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【结 构 式】 
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【分子编号】17461 【品名】ethynyllithium 【CA登记号】 |
【 分 子 式 】C2HLi 【 分 子 量 】31.97094 【元素组成】C 75.14% H 3.15% Li 21.71% |
合成路线1
该中间体在本合成路线中的序号：(XV)Synthesis of the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI): The reaction of the chiral trihydroxy compound (XI) with 2,4-dimethyl-3-pentanone dimethyl acetal (XII) by means of TsOH in THF gives the ketal (XIII), which is treated with TsCl, TEA and DMAP in dichloromethane to yield the silyl ether (XIV). The condensation of (XIV) with ethynyl lithium (XV) in DMSO affords the propargyl derivative (XVI). The reduction of (XVI) with H2 over Lindlar catalyst in hexane containing quinoline provides the allyl derivative (XVII), which is condensed with propane-1,3-dithiol and BF3/Et2O in dichloromethane to give the chiral hydroxy dithiane (XVIII). The cleavage of the ketal group of (XVIII) by means of TsOH in methanol, followed by reaction of the intermediate diol with TsCl and pyridine yields the primary monotosylate (XIX), which is treated with Tbdms-OTf and lutidine in dichloromethane to afford the bis silyl ether (XX). Finally, this compound is iodinated by means of NaI, Cu and AgNO3 in hot acetonitrile/methanol to provide the desired intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI).
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 【2】 Smith, A.B. III; et al.; Formal total synthesis of FK506. Concise construction of the C(10)-C(34) segment via an effective coupling tactic. Tetrahedron Lett 1994, 35, 25, 4271. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 57298 | (2S,3S)-3-{(E,4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-1,2,4-butanetriol | C21H40O7 | 详情 | 详情 | |
| (XII) | 57336 | 3,3-dimethoxy-2,4-dimethylpentane; 1-isopropyl-1-methoxy-2-methylpropyl methyl ether | C9H20O2 | 详情 | 详情 | |
| (XIII) | 57337 | (2S,3E,6S,8S)-2-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-8-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-8-methoxy-4,6-dimethyl-3-octen-1-ol | C28H52O7 | 详情 | 详情 | |
| (XIV) | 57338 | (2S,3E,6S,8S)-2-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-8-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-8-methoxy-4,6-dimethyl-3-octenyl 4-methylbenzenesulfonate | C35H58O9S | 详情 | 详情 | |
| (XV) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 | |
| (XVI) | 57339 | (2R,3S,5R,6S)-2-{(1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-methoxy-3,5-dimethyl-5-decen-9-ynyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; (1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5-decen-9-ynyl methyl ether | C30H52O6 | 详情 | 详情 | |
| (XVII) | 57340 | (2R,3S,5R,6S)-2-{(1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-methoxy-3,5-dimethyl-5,9-decadienyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; (1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5,9-decadienyl methyl ether | C30H54O6 | 详情 | 详情 | |
| (XVIII) | 57341 | (2R,4S,5R,6S,8S,10E,12R)-12-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-2-(1,3-dithian-2-yl)-4,6-dimethoxy-8,10-dimethyl-10,14-pentadecadien-5-ol | C32H58O5S2 | 详情 | 详情 | |
| (XIX) | 57342 | (2S,3R,4E,7S,9S,10R,11S,13R)-3-allyl-13-(1,3-dithian-2-yl)-2,10-dihydroxy-9,11-dimethoxy-5,7-dimethyl-4-tetradecenyl 4-methylbenzenesulfonate | C32H52O7S3 | 详情 | 详情 | |
| (XX) | 57343 | (2S,3R,4E,7S,9S,10R,11S,13R)-3-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-13-(1,3-dithian-2-yl)-9,11-dimethoxy-5,7-dimethyl-4-tetradecenyl 4-methylbenzenesulfonate | C44H80O7S3Si2 | 详情 | 详情 | |
