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【结 构 式】 
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【分子编号】49606 【品名】(1S)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]dodecyl (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoate 【CA登记号】 |
【 分 子 式 】C36H59NO6 【 分 子 量 】601.8676 【元素组成】C 71.84% H 9.88% N 2.33% O 15.95% |
合成路线1
该中间体在本合成路线中的序号：(XVII)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2
该中间体在本合成路线中的序号：(XIII)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 |