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.

Hydrogen-Bonding Trends in a Bithiophene with 3- and/or 4-Pyridyl Substituents

“…Toward this end, we allowed 5 to react with methyltriflate, a methylating reagent, in CH 2 Cl 2 at 0 °C. When 5 and 2 mol equiv of methyltriflate were used, two pyridinium methyl peaks were observed (Scheme 2), one at 4.40 ppm (ascribed to the 3-pyridinium methyl, from 7a) 26 and one at 4.28 ppm (ascribed to the 4-pyridinium methyl, from 7b). 27 We confirmed the position of the methyl shifts by allowing equimolar 2 to react with 2 equiv of methyltriflate and measuring the 1 H NMR spectrum of the product.…”

Catalytic Access to Chiral δ‐Lactams via Nucleophilic Dearomatization of Pyridine Derivatives

“…In recent years, catalytic asymmetric nucleophilic dearomatization of pyridinium ion with various nucleophiles [11] including organometallic reagents [12] has also been reported. Other reported methods to dearomatise pyridinium ions stereoselectively make use of reductions, [13] including the recently reported highly enantioselective chemo‐enzymatic approach for the asymmetric dearomatization of pyridiniums [13c] …”

Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines

“… 16 Previous publications from the group of Ready and our own have reported the generation of N-heterocycle boronate complexes and subsequent 1,2-migration reactions facilitated by N-acylation to provide dihydropyridyl boronic esters ( Figure 1 b, i). 17 , 18 In 2011, Hayashi and co-workers demonstrated the dearomative spirocyclization of N -alkylpyridinium benzocyclobutenol derivatives ( Figure 1 b, ii). 19 In this case, a semi-pinacol rearrangement is triggered by alcohol deacetylation, and the piperidine spirocycle is obtained following hydrogenation.…”