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【结 构 式】 
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【分子编号】50779 【品名】2,2,2-trichloro-1-ethanol 【CA登记号】 |
【 分 子 式 】C2H3Cl3O 【 分 子 量 】149.40332 【元素组成】C 16.08% H 2.02% Cl 71.19% O 10.71% |
合成路线1
该中间体在本合成路线中的序号：(VI)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】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31. |
| 【2】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837. |
| 【3】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669. |
| 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) | 50775 | (2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | C11H21NO4 | 详情 | 详情 | |
| (II) | 44205 | (2-ethoxy-2-oxoethyl)lithium | C4H7LiO2 | 详情 | 详情 | |
| (III) | 50776 | ethyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate | C15H27NO5 | 详情 | 详情 | |
| (IV) | 50777 | tert-butyl (1R,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (V) | 50778 | ethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate | C15H29NO5 | 详情 | 详情 | |
| (VI) | 50779 | 2,2,2-trichloro-1-ethanol | C2H3Cl3O | 详情 | 详情 | |
| (VII) | 50780 | 2,2,2-trichloroethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate | C15H26Cl3NO5 | 详情 | 详情 | |
| (VIII) | 50781 | 2,2,2-trichloroethyl (3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoate | C10H18Cl3NO3 | 详情 | 详情 | |
| (IX) | 50782 | (2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid | C16H23NO5 | 详情 | 详情 | |
| (X) | 50783 | 2,2,2-trichloroethyl (3S,4R,5S)-4-[[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino]-3-hydroxy-5-methylheptanoate | C21H31Cl3N2O5 | 详情 | 详情 | |
| (XI) | 50788 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid | C12H23NO4 | 详情 | 详情 | |
| (XII) | 31819 | (2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid | 16937-99-8 | C11H21NO4 | 详情 | 详情 |
| (XIII) | 50787 | 2,2,2-trichloroethyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate | C39H66Cl3N3O8Si | 详情 | 详情 | |
| (XIV) | 50784 | 2,2,2-trichloroethyl (6R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R)-1-hydroxyethyl]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate | C32H60Cl3N3O8Si | 详情 | 详情 | |
| (XV) | 50747 | (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid | C19H21NO5 | 详情 | 详情 | |
| (XVI) | 39328 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid | C17H17NO5 | 详情 | 详情 | |
| (XVII) | 50785 | 2,2,2-trichloroethyl (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oate | C46H71Cl3N4O10Si | 详情 | 详情 | |
| (XVIII) | 50786 | (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic acid | C44H70N4O10Si | 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 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 |