| (XXI) | 57344 | (1S,2R,3E,6S,8S,9R,10S,12R)-2-allyl-9-{[tert-butyl(dimethyl)silyl]oxy}-1-(iodomethyl)-8,10,13,13-tetramethoxy-4,6,12-trimethyl-3-tridecenyl tert-butyl(dimethyl)silyl ether; (5S,6R,7E,10S,12S,13R)-6-allyl-5-(iodomethyl)-12-methoxy-2,2,3,3,8,10,15,15,16,16-decamethyl-13-[(1S,3R)-1,4,4-trimethoxy-3-methylbutyl]-4,14-dioxa-3,15-disila-7-heptadecene | C36H73IO6Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The intermediate stannane derivative (XVI) has been obtained as follows: The esterification of propynoic acid (XII) with diphenyldiazomethane (XIII) in benzene gives the corresponding ester (XIV), which is then condensed with Me3Sn-Cu(CN)Li (XV) in THF/methanol to yield the desired intermediate (XVI). 3-Hydroxy-2(S)-methylpropionic acid methyl ester (I) is converted into the chiral tosylate (II) by conventional methods. The condensation of (II) with 4-pentenylmagnesium bromide (III) in THF gives the chiral tetrahydropyranyl ether (IV), which is condensed with the phosphonate (V) by means of KHMDS in THF/toluene yielding the chiral nonenoic ester (VI). The reduction of (VI) with DIBAL in the same solvent, followed by protection of the resulting alcohol with TBDPSCl and TEA in dichloromethane affords the protected diol (VII). The selective elimination of the THP protecting group, followed by reaction with TsCl and TEA in dichloromethane affords the tosylate (VIII), which is condensed with lithium acetylide (IX) in DMSO to provide the terminal acetylene (X). The deprotection of (X) with TBAF, followed by reaction with Me3Al, Cp2ZrCl2, and I2 in THF gives the omega iodoundecadienol (XI), which is condensed with the stannane derivative (XVI) by means of PdCl2 in DMF yielding the tetradecatrienoic diphenylmethyl ester (XVII). The chiral epoxidation of (XVII) with Ti(OiPr)4, BuOOH and (R,R)(+)-diisopropyl tartrate (DIPT) in dichloroethane affords the hydroxymethyl-oxirane (XVIII), which is oxidized with tetrapropylammonium perruthenate (TPAP) to provide the oxirane carbaldehyde (XIX).
| 【1】 Bates, R.W.; et al.; Total synthesis of the cholesterol biosynthesis inhibitor 1233A via a (Pi-allyl)tricarbonyliron lactone complex. J Chem Soc - Perkins Trans I 1999, 14, 1917. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 41854 | (2S)-2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl 4-methylbenzenesulfonate | C17H26O5S | 详情 | 详情 | |
| (III) | 39424 | bromo(4-pentenyl)magnesium | C5H9BrMg | 详情 | 详情 | |
| (IV) | 41855 | (3R)-3-methyl-8-nonenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(3R)-3-methyl-8-nonenyl]oxy]tetrahydro-2H-pyran | C15H28O2 | 详情 | 详情 | |
| (V) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (VI) | 41857 | methyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenoate | C17H30O4 | 详情 | 详情 | |
| (VII) | 41858 | tert-butyl[[(Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl ether | C32H48O3Si | 详情 | 详情 | |
| (VIII) | 41859 | (2R,7Z)-9-[[tert-butyl(diphenyl)silyl]oxy]-2-methyl-7-nonenyl 4-methylbenzenesulfonate | C33H44O4SSi | 详情 | 详情 | |
| (IX) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 | |
| (X) | 41860 | tert-butyl[[(Z,8R)-8-methyl-2-undecen-10-ynyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-2-undecen-10-ynyl ether | C28H38OSi | 详情 | 详情 | |
| (XI) | 41861 | (2Z,8R,10E)-11-iodo-8,10-dimethyl-2,10-undecadien-1-ol | C13H23IO | 详情 | 详情 | |
| (XII) | 10398 | 2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether | C13H19IO2 | 详情 | 详情 | |
| (XIII) | 40585 | 1-[diazo(phenyl)methyl]benzene | C13H10N2 | 详情 | 详情 | |
| (XIV) | 41862 | benzhydryl 2-butynoate | C17H14O2 | 详情 | 详情 | |
| (XVI) | 41863 | benzhydryl (E)-3-(trimethylstannyl)-2-butenoate | C20H24O2Sn | 详情 | 详情 | |
