Oxygen → (4S,5S)-3,4,5-tris-benzyloxy-2-{4-fluoro-3-[4-(oxetan-3-yloxy)-benzyl]-phenyl}-6,6-bis-(4-methoxy-benzyloxymethyl)-tetrahydro-pyran-2-ol

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Reaktionsgleichung

[CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O=O.Br[C:9]1[CH:10]=[CH:11][C:12]([F:27])=[C:13]([CH:26]=1)[CH2:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH:20]2[CH2:23][O:22][CH2:21]2)=[CH:17][CH:16]=1.CON(C)[C:31](=[O:83])[C@H:32]([O:75]CC1C=CC=CC=1)[C@@H:33]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C@H:34]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:35]([OH:58])([CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)[CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1.[Al].O1C[CH2:89][CH2:88][CH2:87]1>C(OCC)C>[CH2:1]([O:75][CH:32]1[C@@H:33]([O:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C@H:34]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:35]([CH2:47][O:48][CH2:49][C:50]2[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)([CH2:36][O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[O:58][C:31]1([C:9]1[CH:10]=[CH:11][C:12]([F:27])=[C:13]([CH2:14][C:15]2[CH:25]=[CH:24][C:18]([O:19][CH:20]3[CH2:23][O:22][CH2:21]3)=[CH:17][CH:16]=2)[CH:26]=1)[OH:83])[C:2]1[CH:89]=[CH:88][CH:87]=[CH:4][CH:3]=1

Komponenten

Reaktionsbedingungen

Temperatur: 10 °C

Versuchsvorschrift

n-Butyl lithium (1.12 mL, 2.5 M/hexanes, 3.0 equivalents) was added dropwise (1 drop every 5 seconds) to an oxygen degassed solution of 3-[4-(5-Bromo-2-fluoro-benzyl)-phenoxy]-oxetane (942.0 mg, 2.79 mmol) in anhydrous tetrahydrofuran (3.0 mL) at −78° C. and the resulting solution was stirred at this temperature for 1 hour. A solution of (2R,3S,4S)-2,3,4-tris-benzyloxy-5-hydroxy-6-(4-methoxy-benzyloxy)-5-(4-methoxy-benzyloxymethyl)-hexanoic acid methoxy-methyl-amide I-1g (725.0 mg, 0.930 mmol) in anhydrous tetrahydrofuran (1.5 mL) was then added dropwise very slowly (0.9 ml/hour) and the resulting mixture was stirred at −78° C. for an additional hour before warming to 10° C. over 12 hours (put in a deep Dewar covered with aluminum foil to maintain cold temperature). The reaction was diluted with diethyl ether and quenched by the dropwise addition of aqueous 1N hydrochloric acid solution. The resulting biphasic mixture was stirred at room temperature for 15 minutes. The organic phase was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel (eluting with a gradient of 10 to 40% ethyl acetate in heptane) to afford the product as a mixture of isomers (535 mg, 59% yield).

Aufarbeitung

stirringthe resulting mixture was stirred at −78° C. for an additional hour
temperatureto maintain cold temperature)
customquenched by the dropwise addition of aqueous 1N hydrochloric acid solution
stirringThe resulting biphasic mixture was stirred at room temperature for 15 minutes
customThe organic phase was separated
washwashed with brine
dry with materialdried over magnesium sulfate
filtrationfiltered
concentrationconcentrated under reduced pressure
customThe crude residue was purified by flash chromatography over silica gel (
washeluting with a gradient of 10 to 40% ethyl acetate in heptane)
customto afford the product
additionas a mixture of isomers (535 mg, 59% yield)

Quellen und Nachweise

ORD-Eintrag: ord-e4edcd28f2ba4fe79b79690e7a3ddb8f
Quelldatensatz: uspto-grants-2011_12
DOI: 10.6084/m9.figshare.5104873.v1
Patentnummer: US08080580B2

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