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【结 构 式】

【分子编号】40237

【品名】ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate

【CA登记号】

【 分 子 式 】C8H14O4

【 分 子 量 】174.19676

【元素组成】C 55.16% H 8.1% O 36.74%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(II)

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2

该中间体在本合成路线中的序号:(II)

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
Extended Information