|
【结 构 式】 
|
【分子编号】49598 【品名】(4S,6S)-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one 【CA登记号】 |
【 分 子 式 】C16H30O3 【 分 子 量 】270.4124 【元素组成】C 71.07% H 11.18% O 17.75% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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：(XIV)The reaction of cyclohexane-1,3,5-triol (I) with trimethyl orthobenzoate (II) by means of BF3/Et2O gives the cyclic orthoester (III), which is partially reduced with borane in THF to yield the alcohol (IV). Oxidation with Dess-Martin periodinane affords cyclohexanone (V), which is enantioselectively deprotonated with the chiral lithium (S,S')-alpha,alpha'-dimethyldibenzylamide (VI) in the presence of Tms-Cl in THF to provide the chiral silylated enol ether (VII). Ozonolysis of the double bond of (VII) gives the 6-oxohexanoic acid (VIII), which is reduced with NaBH4 to the corresponding hydroxyacid (IX). The methylation of (IX) with methyl iodide and K2CO3 yields the hydroxyester (X), which is oxidized with oxalyl chloride in DMSO to afford the oxoester (XI). The Wittig condensation of (XI) with decyltriphenylphosphonium bromide (XII) by means of BuLi in THF provides the unsaturated hexadecenoic ester (XIII), which is finally reduced, deprotected and cyclized by treatment with H2 over Pd/C in acetic acid to furnish the target (4S,6S)-4-hydroxy-6-undecyltetrahydrofuran-2-one (XIV). The conversion of (XIV) into tetrahydrolipstatin has already been described in scheme 11082304a.
| 【1】 Ono, S.; Endo, K.; Honda, T.; Construction of an enatiomerically pure 6-substituted 3,5-syn-dihydroxyhexanoic acid system by an enatioselective deprotonation strategy: Formal synthesis of an antiobesity agent, (-)-tetrahydrolipstatin. Chem Pharm Bull 2000, 48, 10, 1545. |
| 【2】 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) | 11800 | 1,3,5-Cyclohexanetriol; cis,cis-1,3,5-Cyclohexanetriol dihydrate | 50409-12-6 | C6H12O3 | 详情 | 详情 |
| (II) | 38531 | dimethoxy(phenyl)methyl methyl ether; 1-(trimethoxymethyl)benzene | 707-07-3 | C10H14O3 | 详情 | 详情 |
| (III) | 49608 | 3-phenyl-2,4,10-trioxatricyclo[3.3.1.1(3,7)]decane | C13H14O3 | 详情 | 详情 | |
| (IV) | 49609 | (1R,5S)-3-phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-ol | C13H16O3 | 详情 | 详情 | |
| (V) | 49610 | (1R,5S)-3-phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-one | C13H14O3 | 详情 | 详情 | |
| (VI) | 49611 | C16H18LiN | 详情 | 详情 | ||
| (VII) | 49612 | trimethyl[[(1S,3S,5R)-3-phenyl-2,4-dioxabicyclo[3.3.1]non-6-en-7-yl]oxy]silane; (1S,3S,5R)-3-phenyl-2,4-dioxabicyclo[3.3.1]non-6-en-7-yl trimethylsilyl ether | C16H22O3Si | 详情 | 详情 | |
| (VIII) | 49613 | 2-[(2S,4S,6R)-6-formyl-2-phenyl-1,3-dioxan-4-yl]acetic acid | C13H14O5 | 详情 | 详情 | |
| (IX) | 49614 | 2-[(2S,4S,6R)-6-(hydroxymethyl)-2-phenyl-1,3-dioxan-4-yl]acetic acid | C13H16O5 | 详情 | 详情 | |
| (X) | 49615 | methyl 2-[(2S,4S,6R)-6-(hydroxymethyl)-2-phenyl-1,3-dioxan-4-yl]acetate | C14H18O5 | 详情 | 详情 | |
| (XI) | 49616 | methyl 2-[(2S,4S,6R)-6-formyl-2-phenyl-1,3-dioxan-4-yl]acetate | C14H16O5 | 详情 | 详情 | |
| (XII) | 49618 | n-Decyl triphenylphosphonium bromide | 32339-43-8 | C28H36BrP | 详情 | 详情 |
| (XIII) | 49617 | methyl 2-[(2S,4S,6R)-2-phenyl-6-[(E)-1-undecenyl]-1,3-dioxan-4-yl]acetate | C24H36O4 | 详情 | 详情 | |
| (XIV) | 49598 | (4S,6S)-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one | C16H30O3 | 详情 | 详情 |