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【结 构 式】 
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【分子编号】55241 【品名】(2-ethoxyethynyl)lithium 【CA登记号】 |
【 分 子 式 】C4H5LiO 【 分 子 量 】76.0241 【元素组成】C 63.2% H 6.63% Li 9.13% O 21.05% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)The intermediate chiral phosphonamide (XXXII) has been obtained as follows: The treatment of arabitol (XIX) with the Moffat reagent (alpha-acetoxy-isobutyric acyl chloride) (XX) gives the intermediate (XXI), which, without isolation, by treatment with NaOMe and with Tbdms-Cl yields the silylated diepoxide (XXII). The condensation of (XXII) with ethoxyethynyl lithium (XXIII) by means of BF3/Et2O, HgCl2 and Ts-OH affords the bis(lactone) (XXIV), which is methylated by means of methyl iodide and LDA to provide the dimethyl analogue (XXV). The hydrolysis and desilylation of (XXV) by means of HF, followed by reprotection with benzyl trichloroacetimidate, and exhaustive methylation with NaH and methyl iodide gives the chiral nonanedioic dimethyl ester (XXVI). The reductive cleavage of the benzyl ether group with H2 over Pd(OH)2, followed by cyclization by means of PPTS yields the lactone (XXVII). The reduction of (XXVII) with L-selectride, followed by protection with propane-1,3-dithiol and BF3/Et2O affords the 1,3-dithiane (XXVIII). The reduction of the lactone group of (XXVIII) with LiAlH4, followed by reaction with PPh3 and I2 provides the chiral nonyl iodide (XXIX). The protection of the OH group of (XXIX) by means of Tbdms-OTf gives the silyl ether (XXX), which is finally condensed with lithium derived ethylphosphonamide (XXXI) to yield the intermediate chiral phosphonamide (XXXII).
| 【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 11442 | (2S,4S)-1,2,3,4,5-Pentanepentol; D-Arabinol | 488-82-4 | C5H12O5 | 详情 | 详情 |
| (XX) | 32808 | 2-chloro-1,1-dimethyl-2-oxoethyl acetate | 40635-66-3 | C6H9ClO3 | 详情 | 详情 |
| (XXI) | 57258 | (1R,3R)-3-(acetyloxy)-4-chloro-1-(chloromethyl)-2-hydroxybutyl acetate | C9H14Cl2O5 | 详情 | 详情 | |
| (XXII) | 11445 | tert-Butyl(dimethyl)silyl di[(2S)oxiranyl]methyl ether; tert-Butyl[di[(2S)oxiranyl]methoxy]dimethylsilane | C11H22O3Si | 详情 | 详情 | |
| (XXIII) | 55241 | (2-ethoxyethynyl)lithium | C4H5LiO | 详情 | 详情 | |
| (XXIV) | 11448 | (5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S)-5-oxotetrahydro-2-furanyl]methyl]dihydro-2(3H)-furanone | C15H26O5Si | 详情 | 详情 | |
| (XXV) | 11449 | (3R,5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone | C17H30O5Si | 详情 | 详情 | |
| (XXVI) | 11452 | dimethyl (2R,4S,6S,8R)-5-(benzyloxy)-4,6-dimethoxy-2,8-dimethylnonanedioate | C22H34O7 | 详情 | 详情 | |
| (XXVII) | 11454 | methyl (2R,4S)-4-methoxy-4-[(2S,3S,5R)-3-methoxy-5-methyl-6-oxotetrahydro-2H-pyran-2-yl]-2-methylbutanoate | C14H24O6 | 详情 | 详情 | |
| (XXVIII) | 11456 | (3R,5S,6R)-6-[(1S,3R)-3-(1,3-Dithian-2-yl)-1-methoxybutyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-one | C16H28O4S2 | 详情 | 详情 | |
| (XXIX) | 11458 | (2R,4S,5S,6S,8R)-8-(1,3-Dithian-2-yl)-1-iodo-4,6-dimethoxy-2-methyl-5-nonanol | C16H31IO3S2 | 详情 | 详情 | |
| (XXX) | 11459 | tert-Butyl([(1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl ether | C22H45IO3S2Si | 详情 | 详情 | |
| (XXXI) | 57259 | {1-[bis(dimethylamino)phosphoryl]ethyl}lithium | C6H16LiN2OP | 详情 | 详情 | |
| (XXXII) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |