Large Scale Practical Synthesis of Enantiomerically Pure <i>cis</i>-4-Amino-3-fluoro-1-methylpiperidine via Rhodium-Catalyzed Asymmetric Hydrogenation of a Tetrasubstituted Fluoroalkene

Qu, Bo; Saha, Anjan K.; Li, Guisheng; Zeng, Xiaoming; Wang, Xiaojun; Haddad, Nizar; Hou, Xiaowen; Lorenz, Jon C.; Wu, Lijie; Pennino, Scott; Lee, Heewon; Song, Jinhua J.; Senanayake, Chris H.

doi:10.1021/acs.oprd.0c00525

Cited by 10 publications

(3 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As the cis -4-amino-3-fluoropiperidine moiety is a popular chiral moiety in many pharmaceutical drug candidates such as PTK2 inhibitors, JAK inhibitors, CGRP receptor antagonists, gyrase inhibitors, and antimigraine compounds, Qu and co-workers developed a highly regio-, chemo-, and enantioselective asymmetric hydrogenation for the synthesis of chiral cis -4-amino-3-fluoro-1-methylpiperidine 119 (Scheme a) . The asymmetric hydrogenation of N -benzyl-4-(( tert -butoxycarbonyl) amino)-5-fluoro-tetrahydropyridinium chloride 118 proceeded smoothly at the multikilogram scale to give 119 in 99% ee by employing a catalyst derived from Rh(NBD) 2 (BF 4 )/ L17 .…”

Section: Asymmetric Transition Metal Catalysismentioning

confidence: 99%

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Yang

Stolarzewicz

et al. 2023

Chem. Rev.

View full text Add to dashboard Cite

The proportion of approved chiral drugs and drug candidates under medical studies has surged dramatically over the past two decades. As a consequence, the efficient synthesis of enantiopure pharmaceuticals or their synthetic intermediates poses a profound challenge to medicinal and process chemists. The significant advancement in asymmetric catalysis has provided an effective and reliable solution to this challenge. The successful application of transition metal catalysis, organocatalysis, and biocatalysis to the medicinal and pharmaceutical industries has promoted drug discovery by efficient and precise preparation of enantio-enriched therapeutic agents, and facilitated the industrial production of active pharmaceutical ingredient in an economic and environmentally friendly fashion. The present review summarizes the most recent applications (2008–2022) of asymmetric catalysis in the pharmaceutical industry ranging from process scales to pilot and industrial levels. It also showcases the latest achievements and trends in the asymmetric synthesis of therapeutic agents with state of the art technologies of asymmetric catalysis.

show abstract

Section: Asymmetric Transition Metal Catalysismentioning

confidence: 99%

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Yang

Stolarzewicz

et al. 2023

Chem. Rev.

View full text Add to dashboard Cite

show abstract

“…An alternative strategy involves transition-metal-catalyzed asymmetric cross-couplings of F-incorporated motifs, such as fluorinated enolates (or their equivalents) and α-fluoro alkyl halides, to form the desired C–F stereocenters . Moreover, alkenyl fluorides, one of the most readily available F-containing building blocks, have also been explored as simple precursors for stereodefined C(sp 3 )–F motifs, typically via catalytic asymmetric hydrogenation . Recently, Sigman et al, via Pd-catalyzed asymmetric remote hydroarylation, and Fu et al, via Co-catalyzed asymmetric hydroalkylation with alkyl halides, have disclosed two examples of catalytic asymmetric hydrofunctionalization of alkenyl fluorides (Figure a).…”

Section: Introductionmentioning

confidence: 99%

Selective Hydrofunctionalization of Alkenyl Fluorides Enabled by Nickel-Catalyzed Hydrogen Atoms and Group Transfer: Reaction Development and Mechanistic Study

