Biocatalyzed C−C Bond Formation for the Production of Alkaloids

Abstract

Traditional methods of chemical synthesis of alkaloids exhibit various problems such as lack of enantioselectivity, the use of toxic chemical and intermediates, and multiple numbers of synthetic steps. Consequently, various enzymatic methods for the formation of CÀC bonds in the alkaloid skeleton have been developed. Herein, we report advances achieved in the enzymatic or chemo-enzymatic synthesis of pharmaceutically important alkaloids that employ three CÀC bond forming enzymes: two Pictet-Spenglerases and the oxidative CÀC bond forming flavoenzyme Berberine Bridge Enzyme. Protein engi-neering studies, improving the substrate scope of these enzymes, and thereby leading to the synthesis of non-natural alkaloids possessing higher or newer pharmacological activities, are also discussed. Furthermore, the integration of these biocatalysts with other enzymes, in multi-enzymatic cascades for the enantioselective synthesis of alkaloids, is also reviewed. Current results suggest that these enzymes hold great promise for the generation of CÀC bonds in the selective synthesis of alkaloid compounds possessing diverse pharmacological properties.

Enzymatic Friedel‐Crafts Alkylation Using Squalene‐Hopene Cyclases

“…Moreover, enzymes acting on intramolecular Friedel‐Crafts alkylations enable the biosynthesis of isoquinoline alkaloids [22] and lignan natural products [23] . These biosynthetic and biocatalytic ring‐closing reactions are catalyzed by norcoclaurine synthases used as Pictet‐Spenglerases, [24,25] flavin‐dependent berberine‐bridged enzymes, [26] as well as non‐heme dioxygenases [27,28] …”

“…Additionally, Aac SHC and the cyclase 1 from Zymomonas mobilis ( Zmo SHC1) mediate the Friedel‐Crafts alkylation of polyprenly phenyl ethers. In a recent study, four different model substrates were tested in the SHC‐catalyzed intramolecular Friedel‐Crafts alkylation with the highest activity observed for the substrate geranyl phenyl ether ( 1 ) [25] . While Zmo SHC1 selectively catalyzed the alkylation 2 a of geranyl phenyl ether ( 1 ), the Aac SHC forms a product mixture.…”

Recent trends in biocatalysis

“…Besides engineering BIA pathways in heterogenous hosts, many enzymes (especially the C-C bond forming NCS and BBE) in the biosynthetic pathway could be engineered and evolved for the in vitro synthesis of novel THIQs. [247][248][249] NCS is wellknown for its broad scope for accepting different aldehydes to give THIQs. In 2017, Lichman et al discovered that the TfNCS from Thalictrum flavum catalysed the Pictet-Spengler reaction between dopamine and ketones, leading to novel chiral 1,1 0 -disubstituted and spiro-THIQs (Scheme 2B).…”

Kinetic Resolution of Racemic Amines to Enantiopure (S)-amines by a Biocatalytic Cascade Employing Amine Dehydrogenase and Alanine Dehydrogenase

“…The asymmetric synthesis of amines from prochiral carbonyls and ammonia has also been acknowledged as one of the most highly desired transformations industrially by the ACS Green Chemistry Institute Pharmaceutical Roundtable [4]. The increasing demand for enantiomerically pure compounds and the simultaneous imposition of environmental restrictions by many countries necessitates the effective integration of traditional chemical syntheses with biocatalytic 'greener' methods [5][6][7][8][9]. Traditional organo-catalytic methods for the synthesis of chiral amines use toxic intermediates and require environmentally harsh conditions.…”