(1-benzylazetidine-2,4-diyl)dimethanol

A three-neck flask, equipped with a mechanical stirrer, a temperature probe and a nitrogen inlet was charged with dibenzyl c/s-N-benzylazetidine-2, 4-dicarboxylate (173 g, 416 mmol) followed by methanol (1 .14 L) and tetrahydrofuran (560 ml_). The resulting mixture was stirred at ambient temperature under nitrogen until homogeneity was obtained. The solution was then cooled in a dry ice/acetone bath until an internal temperature of -4°C was reached. Then sodium borohydride (79.0 g, 2.08 mol) was added in portions over 1-1 .5 h, during which time a slight exotherm to a maximum temperature of 6°C was observed. Following the addition, the resulting mixture was stirred under nitrogen while gradually warming to ambient temperature overnight [Note: during warming, a secondary exotherm up to a maximum temperature of 27°C was observed and was controlled by the use of an ice bath]. LCMS analysis of an aliquot of the reaction mixture diluted in methanol indicated consumption of stating material and formation of product (plus benzyl alcohol). The reaction mixture was then cooled in an ice water bath (internal temperature of 8°C) and quenched by the drop-wise addition of water (100 mL) via addition funnel. The resulting mixture was concentrated under reduced pressure to remove the bulk of volatiles. The remainder was partitioned between 10percent methanol/dichloromethane (500 mL) and water (200 mL). After phase separation, the organic (upper layer) and aqueous phases were collected. The aqueous phase was again extracted with 10percent methanol/dichloromethane (2 x 500 mL; organic layer is now the lower phase). Analysis of an aliquot of the aqueous phase at this stage shows no product present. The combined organic extracts were washed successively with water and saturated aqueous sodium chloride. Analysis of this aqueous (water plus saturated aqueous sodium chloride) phase showed the presence of product (plus benzyl alcohol), so the aqueous phases were back-extracted with 10percent methanol/dichloromethane (3 x). All the methanol/dichloromethane extracts were combined and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, 177 g of a yellow colored oil was obtained. Further concentration of this residue under high vacuum in a water bath at 75°C was performed to remove the bulk of benzyl alcohol. After constant weight was observed, 100 g of an oil remained. This material was dissolved in dichloromethane and concentrated under reduced pressure giving a semisolid. The semisolid was twice suspended in hexanes and subsequently concentrated under reduced pressure. The remaining solid was suspended in hexanes (260 mL) and the resulting suspension was stirred overnight. The suspension was then filtered and the collected solids were washed with hexanes (2 x). LCMS analysis of a sample of the solid dissolved in methanol indicated a product purity of -90percent (contaminated with benzyl alcohol). The solids were again suspended in hexanes (200 mL) and the suspension stirred (on rotovap) for 1 hour at 30°C. The suspension was filtered, and the collected solids were washed with additional hexanes (1 x). LCMS analysis of a sample of the solid dissolved in methanol indicated a product purity >96percent. The solids were further air dried to constant weight, affording 81 .9 g (95percent yield) of c/s-N-benzyl-2, 4-bis(hydroxymethyl)azetidine (intermediate 5) as a white solid. The same procedure to that described for the preparation ofcompound 6 was utilized, except that cis-benzyl 2, 20-(1-benzylazetidine-2, 4-diyl) diacetate was utilized in place of trans-benzyl2, 20-(1-benzylazetidine-2, 4-diyl) diacetate. Compound 16 was obtainedas a white solid, mp 71–73 C, yield, 65percent. 1H NMR(500 MHz, CDCl3) d 7.24–7.31 (m, 5H), 3.69 (s, 2H), 3.28–3.31 (m, 6H), 2.75 (br s, 2H), 1.99–2.05 (m, 2H); 13C (75 MHz, CDCl3): d138.1, 129.3, 128.7, 127.8, 63.6, 63.3, 61.3, 20.5 ppm.To a solution of (2R, 45)-diethyl 1-benzylazetidine-2, 4-dicarboxylate (0.8 g, 2.75 mmol) in EtOHIMeOH (9:1; 10 mL) was added CaCl2 (0.92 g, 8.25 mmol) at r.t. To the resulting stirred mixture was then added NaBH4 (0.63 g, 16.5 mmol) in portions. The reaction mixture was stirred for overnight at r.t. Subsequently H20 (5 mL) was added, and the mixture was stirred for 30 mm. The mixture was then concentrated in vacuum, and partitioned between H20 (10 mL) and CH2C12 (10 mL). The aqueous layer was extracted with CH2C12 (2 x 10 mL), and the organic layers were combined, washed with brine (10 mL), dried over Na2504, and concentrated in vacuo to give 0.25 g product as yellow oil. This product was used in the next step without further purification. MS (ESI): m/z [M + H]: 208.1477.

Molecular Weight:207.27
XLogP3:0.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:207.125928785
Monoisotopic Mass:207.125928785
Topological Polar Surface Area:43.7
Heavy Atom Count:15
Complexity:182
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes