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【结 构 式】 
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【分子编号】22838 【品名】(2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid 【CA登记号】 |
【 分 子 式 】C14H19NO4 【 分 子 量 】265.3092 【元素组成】C 63.38% H 7.22% N 5.28% O 24.12% |
合成路线1
该中间体在本合成路线中的序号：(IX)Protection of the carboxyl group of Boc-L-threonine (I) with [2-(chloromethoxy)ethyl]trimethylsilane (SEM-Cl) (II) by means of Li2CO3 affords protected threonine (III). Separately, Z-L-tyrosine (IV) is treated with dimethyl sulfate and KOH in THF with tetrabutylammonium hydrogen sulfate as a catalyst to furnish N,O-dimethyl-L-tyrosine (V), which is then converted into secondary amine (VI) by coupling with protected threonine (III) either by means of 2,4,6-trichlorobenzoyl chloride in THF and DMAP in benzene or with isopropenyl chloroformate, Et3N and DMAP, followed by elimination of the carbobenzyloxy group by hydrogenation over Pd/C. Coupling of Z-L-leucine (IX) to L-proline methyl ester (X) by means of DCC, HOBt and NMM in CH2Cl2, followed by hydrolysis with LiOH, affords Z-leucylproline (VII), which is then coupled to amine (VI) by means of BOPCl and Et3N in CH2Cl2, and then subjected to deprotection with hydrofluoric acid in acetonitrile affording intermediate (VIII).
| 【1】 Li, W.-R.; et al.; Total synthesis and structural investigations of didemnins A, B, and C. J Am Chem Soc 1990, 112, 21, 7659. |
| 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) | 50745 | N-BOC-L-threonine; Boc-Threonine; N-tert-Butoxycarbonyl-L-threonine; N-(tert-Butoxycarbonyl)-L-threonine; BOC-L-Threonine | 2592-18-9 | C9H17NO5 | 详情 | 详情 |
| (II) | 27243 | [2-(chloromethoxy)ethyl](trimethyl)silane | 76513-69-4 | C6H15ClOSi | 详情 | 详情 |
| (III) | 50746 | [2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate | C15H31NO6Si | 详情 | 详情 | |
| (IV) | 39328 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid | C17H17NO5 | 详情 | 详情 | |
| (V) | 50747 | (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid | C19H21NO5 | 详情 | 详情 | |
| (VI) | 50748 | (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-[[(2S)-3-(4-methoxyphenyl)-2-(methylamino)propanoyl]oxy]butyric acid | C20H30N2O7 | 详情 | 详情 | |
| (VII) | 50749 | (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylic acid | C19H26N2O5 | 详情 | 详情 | |
| (VIII) | 50750 | (2S,3R)-3-[[(2S)-2-[[[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butyric acid | C39H54N4O11 | 详情 | 详情 | |
| (IX) | 22838 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid | C14H19NO4 | 详情 | 详情 | |
| (X) | 29552 | methyl (2S)-2-pyrrolidinecarboxylate | 2133-40-6 | C6H11NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)The Keck's enantioselective allylation of dodecanal (I) with allyl bromide (II) employing a catalytic amount of (R)-BINOL and titanium tetraisopropoxide furnishes the chiral alcohol (III), which is esterified with acryloyl chloride (IV), TEA and DMAP to give the acrylate (V). The olefin metathesis of (V) by means of Grubbs' catalyst and Ti(O-iPr)4 in refluxing dichloromethane yields the dihydropyranone (VI), which is epoxidized with H2O2 and NaOH to afford the chiral epoxide (VII). The reductive cleavage of (VII) with diphenyl diselenide and NaBH4 gives the chiral tetrahydropyranone (VIII), which is silylated with Tbdms-Cl and DIEA, yielding the silyl ether (IX). Opening of the lactone ring of (IX) with TEA and methanol affords the hydroxyester (X), which is treated with dihydropyran and PPTS to provide the tetrahydropyranyl ether (XI). The desilylation of (XI) with TBAF in THF gives the beta-hydroxyester (XII), which is alkylated with hexyl iodide and LDA in THF, yielding the adduct (XIII). The cyclization of (XIII) by hydrolysis with LiOH, followed by treatment with Ph-SO2-Cl, affords the beta-lactone (XIV), which is treated with PPTS to eliminate the tetrahydropyranyl-protecting group and yield the secondary alcohol (XV). The esterification of (XV) with N-(benzyloxycarbonyl)-L-leucine (XVI) by means of DCC and DMAP affords the leucinate (XVII), which is deprotected with H2 over Pd/C, affording (XVIII) with a free amino group that is formylated with acetic formic mixed anhydride to furnish the target (-)-tetrahydrolipstatin.
