【结 构 式】 |
【分子编号】23666 【品名】(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid 【CA登记号】 |
【 分 子 式 】C27H32N2O8 【 分 子 量 】512.55976 【元素组成】C 63.27% H 6.29% N 5.47% O 24.97% |
合成路线1
该中间体在本合成路线中的序号:(VIII)1) The Wittig condensation of dimetbyl 3 methyl-2-oxooct-5-inphosphonate (II) with (1R,5S,6R,7R)-3,3-ethylenedioxy 7-benzoyloxy-6-formylbicyclo[3.3.0]octane by means of NaH in dimethoxy ethane, followed by a bromination with N-bromosuccinimide (NBS), gives the brominated condensation product (III), which is reduced with NaBH4 in methanol, debenzoylated with K2CO3 in methanol and protected with dihydropyran and p-toluenesulfonic acid yielding the protected diol (IV). Dehydrobromination of (IV) with potassium tert-butoxide in DMSO THF, followed by hydrolysis with acetic acid, affords the diacetylenic ketone (V), which is submitted to a Wittig condensation with triethyl phosphonoacetate (VI) usino potassium ten butoxide as base, and to a reduction with LiAlH4 in ether yielding the pentalenylideneethanol (VII). The condensation of (VII) with bromoacetic acid (VIII), by means of NaH in THF affords the protected prostaglandin (IX), which is finally deprotected with aceto acid water THF.
【1】 Haberey, M.; Raduchel, B.; Schillinger, E.; Skuballa, W.; Sturzebecher, C.-S.; Town, M.H.; Vorbruggen, H. (Schering AG); Novel carbacyclins, processes for their preparation and their use as medicinal agents. EP 0119949; US 5013758 . |
【2】 Castaner, J.; Prous, J.; Cicaprost. Drugs Fut 1986, 11, 11, 913. |
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) | 24200 | Benzoic acid (1'R,2'R,3'aR,6'aS)-1'-formylspiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester | C18H20O5 | 详情 | 详情 | |
(II) | 24201 | dimethyl 3-methyl-2-oxo-5-octynylphosphonate | C11H19O4P | 详情 | 详情 | |
(III) | 24202 | Benzoic acid (2'R,3'aR,6'aS)-1'-(2-Bromo-4(S)-methyl-3-oxonon-1(E)-en-6-yn-1-yl)-spiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester | C27H31BrO5 | 详情 | 详情 | |
(IV) | 24203 | 2-Bromo-4(S)-methyl-1-[(2'(R),3'a(R),6'a(S))-2'-(tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalen]-1-yl]non-1(E)-en-6-yn-3-one | C21H29BrO3 | 详情 | 详情 | |
(V) | 24204 | (3aS,5R,6aR)-4-[(3S,4S)-4-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,6-nonadiynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C29H42O5 | 详情 | 详情 | |
(VI) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
(VII) | 24206 | 2-[(3aS,4R,5R,6aR)-4-[(3S,4S)-4-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,6-nonadiynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]-1-ethanol | C31H46O5 | 详情 | 详情 | |
(VIII) | 23666 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid | C27H32N2O8 | 详情 | 详情 | |
(IX) | 24208 | 2-[2-[(3aS,4R,5R,6aR)-4-[(3S,4S)-4-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,6-nonadiynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetic acid | C33H48O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VIII)Acylation of L-leucine benzyl ester (I) with bromoacetic acid (II) in the presence of DCC and DMAP gave bromoacetamide (III), which upon reaction with triphenyl phosphine was converted to phosphonium salt (IV). After treatment of (IV) with Et3N, the resulting ylide was condensed with N-Boc-L-leucine (V) to yield the acyl- phosphonate (VI). Acid deprotection of the N-Boc group of (VI) provided amine (VII), which was condensed with the depsipeptide (VIII) using EDC and HOBt yielding (IX). Removal of the N-Fmoc group from tetrapeptide (IX) was effected by treatment with piperidine in DMF, and the resulting amino compound was further condensed with protected L-asparagine (X) to furnish peptide (XI). After hydrogenolytic removal of the benzyl and carbobenzoxy groups of (XI), treatment with diphenyl phosphoryl azide and NaHCO3 produced the cyclic depsipeptide (XII).
