Similar to biosynthesis! Scientists discover a new method of chiral piperidine synthesis

On October 20, 2022, Xiao Jianliang’s team at the University of Liverpool in the United Kingdom published a research result entitled “Synthesis of chiral piperidines from pyridinium salts via rhodium-catalysed transfer hydrogenation” in the journal Nature Catalysis.

This result reported that under the condition of transfer hydrogenation of chiral amines and water, nitrogen substitution on chiral amines and pyridines was carried out, and a transamination reaction similar to that in biosynthesis was realized, and this transamination mechanism provided a new scheme for the rapid synthesis of chiral piperidine. The corresponding author of the paper is Xiao Jianliang; The first author is Wu Jianjun.

Chiral piperidine structures are widely found in natural products, bioactive molecules, and market-approved drugs (Figure 1). Among the many synthesis methods, chiral piperidine is undoubtedly the most attractive synthesis method directly obtained by asymmetric hydrogenation or transfer hydrogenation reduction pyridine, because it has the characteristics of short synthesis steps, green and clean, high enantioselectivity and cheap and easy availability of raw materials. In the past 20 years, a lot of research work has been carried out in this field at home and abroad, especially the strategy of substrate activation, that is, the acquisition of chiral piperidine through asymmetric hydrogenated pyridine salts, and very good progress has been made. However, high hydrogen pressures, special catalysts, and especially limited substrate ranges, such as incompatibility with substrates containing reducing and coordinating functional groups and fluoropyridine, greatly limit the application of this method.

Figure 1: Chiral piperidine-containing drugs and natural products

In previous research work (Adv. Synth. Catal. 355, 35–40, 2013), Professor Xiao Jianliang’s team unexpectedly discovered a new reaction strategy, “asymmetric reductive transamination” (ART). The core highlight of this reaction is that under the reduction condition of water, chiral amines replace nitrogen on the pyridine ring, and at the same time achieve almost complete chiral induction to obtain chiral piperidines with high enantioselectivity and high yield, especially chiral fluoropiperidine. It is worth mentioning that the reaction mechanism shows that about 10 independent chemical transformations are involved, such as hydrogen addition, hydrolysis of the open ring, amine replacement, re-closing of the ring, and finally asymmetric reduction, thus successfully realizing the synthesis from the raw material pyridine to chiral piperidine (Figure 2). Considering the widespread availability of primary amines (primary amines) and the cheap availability of the raw material pyridine, this ART study also provides a powerful new tool for piperidine modification, enabling 15N isotopic labeling of piperidine and piperidine alkylation that is difficult to achieve with conventional methods.

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Figure 2: Transfer hydrogenation and ART working and reaction mechanisms

Under optimal ART reaction conditions, the authors examined the range of substrates for the reaction and showed that both 2-aryl and alkyl groups achieve efficient conversion, especially reducing groups such as halogens, nitro, cyano, ketones, esters, and olefins that are incompatible with traditional hydrogenation methods (Figure 3). Coordination groups such as heteroaromatic rings, alcohols, and protective amino groups do not inhibit the reaction. The use of chiral α-phenethylamine to obtain chiral piperidine is the first application of this ART reaction, and further research has found that other primary amines can also be used as alkylation reagents to directly synthesize N-alkylated piperidine from pyridine salts. This method has significant advantages for unstable alkylating reagents or piperidines that are not readily available. In addition, in addition to chiral α-phenylethylamine, other chiral primary amines include amino acid derivatives, which can also be converted into corresponding piperidine derivatives while retaining high enantioselectivity. Because both the R and S configurations of α-phenethylamine are commercially available and inexpensive reagents, the two enantiomers of the corresponding chiral piperidine product are readily available by this method. At the same time, most of the chiral α-phenethylamine can be recovered after the end of the reaction; The use of recovered α-phenethylamine does not affect the results of this reaction.

Despite the importance of fluorine and piperidine in drug development, the preparation of chiral fluoropiperidine directly from fluoropyridine is rare. The authors found that under standard ART conditions, a series of 3-fluoropyridine raw materials can be converted to chiral 3-fluoropiperidine, and two chiral centers are generated simultaneously, of which the cis-absolute configuration predominates. Consistent with the 2-substituted substrate, a wide range of reducibility and coordination groups are well compatible (Figure 3).

Figure 3: Partially asymmetrically transferred amination products

The further application of ART reactions to the synthesis of natural products and the labeling of 15N isotopes, as well as the late modification of complex marketed drugs, provides a new approach to potential drug modification. Finally, the authors collaborated with Sigma-Aldrich, a reagent company owned by Merck, to successfully scale up the reaction to the level of 100 grams or even kilograms using ART, realizing the commercialization of a variety of novel chiral building blocks (Figure 4).

Figure 4: Application of asymmetric transfer amination reaction

Finally, it’s worth mentioning that most of this ART work was completed a decade ago. Based on the PCT patent of the project, Professor Xiao Jianliang’s team founded Liverpool ChiroChem and Kainuok (Taizhou) Drug R&D Co., Ltd. in China and the UK. In addition, as one of the four achievements submitted by the Department of Chemistry of the University of Liverpool, the ART results participated in the 2021 seven-year scientific research evaluation of British universities, and the impact of the scientific research achievements of the Department of Chemistry of the University of Liverpool was rated as the third in the UK, see the following report for details:

The work was supported by Pfizer, AstraZeneca, the University of Liverpool and the Innovate UK Knowledge Transfer Partnership (KTP11214, R.G.). In particular, the second author Chen Zhenyu independently discovered the application of ART reaction to chiral fluoropiperidine, which makes ART reaction provide a new scheme for the preparation of chiral fluoropiperidine. (Source: Web of Science)

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