Regioselective Late-Stage Alkylation of Complex Molecules

Chemistry has always had as a target the conversion of molecules into valuable materials. Nevertheless, the aim of past synthesis has primarily focused on achieving a given transformation, regardless of the environmental impact of the synthetic route. Given the current global situation, the demand for sustainable alternatives has substantially increased. Our group focuses on developing selective chemical transformations that benefit from mild conditions, improved atom economy, and that can make use of renewable feedstocks as starting materials. This account summarizes our work over the past two decades specifically regarding the selective removal, conversion, and addition of functional groups that can, later on, be applied at a late stage for the modification of complex molecules.

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Organocatalytic Atom-Transfer C(sp3)–H Oxidation

Synlett ◽

10.1055/s-0037-1610432 ◽

2018 ◽

Vol 29 (18) ◽

pp. 2331-2336 ◽

Cited By ~ 3

Author(s):

Michael Hilinski ◽

Shea Johnson ◽

Logan Combee

Keyword(s):

Transition Metal ◽

Late Stage ◽

Transition Metal Catalysis ◽

Great Promise ◽

Atom Transfer ◽

Complex Molecules ◽

Metal Catalysis ◽

Iminium Salt ◽

Site Selective

Predictably site-selective catalytic methods for intermolecular C(sp3)–H hydroxylation and amination hold great promise for the synthesis and late-stage modification of complex molecules. Transition-metal catalysis has been the most common approach for early investigations of this type of reaction. In comparison, there are far fewer reports of organocatalytic methods for direct oxygen or nitrogen insertion into C–H bonds. Herein, we provide an overview of early efforts in this area, with particular emphasis on our own recent development of an iminium salt that catalyzes both oxygen and nitrogen insertion.1 Introduction2 Background: C–H Oxidation Capabilities of Heterocyclic Oxidants3 Oxaziridine-Mediated Catalytic Hydroxylation4 Dioxirane-Mediated Catalytic Hydroxylation5 Iminium Salt Catalysis of Hydroxylation and Amination6 Conclusion and Outlook

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The Enones as New Alkenyl Reagents via Ligand Promoted C–C Bonds Activation

10.26434/chemrxiv.14167361.v1 ◽

2021 ◽

Author(s):

Hanyuan Li ◽

Mei-Ling Wang ◽

Yue-Wen Liu ◽

Ling-Jun Li ◽

Hui Xu ◽

...

Keyword(s):

Natural Products ◽

Late Stage ◽

Functional Group ◽

Bond Activation ◽

Potential Utility ◽

One Pot ◽

Complex Molecules ◽

The Past

Complementary to C–H bond activation, C–C bond activation has emerged over the past few years as an increasingly powerful tool to access and modify complex molecules. Ketones, owing to their versatility and availability, provide a significant platform for C–C bond activating reactions. Herein, we reported a β-carbon elimination strategy for alkene(sp2)–C(O) bonds to realize the olefination of unstrained enones via a vinyl palladium species, which delivers a series of conjugated polyene compounds. The protocol features broad substrate scope, excellent functional group tolerance and can be extended to dba (dibenzylideneacetone) substrates for olefination, alkynylation, arylation and amination, which demonstrates the generality of the approach and affords two valuable products in one pot. Furthermore, the late-stage functionalization of natural products (β-ionone and acetyl cedrene) and synthesis of natural products (piperine, lignarenone, novenone) highlight the potential utility of the reaction.

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The Enones as New Alkenyl Reagents via Ligand Promoted C–C Bonds Activation

10.26434/chemrxiv.14167361 ◽

2021 ◽

Author(s):

Hanyuan Li ◽

Mei-Ling Wang ◽

Yue-Wen Liu ◽

Ling-Jun Li ◽

Hui Xu ◽

...