| (XVII) | 41864 | benzhydryl (2E,4E,7R,12Z)-14-hydroxy-3,5,7-trimethyl-2,4,12-tetradecatrienoate | C30H38O3 | 详情 | 详情 | |
| (XVIII) | 41865 | benzhydryl (2E,4E,7R)-11-[(2R,3S)-3-(hydroxymethyl)oxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H38O4 | 详情 | 详情 | |
| (XIX) | 41866 | benzhydryl (2E,4E,7R)-11-[(2R,3R)-3-formyloxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H36O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：A new asymmetric synthesis of stavudine has been described: The regioselective epoxidation of allyl alcohol (I) by means of titanium tetraisopropoxide and alpha,alpha-dimethylbenzylperoxide, catalyzed by diisopropyl D-tartrate, followed by esterification with pivaloyl chloride yields the epoxide (II), which is then condensed with lithium acetylide catalyzed by boron trifluoride ethearate in THF, yielding the acetylenic alcohol (III). The cyclization of (III) catalyzed by Mo(CO)6 and trimethylamine oxide affords the dihydrofuran (IV), which is condensed with N,N'-bis(trimethylsilyl)thymine (V) and I2 to give the iodonucleoside (VI). Finally, this compound is dehydroiodinated and deprotected with sodium methoxide in methanol.
| 【1】 Gleason, M.M.; McDonald, F.E.; Asymmetric syntheses of stavudine (d4T) and cordycepin by cycloisomerization of alkynyl alcohols to endocyclic enol ethers. Angew Chem. Int Ed Engl 1995, 34, 3, 350. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17461 | ethynyllithium | C2HLi | 详情 | 详情 | ||
| (I) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (II) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (III) | 12236 | (2S)-2-hydroxy-4-pentynyl pivalate | C10H16O3 | 详情 | 详情 | |
| (IV) | 12226 | (2S)-2,3-dihydro-2-furanylmethyl pivalate | C10H16O3 | 详情 | 详情 | |
| (V) | 12238 | 5-Methyl-1,3-bis(trimethylsilyl)-2,4(1H,3H)-pyrimidinedione | 3444-09-5 | C11H22N2O2Si2 | 详情 | 详情 |
| (VI) | 12239 | [(2S,4R,5R)-4-iodo-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl pivalate | C15H21IN2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(L)4) Lactone form: The condensation of 2(S)-(chloromethyl)oxirane (XXXIII) with trimethylsilylacetylene (XXXIV) by means of butyllithium and BF3 ethearate in THF gives 5-chloro-4(S)-hydroxy-1-(trimethylsilyl)-1-pentyne (XXXV), which is cyclized with KOH in THF to the chiral epoxide (XXXVI). The condensation of (XXXVI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII, see Scheme 5) by means of butyllithium in THF affords the silylated heptynol (XXXVIII), which is desilylated with K2CO3 in methanol to the terminal acetylene (XXXIX). The carboxylation of (XXXIX) with CO by means of PdCl2/CuCl2 in methanol yields the heptynoic acid ester (XL), which is selectively reduced with H2 over the Lindlar catalyst in methanol to the cis-heptenoic ester (XLI). The cyclization of (XLI) with PPTS in refluxing toluene affords the (S)-unsaturated lactone (XLII), which is oxidized with m-chloroperbenzoic acid to the corresponding sulfinyl derivative (XLIII).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 17460 | 1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-[(2R)oxiranyl]ethyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[2-[(2R)oxiranyl]-1-(phenylsulfanyl)ethyl]quinoline | C28H24FNOS | 详情 | 详情 | |
| (XXXIII) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (XXXIV) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (XXXV) | 17449 | (2S)-1-chloro-5-(trimethylsilyl)-4-pentyn-2-ol | C8H15ClOSi | 详情 | 详情 | |
| (XXXVI) | 17450 | trimethyl[3-[(2S)oxiranyl]-1-propynyl]silane | C8H14OSi | 详情 | 详情 | |
