|
【结 构 式】 
|
【分子编号】11089 【品名】(4S)-1-Pentadecen-4-ol 【CA登记号】 |
【 分 子 式 】C15H30O 【 分 子 量 】226.4026 【元素组成】C 79.58% H 13.36% O 7.07% |
合成路线1
该中间体在本合成路线中的序号：(XXXII)The chiral aldehyde (XI) can also be obtained as follows: The reaction of dodecanal (XXV) with allylmagnesium bromide (XXVI) in THF gives 1-pentadecen-4-ol (XXVII) as a racemic mixture, which is esterified with 2(R)-acetoxy-2-phenylacetic acid (XXVIII) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) to yield the diastereoisomeric mixture of esters (XXIX) and (XXX), which are separated by flash chromatography. The hydrolysis of (XXIX) and (XXX) with KOH in methanol affords the alcohols (XXXI) and (XXXII). The unwanted isomer (XXXII) can be isomerized to (XXXI) through the formation of the 4-nitrobenzoyl ester and hydrolysis with K2CO3. The benzylation of (XXXI) with benzyl bromide and KH in THF gives the benzyl ether (XXXIII), which is finally ozonolyzed to the desired aldehyde (XI) with O3 in methanol-dichloromethane.
| 【1】 Prous, J.; Mealy, N.; Castaner, J.; Orlistat. Drugs Fut 1994, 19, 11, 1003. |
| 【2】 Tehim, A.; Chen, P.; Hanessian, S.; Total synthesis of (-)-tetrahydrolipstatin. J Org Chem 1993, 58, 27, 7768-81. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 11068 | (3R)-3-(Benzyloxy)tetradecanal | C21H34O2 | 详情 | 详情 | |
| (XXV) | 11082 | Lauraldehyde; Dodecanal | 112-54-9 | C12H24O | 详情 | 详情 |
| (XXVI) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (XXVII) | 11084 | 1-Pentadecen-4-ol | C15H30O | 详情 | 详情 | |
| (XXVIII) | 11085 | (2R)-3-Methoxy-3-oxo-2-phenylpropionic acid | C10H10O4 | 详情 | 详情 | |
| (XXIX) | 11086 | 1-methyl 3-[(1R)-1-undecyl-3-butenyl] (2S)-2-phenylpropanedioate | C25H38O4 | 详情 | 详情 | |
| (XXX) | 11087 | 1-methyl 3-[(1S)-1-undecyl-3-butenyl] (2S)-2-phenylpropanedioate | C25H38O4 | 详情 | 详情 | |
| (XXXI) | 11088 | (4R)-1-Pentadecen-4-ol | C15H30O | 详情 | 详情 | |
| (XXXII) | 11089 | (4S)-1-Pentadecen-4-ol | C15H30O | 详情 | 详情 | |
| (XXXIII) | 11090 | (4R)-4-(Benzyloxy)-1-pentadecene; Benzyl (1R)-1-undecyl-3-butenyl ether | C22H36O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)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 |