Ethyl Acetate → (1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol

HRID 625850Notes

Reaction equation

HRID 625850 reaction equation
C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50][F:51])[CH2:11][O:12]2)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.O1CCCC1.[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:50][F:51])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1

Participants

6

Reactant 2

HCID 8857Ethyl AcetateHCID 67153916HCID 67153916, compound

Product 1

HCID 52931704(1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triolYield 63%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of {(1S,2S,3S,4R,5S)-2,3,4-Tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-1-yl}-methanol (616 mg, 0.871 mmol) in dichloromethane (3 mL) at 0 degrees Celsius was added diethylaminosulfur trifluoride (170 microL, 1.3 mmol) and the resulting mixture was slowly warmed to room temperature and stirred at this temperature for 16 hours. The mixture was diluted with dichlorometane and washed with a saturated solution of aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a 40 g redisep silica cartridge (eluting with a gradient of 0 to 20% ethyl acetate in heptane) to afford (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane as a colorless oil (40 mg, 7% yield). (LCMS) 753.4 (M+HCOO−: negative mode). To a suspension of (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane (40 mg, 0.06 mmol) and palladium black (40 mg, 0.38 mmol, Aldrich® high surface area) in ethanol (0.5 mL) and tetrahydrofuran (0.1 mL) was added fomic acid (0.085 mL, 2.24 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added and the mixture was filtered through a short pad of Celite® and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using a 4 g redisep silica cartridge (eluting with a gradient of 50 to 100% ethyl acetate in heptane) to afford the title compound as a solid (15.6 mg, 63% yield). (LCMS) 483.0 (M+HCOO−: negative mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 7.44 (s, 1H), 7.38 (s, 1H), 7.37 (s, 1H), 7.09-7.12 (m, 2H), 6.80-6.83 (m, 2H), 4.71 (dd, J=46.59, 10.49 Hz, 1H), 4.50 (dd, J=48.30, 10.73 Hz, 1H), 4.19 (dd, J=7.56, 0.98 Hz, 1H), 4.04 (d, J=0.98 Hz, 2H), 4.00 (q, J=6.99 Hz, 2H), 3.80 (dd, J=8.29, 0.98 Hz, 1H), 3.67 (t, J=8.17 Hz, 1H), 3.54-3.57 (m, 2H), 1.37 (t, 3H).

Workup

  1. filtrationthe mixture was filtered through a short pad of Celite®
  2. concentrationconcentrated in vacuo
  3. customThe crude material was purified by flash chromatography over silica gel using a 4 g redisep silica cartridge (
  4. washeluting with a gradient of 50 to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-cf1cbb728f464938b3222c01442f094b
Source dataset
uspto-grants-2016_04
Patent number
US09308204B2

Reaction notes

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