Keyword(s):

Natural Products ◽

Late Stage ◽

Functional Group ◽

Bond Activation ◽

Potential Utility ◽

One Pot ◽

Complex Molecules ◽

The Past

Complementary to C–H bond activation, C–C bond activation has emerged over the past few years as an increasingly powerful tool to access and modify complex molecules. Ketones, owing to their versatility and availability, provide a significant platform for C–C bond activating reactions. Herein, we reported a β-carbon elimination strategy for alkene(sp2)–C(O) bonds to realize the olefination of unstrained enones via a vinyl palladium species, which delivers a series of conjugated polyene compounds. The protocol features broad substrate scope, excellent functional group tolerance and can be extended to dba (dibenzylideneacetone) substrates for olefination, alkynylation, arylation and amination, which demonstrates the generality of the approach and affords two valuable products in one pot. Furthermore, the late-stage functionalization of natural products (β-ionone and acetyl cedrene) and synthesis of natural products (piperine, lignarenone, novenone) highlight the potential utility of the reaction.

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Exploring Electrochemical C(sp3)–H Oxidation for the Late-Stage Methylation of Complex Molecules

Journal of the American Chemical Society ◽

10.1021/jacs.1c09412 ◽

2022 ◽

Author(s):

Luiz F. T. Novaes ◽

Justin S. K. Ho ◽

Kaining Mao ◽

Kaida Liu ◽

Mayank Tanwar ◽

...

Keyword(s):

Late Stage ◽

Complex Molecules

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Closing the gap between 19F and 18F chemistry

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-021-00143-y ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Javier Ajenjo ◽

Gianluca Destro ◽

Bart Cornelissen ◽

Véronique Gouverneur

Keyword(s):

Late Stage ◽

Transition Metal Catalysis ◽

Direct Impact ◽

Complex Molecules ◽

Metal Catalysis ◽

Positron Emission ◽

Invaluable Tool ◽

Fast Pace ◽

Closing The Gap ◽

Pet Radiopharmaceuticals

AbstractPositron emission tomography (PET) has become an invaluable tool for drug discovery and diagnosis. The positron-emitting radionuclide fluorine-18 is frequently used in PET radiopharmaceuticals due to its advantageous characteristics; hence, methods streamlining access to 18F-labelled radiotracers can make a direct impact in medicine. For many years, access to 18F-labelled radiotracers was limited by the paucity of methodologies available, and the poor diversity of precursors amenable to 18F-incorporation. During the last two decades, 18F-radiochemistry has progressed at a fast pace with the appearance of numerous methodologies for late-stage 18F-incorporation onto complex molecules from a range of readily available precursors including those that do not require pre-functionalisation. Key to these advances is the inclusion of new activation modes to facilitate 18F-incorporation. Specifically, new advances in late-stage 19F-fluorination under transition metal catalysis, photoredox catalysis, and organocatalysis combined with the availability of novel 18F-labelled fluorination reagents have enabled the invention of novel processes for 18F-incorporation onto complex (bio)molecules. This review describes these major breakthroughs with a focus on methodologies for C–18F bond formation. This reinvigorated interest in 18F-radiochemistry that we have witnessed in recent years has made a direct impact on 19F-chemistry with many laboratories refocusing their efforts on the development of methods using nucleophilic fluoride instead of fluorination reagents derived from molecular fluorine gas.

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Copper-catalyzed carbo-difluoromethylation of alkenes via radical relay

Nature Communications ◽

10.1038/s41467-021-23590-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Aijie Cai ◽

Wenhao Yan ◽

Xiaojun Zeng ◽

Samson B. Zacate ◽

Tzu-Hsuan Chao ◽

...

Keyword(s):

Late Stage ◽

Density Functional ◽

Organic Molecules ◽

Functional Group ◽

Density Functional Theory Calculations ◽

Bioactive Molecules ◽

Mechanistic Studies ◽

Ligand Effect ◽

Functional Theory ◽

Complex Molecules

AbstractOrganic molecules that contain alkyl-difluoromethyl moieties have received increased attention in medicinal chemistry, but their synthesis in a modular and late-stage fashion remains challenging. We report herein an efficient copper-catalyzed radical relay approach for the carbo-difluoromethylation of alkenes. This approach simultaneously introduces CF2H groups along with complex alkyl or aryl groups into alkenes with regioselectivity opposite to traditional CF2H radical addition. We demonstrate a broad substrate scope and a wide functional group compatibility. This scalable protocol is applied to the late-stage functionalization of complex molecules and the synthesis of CF2H analogues of bioactive molecules. Mechanistic studies and density functional theory calculations suggest a unique ligand effect on the reactivity of the Cu-CF2H species.

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