Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines

Abstract

The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature is yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.

Figure 1

High-value stereo-enriched 3- and 3,4-substituted piperidines and strategies for their synthesis. (a) Representative examples of biologically active chiral substituted piperidines. (b) Previous work: Asymmetric transition-metal-catalyzed synthesis of 3-substituted piperidines. (c) This work: Chemo-enzymatic dearomatization of pyridines for the synthesis of chiral 3- and 3,4-substituted piperidines.

Figure 2

Proposed mechanism for the 6-HDNO-EneIRED cascade. (a) Kinetic profile from in situ ¹⁹F NMR reaction monitoring of THP-6b. ^aReactions run at 1 mmol. (b) Enamine 10e is used to probe the role of this species as an intermediate in the cascade. (c) Proposed catalytic sequence for the AmOxEneIRED biocatalytic cascade. ^bTwo equivalents of NAD(P)H consumed to form piperidine. (d) Structure of the dimer of EneIRED-07 in the ribbon format with subunits shown in green and blue. NADP⁺ can be seen bound at the two active sites. (e) Active site of EneIRED-07 with the (S)-enantiomer of iminium ion intermediate 3f modeled into the active site.

Figure 3

Application of the chemo-enzymatic dearomatization of pyridines for the preparation of APIs. (a) Synthesis of the antipsychotic drug (−)-preclamol. (b) Synthesis of (−)-OSU6162. (c) Two synthetic routes to Niraparib.