Efficient chemoenzymatic dynamic kinetic resolution of 1-heteroaryl ethanols.
The scope and limitation of the combined ruthenium-lipase induced dynamic kinetic resolution (DKR) through O-acetylation of racemic heteroaromatic secondary alcohols, i.e., 1-heteroaryl substituted ethanols, was investigated. After initial screening of reaction conditions, Candida antarctica lipase B (Novozyme 435, N435) together with 4-chloro-phenylacetate as acetyl-donor for kinetic resolution (KR), in conjunction with the ruthenium-based Shvo catalyst for substrate racemization in toluene at 80 degrees C, enabled DKR with high yields and stereoselectivity of various 1-heteroaryl ethanols, such as oxadiazoles, isoxazoles, 1H-pyrazole, or 1H-imidazole. In addition, DFT calculations based on a simplified catalyst complex model for the catalytic (de)hydrogenation step are in agreement with the previously reported outer sphere mechanism. These results support the further understanding of the mechanistic aspects behind the difference in reactivity of 1-heteroaryl substituted ethanols in comparison to reference substrates, as often referred to in the literature.
Medicinal Chemistry, CNS & Pain Control, AstraZeneca R&D Sodertalje, SE-15185 Sodertalje, Sweden.
Karl S A
KS
Vallin
David
D
Wensbo Posaric
Zdenko
Z
Hamersak
Mats A
MA
Svensson
Alexander B E
AB
Minidis
D055162:Biocatalysis; D004800:Enzymes, Immobilized; D000431:Ethanol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005656:Fungal Proteins; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006865:Hydrogenation; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry; D007700:Kinetics; D008049:Lipase / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry*; D013237:Stereoisomerism
D004800:Enzymes, Immobilized; D005656:Fungal Proteins; D006571:Heterocyclic Compounds; D007093:Imidazoles; D007555:Isoxazoles; D010069:Oxadiazoles; D011720:Pyrazoles; D000431:Ethanol; C031280:pyrazole; C029899:imidazole; D012428:Ruthenium; C093667:Novozyme 435; D008049:Lipase; C431349:lipase B, Candida antarctica