【1】 Wasserman, H.H.; et al.; The chemistry of vicinal tricarbonyls: Total syntheses of elastase inhibitors YM-47141 and YM-47142. Helv Chim Acta 2000, 83, 9, 2607. |
【2】 Wasserman, H.H.; et al.; Total syntheses of depsipeptide elastase inhibitor. J Am Chem Soc 1999, 121, 6, 1401. |
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) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
(II) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
(III) | 23661 | benzyl (2S)-2-[(2-bromoacetyl)amino]-4-methylpentanoate | C15H20BrNO3 | 详情 | 详情 | |
(IV) | 23662 | benzyl (2S)-4-methyl-2-[[2-(triphenylphosphoranyl)acetyl]amino]pentanoate | C33H36NO3P | 详情 | 详情 | |
(V) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid;N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
(VI) | 23664 | benzyl (2S)-2-[[(4S)-4-[(tert-butoxycarbonyl)amino]-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C44H53N2O6P | 详情 | 详情 | |
(VII) | 23665 | benzyl (2S)-2-[[(4S)-4-amino-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C39H45N2O4P | 详情 | 详情 | |
(VIII) | 23666 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid | C27H32N2O8 | 详情 | 详情 | |
(IX) | 23667 | benzyl (5R,8S,9S,12S,17S)-9-[(tert-butoxycarbonyl)amino]-1-(9H-fluoren-9-yl)-12,17-diisobutyl-5,8-dimethyl-3,6,10,13,15-pentaoxo-14-(triphenylphosphoranylidene)-2,7-dioxa-4,11,16-triazaoctadecan-18-oate | C66H75N4O11P | 详情 | 详情 | |
(X) | 23668 | C13H16N2O5 | 详情 | 详情 | ||
(XI) | 23669 | C64H79N6O13P | 详情 | 详情 | ||
(XII) | 23670 | C49H65N6O10P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VIII)Acylation of L-leucine benzyl ester (I) with bromoacetic acid (II) in the presence of DCC and DMAP gave bromoacetamide (III), which upon reaction with triphenyl phosphine was converted to phosphonium salt (IV). After treatment of (IV) with Et3N, the resulting ylide was condensed with N-Boc-L-leucine (V) to yield the acyl- phosphonate (VI). Acid deprotection of the N-Boc group of (VI) provided amine (VII), which was condensed with the depsipeptide (VIII) using EDC and HOBt yielding (IX). Removal of the N-Fmoc group from tetrapeptide (IX) was effected by treatment with piperidine in DMF, and the resulting amino compound was further condensed with protected L-asparagine (X) to furnish peptide (XI). After hydrogenolytic removal of the benzyl and carbobenzoxy groups of (XI), treatment with diphenyl phosphoryl azide and NaHCO3 produced the cyclic depsipeptide (XII).
【1】 Wasserman, H.H.; et al.; The chemistry of vicinal tricarbonyls: Total syntheses of elastase inhibitors YM-47141 and YM-47142. Helv Chim Acta 2000, 83, 9, 2607. |
【2】 Wasserman, H.H.; et al.; Total syntheses of depsipeptide elastase inhibitor. J Am Chem Soc 1999, 121, 6, 1401. |
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) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
(II) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
(III) | 23661 | benzyl (2S)-2-[(2-bromoacetyl)amino]-4-methylpentanoate | C15H20BrNO3 | 详情 | 详情 | |
(IV) | 23662 | benzyl (2S)-4-methyl-2-[[2-(triphenylphosphoranyl)acetyl]amino]pentanoate | C33H36NO3P | 详情 | 详情 | |
(V) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid;N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
(VI) | 23664 | benzyl (2S)-2-[[(4S)-4-[(tert-butoxycarbonyl)amino]-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C44H53N2O6P | 详情 | 详情 | |
(VII) | 23665 | benzyl (2S)-2-[[(4S)-4-amino-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C39H45N2O4P | 详情 | 详情 | |
(VIII) | 23666 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid | C27H32N2O8 | 详情 | 详情 | |
(IX) | 23667 | benzyl (5R,8S,9S,12S,17S)-9-[(tert-butoxycarbonyl)amino]-1-(9H-fluoren-9-yl)-12,17-diisobutyl-5,8-dimethyl-3,6,10,13,15-pentaoxo-14-(triphenylphosphoranylidene)-2,7-dioxa-4,11,16-triazaoctadecan-18-oate | C66H75N4O11P | 详情 | 详情 | |
(X) | 23668 | C13H16N2O5 | 详情 | 详情 | ||
(XI) | 23669 | C64H79N6O13P | 详情 | 详情 | ||
(XII) | 23670 | C49H65N6O10P | 详情 | 详情 |