6-Methoxy-2H-chromene-3-carboxylic acid 12.56g (60.9 mmol) suspension in anhydrous dichloromethane 100mL was combined with 7.0 mL of neat oxalyl chloride, followed by 4 drops of DMF. The mixture was stirred under gas outlet tube filled with Drierite for 1 day; by this time the gas evolution ceased. The homogenous reaction mixture was evaporated to dryness, the residue was briefly dried on highvac, the resulting solid was crushed with a spatula and re-dried on highvac for 1 day. Y=13.66g (100%) of a yellow solid. [This acyl chloride readily decomposes on storage – it is best kept under high vacuum while protected from a direct sunlight, and used on the same day.]
Oppolzer (+)sultam auxiliary 5.785g (26.87 mmol) solid in a 0.5L flask was flushed with dry Ar, 60% NaH in mineral oil 1.505g (37.6 mmol) was added followed by anhydrous toluene 250mL (gas evolution). The slurry was briefly sonicated for 5 min on a sonicator bath, then stirred at ambient temperature under Ar for 2h45 min. The mix was then cooled to 0 C, a solid acyl chloride 5.983g (26.87 mmol) was added in one portion, the mixture was placed placed on ambient water bath and stirred vigorously for 2 hours under Ar. (There was a delayed gas evolution accompanied by foaming). At the completion of the acylation, the reaction was quenched by addition of silica (50g) followed by hexanes (100mL). After additional 10 minutes, the entire reaction mix was applied onto a column of silica (500g) in hexanes-ethyl acetate 10:1, then rapidly eluted with the 10:1 mix and then with hexanes-ethyl acetate 7:3 mix (3L). (There is a risk of the product crystallizing on the column if the elution is too slow.) A yellow band was collected. Combined fractions provided upon evaporation and drying on highvac 9.965g (92% th) of the chromene-acylated auxiliary as a yellow fluorescent solid. 1H(CDCl3, 400MHz): 7.31(br s, 1H), 6.80(m, 2H), 6.73(d, 2.4Hz, 1H), 5.03(dd, 13.6Hz, 1.2Hz, 1H), 4.81(dd, 14.0Hz, 1.2Hz, 1H), 4.12(dd, 7.6Hz, 4.8Hz, 1H), 3.77(s, 3H), 3.54(d, 13.6Hz, 1H), 3.43(d, 13.6Hz, 1H), 2.05(m, 1H), 1.93(m, 4H), 1.43(m, 2H), 1.30(s, 3H), 1.02(s, 3H) [Note 1]
The intermediate from the previous step 2.020g (5.00 mmol) in a 300mL RB flask was dissolved in anh THF 50mL under Ar and the solution was cooled to -50 C. L-Selectride 1M solution in THF 6.5 mL was added dropwise with vigorous stirring over 5 min period and the reaction was then maintained at -50C for additional 45 min. The reaction was quenched at -55 C by dropwise addition of 2M sulfuric acid 25 mL, the cooling bath was removed and the reaction mixture was stirred at ambient temperature in an open flask for 2 hours. The reaction mix was then partitioned between ether 120 mL and water 80 mL. The organic phase was separated, washed with water 100mL and saturated sodium bicarbonate 100mL. The aqueous phases were re-extracted with ether 130 mL. The combined organic extracts were dried (MgSO4) and evaporated. The evaporation residue was kept under Ar [Note 2] until it could be purified on a column of silica (120g) in ethyl acetate gradient in hexanes (0 to 30% EtOAc). The obtained column-purified material (1.57g; 98:2 dr by 1H-NMR) was suspended in cyclohexane 60mL, the slurry was refluxed for 10 min and then allowed to sit at ambient temperature overnight. The solid product was collected by flitration, washed with hexanes, dried by suction and on highvac. Y=1.410g (69.5% th) of a diastereomerically pure material. 1H(CDCl3, 400MHz): 6.77(d, 8.9Hz, 1H), 6.69(dd, 8.9Hz, 3.0Hz, 1H), 6.59(d, 2.9Hz, 1H), 4.44(ddd, 10.7Hz, 3.3Hz, 2.0Hz, 1H), 4.04(t, 10.3Hz, 1H), 3.92(t, 6.3Hz, 1H), 3.74(s, 3H), 3.58(m, 1H), 3.54(d, 13.9Hz, 1H), 3.47(d, 13.9Hz, 1H), 3.03(m, 2H), 2.08(m, 2H), 1.90(m, 2H), 1.41(m, 2H0, 1.20(s, 3H), 0.99(s, 3H) [Note 2]
This reduced chromane-auxiliary intermediate 1.410g (3.477 mmol) was dissolved in THF 140 mL and the solution was cooled to 0 C. Water 36mL and 50% H2O2 15mL was added, followed by 1M aqueous LiOH 5.0mL (prepared freshly from Aldrich LiOH monohydrate). The reaction mixture was stirred at 0 C for for 20 min, then quenched with 2M H2SO4 1.5mL and warmed to ambient temperature. The reaction mix was partitioned between ether 300 mL and water 150 mL. The organic phase was washed with additional water 200mL, then shaken for 5 min with 1M Na2SO3 200mL (to convert the peroxyacid into a carboxylic acid) . The aqueous phases were sequentially re-extracted with additional ether 300mL.
The combined organic phases containing a mixture of the product and the liberated auxiliary were extracted twice with 3:1 mix of water with conc. aqueous ammonia (2x100mL) and then with water. These combined ammonia extracts were then acidified with 6M HCl (140mL) with cooling on ice bath, the acidified mixture was then extracted 3-times with dichloromethane (3x150mL). The dichloromethane extracts were washed with water (100mL), combined, dried (MgSO4) and evaporated. The residue was re-crystallized from cyclohexane 60mL at reflux (then kept at ambient temperature overnight), the precipitated product was collected by filtration, washed with hexanes (2x10mL) and dried on highvac. Y=682mg of white cotton-like fluffy needles (94% th, (S)-enantiomer, >99% ee) [note 3] 1H(CDCl3, 400MHz): 6.77(d, 8.8Hz, 1H), 6.69(dd, 8.8Hz, 2.8Hz, 1H), 6.63(d, 2.8Hz, 1H), 4.39(m, 1H), 4.16(m, 1H), 3.75(s, 3H), 3.06(m, 3H); 13C(CDCl3, 100MHz): 177.9, 153.7, 148.0, 120.5, 117.4, 114.0, 113.8, 66.2, 55.7, 38.4, 27.3; [alpha]D27= +2.04(c=0.981) Chiral HPLC assay: Chiralpak AD-RH, 17 to 20% MeCN in water with 0.1% TFA, at 75C @ 0.8 mL/min
Note 1: Using the same procedure, Oppolzer (-) sultam auxiliary 6.238g (29 mmol) with 60% NaH 1.625g (40.6 mmol) and acylchloride 6.967g (31 mmol) provided 11.06g of the opposite enantiomer (94.5% th)
Note 2: The L-Selectride reduction procedure can be difficult to manage on a large scale. Air oxidation of borane species that carried over into the crude product inspite the workup seems to be responsible for variable yields (40-50%) on a larger scale. [A careful workup with perborate would probably solve this problem.]
Note 3: Using the above procedure, L-Selectride reduction of the acylated intermediate prepared from the (-) auxiliary provided 1.210g (59.5%th) of the reduced intermediate, which was then hydrolyzed as above in 93% yield to provide 580mg of pure (R)-enantiomer (>99% ee)
Note 4: A more direct approach to the optically pure chromane acid, by asymmetric hydrogenation with a Ru catalyst, is described here
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