Diastereoselective Palladium-Catalyzed α-Arylation of 4-Substituted Cyclohexyl Esters

Bercot, Eric A.; Caille, Seb; Bostick, Tracy; Ranganathan, Krishnakumar; Jensen, Randy M.; Faul, Margaret M.

doi:10.1021/ol8021758

Cited by 32 publications

(12 citation statements)

References 38 publications

(14 reference statements)

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“…Researchers at Amgen reported a diastereoselective aarylation of cyclic ester derivatives, where the use of palladium(I) dimer 33 resulted in a good yield and diastereomeric excess of the desired product. [125] Interestingly, the in situ catalyst system [Pd 2 (dba) 3 ]/PtBu 3 gave products in significantly inferior yields to those obtained with the preformed catalyst (Scheme 51).…”

Section: A-arylation Of Estersmentioning

confidence: 99%

Metal‐Catalyzed α‐Arylation of Carbonyl and Related Molecules: Novel Trends in CC Bond Formation by CH Bond Functionalization

2010

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Alpha-arylated carbonyl compounds are commonly occurring motifs in biologically interesting molecules and are therefore of high interest to the pharmaceutical industry. Conventional procedures for their synthesis often result in complications in scale-up, such as the use of stoichiometric amounts of toxic reagents and harsh reaction conditions. Over the last decade, significant efforts have been directed towards the development of metal-catalyzed alpha-arylations of carbonyl compounds as an alternative synthetic approach that operates under milder conditions. This Review summarizes the developments in this area to date, with a focus on how the substrate scope has been expanded through selection of the most appropriate synthetic method, such as the careful choice of ligands, precatalysts, bases, and reaction conditions.

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Section: A-arylation Of Estersmentioning

confidence: 99%

Metal‐Catalyzed α‐Arylation of Carbonyl and Related Molecules: Novel Trends in CC Bond Formation by CH Bond Functionalization

2010

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“…So berichteten Forscher bei Amgen über eine diastereoselektive α‐Arylierung cyclischer Esterderivate, wobei das Palladium(I)‐Dimer 33 als Katalysator die Produkte in guten Ausbeuten und Diastereomerenüberschüssen ergab 125. Dabei lieferte das in situ aus [Pd 2 (dba) 3 ] und P t Bu 3 generierte Katalysatorsystem die Produkte in signifikant geringeren Ausbeuten als der vorab gebildete Katalysator (Schema ).…”

Section: Asymmetrische α‐Arylierungenunclassified

Metallkatalysierte α‐Arylierungen von Carbonylen und verwandten Molekülen: aktuelle Trends bei der C‐C‐Kupplung über C‐H‐Funktionalisierung

2010

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In α‐Stellung arylierte Carbonyleinheiten sind in biologisch interessanten Molekülen häufig vertreten und daher von großem Interesse für die pharmazeutische Industrie. Die herkömmlichen Syntheseverfahren führen bei der Aufskalierung häufig zu Problemen, z. B. wegen der Verwendung stöchiometrischer Mengen an toxischen Reagentien und drastischer Reaktionsbedingungen. Im letzten Jahrzehnt wurden signifikante Fortschritte bei der Entwicklung alternativer Synthesewege unter milderen Bedingungen für die metallkatalysierte α‐Arylierung von Carbonylverbindungen erzielt. In diesem Aufsatz wird der aktuelle Stand dieses Gebietes zusammengefasst; dabei wird aufgezeigt, wie es gelang, die Substratbreite mithilfe geeigneter Herstellungsverfahren, z. B. durch Wahl der Liganden, Präkatalysatoren, Basen und Reaktionsbedingungen, zu erweitern.

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“…Methyl tetrahydro-2 H -pyran-4-carboxylate 60 was reacted according to the method of Bercot, E. A. et al to afford the title compound 61 (1.6 g, 45%).…”

Section: Methodsmentioning

confidence: 99%

Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle

Mackman

Steadman²,

Dean³

et al. 2018

J. Med. Chem.

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Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( K = 5 nM), potent anti-HCV 2a activity (EC = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.

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Diastereoselective Palladium-Catalyzed α-Arylation of 4-Substituted Cyclohexyl Esters

Abstract: A diastereoselective palladium-catalyzed arylation of 4-substituted cyclohexyl esters has been developed. The reaction proceeds at room temperature in the presence of [(t-Bu3P)PdBr]2 providing products in up to 37:1 dr.

Cited by 32 publications

References 38 publications

Metal‐Catalyzed α‐Arylation of Carbonyl and Related Molecules: Novel Trends in CC Bond Formation by CH Bond Functionalization

Metal‐Catalyzed α‐Arylation of Carbonyl and Related Molecules: Novel Trends in CC Bond Formation by CH Bond Functionalization

Metallkatalysierte α‐Arylierungen von Carbonylen und verwandten Molekülen: aktuelle Trends bei der C‐C‐Kupplung über C‐H‐Funktionalisierung

Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle

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