| 【1】 Ghosh, A.K.; Liu, C.; A stereoselective synthesis of (-)-tetrahydrolipstatin. Chem Commun (London) 1999, 1743. |
| 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) | 11082 | Lauraldehyde; Dodecanal | 112-54-9 | C12H24O | 详情 | 详情 |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 11089 | (4S)-1-Pentadecen-4-ol | C15H30O | 详情 | 详情 | |
| (IV) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (V) | 49595 | (1S)-1-undecyl-3-butenyl acrylate | C18H32O2 | 详情 | 详情 | |
| (VI) | 49596 | (6S)-6-undecyl-5,6-dihydro-2H-pyran-2-one | C16H28O2 | 详情 | 详情 | |
| (VII) | 49597 | (1S,4S,6S)-4-undecyl-3,7-dioxabicyclo[4.1.0]heptan-2-one | C16H28O3 | 详情 | 详情 | |
| (VIII) | 49598 | (4S,6S)-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one | C16H30O3 | 详情 | 详情 | |
| (IX) | 49599 | (4S,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-undecyltetrahydro-2H-pyran-2-one | C22H44O3Si | 详情 | 详情 | |
| (X) | 49600 | methyl (3S,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxyhexadecanoate | C23H48O4Si | 详情 | 详情 | |
| (XI) | 49601 | methyl (3S,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate | C28H56O5Si | 详情 | 详情 | |
| (XII) | 49602 | methyl (3S,5S)-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate | C22H42O5 | 详情 | 详情 | |
| (XIII) | 49603 | methyl (2S,3S,5S)-2-hexyl-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate | C28H54O5 | 详情 | 详情 | |
| (XIV) | 49604 | (3S,4S)-3-hexyl-4-[(2S)-2-(tetrahydro-2H-pyran-2-yloxy)tridecyl]-2-oxetanone | C27H50O4 | 详情 | 详情 | |
| (XV) | 49605 | (3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridecyl]-2-oxetanone | C22H42O3 | 详情 | 详情 | |
| (XVI) | 22838 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid | C14H19NO4 | 详情 | 详情 | |
| (XVII) | 49606 | (1S)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]dodecyl (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoate | C36H59NO6 | 详情 | 详情 | |
| (XVIII) | 49607 | (1S)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]dodecyl (2S)-2-amino-4-methylpentanoate | C28H53NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)The hydrolysis of methyl (2E, 4E)-hexadecadienoate (I) with KOH in THF gives the corresponding free acid (II), which is treated with (COCl)2 in dichloromethane to yield the acid chloride (III). The esterification of (III) with trichloroethanol (IV), TEA and DMAP affords the trichloroethyl ester (V), which is stereospecifically dihydroxylated by means of AD-mix-alpha, methanesulfonamide and NaHCO3 in t-butanol/water to provide the dihydroxyester (VI). The reaction of (VI) with SOCl2 in refluxing CCl4 gives the cyclic sulfite (VII), which is alkylated by means of CuCN, Li-C6H13 and BF3/Et2O in THF to give 5(S)-hydroxy-2(S)-hexyl-3(E)-hexadecanoic acid trichloroethyl ester (VIII). The cleavage of the ester group of (VIII) by means of Zn/AcOH yields the corresponding free acid (IX), which is submitted to cyclization by reaction with Br2 in CCl4/MeOH in the presence of NaHCO3 to afford the brominated beta lactone (X). Radical debromination of (X) by means of di-tert-butyl peroxide (DBPO), Ph2Se2, and Bu3SnH in toluene provides the beta lactone (XI), which is condensed with N-(benzyloxycarbonyl)-L-leucine (XII) by means of DCC and DMAP in dichloromethane to furnish the ester (XIII). The cleavage of the Boc group of (XIII) by means of H2 over Pd/C in THF gives the free amino acid ester (XIV), which is finally N-formylated by means of acetic formic anhydride (XV) in ethyl ether to yield the target tetrahydrolipstatin.
