Stereoselective Nickel(II)-Catalyzed Addition of Aryl Grignards to Diphenylacetylene in the Synthesis of Zuclomiphene

Karadeolian, Avedis; Emmett, Michael R.; Souza, Fabio E. S.; Chung, Andrew D.; Blazecka, Peter G.; Sueur, Richard Le; Patel, Dineshkumar; Zhao, Yajun; Rey, Allan W.; Green, Stuart

doi:10.1021/acs.oprd.1c00366

Cited by 6 publications

(4 citation statements)

References 21 publications

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“…Karadeolian and co-workers at Apotex Pharmachem reported a stereoselective synthesis of zuclomiphene using a Ni-catalyzed addition of aryl Grignards to 1,2-diphenylacetylene (Scheme ). All previously known methods for the synthesis of this drug require multiple crystallizations of this desired Z isomer from clomiphene citrate (a mixture of E and Z isomers that typically contains 40% Z isomer). Based on literature precedent, − the authors proposed that they could synthesize zuclomiphene through the Z -selective formation of vinyl Grignard intermediates by Ni catalysis, followed by quenching with a chlorinating reagent.…”

Section: Recent Reports On Ni-catalyzed Reactionsmentioning

confidence: 99%

Recent Advances in Nonprecious Metal Catalysis

Haibach

Shekhar

Ahmed

et al. 2023

Org. Process Res. Dev.

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Nonprecious-metal-catalyzed alternatives to powerful precious metal transformations are of increasing interest in academia and the pharmaceutical industry due to the lower cost, better sustainability, and lower toxicity. With the continual growth in the broad field of nonprecious metal catalysis (NPMC), we have chosen to highlight selected articles published from March to June 2022 which are intended to highlight examples of NPMC that we feel may be especially relevant to pharmaceutical development. We aim to inspire academic and industrial innovation in NPMC through the discussion herein.

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Section: Recent Reports On Ni-catalyzed Reactionsmentioning

confidence: 99%

Recent Advances in Nonprecious Metal Catalysis

Haibach

Shekhar

Ahmed

et al. 2023

Org. Process Res. Dev.

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“…This is an advantage for large-scale syntheses, including alkoxide S N Ar reactions used to prepare the pharmaceuticals clomiphene and duloxetine (Scheme 2b). [20] Many nucleophiles and arenes are suitable for defluorinative S N Ar reactions; weak nucleophiles require electron-deficient fluoroarenes, while strong nucleophiles can substitute electron-rich arenes. This trend is exemplified by a cyanation reaction reported by Jenkins and coworkers [21] and an α-arylation of alkyl nitriles reported by Caron and co-workers at Pfizer [22] in Scheme 2c.…”

Section: Defluorinative Substitution Reactionsmentioning

confidence: 99%

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Hooker,

Bandar

2023

Angew Chem Int Ed

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Much progress has been made in the development of methods to both create compounds that contain C−F bonds and to functionalize C−F bonds. As such, C−F bonds are becoming common and versatile synthetic functional handles. This review summarizes the advantages of defluorinative functionalization reactions for small molecule synthesis. The coverage is organized by the type of carbon framework the fluorine is attached to for mono‐ and polyfluorinated motifs. The main challenges, opportunities and advances of defluorinative functionalization are discussed for each class of organofluorine. Most of the text focuses on case studies that illustrate how defluorofunctionalization can improve routes to synthetic targets or how the properties of C−F bonds enable unique mechanisms and reactions. The broader goal is to showcase the opportunities for incorporating and exploiting C−F bonds in the design of synthetic routes, improvement of specific reactions and advent of new methods.

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“…The Suzuki-Miyaura cross-coupling of borylchlorinated product 2ag directly yielded zuclomifene (5), which is the Z isomer of the drug molecule clomifene, which is sold as a mixture of stereoisomers and usually requires multistep synthesis 54 (Fig. 3a).…”

Section: Transformations Of the Reaction Productsmentioning

confidence: 99%

Reductive stereo- and regiocontrolled boryllithiation and borylsodiation of arylacetylenes using flow microreactors

Jiang,

Kurogi,

Yorimitsu

2023

Nat. Synth

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Given their prevalence within valuable organic compounds, constructing multisubstituted alkenes while stereo- and regiochemically controlling the substituents on the alkene stands as a pivotal objective in organic synthesis. Now, the stereo- and regioselective syn-boryllithiation and syn-borylsodiation of arylacetylenes have been achieved by reductive borylmetallation using flow microreactors. This method involves the fast mixing of a solution of an alkyne and stoichiometric alkoxypinacolborane with an alkali metal arenide solution, which efficiently generates highly reactive β-borylalkenyllithium and β-borylalkenylsodium species by suppressing the undesired diboration that inevitably occurs in a batch reactor. Unlike conventional three-component borofunctionalization, the intermediates can be generated in the absence of electrophiles, which has enabled diverse electrophiles to participate in various syn-borofunctionalizations such as borylsilylation, borylhalogenation, borylcarbonylation, borylsulfenylation and borylarylation. Trapping with aldehydes and ketones provides a series of oxaboroles of biological interest. Furthermore, unsymmetric diarylacetylenes undergo highly regioselective borylmetallation, which is applicable to the stereo- and regiocontrolled syntheses of multisubstituted oxaboroles and differently tetrasubstituted alkenes.

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Stereoselective Nickel(II)-Catalyzed Addition of Aryl Grignards to Diphenylacetylene in the Synthesis of Zuclomiphene

Cited by 6 publications

References 21 publications

Recent Advances in Nonprecious Metal Catalysis

Recent Advances in Nonprecious Metal Catalysis

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Reductive stereo- and regiocontrolled boryllithiation and borylsodiation of arylacetylenes using flow microreactors

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