Resolution of 2,3-dihydro-benzofuran-3-ols
461
only): 173.5, 158.3, 134.1, 129.8, 129.3, 113.7, 112.7, 128.5, 112.9, 112.3, 91.5, 76.1, 52.8, 25.7, 18.2, 18.0,
91.7, 76.0, 53.4, 17.9.
−4.2, −4.6.
Syn isomer 1H NMR (300 MHz; CDCl3) δ ppm: 7.3
(m, 2H), 6.81 (d, 1H, J = 8.59 Hz), 5.0 (s, 1H), 3.76 (s,
3H), 1.59 (s, 3H), 0.85 (s, 9H), 0.15 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ ppm: 169.9, 158.0, 133.2, 129.5,
128.5, 112.7, 112.6, 92.2, 80.0, 52.3, 25.5, 22.1, 17.9,
−4.1, −4,6.
2.6 6-Dimethylamino-3-ter-butyltrimethylsilyloxy-2-
methyl-2,3-dihydro-benzofuran-2-carboxylic acid
methyl ester 11a (anti only)
Imidazole (0.81 g) was added to a solution of 6a
(2 g, 7.96 mmol) in DMF (20 ml). After 15 min.
of stirring under nitrogen atmosphere, TBDMS-Cl 2.9 General procedure for hydrolysis of esters 11 to
(1.79 g, 8 mmol) was added. The solution was stirred acid 12. To a solution of ester 11 (3 mmol) in THF
overnight at room temperature and then diluted with
MeOH (5 : 1, 12 ml) an aqueous solution of LiOH
(2.5 M, 2 ml) was added. After stirring overnight at
ambient temperature, the mixture was acidified to pH
1 with HCl (6N). The mixture was then diluted with
H2O (50 ml) and saturated with NaCl and extracted with
EtOAc (6 × 50 ml) until no more acid was found in the
aqueous layer. The combined organic layers were dried
(MgSO4) and concentrated to give the crude acid. Min-
imum CH2Cl2 was then added to dissolve the acid, and
100 ml of PE was added to obtain the acid as a white
precipitate. After removal of the supernatant liquid, the
acid was obtained as a white solid. This purification was
repeated twice to have the acid pure enough for the next
step, and in nearly quantitative yields.
water (20 ml). The resulting mixture was extracted with
Et2O (3 × 50 ml) and the combined organic layers
washed with water (50 ml), dried over MgSO4 and
concentrated. Purification (flash chromatography, sil-
ica, PE:EtOAc 97:3) gave 2.24 g of 11a as an oil (87%).
1H NMR (300 MHz, CDCl3) δ ppm: 7.08 (d, 1H, J =
8.1 Hz), 6.30 (m, 2H), 6.1 (m, 1H), 5.31 (s, 1H), 3.72
(s, 3H), 2.91 (s, 6H), 1.6 (s, 3H), 0.91 (s, 9H), 0.19 (s,
3H), 0.17 (s, 3H); 13C (75 MHz, CDCl3) δ ppm: 174.2,
160.5, 152.8, 125.8, 115.4, 105.9, 94.1, 91.5, 76.3, 52.7,
40.6, 25.8, 18.7, 18.2, −44.1,−4.6.
2.7 6-Chloro-3-ter-butyltrimethylsilyloxy-2-methyl-
2,3-dihydro-benzofuran-2-carboxylic acid methyl-
ester 11b
2.10 6-Diméthylamino-3-ter-butyltrimethylsilyloxy-2-
methyl-2,3-dihydro-benzofuran-2-carboxylic acid
pentolactone ester
Obtained as 11a as oil with a yield of 73%. Anti isomer
1H NMR (300 MHz, CDCl3) δ ppm: 6.90 (d, 1H, J =
8.0 Hz), 6.70 (m, 2H), 5.15 (s, 1H), 3.62 (s, 3H), 1.6
(s, 3H), 0.91 (s, 9H), 0.19 (s, 3H), 0.17 (s, 3H); 13C
(75 MHz, CDCl3) δ ppm: 173.3, 159.6, 135.8, 126.7,
126.3, 111.4, 91.9, 75.9, 52.9, 25.8, 21.1, 18.4, −4.0,
−4.4.
To a solution of acid 12a (6 g, 25.5 mmol) in
CH2Cl2 (65 ml) EDC (3.4 g), (R)-pentolactone (6.05 g,
45 mmol) and DMAP (350 mg) were added. The
solution was stirred overnight, hydrolysed with water
(100 ml) and extracted with CH2Cl2 (2 × 100 ml). The
combined organic layers were dried over MgSO4 and
concentrated. Purification (flash chromatography, sil-
ica, PE:EtOAc 30:70) gave 3.8 g (32%) of the less polar
isomer as an yellow solid and 3.3 g (28%) of the more
polar isomer as an yellow solid.
Syn isomer 1H NMR (300 MHz, CDCl3) δ ppm: 6.94
(d, 1H, J = 8.0 Hz), 6.70 (m, 2H), 4.88 (s, 1H), 3.65
(s, 3H), 1.6 (s, 3H), 0.91 (s, 9H), 0.19 (s, 3H), 0.17 (s,
3H); 13C NMR (75 MHz, CDCl3) δ ppm : 170.1, 157.8,
136.0, 126.4, 126.0, 111.8, 92.8, 79.9, 52.3, 25.7, 22.2,
18.2, −4.1, −4.4.
1
Less polar isomer: H NMR (300 MHz, CDCl3) δ
ppm: 7,08 (d, 1H, J = 8.1 Hz), 6.28 (m, 2H), 5.37 (s,
1H), 5.31 (s, 1H), 4.0 (m, 2H), 2.93 (s, 6H), 1.70 (s,
3H), 1.16 (s, 3H), 1.01(s, 3H), 0.92 (s, 9H), 0,17 (s,
3H), 0.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ ppm:
172.2, 171.5, 160.7, 153.0, 125.9, 115.5, 106.0, 94.1,
2.8 5-Bromo-3-ter-butyltrimethylsilyloxy-2-methyl-
2,3-dihydro-benzofuran-2-carboxylic acid methyl ester
11c. Obtained as 11a as oil with a yield of 84%
1
Anti isomer. H NMR (300 MHz; CDCl3) δ ppm: 7.3 91.4, 76.3, 76.2, 75.8, 40.7, 40.1, 25.9, 23.1, 19.9, 18.4,
(m, 2H), 6.81 (d, 1H, J = 8.6 Hz), 5.37 (s, 1H), 3.75 (s, 18.3, −4.1, −4.4.
1
3H), 1.61 (s, 3H), 0.91 (s, 9H), 0.20 (s, 6H); 13C NMR
More polar isomer: H NMR (300 MHz, CDCl3) δ
(75 MHz; CDCl3) δ ppm: 173.1, 157.7, 133.1, 130.1, ppm: 7,0 (d, 1H, J = 8.1 Hz), 6.28 (m, 2H), 5.39 (s,