Efficient resolution of racemic crown-shaped cyclotriveratrylene derivatives and isolation and characterization of the intermediate saddle isomer

The preparative resolution of a trifunctionalized C3-symmetrical chiral cyclotriveratrylene derivative was achieved via high-performance liquid chromatography (HPLC) on a chiral stationary phase. This approach is a promising alternative to the previously reported resolution through formation of diastereomeric esters because it involves fewer synthetic steps and is less prone to thermal (re)racemization. During these studies an intermediate saddle conformer could also be isolated and characterized by 1H and 13C NMR spectroscopy. The HPLC separation method was further developed in order to allow investigations on the racemization behavior of the cyclotriveratrylene derivative.


Synthetic procedures 2,7,12-Trimethoxy-10,15-dihydro-5H-tribenzo[a,d,g]cyclononene (3)
A suspension of phosphorus pentoxide (9.77 g, 68.81 mmol) in 80 mL of dichloromethane was heated to 40 °C. Then, 3-methoxybenzyl alcohol (2, 18.86 g, 136.50 mmol) was added and the mixture was refluxed for 1 hour. The mixture was filtrated and the residue extracted three times with dichloromethane. The extract was concentrated under reduced pressure and combined with the filtrate. The solution was filtrated over a 50 g pad of silica and the filtrate was concentrated under reduced pressure. After the addition of 5 mL of diethyl ether, the solution was kept overnight at 0 °C. The white precipitate was filtrated, washed with 5 × 1 mL of diethyl ether and dried in high vacuum. The product (0.760 mg, 2.11 mmol, 5%) was obtained as a white solid. The analytical data are in accordance with those reported in the literature. [1] 10,15-Dihydro-5H-tribenzo[a,d,g]cyclononene-2,7,12-triol ((rac)-1) Trimethoxycyclotriveratrylene 3 (3.43 g, 10.77 mmol) was suspended in 16 mL of dry dichloromethane and cooled to 0 °C. Boron tribromide (17.29 g, 69 mmol as solution in dichloromethane) was slowly added and the mixture was stirred overnight at room temperature. The reaction was quenched by the addition of an ice water mixture and brought to pH 6 with a saturated aqueous sodium carbonate solution. The residue was washed with 5 × 10 mL of hot water. The residue was dissolved in 12 mL of acetonitrile and treated with supersonic for 40 minutes. The formed precipitate was filtrated, washed with 5 × 5 mL of acetonitrile and recrystallized from acetonitrile. The product (2.30 g, 7.24 mmol, 76%) was obtained as white solid. The analytical data are in accordance with those reported in the literature.
These impurities were not analyzed in detail.

HPLC separations
Chiral resolutions of 1 were performed on an analytical ultra-high pressure gradient liquid chromatography system (UHPLC) from the PLATINblue series from Knauer and a semi-preparative system from the Smartline series from Knauer.
 Separation on a semi-preparative CHIRALPAL IB column, 100% MeOH as the mobile phase, flow rate: 10 mL/min, UV detection at 230 nm.  The retention time of 1-S was 4.20 minutes. Figure S4: of a semi-preparative separation of (rac)-1 on an (S,S)-Whelk O1 column as the stationary phase and n-hexane/EtOH 70:30 as the mobile phase.

Kinetics of racemization Racemization experiments with (+)-1 and (−)-1
About 1 mg of (+)-1 or (−)-1 were dissolved in 1 mL of EtOH and the starting ee value was determined by HPLC. Then, the sample was placed in a preheated oil bath and heated to desired temperature. After the given time intervals, 10 µL of the solution were injected onto the CHIRALPAK IB column and the ee values were determined by integration.

Determination of the rate constants and half-lifes
The