Chemoenzymatic method to enantiopure sulphur heterocyclic β-hydroxy nitriles

Abstract

Sulphur heterocyclic β-hydroxy nitriles are prepared from the suitable aldehyde and (trimethylsilyl)acetonitrile in the presence of lithium acetate at good yields. Burkholderia cepacia lipase allowed the formation of the both enantiomers of β-hydroxy nitriles in highly enantiopure forms (ee 99%) through acylation of a racemic mixture and alcoholysis of the acylated enantiomer in tert-butyl methyl ether.

A Chemoenzymatic Dynamic Kinetic Resolution Approach to Enantiomerically Pure (R)- and (S)-Duloxetine

“…The crude product was purified by flash chromatography (SiO 2 , pentane/EtOAc 4:1) yielding 1 (1.4 g, 9.1 mmol, 91%) as a yellow oil. Spectral data were in accordance with those reported in the literature …”

“…Purification by column chromatography (SiO 2 ; pentane/Et 2 O 4:1) afforded 85 mg (0.435 mmol, 87%) of ( R )- 2 in 98% ee. Spectral data were in accordance with those reported in the literature …”

“…From our previous work it was known that enzymatic resolution of β-hydroxynitriles with Candida antarctica lipase B (CALB) works very well . In the literature, however, Burkholderia cepacia lipase (previously Pseudomonas cepacia lipase) is most commonly used in the KR of rac - 1 . , The enantioselectivity ( E value) of the kinetic resolution was measured in toluene using isopropenyl acetate or trifluoroethyl butyrate as acyl donor. Both ( R )- and ( S )-selective enzymes were investigated for their selectivity.…”

“…13 C NMR (100 MHz, CDCl 3 ): δ 169.4, 139.3, 127.0, 126.5, 126.4, 115.7, 66.2, 25.6, 20.8. [α] 20 D = +94 ( c 1.16, MeOH), [α] 20 D = +96 ( c 0.93, CHCl 3 ); lit . [α] 20 D = +94 ( c 1, CHCl 3 , 95% ee ( R )-enantiomer).…”