-6-oxotetrahydro-4H-furo[3,2-d][1,3]dioxine-4-carbaldehyde | C10H14O6 | 详情 | 详情 | |
| (VI) | 47772 | 1,1-diiodo-2-methylpropane | C4H8I2 | 详情 | 详情 | |
| (VII) | 47773 | (4R,4aR,7R,7aS)-7-methoxy-2,2-dimethyl-4-[(E)-3-methyl-1-butenyl]tetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one | C14H22O5 | 详情 | 详情 |
合成路线2
Cyclization of 5(R)-hydroxy-L-lysine (VIII) by means of EDC and HOBt, followed by treatment of the resulting amino lactam (IX) with Boc2O, furnished the N-Boc aminolactam (X). The configuration of the (R)-secondary alcohol was inverted by Mitsunobu coupling with p-nitrobenzoic acid (XI) to produce the (S)-p-nitrobenzoate ester (XII). Methylation of the lactam N of (XII) yielded (XIII), and hydrolysis of the p-nitrobenzoate ester of (XIII) with LiOH afforded the (S)-hydroxy lactam (XIV). Esterification of (XIV) with myristic acid (XV) in the presence of EDC and DMAP produced the myristate ester (XVI). Treatment of (XVI) with trifluoroacetic acid removed the Boc protecting group to yield amine (XVII). This was then condensed with the intermediate lactone (VIII) in refluxing isopropanol to produce amide (XVIII). Finally, acetonide hydrolysis in (XVIII) employing trifluoroacetic acid generated the title compound.
| 【1】 Kinder, F.R. Jr.; et al.; Total synthesis of bengamides B and E. J Org Chem 2001, 66, 6, 2118. |
| 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) | 47773 | (4R,4aR,7R,7aS)-7-methoxy-2,2-dimethyl-4-[(E)-3-methyl-1-butenyl]tetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one | C14H22O5 | 详情 | 详情 | |
| (VIII) | 47774 | (2S,5R)-2,6-diamino-5-hydroxyhexanoic acid | C6H14N2O3 | 详情 | 详情 | |
| (IX) | 47775 | (3S,6R)-3-amino-6-hydroxy-2-azepanone | C6H12N2O2 | 详情 | 详情 | |
| (X) | 47776 | tert-butyl (3S,6R)-6-hydroxy-2-oxoazepanylcarbamate | C11H20N2O4 | 详情 | 详情 | |
| (XI) | 18119 | 4-nitrobenzoic acid; p-nitrobenzoic acid | 62-23-7 | C7H5NO4 | 详情 | 详情 |
| (XII) | 47777 | (3S,6S)-6-[(tert-butoxycarbonyl)amino]-7-oxoazepanyl 4-nitrobenzoate | C18H23N3O7 | 详情 | 详情 | |
| (XIII) | 47778 | (3S,6S)-6-[(tert-butoxycarbonyl)amino]-1-methyl-7-oxoazepanyl 4-nitrobenzoate | C19H25N3O7 | 详情 | 详情 | |
| (XIV) | 47779 | tert-butyl (3S,6S)-6-hydroxy-1-methyl-2-oxoazepanylcarbamate | C12H22N2O4 | 详情 | 详情 | |
| (XV) | 47780 | myristic acid | C14H28O2 | 详情 | 详情 | |
| (XVI) | 47781 | (3S,6S)-6-[(tert-butoxycarbonyl)amino]-1-methyl-7-oxoazepanyl myristate | C26H48N2O5 | 详情 | 详情 | |
| (XVII) | 47783 | (3S,6S)-6-amino-1-methyl-7-oxoazepanyl myristate | C21H40N2O3 | 详情 | 详情 | |
| (XVIII) | 47782 | (3S,6S)-6-[((2R)-2-[(4R,5R,6R)-5-hydroxy-2,2-dimethyl-6-[(E)-3-methyl-1-butenyl]-1,3-dioxan-4-yl]-2-methoxyethanoyl)amino]-1-methyl-7-oxoazepanyl myristate | C35H62N2O8 | 详情 | 详情 |
合成路线3
The condensation of the chiral imide (I) with aldehyde (II) by means of Et2B-OTf and DIEA in dichloromethane gives the hydroxy-imide (III), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (IV). The cleavage of the chiral auxiliary of (IV), followed by reduction with DIBAL in THF affords the aldehyde (V), which is condensed with the silylated enol ether (VI) by means of SnCl4 in dichloromethane to provide the target intermediate, the phenyl thioester (VII).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 57110 | 4,5,5-trimethyl-2-[2-(2-naphthyloxy)acetyl]-2-azabicyclo[2.2.1]heptan-3-one | C21H23NO3 | 详情 | 详情 | |
| (II) | 57111 | 4-Methyl-2-pentenal | 5362-56-1 | C6H10O | 详情 | 详情 |
| (III) | 57112 | 2-[(2S,3R,4E)-3-hydroxy-6-methyl-2-(2-naphthyloxy)-4-heptenoyl]-4,5,5-trimethyl-2-azabicyclo[2.2.1]heptan-3-one | C27H33NO4 | 详情 | 详情 | |
| (IV) | 57113 | 2-[(2S,3R,4E)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-2-(2-naphthyloxy)-4-heptenoyl]-4,5,5-trimethyl-2-azabicyclo[2.2.1]heptan-3-one | C33H47NO4Si | 详情 | 详情 | |
| (V) | 57114 | (2S,3R,4E)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-2-(2-naphthyloxy)-4-heptenal | C24H34O3Si | 详情 | 详情 | |
| (VI) | 57115 | (Z)-2-methoxy-1-(phenylsulfanyl)ethenyl trimethylsilyl ether; {[(Z)-2-methoxy-1-(phenylsulfanyl)ethenyl]oxy}(trimethyl)silane | C12H18O2SSi | 详情 | 详情 | |
| (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 |
合成路线4
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 |