| 【1】 Bodkin, J.A.; Humphries, E.J.; McLeod, M.D.; The total synthesis of (-)-tetrahydrolipstatin. Tetrahedron Lett 2003, 44, 14, 2869. |
| 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) | 64250 | methyl (2E,4E)-2,4-hexadecadienoate | C17H30O2 | 详情 | 详情 | |
| (II) | 64251 | (2E,4E)-2,4-hexadecadienoic acid | C16H28O2 | 详情 | 详情 | |
| (III) | 64252 | (2E,4E)-2,4-hexadecadienoyl chloride | C16H27ClO | 详情 | 详情 | |
| (IV) | 50779 | 2,2,2-trichloro-1-ethanol | C2H3Cl3O | 详情 | 详情 | |
| (V) | 64255 | 2,2,2-trichloroethyl (2E,4E)-2,4-hexadecadienoate | C18H29Cl3O2 | 详情 | 详情 | |
| (VI) | 64254 | 2,2,2-trichloroethyl (E,4S,5S)-4,5-dihydroxy-2-hexadecenoate | C18H31Cl3O4 | 详情 | 详情 | |
| (VII) | 64253 | 2,2,2-trichloroethyl (E)-3-[(4S,5S)-2-oxo-5-undecyl-1,3,2lambda~4~-dioxathiolan-4-yl]-2-propenoate | C18H29Cl3O5S | 详情 | 详情 | |
| (VIII) | 64256 | 2,2,2-trichloroethyl (2S,3E,5S)-2-hexyl-5-hydroxy-3-hexadecenoate | C24H43Cl3O3 | 详情 | 详情 | |
| (IX) | 64257 | (2S,3E,5S)-2-hexyl-5-hydroxy-3-hexadecenoic acid | C22H42O3 | 详情 | 详情 | |
| (X) | 64258 | (3S,4R)-4-[(1S,2S)-1-bromo-2-hydroxytridecyl]-3-hexyl-2-oxetanone | C22H41BrO3 | 详情 | 详情 | |
| (XI) | 49605 | (3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridecyl]-2-oxetanone | C22H42O3 | 详情 | 详情 | |
| (XII) | 22838 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid | C14H19NO4 | 详情 | 详情 | |
| (XIII) | 49606 | (1S)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]dodecyl (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoate | C36H59NO6 | 详情 | 详情 | |
| (XIV) | 49607 | (1S)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]dodecyl (2S)-2-amino-4-methylpentanoate | C28H53NO4 | 详情 | 详情 | |
| (XV) | 29135 | Acetyl formyl mixed anhydride | C3H4O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)-(Benzyloxycarbonyl)-L-leucine (I) was activated as the mixed anhydride with isobutyl chloroformate and then coupled with N,O-dimethylhydroxylamine to produce the N-methoxyamide (II). Reduction of (II) with LiAlH4 at -78 C furnished aldehyde (III), which was converted to the corresponding diethyl acetal (IV) upon treatment with triethyl orthoformate. Subsequent hydrogenolytic removal of the benzyloxycarbonyl group of (IV) afforded leucinal diethylacetal (V). Coupling of N-Fmoc-nitroarginine (VI) with aminoacetal (V) via activation as the mixed anhydride with isobutyl chloroformate provided the protected dipeptide aldehyde (VII). The Fmoc protecting group of (VII) was then cleaved by using diethylamine in DMF-EtOAc to provide the intermediate (VIII).
