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【结 构 式】 
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【分子编号】12235 【品名】(2S)oxiranylmethyl pivalate 【CA登记号】 |
【 分 子 式 】C8H14O3 【 分 子 量 】158.19736 【元素组成】C 60.74% H 8.92% O 30.34% |
合成路线1
该中间体在本合成路线中的序号：(II)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2
该中间体在本合成路线中的序号：(IV)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 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The enantiopure diol (II) was prepared by the Sharpless asymmetric dihydroxylation of ethyl sorbate (I). Catalytic hydrogenation of (II) generated the gamma-lactone (III). After conversion of the hydroxyl group of (III) to the corresponding mesylate, displacement by NaN3 afforded azide (IV). Reduction of (IV) to amine gave rise to the formation of lactam (V). Sequential protection of alcohol and amide functions provided (VI), which was treated with lithium hexamethyldisilazide and Comin's reagent to furnish the aminovinyl triflate (VII). The enantiopure propargyl alcohol (X), prepared by treatment of (S)-glycidol pivalate (VIII) with lithium trimethylsilylacetylide (IX) followed by desilylation with tetrabutylammonium fluoride, was then coupled with triflate (VII) in the presence of Pd(PPh3)4 and CuI to yield adduct (XI), which was reduced to the trisubstituted piperidine (XII) by means of NaBH3CN and trifluoroacetic acid. Hydrogenation of the alkyne function of (XII) with concomitant removal of the benzyloxycarbonyl group gave (XIII). This was further protected as the allyl carbamate (XIV) by treatment with allyl chloroformate. The secondary alcohol of (XIV) was then protected as the tetrahydropyranyl ether (XV), and subsequent reductive cleavage of the pivaloyl ester with DIBAL liberated the primary alcohol (XVI).
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 40236 | ethyl (2E,4E)-2,4-hexadienoate | 2396-84-1 | C8H12O2 | 详情 | 详情 |
| (II) | 40237 | ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate | C8H14O4 | 详情 | 详情 | |
| (III) | 40238 | (5R)-5-[(1R)-1-hydroxyethyl]dihydro-2(3H)-furanone | C6H10O3 | 详情 | 详情 | |
| (IV) | 40239 | (5R)-5-[(1R)-1-azidoethyl]dihydro-2(3H)-furanone | C6H9N3O2 | 详情 | 详情 | |
| (V) | 40240 | (5R,6S)-5-hydroxy-6-methyl-2-piperidinone | C6H11NO2 | 详情 | 详情 | |
| (VI) | 40241 | benzyl (2S,3R)-2-methyl-6-oxo-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C23H37NO4Si | 详情 | 详情 | |
| (VII) | 40242 | benzyl (2S,3R)-2-methyl-6-[[(trifluoromethyl)sulfonyl]oxy]-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C24H36F3NO6SSi | 详情 | 详情 | |
| (VIII) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (IX) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (X) | 12236 | (2S)-2-hydroxy-4-pentynyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XI) | 40243 | benzyl (2S,3R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C33H51NO6Si | 详情 | 详情 | |
| (XII) | 40244 | benzyl (2S,3R,6R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C33H53NO6Si | 详情 | 详情 | |
| (XIII) | 40245 | (2R)-2-hydroxy-5-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]pentyl pivalate | C25H51NO4Si | 详情 | 详情 | |
| (XIV) | 40246 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxypentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 | |
| (XV) | 40247 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C34H63NO7Si | 详情 | 详情 | |
| (XVI) | 40248 | allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The enantiopure diol (II) was prepared by the Sharpless asymmetric dihydroxylation of ethyl sorbate (I). Catalytic hydrogenation of (II) generated the gamma-lactone (III). After conversion of the hydroxyl group of (III) to the corresponding mesylate, displacement by NaN3 afforded azide (IV). Reduction of (IV) to amine gave rise to the formation of lactam (V). Sequential protection of alcohol and amide functions of (V) provided (VI), which was treated with lithium hexamethyldisilazide and Comin's reagent to furnish the aminovinyl triflate (VII). The enantiopure propargyl alcohol (X), prepared by treatment of (S)-glycidol pivalate (VIII) with lithium trimethylsilylacetylide (IX) followed by desilylation with tetrabutylammonium fluoride, was then coupled with triflate (VII) in the presence of Pd(PPh3)4 and CuI to yield adduct (XI), which was reduced to the trisubstituted piperidine (XII) by means of NaBH3CN and trifluoroacetic acid. Hydrogenation of the alkyne function of (XII) with concomitant removal of the benzyloxycarbonyl group gave (XIII). This was further protected as the allyl carbamate (XIV) by treatment with allyl chloroformate. The secondary alcohol of (XIV) was then protected as the tetrahydropyranyl ether (XV), and subsequent reductive cleavage of the pivaloyl ester with DIBAL liberated the primary alcohol (XVI).
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 40236 | ethyl (2E,4E)-2,4-hexadienoate | 2396-84-1 | C8H12O2 | 详情 | 详情 |
| (II) | 40237 | ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate | C8H14O4 | 详情 | 详情 | |
| (III) | 40238 | (5R)-5-[(1R)-1-hydroxyethyl]dihydro-2(3H)-furanone | C6H10O3 | 详情 | 详情 | |
| (IV) | 40239 | (5R)-5-[(1R)-1-azidoethyl]dihydro-2(3H)-furanone | C6H9N3O2 | 详情 | 详情 | |
| (V) | 40240 | (5R,6S)-5-hydroxy-6-methyl-2-piperidinone | C6H11NO2 | 详情 | 详情 | |
| (VI) | 40241 | benzyl (2S,3R)-2-methyl-6-oxo-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C23H37NO4Si | 详情 | 详情 | |
| (VII) | 40242 | benzyl (2S,3R)-2-methyl-6-[[(trifluoromethyl)sulfonyl]oxy]-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C24H36F3NO6SSi | 详情 | 详情 | |
| (VIII) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (IX) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (X) | 12236 | (2S)-2-hydroxy-4-pentynyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XI) | 40243 | benzyl (2S,3R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C33H51NO6Si | 详情 | 详情 | |
| (XII) | 40244 | benzyl (2S,3R,6R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C33H53NO6Si | 详情 | 详情 | |
| (XIII) | 40245 | (2R)-2-hydroxy-5-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]pentyl pivalate | C25H51NO4Si | 详情 | 详情 | |
| (XIV) | 40246 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxypentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 | |
| (XV) | 40247 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C34H63NO7Si | 详情 | 详情 | |
| (XVI) | 40248 | allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 |