Development of a Telescoped Alkylation/Reduction Reaction Sequence and an Asymmetric Hydrogenation to Enable the Kilogram Synthesis of ABBV-3748

Kallemeyn, Jeffrey M.; Hartung, J. B.; Connolly, Timothy; Ickes, Andrew R.; Kotecki, Brian J.; Haandel, Leon van; Nazari, Milad; Manjrekar, Onkar N.; Chen, Shuang

doi:10.1021/acs.oprd.2c00245

Cited by 5 publications

(2 citation statements)

References 20 publications

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“…A late-stage enantioselective hydrogenation was employed by Kallemeyn and co-workers in the kilogram synthesis of ABBV-3748 (82), a corrector in the modulation therapy of cystic fibrosis transmembrane receptor (Scheme 18c). 61 By using Rh-Mandyphos M012-2 (L5) as the catalyst, the α,β-unsaturated Nsulfonyl amide 81 was effectively reduced at a kilogram scale to afford the final pharmaceutical molecule in 89% ee. The optical purity of 82 was further improved to >99% ee after recrystallization and an isolated yield of 66% was achieved.…”

Section: Asymmetric (Transfer) Hydrogenationmentioning

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: Asymmetric (Transfer) Hydrogenationmentioning

confidence: 99%

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Yang

Stolarzewicz

et al. 2023

Chem. Rev.

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“…The route also enabled the synthesis of decagram quantities of 1 through a comparable 9-step longest-linear sequence. Further refinements by process chemistry ultimately adapted the synthesis to >100 g while exploring alternatives for subsequent multikilogram deliveries . Highlights of the enabling route include an efficient intramolecular hydroarylation reaction that rapidly assembled the chromane ring system, an asymmetric hydrogenation of a primary enamide that gave high enantioselectivity and yield on multi-100 g scale, and optimization of a challenging acyl sulfonamide coupling that identified t BuMgCl as a uniquely effective strong base for that transformation.…”

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confidence: 99%

Enabling Asymmetric Synthesis of ABBV-3748, a Corrector Compound for the Treatment of Cystic Fibrosis

et al. 2022

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ABBV-3748 is a C2 corrector for the treatment of cystic fibrosis profiled among AbbVie's CFTR portfolio. A decagram-scale enabling asymmetric synthesis is described which addresses numerous shortcomings of the original route. Highlights include an InBr 3 -catalyzed intramolecular hydroarylation reaction that rapidly assembles the chromane core, an exceptionally efficient asymmetric hydrogenation of a primary enamide, and identification of tBuMgCl as a uniquely effective base in a challenging acyl sulfonamide formation.

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Unlocking the Asymmetric Hydrogenation of Tetrasubstituted Acyclic Enones

Faiges,

Biosca,

Pericàs

et al. 2023

Angewandte Chemie

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Asymmetric hydrogenation (AH) of tetrasubstituted olefins generating two stereocenters is still an open topic. There are only a few reports on the AH of tetrasubstituted olefins with conjugated functional groups, while this process can create useful intermediates for the subsequent elaboration of relevant end products. Most of the tetrasubstituted olefins successfully submitted to AH belong to a small number of functional classes; remarkably, the AH of tetrasubstituted acyclic enones still represents an unsolved challenge. Herein, we disclose a class of air‐stable Ir−P,N catalysts, prepared in three steps from commercially available amino alcohols, that can hydrogenate, in minutes, a wide range of electronically and sterically diverse acyclic tetrasubstituted enones (including exocyclic ones) with high yields and high enantioselectivities. The factors responsible for the excellent selectivities were elucidated by combining deuterogenation experiments and theoretical calculations. The calculations indicated that the reduction follows an IrI/IrIII mechanism, in which enantioselectivity is controlled in the first migratory insertion of the hydride to the most electrophilic olefinic Cβ and the formation of the hydrogenated product via reductive elimination takes place prior to the coordination of dihydrogen and the subsequent oxidative addition. The potential of the new catalytic systems is demonstrated by the derivatization of hydrogenation products.

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Development of a Telescoped Alkylation/Reduction Reaction Sequence and an Asymmetric Hydrogenation to Enable the Kilogram Synthesis of ABBV-3748

Cited by 5 publications

References 20 publications

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Enabling Asymmetric Synthesis of ABBV-3748, a Corrector Compound for the Treatment of Cystic Fibrosis

Unlocking the Asymmetric Hydrogenation of Tetrasubstituted Acyclic Enones

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