scholarly journals Late-stage C–H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Jing He ◽  
Lawrence G. Hamann ◽  
Huw M. L. Davies ◽  
Rohan E. J. Beckwith
Keyword(s):  
Late Stage ◽  
Drug Molecules ◽  
Rhodium Carbenoid

scholarly journals General α-Amino 1,3,4-Oxadiazole Synthesis via Late-Stage Reductive Functionalization of Tertiary Amides and Lactams

2021 ◽  
Author(s):  
Daniel Matheau-Raven ◽  
Darren J. Dixon
Keyword(s):  
Carboxylic Acid ◽  
Late Stage ◽  
Coupling Reaction ◽  
Reductive Activation ◽  
Mild Conditions ◽  
Drug Molecules ◽  
Drug Conjugates ◽  
Iminium Ion ◽  
Tertiary Amides ◽  
Coupling Partner

An iridium-catalyzed reductive three-component coupling reaction for the synthesis of medicinally relevant α-amino 1,3,4-oxadiazoles from abundant tertiary amides or lactams, carboxylic acids, and (N-isocyanimino) triphenylphosphorane, is described. Proceeding under mild conditions using (<1 mol%) Vaska’s complex (IrCl(CO)(PPh<sub>3</sub>)<sub>2</sub>) and tetramethyldisiloxane to access the key reactive iminium ion intermediates, a broad range of structurally complex α-amino 1,3,4-oxadiazole architectures were efficiently accessed from diverse carboxylic acid feedstock coupling partners. Extension to α-amino heterodiazole synthesis was readily achieved by exchanging the carboxylic acid coupling partner for C-, S-, or N-centered Brønsted acids, and provided rapid and modular access to these desirable, yet difficult-to-access, heterocycles. Furthermore, the high chemoselectivity of the catalytic reductive activation step allowed the late-stage functionalization of 10 drug molecules, including the synthesis of novel heterodiazole-fused drug-drug conjugates.<br>

scholarly journals Nickel-Catalyzed Three-Component Olefin Reductive Dicarbofunctionalization to Access Highly Functionalized Alkylborates

2020 ◽  
Author(s):  
Xiao-Xu Wang ◽  
Xi Lu ◽  
Shi-Jiang He ◽  
Yao Fu
Keyword(s):  
Natural Products ◽  
Late Stage ◽  
Functional Group ◽  
Coupling Efficiency ◽  
Convergent Synthesis ◽  
Drug Molecules ◽  
Aryl Iodides ◽  
Alkyl Bromides ◽  
Vinyl Boronates ◽  
Convenient Access

We report a three-component olefin reductive dicarbofunctionalization for constructing densely functionalized alkylborates, specifically, nickel-catalyzed reductive dialkylation and alkylarylation of vinyl boronates with a variety of alkyl bromides and aryl iodides. This reaction exhibits good coupling efficiency and excellent functional group compatibility, providing convenient access to the late-stage modification of complex natural products and drug molecules. Combined with versatile alkylborate transformations, this reaction could also find applications in the modular and convergent synthesis of complex, densely functionalized compounds.

Electrochemical bromination of late stage intermediates and drug molecules

2017 ◽  
Vol 58 (31) ◽  
pp. 3014-3018 ◽  
Author(s):  
Zheng Tan ◽  
Yong Liu ◽  
Roy Helmy ◽  
Nelo R. Rivera ◽  
David Hesk ◽  
...  
Keyword(s):  
Late Stage ◽  
Drug Molecules

scholarly journals Bio-Inspired Primary Amine α-C–H Functionalization

2018 ◽  
Author(s):  
Dhananjayan Vasu ◽  
Ángel L. Fuentes de Arriba ◽  
Jamie A. Leitch ◽  
Antoine de Gombert ◽  
Darren J. Dixon
Keyword(s):  
Drug Discovery ◽  
Late Stage ◽  
Primary Amine ◽  
Amine Oxidase ◽  
Primary Amines ◽  
Reverse Polarity ◽  
Copper Amine Oxidase ◽  
Drug Molecules ◽  
Organolithium Reagents