Chen,

Zhang,

et al. 2024

J. Am. Chem. Soc.

View full text Add to dashboard Cite

Due to the unique effect of fluorine atoms, the efficient construction of high-value alkyl fluorides has attracted significant interest in modern drug development. However, enantioselective catalytic strategies for the efficient assembly of highly functionalized chiral C(sp 3 )-F scaffolds from simple starting materials have been underutilized. Herein, we demonstrate a nickel-catalyzed radical transfer strategy for the efficient, modular, asymmetric hydrogenation and hydroalkylation of alkenyl fluorides with primary, secondary, and tertiary alkyl halides under mild conditions. The transformation provides facile access to various structurally complex secondary and tertiary α-fluoro amide products from readily available starting materials with excellent substrate compatibility and distinct selectivity. Furthermore, the utility of this method is demonstrated by late-stage modifications and product derivatizations. Detailed mechanistic studies and DFT calculations have been conducted, showing that the ratedetermining step for asymmetric hydrogenation reaction is NiH-HAT toward alkenyl fluorides and the stereo-determining step is alcohol coordination to Ni-enolates followed by a barrierless protonation. The mechanism for the asymmetric hydroalkylation reaction is also delivered in this investigation.

show abstract

“…The rich chemistries afforded by homogeneous Rh(I) catalysis have been studied within academia for decades and more recently have attracted attention within process research and development in the fine chemical industry. For example, Rh(I)-catalyzed hydrogenation has been a popular transformation on process scale, and other industrial applications include Rh(I)-catalyzed hydroformylation, conjugate addition, C–H functionalization, and transfer hydrogenation …”

Section: Introductionmentioning

confidence: 99%

Thermal Instability and Associated Potential Safety Hazards of Rhodium(I) Precatalyst Complexes with Weakly Coordinated Ligands

Sheng

Huff

Schafer

et al. 2021

Org. Process Res. Dev.

View full text Add to dashboard Cite

Rhodium is a critical transition metal in catalyzing chemical transformations in both academia and industry. Over the years Rh(I)-catalyzed chemical transformations such as hydroformylation, conjugate addition, C–H functionalization, and transfer hydrogenation have found broad application in the fine chemical industry. However, Rh(I) precatalyst complexes with weakly coordinated ligands are inherently unstable and thermally decompose to generate a variety of noncondensable, flammable, and/or toxic products. Exposure of [Rh(ethylene)2Cl]2 to air promotes its thermal decomposition at temperatures as low as ∼44 °C by differential scanning calorimetry (DSC) analysis, thus significantly increasing the thermal instability hazards and leading to high potential for fire or explosion risk. A thermokinetic model predicts that the adiabatic induction time of [Rh(ethylene)2Cl]2 in the presence of air is only 3.1 days at 25 °C and 24 h at 31.7 °C, indicating that exposure of [Rh(ethylene)2Cl]2 to air significantly increases the thermal instability hazards of this catalyst. DSC screening of a variety of other Rh(I) precatalyst complexes with loosely coordinated ligands revealed similar thermal instability hazards, and these hazards were significantly increased when the complexes were evaluated with an air headspace compared with those under an inert atmosphere. We expect this contribution to promote awareness of these potential safety hazards within the wider scientific community. Scientists should understand the thermal instability hazards of their specific Rh(I) precatalyst complexes and employ safer measures, for example, inert atmosphere and safe temperature windows, to prevent related incidents when handling such Rh(I) precatalyst complexes during their research, especially on scale.

show abstract

Large Scale Practical Synthesis of Enantiomerically Pure cis-4-Amino-3-fluoro-1-methylpiperidine via Rhodium-Catalyzed Asymmetric Hydrogenation of a Tetrasubstituted Fluoroalkene

Cited by 10 publications

References 23 publications

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Selective Hydrofunctionalization of Alkenyl Fluorides Enabled by Nickel-Catalyzed Hydrogen Atoms and Group Transfer: Reaction Development and Mechanistic Study

Thermal Instability and Associated Potential Safety Hazards of Rhodium(I) Precatalyst Complexes with Weakly Coordinated Ligands

Contact Info

Product

Resources

About