| 【1】 Iqbal, M.; et al.; Potent inhibitors of proteasome. J Med Chem 1995, 38, 13, 2276. |
| 【2】 Iqbal, M.; Diebold, J.; Siman, R.; Chatterjee, S.; Kauer, J.C. (Cephalon, Inc.); Multicatalytic protease inhibitors. JP 1998507465; JP 2000290197; WO 9614857 . |
| 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) | 22838 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid | C14H19NO4 | 详情 | 详情 | |
| (II) | 49094 | benzyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C16H24N2O4 | 详情 | 详情 | |
| (III) | 49095 | benzyl (1S)-1-formyl-3-methylbutylcarbamate | C14H19NO3 | 详情 | 详情 | |
| (IV) | 49096 | benzyl (1S)-1-(diethoxymethyl)-3-methylbutylcarbamate | C18H29NO4 | 详情 | 详情 | |
| (V) | 49097 | (2S)-1,1-diethoxy-4-methyl-2-pentanamine; (1S)-1-(diethoxymethyl)-3-methylbutylamine | C10H23NO2 | 详情 | 详情 | |
| (VI) | 49098 | C21H23N5O6 | 详情 | 详情 | ||
| (VII) | 49099 | C31H44N6O7 | 详情 | 详情 | ||
| (VIII) | 49100 | C16H34N6O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(LIX)N-Benzyloxycarbonyl-N-methyl-D-leucine (LX) was prepared by methylation of the N-protected D-leucine (LIX) with iodomethane in the presence of NaH. Acylation of macrocyclic amine (XXV) with the N-protected aminoacid (LX) furnished the N-carbobenzoxy didemnin A (LXI). The title compound was then obtained by hydrogenolysis of the N-carbobenzoxy group of (LXI), followed by acylation with pyruvyl proline (XXXII) by means of diisopropyl carbodiimide
| 【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 50768 | (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone | C42H65N5O11 | 详情 | 详情 | |
| (XXXII) | 62542 | (2S)-1-pyruvoyl-2-pyrrolidinecarboxylic acid | C8H11NO4 | 详情 | 详情 | |
| (LIX) | 22838 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid | C14H19NO4 | 详情 | 详情 | |
| (LXI) | 50810 | benzyl (1R)-1-[([(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin | C57H84N6O14 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)3-Pyrroline (I) was protected with di-tert-buyl dicarbonate to give N-Boc-pyrroline (II), which was then epoxidized with meta-chloroperbenzoic acid. The resulting epoxide (III) was opened with sodium azide in aqueous MeOH to yield trans-azidoalcohol (IV). Subsequent reduction of the azide (IV) to aminoalcohol (V) was effected by hydrogenation over Pd/C (1). Condensation of the racemic trans-aminoalcohol (V) with N-Cbz-L-leucine (VI) in the presence of EDC and HOBt provided amide (VII) as a diastereomeric mixture. The N-Boc group of (VII) was then deprotected with HCl in EtOAc, and the resulting amine (VIII) was coupled with another N-Cbz-L-leucine (VI) unit to give (IX). Oxidation of the alcohol group of (IX) to the target ketone was accomplished with Jones reagent in acetone. The diastereomeric mixture was separated by reverse phase-HPLC, however the diastereomers were not configurationally stable and reequilibrated spontaneusly to the original mixture.
| 【1】 Marquis, R.W.; Yamashita, D.S.; Ru, Y.; LoCastro, S.M.; Oh, H.J.; Erhard, K.F.; DesJarlais, R.L.; Head, M.S.; Smith, W.W.; Zhao, B.; Janson, C.A.; Abdel-Meguid, S.S.; Tomaszek, T.A.; Levy, M.A.; Veber, D.F.; Conformationally constrained 1,3-diamino ketones: a series of potent inhibitors of the cysteine protease cathepsin K. J Med Chem 1998, 41, 19, 3563. |
| 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) | 22833 | 2,5-dihydro-1H-pyrrole;3-Pyrroline | 109-96-6 | C4H7N | 详情 | 详情 |
| (II) | 22834 | 2,5-Dihydro-1H-pyrrole-1-carboxylic acid 1,1-d;2,5-Dihydropyrrole-1-carboxylic acid tert-butyl ester;tert-Butyl 2H-pyrrole-1(5H)-carboxylate;1-tert-Butoxycarbonylpyrroline;tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate | 73286-70-1 | C9H15NO2 | 详情 | 详情 |
| (III) | 22835 | tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate | C9H15NO3 | 详情 | 详情 | |
| (IV) | 22836 | tert-butyl (3R,4S)-3-azido-4-hydroxy-1-pyrrolidinecarboxylate | 143700-05-4 | C9H16N4O3 | 详情 | 详情 |
| (V) | 22837 | tert-butyl (3S,4S)-3-amino-4-hydroxy-1-pyrrolidinecarboxylate | 190792-74-6 | C9H18N2O3 | 详情 | 详情 |
| (VI) | 22838 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid | C14H19NO4 | 详情 | 详情 | |
| (VII) | 22839 | tert-butyl 3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinecarboxylate | C23H35N3O6 | 详情 | 详情 | |
| (VIII) | 22840 | benzyl (1S)-1-[[(4-hydroxy-3-pyrrolidinyl)amino]carbonyl]-3-methylbutylcarbamate | C18H27N3O4 | 详情 | 详情 | |
| (IX) | 22841 | benzyl (1S)-1-([3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinyl]carbonyl)-3-methylbutylcarbamate | C32H44N4O7 | 详情 | 详情 |