Abstract
Biocatalytic approaches to the synthesis of optically pure chiral amines, starting from simple achiral building blocks, are highly desirable because such motifs are present in a wide variety of important natural products and pharmaceutical compounds. Herein, a novel one-pot ω-transaminase (TA)/monoamine oxidase (MAO-N) cascade process for the synthesis of chiral 2,5-disubstituted pyrrolidines is reported. The reactions proceeded with excellent enantio- and diastereoselectivity (>94 % ee; >98 % de) and can be performed on a preparative scale. This methodology exploits the complementary regio- and stereoselectivity displayed by both enzymes, which ensures that the stereogenic center established by the transaminase is not affected by the monoamine oxidase, and highlights the potential of this multienzyme cascade for the efficient synthesis of chiral building blocks.
Highlights
Biocatalytic approaches to the synthesis of optically pure chiral amines, starting from simple achiral building blocks, are highly desirable because such motifs are present in a wide variety of important natural products and pharmaceutical compounds
TAs are capable of mediating the selective reductive amination of prochiral ketones, thereby providing the corresponding chiral amines.[3a–e] monoamine oxidase from Aspergillus niger (MAO-N) catalyzes the oxygen-dependent conversion of amines into imines and is typically selective for the (S)-enantiomer.[3f–l] Variants of MAO-N have been exploited for the deracemization of primary, secondary, and tertiary amines with diverse structural motifs.[3a,f–j] The development of several chemoenzymatic routes[3c,4] to industrially important target molecules by employing these two enzyme classes is testament to the advances in protein engineering[1a,5] that have resulted in the development of biocatalysts with the desired substrate scope, selectivity, and stability
2,5-Disubstituted pyrrolidines are important scaffolds in pharmaceutical compounds[6] and natural products,[7] and considerable efforts have been devoted to developing asymmetric routes to both cis- and trans-disubstituted derivatives that show moderate to good stereoselectivity.[8]
Summary
Biocatalytic approaches to the synthesis of optically pure chiral amines, starting from simple achiral building blocks, are highly desirable because such motifs are present in a wide variety of important natural products and pharmaceutical compounds. Our approach (Scheme 1) features a highly selective TA-mediated reductive amination of an achiral 1,4-diketone to generate an optically active pyrroline followed by diastereoselective chemoenzymatic conversion into the corresponding pyrrolidine by MAO-N/NH3·BH3.
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