Scalable Synthesis of (R,R)-N,N-Dibenzyl-2-fluorocyclohexan-1-amine with CsF under Hydrogen Bonding Phase-Transfer Catalysis

Vicini, Anna Chiara; Alozie, Diké-Michel; Courtes, Philippe; Roagna, Giulia; Aubert, C.; Certal, Victor; El-Ahmad, Youssef; Roy, Sébastien; Gouverneur, Véronique

doi:10.1021/acs.oprd.1c00312

Cited by 7 publications

(8 citation statements)

References 30 publications

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“…This metal-free organocatalyzed asymmetric fluorination has been successfully applied to the synthesis of a trans-2fluorocyclohexan-1-amine motif that is featured in several bioactive pharmaceutical molecules. 185 As shown in Scheme 60a, the enantioselective fluorination of racemic trans-N,Ndibenzyl-2-bromocyclohexan-1-amine 279 with CsF proceeded smoothly in the presence of N-alkyl bis-urea C34. The reaction gave β-fluoroamine [(R,R)-N,N-dibenzyl-2-fluorocyclohexan-1amine] 280 in 95% yield and 63% ee.…”

Section: Fluorinationmentioning

confidence: 99%

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Yang

Stolarzewicz

et al. 2023

Chem. Rev.

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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.

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Section: Fluorinationmentioning

confidence: 99%

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Yang

Stolarzewicz

et al. 2023

Chem. Rev.

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“…Furthermore, the protocol did not require dry conditions or pre-treatment of KF. We also developed a protocol to synthesize decagram quantities (>30 g) of bis-urea ( S )- 33b and ( S )- 33c , and subsequently employed the latter in the 200 g scale fluorination of 35f (this time with CsF) in a mechanical stirred 1 L glass reactor (Scheme C) . This substrate was selected because the corresponding deprotected β-fluoroamine is a valuable building block in drug discovery .…”

Section: Fluorination Via Solid–liquid Phase-transfer: Hydrogen Bondi...mentioning

confidence: 99%

Hydrogen Bonding Phase-Transfer Catalysis with Alkali Metal Fluorides and Beyond

Pupo

Gouverneur

2022

J. Am. Chem. Soc.

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Phase-transfer catalysis (PTC) is one of the most powerful catalytic manifolds for asymmetric synthesis. Chiral cationic or anionic PTC strategies have enabled a variety of transformations, yet studies on the use of insoluble inorganic salts as nucleophiles for the synthesis of enantioenriched molecules have remained elusive. A long-standing challenge is the development of methods for asymmetric carbon–fluorine bond formation from readily available and cost-effective alkali metal fluorides. In this Perspective, we describe how H-bond donors can provide a solution through fluoride binding. We use examples, primarily from our own research, to discuss how hydrogen bonding interactions impact fluoride reactivity and the role of H-bond donors as phase-transfer catalysts to bring solid-phase alkali metal fluorides in solution. These studies led to hydrogen bonding phase-transfer catalysis (HB-PTC), a new concept in PTC, originally crafted for alkali metal fluorides but offering opportunities beyond enantioselective fluorination. Looking ahead, the unlimited options that one can consider to diversify the H-bond donor, the inorganic salt, and the electrophile, herald a new era in phase-transfer catalysis. Whether abundant inorganic salts of lattice energy significantly higher than those studied to date could be considered as nucleophiles, e.g., CaF 2 , remains an open question, with solutions that may be found through synergistic PTC catalysis or beyond PTC.

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“…In 2019, Gouverneur and co‐authors reported asymmetric synthesis of fluorinated dibenzylamines 86 involving the use of chiral hydrogen bonding phase‐transfer catalyst 85 (Scheme 30). [77] Albeit the method had moderate enantioselectivity, it could be used at up to 200 g (0.5 mol % of 85 , CsF as the fluoride source, n=2) since the er value of the product could be improved to 98 : 2 after a single recrystallization [78] …”

Section: Synthesis Of Monofluorinated Cycloalkyl Building Blocksmentioning

confidence: 99%

“…[77] Albeit the method had moderate enantioselectivity, it could be used at up to 200 g (0.5 mol % of 85, CsF as the fluoride source, n = 2) since the er value of the product could be improved to 98 : 2 after a single recrystallization. [78] Obviously, the reaction mechanism involved the formation of symmetric bicyclic aziridinium intermediates (see also below).…”

Section: Synthesis Of β-Fluorinated Cycloalkyl Building Blocksmentioning

confidence: 99%

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

et al. 2022

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The review covers various aspects of fluorinated cycloalkyl (C3−C7) building blocks for drug discovery, including their synthesis, key physicochemical properties, and biological and medicinal applications of their derivatives. The discussed synthetic methods include classical nucleophilic fluorinations of various substrates, the addition of fluorine and another heteroatom to double bonds, cycloadditions and other transformations of fluorine‐containing substrates, as well as some newer reactions like fluorination of non‐activated and remotely activated C−H bonds, decarboxylative and deborylative fluorinations, etc. The known data on the effect of introducing the fluorinated cycloalkyl groups on the compound's key in vitro parameters (such as acidity/basicity, lipophilicity, conformational behavior, and short contact capabilities) are surveyed. Finally, applications of fluorinated cycloalkyl building block derivatives in the design of biologically active compounds (including marketed drugs Maraviroc, Ivosidenib, and Sitafloxacin) are covered, with a focus on the fluorination impact.

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Scalable Synthesis of (R,R)-N,N-Dibenzyl-2-fluorocyclohexan-1-amine with CsF under Hydrogen Bonding Phase-Transfer Catalysis

Cited by 7 publications

References 30 publications

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Hydrogen Bonding Phase-Transfer Catalysis with Alkali Metal Fluorides and Beyond

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

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