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【结 构 式】 
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【分子编号】12226 【品名】(2S)-2,3-dihydro-2-furanylmethyl pivalate 【CA登记号】 |
【 分 子 式 】C10H16O3 【 分 子 量 】184.23524 【元素组成】C 65.19% H 8.75% O 26.05% |
合成路线1
该中间体在本合成路线中的序号：(XXXI)Other methods based on the modification of carbohydrates have also been described: 7) Protection of readily available (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (XIX) with tert-butyldiphenylsilyl chloride gives ether (XX), which is converted to the seleno derivative (XXI) on treatment with lithium hexamethyldisilazide and trimethylchlorosilane in tetrahydrofuran, followed by reaction with phenylselenylbromide. Reduction of (XXI) with diisobutylaluminum hydride in toluene followed by acetylation gives compound (XXII), which is reacted with (XXIII) and trimethylsilyltriflate in dichloroethane to afford stereoselectively compound (XXIV). The latter is finally submitted to elimination and deprotected by successive treatment with hydrogen peroxide in pyridine and tetrabutylammonium fluoride in tetrahydrofuran. 8) A related route involves treatment of (XX) with lithium diisopropylamide in tetrahydrofuran and diphenylsulfide in HMPA to give (XXV), which is reduced and acetylated to yield (XXVI). Compound (XXVI) is treated with (XXIII) in the presence of tin tetrachloride in dichloromethane to afford (XXVII), which is oxidized with sodium periodate and submitted to elimination by treating in toluene-pyridine, to yield compound (XXVIII). Finally, compound (XXVIII) is deprotected with tetrabutylammonium fluoride in tetrahydrofuran. 9) A third procedure begins with the protection of (XIX) as a tert-butoxycarbonyl ester to yield (XXIX), reduction with diisobutylaluminum hydride in tetrahydrofuran to afford (XXX) and elimination after treatment with thionyl chloride in dichloromethane and potassium tert-butoxide in tetrahydrofuran to give (XXXI). Subsequent reaction of compound (XXXI) with thymine (IX) in the presence of hexamethyldisilazane and trimethylsilyl chloride and N-chlorosuccinimide in tetrahydrofuran gives compound (XXXII), which is treated with potassium tert-butoxide in tetrahydrofuran and deprotected with sodium methoxide in methanol.
| 【1】 Kim, C.U.; Martin, J.C. (Bristol-Myers Squibb Co.); Processes for preparation of nucleoside derivs. EP 0501511 . |
| 【2】 Hammoudeh, A.J.; Haft, J.I.; Conte, P.J.; A general method for controlled glycosylation stereochemistry in the synthesis of 2'-deoxyribose nucleosides. Tetrahedron Lett 1990, 31, 2, 1815-8. |
| 【3】 Robinson, C.; Castaner, J.; Stavudine. Drugs Fut 1994, 19, 10, 925. |
| 【4】 Babu, J.R.; Beach, J.W.; Ahn, S.K.; Jeong, L.S.; Chu, C.K.; Huang, Huang, H.; Lee, S.J.; A highly stereoselective glycosylation of 2-(phenylselenyl)-2,3-dideoxyribose derivative with thymine: Synthesis of 3'-deoxy-2',3'-didehydrothymidine and 3'-deoxythymidine. J Org Chem 1990, 55, 1418-20. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (XIX) | 12008 | (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone | 32780-06-6 | C5H8O3 | 详情 | 详情 |
| (XX) | 12215 | (5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C21H26O3Si | 详情 | 详情 | |
| (XXI) | 12216 | (3R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)dihydro-2(3H)-furanone | C27H30O3SeSi | 详情 | 详情 | |
| (XXII) | 12217 | (3R,5S)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanyl acetate | C29H34O4SeSi | 详情 | 详情 | |
| (XXIII) | 12218 | 5-Methyl-2,4-bis[(trimethylsilyl)methyl]pyrimidine | C13H26N2Si2 | 详情 | 详情 | |
| (XXIV) | 12219 | 1-[(2R,3R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C32H36N2O4SeSi | 详情 | 详情 | |
| (XXV) | 12220 | (3R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-3-(phenylsulfanyl)dihydro-2(3H)-furanone | C27H30O3SSi | 详情 | 详情 | |
| (XXVI) | 12221 | (3R,5S)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylsulfanyl)tetrahydro-2-furanyl acetate | C29H34O4SSi | 详情 | 详情 | |
| (XXVII) | 12222 | 1-[(2R,3R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-3-(phenylsulfanyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C32H36N2O4SSi | 详情 | 详情 | |
| (XXVIII) | 12223 | 1-[(2R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-2,5-dihydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C26H30N2O4Si | 详情 | 详情 | |
| (XXIX) | 12224 | [(2S)-5-oxotetrahydro-2-furanyl]methyl pivalate | C10H16O4 | 详情 | 详情 | |
| (XXX) | 12225 | [(2S)-5-hydroxytetrahydro-2-furanyl]methyl pivalate | C10H18O4 | 详情 | 详情 | |
| (XXXI) | 12226 | (2S)-2,3-dihydro-2-furanylmethyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XXXII) | 12227 | [(2S,4R,5R)-4-chloro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl pivalate | C15H21ClN2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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3
该中间体在本合成路线中的序号：(VII)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 |