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【结 构 式】 
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【分子编号】55249 【品名】6-[(1R,3S,4R)-3-(acetyloxy)-4-(benzyloxy)-1-methyl-5-hexenyl]-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate 【CA登记号】 |
【 分 子 式 】C30H44O8Si 【 分 子 量 】560.76006 【元素组成】C 64.26% H 7.91% O 22.83% Si 5.01% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The total synthesis of (+)-resiniferatoxin started with the asymmetric Sharpless epoxidation of 1,4-pentadien-3-ol (I) to afford the epoxy-alcohol (II), which was further protected as the benzyl ether (III). Epoxide ring opening in (III) with the lithium acetylide (IV) in the presence of BF3 at -78 ºC yielded the acetylenic alcohol (V), which was subsequently cyclized to lactone (VI) under acidic conditions. Methylation of the lithium enolate of lactone (VI) gave rise to the trans- lactone (VII) as the major diastereoisomer. Addition of the lithiated derivative of O-(tert-butyldimethylsilyl)furfuryl alcohol (VIII) to the lactone (VII) produced the furyl ketone (IX). After protection of the hydroxyl group of (IX) as the corresponding acetate ester (X), reduction of its ketone function with NaBH4 furnished alcohol (XI). Oxidation of the furan nucleus of (XI) with m-CPBA produced the intermediate diketone (XII) which spontaneously cyclized to the pyranone (XIII). Acetylation of the hydroxyl group of (XIII) gave the (acetyloxy)pyranone (XIV).
| 【1】 Boger, D.L.; Searcey, M.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of (+)-resiniferatoxin. Chemtracts - Org Chem 1998, 11, 9, 647. |
| 【2】 Wender, P.A.; et al.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of resiniferatoxin. J Am Chem Soc 1997, 119, 52, 12976. |
| 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) | 11471 | 1,4-Pentadien-3-ol | 922-65-6 | C5H8O | 详情 | 详情 |
| (II) | 11501 | (1R)-1-[(2S)Oxiranyl]-2-propen-1-ol | C5H8O2 | 详情 | 详情 | |
| (III) | 11502 | (2S)-2-[(1R)-1-(Benzyloxy)-2-propenyl]oxirane; benzyl (1R)-1-[(2S)Oxiranyl]-2-propenyl ether | C12H14O2 | 详情 | 详情 | |
| (IV) | 55241 | (2-ethoxyethynyl)lithium | C4H5LiO | 详情 | 详情 | |
| (V) | 55242 | (3R,4S)-3-(benzyloxy)-7-ethoxy-1-hepten-6-yn-4-ol | C16H20O3 | 详情 | 详情 | |
| (VI) | 11503 | (5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]dihydro-2(3H)-furanone | C14H16O3 | 详情 | 详情 | |
| (VII) | 11504 | (3R,5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]-3-methyldihydro-2(3H)-furanone | C15H18O3 | 详情 | 详情 | |
| (VIII) | 55243 | tert-butyl(2-furylmethoxy)dimethylsilane; tert-butyl(dimethyl)silyl 2-furylmethyl ether | C11H20O2Si | 详情 | 详情 | |
| (IX) | 55244 | (2R,4S,5R)-5-(benzyloxy)-1-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-furyl]-4-hydroxy-2-methyl-6-hepten-1-one | C26H38O5Si | 详情 | 详情 | |
| (X) | 55245 | (1S,2R)-2-(benzyloxy)-1-{(2R)-3-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-furyl]-2-methyl-3-oxopropyl}-3-butenyl acetate | C28H40O6Si | 详情 | 详情 | |
| (XI) | 55246 | (1S,2R)-2-(benzyloxy)-1-{(2R)-3-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-furyl]-3-hydroxy-2-methylpropyl}-3-butenyl acetate | C28H42O6Si | 详情 | 详情 | |
| (XII) | 55247 | (1S,3R,6Z)-1-[(1R)-1-(benzyloxy)-2-propenyl]-9-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-3-methyl-5,8-dioxo-6-nonenyl acetate | C28H42O7Si | 详情 | 详情 | |
| (XIII) | 55248 | (1S,2R)-2-(benzyloxy)-1-{(2R)-2-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl]propyl}-3-butenyl acetate | C28H42O7Si | 详情 | 详情 | |
