A Robust, Recyclable Resin for Decagram Scale Resolution of (<i>±</i>)‐Mefloquine and Other Chiral N‐Heterocycles

Kreituss, Imants; Chen, Kuang‐Yen; Eitel, Simon H.; Adam, Jean-Michel; Wuitschik, Georg; Fettes, Alec; Bode, Jeffrey W.

doi:10.1002/anie.201509256

Cited by 21 publications

(11 citation statements)

References 38 publications

(13 reference statements)

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“…1c). 20 Using the PEARL reagents, we could obtain enantiopure amines from their racemates, albeit in diminished yields at the expense of the scalemic product. As both enantiomers of the PEARL reagents are readily available on scale, we sought to tackle the resolution of saturated N-heterocycles via parallel kinetic resolution.…”

mentioning

confidence: 99%

Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Kreituss

Bode

2016

Nature Chem

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Kinetic resolution is a common method to obtain enantioenriched material from a racemic mixture. This process will always deliver enantiopure unreacted material if the reactions are allowed to proceed to sufficient conversion and the selectivity is not unity (s > 1). However, the scalemic reaction product often is discarded, meaning, that the yield of this process seldom exceeds 40-45%. Parallel kinetic resolution can grant access to two distinct, highly enantioenriched products from a single racemic starting material. Here we describe the development of a flow-based system that enables practical parallel kinetic resolution (PKR) of a broad range of racemic saturated N-heterocycles. This process provides access to both enantiomers of the racemic starting material in good yield and high enantiopurity; similar results with classical kinetic resolution would require selectivities in the range of s = 100. To achieve this, two immobilized quasienantiomeric acylating agents were designed for the asymmetric acylation of racemic saturated N-heterocycles. Using the flow-based system we could efficiently separate, recover and reuse the polymer-supported reagents. The amide products were obtained in good yields and high enantiopurities and could be readily separated and hydrolyzed to the corresponding amines without detectable epimerization.

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confidence: 99%

Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Kreituss

Bode

2016

Nature Chem

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“…11 NB-PMA was synthesized by atom transfer radical polymerization (ATRP) beginning with a norbornene-amide initiator (NB-int). 12 The resulting NB-PMA was turned into the corresponding bottlebrush polymer, poly(NB-PMA) with 99% conversion via grafting-through ROMP by G3 (1 mol%) and exhibited a steady molecular weight growth as the ratio of macromonomer to G3 was increased (- Table S1 and Figure S1), which confirmed the quality as a macromonomer. The transesterification of NB-PMA with Ti(Oi-Pr) 4 and benzyl alcohol produced norbornenylterminated poly(benzyl acrylate) (NB-PBzA) quantitatively.…”

Section: Robust Macromonomer Developmentmentioning

confidence: 78%

“…We thus designed NB‐PMA which exhibits good modification efficiency and structural robustness during Ti‐mediated transesterification (Scheme 1). 11 NB‐PMA was synthesized by atom transfer radical polymerization (ATRP) beginning with a norbornene‐amide initiator (NB‐int) 12 . The resulting NB‐PMA was turned into the corresponding bottlebrush polymer, poly(NB‐PMA) with 99% conversion via grafting‐through ROMP by G3 (1 mol%) and exhibited a steady molecular weight growth as the ratio of macromonomer to G3 was increased (Table S1 and Figure S1), which confirmed the quality as a macromonomer.…”

Section: Resultsmentioning

confidence: 99%

Divergent strategy for the synthesis of bottlebrush polymers via postpolymerization modification of macromonomer

Lee

Kim

Yoo

et al. 2020

Journal of Polymer Science

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A simple and divergent synthetic strategy of bottlebrush polymers (BBPs) is presented, consisting of postpolymerization modification of a macromonomer and grafting-through polymerization. Beginning with a single macromonomer, its direct modification could build a library of macromonomers with an identical chain length, thus guaranteeing the precision in the synthesis of BBPs. In this study, a newly designed norbornenyl-terminated poly(methyl acrylate) (NB-PMA) is proposed as a chemically robust template. Ti-mediated transesterification of NB-PMA successfully produces structurally diverse polyacrylates while maintaining the terminal norbornenyl group intact. All macromonomers obtained from transesterification possess a good grafting-through ring-opening metathesis polymerization reactivity, furnishing homo, random, and block BBPs in a controllable manner. Moreover, atomic force microscopy analysis supports the controlled side-chain length distribution in the resulting BBPs.

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“…Kinetic resolutions of racemic tetrahydro-β-carbolines 1 are known but lead to a maximum of 50% yield, unless the catalytic system operates as a dynamic process. 9 Turner reported the preparation of novel monoamine oxidases (MAO-N) via mutagenesis directed evolution, 44 and their use in the dynamic kinetic resolution of racemic tetrahydro-β-carbolines 1 (Scheme 20). The MAO-N D9 variant was used in the presence of oxygen and the ammonia-borane adduct in a phosphate buffer, affording compounds (S)-1 in excellent conversions and ee's, mostly higher than 92%, with various alkyl substituents.…”

Section: Biocatalyzed Dynamic Kinetic Resolution Of Tetrahydro-β-carbmentioning

confidence: 99%

“…This review focuses on all the catalytic asymmetric methods enabling the synthesis of tetrahydro-β-carbolines and their uses/adaptations in the synthesis of chiral related compounds. The use of stoichiometric chiral reagents, 7 diastereoselective reactions, 8 or kinetic resolution 9 is therefore not included in this review.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Catalytic Methods for the Elaboration of Chiral Tetrahydro-β-carbolines and Related Scaffolds

Glinsky-Olivier

Guinchard

2017

Synthesis

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Tetrahydro-β-carbolines are important synthetic intermediates in the total synthesis of natural products and of compounds exhibiting strong bioactivities. Over the last decades, catalytic methods using chiral catalysts have been described for their synthesis. This review covers catalytic and enantioselective methods to access chiral tetrahydro-β-carbolines and their applications in the elaboration of complex chiral molecules.1 Introduction2 Asymmetric Reduction of Dihydro-β-carbolines2.1 Asymmetric Transfer Hydrogenation Reactions2.2 Asymmetric Hydrogenation Reactions2.3 Biocatalyzed Reduction of Dihydro-β-carbolines3 Organocatalyzed Pictet–Spengler Reactions3.1 Chiral Thiourea-Catalyzed Reactions3.2 Chiral Phosphoric Acid Catalyzed Reactions4 Pictet–Spengler Reactions of In Situ Generated Cyclic Iminiums5 Organocatalyzed Functionalization of Dihydro-β-carboliniums6 Organocatalyzed Alkylation of Tetrahydro-β-carbolines7 Biocatalyzed Dynamic Kinetic Resolution of Tetrahydro-β-carbolines8 Conclusion and Perspectives

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A Robust, Recyclable Resin for Decagram Scale Resolution of (±)‐Mefloquine and Other Chiral N‐Heterocycles

Cited by 21 publications

References 38 publications

Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Divergent strategy for the synthesis of bottlebrush polymers via postpolymerization modification of macromonomer

Enantioselective Catalytic Methods for the Elaboration of Chiral Tetrahydro-β-carbolines and Related Scaffolds

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