Asymmetric Synthesis of Fused-Ring Tetrahydroisoquinolines and Tetrahydro-β-carbolines from 2-Arylethylamines via a Chemoenzymatic Approach

Abstract

While chiral fused-ring tetrahydroisoquinoline (THIQ) and tetrahydro-β-carboline (THβC) scaffolds have attracted considerable interest due to their wide spectrum of biological activities, the synthesis of optically pure chiral fused-ring THIQs and THβCs remains a challenging task. Herein, a group of active imine reductases were identified to convert the imine precursors into the corresponding enantiocomplementary fused-ring THIQs and THβCs with high enantioselectivity and conversion, establishing an efficient and green chemoenzymatic approach to fused-ring alkaloids from 2arylethylamines.

Biocatalytic reductive aminations with NAD(P)H-dependent enzymes: enzyme discovery, engineering and synthetic applications

“…A number of fused-ring THIQ and THβCs were synthesized at preparative scales including natural alkaloids with stereo-complementary IREDs in high yields (up to 85%) (Table 3, entry 35). 141…”

“…A number of fused-ring THIQ and THbCs were synthesized at preparative scales including natural alkaloids with stereo-complementary IREDs in high yields (up to 85%) (Table 3, entry 35). 141 Very recently, the Zheng group discovered an IRED from Penicillium camemberti (PcIRED). Targeting the calcimimetic drug Cinacalcet, ISM was performed on this enzyme.…”

Asymmetric Synthesis of Sterically Hindered 1-Substituted Tetrahydro-β-carbolines Enabled by Imine Reductase: Enzyme Discovery, Protein Engineering, and Reaction Development

“…12 Very recently, the Qu group reported the efficient synthesis of 1aryl-THβCs using engineered IRED enzymes, 13 while the Zhu group disclosed the IRED-catalyzed asymmetric synthesis of fused-ring THβCs. 14 To the best of our knowledge, IREDcatalyzed reduction of DHβCs bearing a quaternary carbon attached to C1 has not been reported until now. Herein, we report the discovery, engineering, and application of IREDs for the asymmetric synthesis of chiral, sterically hindered 1substituted THβCs, including those containing a quaternary carbon (Scheme 1).…”

“…There were reports on the IRED-catalyzed reduction of 1-substituted DHβCs to THβCs when we initiated our study . Very recently, the Qu group reported the efficient synthesis of 1-aryl-THβCs using engineered IRED enzymes, while the Zhu group disclosed the IRED-catalyzed asymmetric synthesis of fused-ring THβCs . To the best of our knowledge, IRED-catalyzed reduction of DHβCs bearing a quaternary carbon attached to C1 has not been reported until now.…”

Asymmetric Synthesis of Bulky N-Cyclopropylmethyl-1-aryl-1-phenylmethylamines Catalyzed by Engineered Imine Reductases

“…GF3546, respectively, possessing activity toward the substrate 2-methyl-1-pyrroline . In the past decade, research on IREDs has showed a booming development trend. − Turner et al reported the discovery of a reductive aminase from Aspergillus oryzae ( Asp RedAm) that can catalyze the reductive coupling of a broad set of carbonyl compounds with a variety of primary and secondary amines . Gröger et al presented a panel of IREDs enabling the reduction of 3-thiazolines with high conversion and high to excellent enantioselectivity (>96% and up to 99% ee, respectively) .…”