Kinetic Resolution of Trans2Tert ButyldimethylsilyloxymethylCyclopentanol Rac7 2021

The value of the enantiomeric ratio (E value) (a measure for the selectivity of a kinetic resolution [see Note 14]) of this reaction under the below-described optimal conditions is 57. In order to obtain both enantiomers with an enantiomeric excess higher than 90%, the reaction has to be stopped when 40% of the product was formed. After separation of the products, a second resolution step of the enantiomerically enriched starting material was applied.

1. A solution of trans-2-(tert-butyldimethylsilyloxymethyl)cyclopentanol (rac-7) (3.6 g, 15.5 mmol) in tert-butyl methyl ether (110 mL) (see Note 15) is treated in sequence with vinyl acetate (10.8 mL, 117 mmol) and lipase from Ps. cepacia (0.72 g) (see Note 16).

2. The reaction mixture is stirred at room temperature for about 4 h until the conversion of the starting material rac-7 reached 40% (see Note 17).

3. The lipase is subsequently filtered off through a sintered glass funnel covered with a pad of Celite. The filter cake is washed with tert-butyl methyl ether (3 x 20 mL).

4. The combined filtrates are concentrated under reduced pressure. The products are separated by flash chromatography (see Note 18) to afford in the order of elution the acetate (1R,2S)-8 (1.60 g, 38%) with an enantiomeric excess of 94% (see Note 19) and the alcohol (1S,2R)-7 (2.06 g, 57%) with an enantiomeric excess of 51% (see Note 19).

The enantiomerically enriched alcohol (1S,2R)-7 (2.06 g) was subjected to a second lipase-catalyzed transesterification: A solution of the enantiomerically enriched alcohol (1S,2R)-7 (100-mL-round-bottom flask) in ieri-butyl methyl ether (60 mL) was treated in sequence with vinyl acetate (6.0 mL, 65 mmol) and lipase from Ps. cepacia (0.575 g). The reaction mixture was stirred at room temperature for about 24 h until the conversion of the starting material reached 20% (for conditions, see Note 17). The reaction mixture was filtered through a sintered glass funnel covered with a pad of Celite. The filter cake was washed with tert-butyl methyl ether (3 x 10 mL). The combined filtrates were concentrated under reduced pressure. The products were separated by flash chromatography (see Note 20) to afford, in the order of elution, the acetate (1R,2S)-8 (0.44 g, 18%) with an enantiomeric excess of 98 % and the alcohol (1S,2R)-7 (1.56 g, 78%) with an enantiomeric excess of >99 %.

(1R,2S)-8: colorless liquid; [a]D20: -6.24° (c 1.0, CHCl3); ^-NMR (CDCl3): 0.02 (3 H, s), 0.03 (3 H, s), 0.87 (9 H, s), 1.38 (1 H, m), 1.56-1.74 (3 H, m), 1.761.95 (2 H, m), 2.00 (3 H, s), 2.09 (1 H, m), 3.57 (2 H, dd, J = 6.0 and 4.0 Hz), 4.94 (1 H, dd, J = 6.7 and 3.7 Hz); 13C-NMR (CDCl3) -5.46, -5.45, 18.25, 21.35, 23.38, 25.87, 27.20, 32.68, 47.89, 64.29, 78.66, 170.87.

(1S,2R)-7: colorless liquid; [a] D20: +2.0° (c 1.0, CHCl3); 1H-NMR (CDCl3): 0.00 (6 H, s), 0.83 (9 H, s), 1.10 (1 H, m), 1.42-1.56 (2 H, m), 1.62-1.74 (2 H, m), 1.83-1.92 (2 H, m), 2.53 (1 H, br s), 3.41 (1 H, dd, J = 2 x 9.5 Hz), 3.73 (1 H, dd, J = 9.5 and 5.2 Hz), 3.91 (1 H, m); 13C-NMR (CDCl3) -5.56, -5.50, 18.17, 21.56, 25.87, 33.81, 49.24, 63.18, 66.86, 78.35.

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