<div>The selective manipulation of complex amine architectures has received great attention in recent years with widespread applications including inter alia drug discovery. Inspired by an enzymatic copper amine oxidase process, a synthetic quinone co-factor mediated general platform for the construction of α-fully substituted primary amines from abundant α-branched primary amine starting materials is described. This procedure pivots on the efficient generation of reactive ketimine intermediates in situ which are primed to react with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN. Extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. Subsequent oxidative hydrolysis releases the unprotected α-fully substituted primary amine product. This efficient, broadly applicable and scaleable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules.</div>

scholarly journals Nickel-Catalyzed Three-Component Olefin Reductive Dicarbofunctionalization to Access Highly Functionalized Alkylborates

2020 ◽  
Author(s):  
Xiao-Xu Wang ◽  
Xi Lu ◽  
Shi-Jiang He ◽  
Yao Fu
Keyword(s):  
Natural Products ◽  
Late Stage ◽  
Functional Group ◽  
Coupling Efficiency ◽  
Convergent Synthesis ◽  
Drug Molecules ◽  
Aryl Iodides ◽  
Alkyl Bromides ◽  
Vinyl Boronates ◽  
Convenient Access

We report a three-component olefin reductive dicarbofunctionalization for constructing densely functionalized alkylborates, specifically, nickel-catalyzed reductive dialkylation and alkylarylation of vinyl boronates with a variety of alkyl bromides and aryl iodides. This reaction exhibits good coupling efficiency and excellent functional group compatibility, providing convenient access to the late-stage modification of complex natural products and drug molecules. Combined with versatile alkylborate transformations, this reaction could also find applications in the modular and convergent synthesis of complex, densely functionalized compounds.

scholarly journals Primary α-Tertiary Amine Synthesis via α-C–H Functionalization

2018 ◽  
Author(s):  
Dhananjayan Vasu ◽  
Ángel L. Fuentes de Arriba ◽  
Jamie Leitch ◽  
Antoine de Gombert ◽  
Darren J. Dixon
Keyword(s):  
Tertiary Amine ◽  
Late Stage ◽  
Tertiary Amines ◽  
Reverse Polarity ◽  
Subsequent Reaction ◽  
Quaternary Centers ◽  
Drug Molecules ◽  
Organolithium Reagents ◽  
In Situ Generation

<i>A quinone-mediated general platform for the construction of primary α-tertiary amines from abundant primary α-branched amine starting materials is described. This procedure pivots on the efficient in situ generation of reactive ketimine intermediates and subsequent reaction with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN, creating quaternary centers. Furthermore, extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. This efficient, broadly applicable and scalable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules. </i><br>

scholarly journals Palladium-Catalyzed Decarbonylative Catellani Reaction

2021 ◽  
Author(s):  
Huixiong Dai ◽  
Ming-Liang Han ◽  
Jun-Jie Chen ◽  
Hui Xu ◽  
Wei Huang ◽  
...  
Keyword(s):  
Transition Metal ◽  
Late Stage ◽  
Aryl Halides ◽  
Potential Utility ◽  
Aromatic Acids ◽  
Alkyl Aryl ◽  
Drug Molecules ◽  
Palladium Catalyzed ◽  
Practical Tool ◽  
Metal Catalyzed

<p><b>The transition metal-catalyzed Catellani reaction of aryl halides has drawn significant attentions as an efficient and practical tool for the synthesis of substituted arenes. We describe herein the palladium-catalyzed, norbornene (NBE)-mediated synthesis of polysubstituted arenes from aromatic acids via decarbonylative Catellani reaction. A variety of alkenyl, alkyl, aryl and sulfur moieties could be conveniently introduced into the<i> ipso</i>-positions of aromatic thioesters. By merging carboxyl-directed C−H functionalization and the classical Catellani reactions, our protocol allowed the construction of 1,2,3-trisubstituted and 1,2,3,4-tetrasubstituted arenes from simple aromatic acids. Furthermore, the late-stage functionalization of a series of drug molecules highlights the potential utility of the reaction.</b></p>

