Enantioselective Oxidative Aerobic Dealkylation of N‐Ethyl Benzylisoquinolines by Employing the Berberine Bridge Enzyme

Abstract

N-Dealkylation methods are well described for organic chemistry and the reaction is known in nature and drug metabolism; however, to our knowledge, enantioselective N-dealkylation has not been yet reported. In this study, exclusively the (S)-enantiomers of racemic N-ethyl tertiary amines (1-benzyl-N-ethyl-1,2,3,4-tetrahydroisoquinolines) were dealkylated to give the corresponding secondary (S)-amines in an enantioselective fashion at the expense of molecular oxygen. The reaction is catalyzed by the berberine bridge enzyme, which is known for CC bond formation. The dealkylation was demonstrated on a 100 mg scale and gave optically pure dealkylated products (ee>99 %).

Biocatalytic Oxidation Reactions: A Chemist's Perspective

“…[135] An intramolecular version of the aforementioned electrophilic attack at in situ generated imines and iminium ions is catalysed by the so-called berberine bridging enzyme (BBE). [136] Av ery interesting new development in the oxidation of amines was reported by Asano and co-workers. [137] Using amutant of the d-amino acid oxidase from porcine kidney in the presence of cyanides,they demonstrated the conversion of amines into a-aminonitriles,s erving as starting materials for further reactions (Scheme 37).…”

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

“…Instead of undergoing cyclisation to berbines, several N-ethylbenzylisoquinolines (211) with varied substitution at the two aromatic rings were oxidatively cleaved to give the secondary amines (212) and acetaldehyde (Scheme 26b). 115 Like the natural BBE activity, this dealkylation was highly selective for the (S)enantiomer of the substrates (E >100), leaving the (R)-enantiomer untouched, but due to the relatively low reaction rate, maximum conversion (50%) was not attained in this kinetic resolution process. Consequently, the products (S)-212 were formed in >98% ee, while the optical purity of the remaining substrates (R)-211 varied between 21% and 80% ee, depending on the extent of conversion.…”

Recent trends in biocatalysis

“… 256 Besides NCS, another important C–C bond forming enzyme, BBE, has been explored for synthetic purposes, such as preparation of ( S )-scoulerine and its analogues via kinetic resolution 257 or deracemization 258 of the corresponding THIQs, and enantioselective dealkylation of N -ethyl THIQs. 259 …”