| (XIV) | 55249 | 6-[(1R,3S,4R)-3-(acetyloxy)-4-(benzyloxy)-1-methyl-5-hexenyl]-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate | C30H44O8Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Treatment of pyranone (XIV) with DBU in boiling acetonitrile generated the pyrilium intermediate (XV) which underwent intramolecular cycloaddition to the desired endo cycloadduct (XVI). Catalytic double bond hydrogenation of enone (XVI) provided the saturated ketone (XVII). Wittig reaction of (XVII) with methylene triphenylphosphorane, followed by reacetylation with acetyl chloride furnished the exocyclic methylene derivative (XVIII). Allylic oxidation of (XVIII) by means of SeO2 and t-BuOOH, and further MnO2 oxidation of the resultant alcohol led to the methylene ketone (XIX). This was then subjected to conjugate addition of vinyl cuprate to provide ketone (XX). Diastereoselective addition of the lithium acetylide (XXI) to ketone (XX) followed by quenching with N-methyl-N-(trimethylsilyl)trifluoroacetamide furnished the silyl ether (XXII) along with some unsilylated carbinol, which was converted to (XXII) by independent silylation with chlorotrimethylsilane and imidazole. The tricyclic system (XXIII) was then obtained by zirconocene-mediated cyclization of (XXII), followed by selective acetate hydrolysis with 90 % AcOH.
| 【1】 Boger, D.L.; Searcey, M.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of (+)-resiniferatoxin. Chemtracts - Org Chem 1998, 11, 9, 647. |
| 【2】 Wender, P.A.; et al.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of resiniferatoxin. J Am Chem Soc 1997, 119, 52, 12976. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 55249 | 6-[(1R,3S,4R)-3-(acetyloxy)-4-(benzyloxy)-1-methyl-5-hexenyl]-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate | C30H44O8Si | 详情 | 详情 | |
| (XV) | 55250 | 2-[(1R,3S,4R)-3-(acetyloxy)-4-(benzyloxy)-1-methyl-5-hexenyl]-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-pyraniumolate | C28H40O6Si | 详情 | 详情 | |
| (XVI) | 55251 | (1R,2R,4S,5R,6S,8S)-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-11-oxo-12-oxatricyclo[6.3.1.0~1,6~]dodec-9-en-4-yl acetate | C28H40O6Si | 详情 | 详情 | |
| (XVII) | 55252 | (1R,2R,4S,5R,6S,8R)-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-11-oxo-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate | C28H42O6Si | 详情 | 详情 | |
| (XVIII) | 55253 | (1R,2R,4S,5R,6S,8R)-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-11-methylene-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate | C29H44O5Si | 详情 | 详情 | |
| (XIX) | 55254 | (1R,2R,4S,5R,6S,8S)-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-11-methylene-10-oxo-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate | C29H42O6Si | 详情 | 详情 | |
| (XX) | 55255 | (1R,2R,4S,5R,6S,8S,11S)-11-allyl-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-10-oxo-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate | C31H46O6Si | 详情 | 详情 | |
| (XXI) | 52731 | (2-phenylethynyl)lithium | C8H5Li | 详情 | 详情 | |
| (XXII) | 55256 | (1R,2R,4S,5R,6S,8S,10R,11S)-11-allyl-5-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methyl-10-(2-phenylethynyl)-10-[(trimethylsilyl)oxy]-12-oxatricyclo[6.3.1.0~1,6~]dodec-4-yl acetate | C42H60O6Si2 | 详情 | 详情 | |
| (XXIII) | 55257 | (1R,2S,4S,6R,8S,10S,11R,12S,14R)-11-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,14-dimethyl-5-[(Z)-phenylmethylidene]-6-[(trimethylsilyl)oxy]-15-oxatetracyclo[6.6.1.0~1,10~.0~2,6~]pentadecan-12-ol | C40H60O5Si2 | 详情 | 详情 |