Chemoenzymatic Preparation of 1-Heteroarylethanamines of Low Solubility

• Published in: European journal of organic chemistry Vol. 2012; no. 17; pp. 3288 - 3294
• Main Authors: Brem, Jürgen, Bencze, László-Csaba, Liljeblad, Arto, Turcu, Mihaela C., Paizs, Csaba, Irimie, Florin-Dan, Kanerva, Liisa T.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-06-2012; WILEY‐VCH Verlag; Wiley-VCH
• Subjects: Acylation; Amides; Asymmetric catalysis; Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Chemistry; Enantioselectivity; Exact sciences and technology; Fundamental and applied biological sciences. Psychology; General and physical chemistry; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Hydrolysis; Kinetic resolution; Methods. Procedures. Technologies; Organic chemistry; Preparations and properties; Solubility; Solutions; Water; candida antarctica; Enantioselectivity; Nitrogen heterocycle; Deprotection; Furan derivatives; Lactam; Triacylglycerol lipase; Amides; Esterases; Selectivity; Oxygen heterocycle; Asymmetric catalysis; Fungi; Benzothiophene derivatives; Racemic; Enantiomer; Fungi Imperfecti; Chemical synthesis; Acylation; Catalytic reaction; Enzyme; Solubility; Theoretical study; Carboxylic ester hydrolases; Hydrolysis; Enzymatic method; Cosolvent; Sulfur heterocycle; Optical resolution; Hydrolases; Carboxamide; Benzofuran derivatives; Kinetic resolution
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201200330

Both enantiomers of biologically and pharmaceutically interesting benzofuran‐, benzothiophen‐, and phenylfuran‐based 1‐heteroarylethanamines were prepared at close to theoretical yields by using Candida antarctica lipase B (Novozym 435) catalyzed (R)‐selective N‐acylation with isopropyl butanoate (enantiomeric ratio E > 200). The use of N‐methyl‐2‐pyrrolidinone (NMP) as a cosolvent (1:30) in isopropyl butanoate solved the problem of low solubility of the compounds. Instability of the heterocyclic ring systems against traditional acid‐ and base‐catalyzed hydrolysis was solved by using Candida antarctica lipase A as a commercial CAL‐A‐CLEA preparation for deprotection of the N‐acylated (R) enantiomers in water. The slow, highly enantioselective (E > 200) hydrolyses of racemic butanamides was also observed in the presence of Novozym 435.
Both enantiomers of seven 1‐heteroarylethanamines were prepared by starting from the ketones. Enantiopurity was introduced by Candida antarctica lipase B catalyzed (R)‐selective N‐acylation. Low solubility issues were solved by the use of N‐methylpyrrolidine as a cosolvent. (R)‐Butanamides were deprotected by Candida antarctica lipase A catalyzed hydrolysis in water, to yield the (R)‐amines.