| (XXXVII) | 17451 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[(phenylsulfanyl)methyl]quinoline | C25H20FNS | 详情 | 详情 | |
| (XXXVIII) | 17452 | (3S)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-1-(phenylsulfanyl)-6-(trimethylsilyl)-5-hexyn-3-ol | C33H34FNOSSi | 详情 | 详情 | |
| (XXXIX) | 17453 | (3S)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-1-(phenylsulfanyl)-5-hexyn-3-ol | C30H26FNOS | 详情 | 详情 | |
| (XL) | 17454 | methyl (5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-7-(phenylsulfanyl)-2-heptynoate | C32H28FNO3S | 详情 | 详情 | |
| (XLI) | 17455 | methyl (Z,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-7-(phenylsulfanyl)-2-heptenoate | C32H30FNO3S | 详情 | 详情 | |
| (XLII) | 17456 | (6S)-6-[2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-(phenylsulfanyl)ethyl]-5,6-dihydro-2H-pyran-2-one | C31H26FNO2S | 详情 | 详情 | |
| (XLIII) | 17457 | (6S)-6-[2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-(phenylsulfinyl)ethyl]-5,6-dihydro-2H-pyran-2-one | C31H26FNO3S | 详情 | 详情 | |
| (XLVII) | 38067 | (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin | 51594-55-9 | C3H5ClO | 详情 | 详情 |
| (XLVIII) | 17459 | (2R)-1-chloro-4-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-4-(phenylsulfanyl)-2-butanol | C28H25ClFNOS | 详情 | 详情 | |
| (L) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The enantioselective epoxidation of allyl alcohol (I) with 2-phenylisopropyl hydroperoxide (II) and Ti(iPrO)4 in the presence of D-diisopropyl tartrate gives the chiral epoxide (III), which is esterified with pivaloyl chloride to yield the pivalate (IV). The opening of the epoxide ring of (IV) by means of lithium acetylide (V) and BF3/Et2O affords the alkynyl alcohol (VI), which is cyclized by means of Mo(CO)6 and trimethylamine oxide to provide the chiral dihydrofuran (VII). The oxidation of (VII) with OsO4 and 4-methylmorpholine-N-oxide (NMMO) gives the diol (VIII), which is treated with Ac2O to yield the diacetate (IX). The condensation of (IX) with N6-benzoyl-N6,7-bis(trimethylsilyl)adenine (X) by means of Tms-OTf affords the nucleoside (XI). Finally, this compound is deprotected by means of NaOMe in methanol.
| 【1】 Gleason, M.M.; McDonald, F.E.; Asymmetric synthesis of nucleosides via molybdenum-catalyzed alkynol cycloisomerization coupled with stereoselective glycosylations of deoxyfuranose glycals and 3-amidofuranose glycals. J Am Chem Soc 1996, 118, 28, 6648. |
| 【2】 Gleason, M.M.; McDonald, F.E.; Asymmetric syntheses of stavudine (d4T) and cordycepin by cycloisomerization of alkynyl alcohols to endocyclic enol ethers. Angew Chem. Int Ed Engl 1995, 34, 3, 350. |
| 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) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (II) | 49206 | alpha,alpha-Dimethylbenzyl hydroperoxide; Cumyl hydroperoxide; Cumene Hydroperoxide | 80-15-9 | C9H12O2 | 详情 | 详情 |
| (III) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (IV) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (V) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 | |
| (VI) | 12260 | diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate | C15H15F3O6 | 详情 | 详情 | |
| (VII) | 12226 | (2S)-2,3-dihydro-2-furanylmethyl pivalate | C10H16O3 | 详情 | 详情 | |
| (VIII) | 49207 | [(2S,4R,5R)-4,5-dihydroxytetrahydro-2-furanyl]methyl pivalate | C10H18O5 | 详情 | 详情 | |
| (IX) | 49208 | [(2S,4R,5S)-4,5-bis(acetoxy)tetrahydro-2-furanyl]methyl pivalate | C14H22O7 | 详情 | 详情 | |
| (X) | 49209 | N-(trimethylsilyl)-N-[7-(trimethylsilyl)-7H-purin-6-yl]benzamide | C18H25N5OSi2 | 详情 | 详情 | |
| (XI) | 49210 | [(2S,4R,5R)-4-(acetoxy)-5-[6-(benzoylamino)-9H-purin-9-yl]tetrahydro-2-furanyl]methyl pivalate | C24H27N5O6 | 详情 | 详情 |