Bio-Inspired Primary Amine α-C–H Functionalization

2018 ◽  
Author(s):  
Dhananjayan Vasu ◽  
Ángel L. Fuentes de Arriba ◽  
Jamie A. Leitch ◽  
Darren J. Dixon
Keyword(s):  
Drug Discovery ◽  
Late Stage ◽  
Primary Amine ◽  
Amine Oxidase ◽  
Primary Amines ◽  
Reverse Polarity ◽  
Copper Amine Oxidase ◽  
Drug Molecules ◽  
Organolithium Reagents

<div>The selective manipulation of complex amine architectures has received great attention in recent years with widespread applications including inter alia drug discovery. Inspired by an enzymatic copper amine oxidase process, a synthetic quinone co-factor mediated general platform for the construction of α-fully substituted primary amines from abundant α-branched primary amine starting materials is described. This procedure pivots on the efficient generation of reactive ketimine intermediates in situ which are primed to react with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN. Extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. Subsequent oxidative hydrolysis releases the unprotected α-fully substituted primary amine product. This efficient, broadly applicable and scaleable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules.</div>

scholarly journals General α-Amino 1,3,4-Oxadiazole Synthesis via Late-Stage Reductive Functionalization of Tertiary Amides and Lactams

2021 ◽  
Author(s):  
Daniel Matheau-Raven ◽  
Darren J. Dixon
Keyword(s):  
Carboxylic Acid ◽  
Late Stage ◽  
Coupling Reaction ◽  
Reductive Activation ◽  
Mild Conditions ◽  
Drug Molecules ◽  
Drug Conjugates ◽  
Iminium Ion ◽  
Tertiary Amides ◽  
Coupling Partner

An iridium-catalyzed reductive three-component coupling reaction for the synthesis of medicinally relevant α-amino 1,3,4-oxadiazoles from abundant tertiary amides or lactams, carboxylic acids, and (N-isocyanimino) triphenylphosphorane, is described. Proceeding under mild conditions using (<1 mol%) Vaska’s complex (IrCl(CO)(PPh<sub>3</sub>)<sub>2</sub>) and tetramethyldisiloxane to access the key reactive iminium ion intermediates, a broad range of structurally complex α-amino 1,3,4-oxadiazole architectures were efficiently accessed from diverse carboxylic acid feedstock coupling partners. Extension to α-amino heterodiazole synthesis was readily achieved by exchanging the carboxylic acid coupling partner for C-, S-, or N-centered Brønsted acids, and provided rapid and modular access to these desirable, yet difficult-to-access, heterocycles. Furthermore, the high chemoselectivity of the catalytic reductive activation step allowed the late-stage functionalization of 10 drug molecules, including the synthesis of novel heterodiazole-fused drug-drug conjugates.<br>

scholarly journals Primary α-Tertiary Amine Synthesis via α-C–H Functionalization

2018 ◽  
Author(s):  
Dhananjayan Vasu ◽  
Ángel L. Fuentes de Arriba ◽  
Jamie Leitch ◽  
Antoine de Gombert ◽  
Darren J. Dixon
Keyword(s):  
Tertiary Amine ◽  
Late Stage ◽  
Tertiary Amines ◽  
Reverse Polarity ◽  
Subsequent Reaction ◽  
Quaternary Centers ◽  
Drug Molecules ◽  
Organolithium Reagents ◽  
In Situ Generation

<i>A quinone-mediated general platform for the construction of primary α-tertiary amines from abundant primary α-branched amine starting materials is described. This procedure pivots on the efficient in situ generation of reactive ketimine intermediates and subsequent reaction with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN, creating quaternary centers. Furthermore, extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. This efficient, broadly applicable and scalable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules. </i><br>

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