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

He, Jing; Hamann, Lawrence G.; Davies, Huw M. L.; Beckwith, Rohan E. J.

doi:10.1038/ncomms6943

Cited by 124 publications

(61 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transition metal-catalyzed C–H bond functionalization offers a powerful approach for the late stage functionalization of bioactive molecules, 1-4 and recent progress in this field has led to thousands of new synthetic methods for selective C–H functionalization in a variety of molecular contexts 3-6,8,9 . However, methods for the C–H functionalization of saturated nitrogen heterocycles remain extremely limited 5,6 , and are dominated by functionalization of the highly activated C–H bonds α-to nitrogen 10,11,12,13,14 (Fig. 1B, i) or of C–H bonds on exocyclic alkyl groups 15,16 (Fig.…”

mentioning

confidence: 99%

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Topczewski

Cabrera

Saper

et al. 2016

Nature

301

157

View full text Add to dashboard Cite

The discovery of pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. Carbon-hydrogen bonds are present in almost all pharmaceutical agents. As such, the development of selective, rapid, and efficient methods for converting carbon-hydrogen bonds into new chemical entities has the potential to dramatically streamline pharmaceutical development1,2,3,4. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, including treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukemia (alvocidib), schizophrenia (risperidone, belaperidone), and nicotine addiction (cytisine and varenicline)5. However, existing methods for the C–H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited 6,7. Here we report a new approach to selectively manipulate the carbon–hydrogen bonds of alicyclic amines at sites remote to nitrogen. Our reaction leverages the boat conformation of the substrates to achieve the palladium-catalyzed amine-directed conversion of C–H bonds to C–C bonds on various alicyclic amine scaffolds. This approach is applied to the synthesis of novel derivatives of several bioactive molecules, including the top-selling smoking cessation drug varenicline (Chantix®). We anticipate that this method should prove broadly useful in medicinal chemistry.

show abstract

mentioning

confidence: 99%

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Topczewski

Cabrera

Saper

et al. 2016

Nature

301

157

View full text Add to dashboard Cite

show abstract

“…Over 200,000 such substances have been characterized to date. Of growing importance are methods for chemically modifying natural products through a reaction that produces a relatively small change in structure (e.g., C–H hydroxylation 1 , hetero-Diels-Alder cycloaddition 2 , O–H functionalization 3 , arene fluorination 4 , arene bromination 5 , C–H carbenoid insertion 6 , C–H azidation, 7 C–H amination 8 ). The primary motivation for pursuing such methodology has often been to probe the structure-activity profile of a natural substance having a preexisting, valuable biological property.…”

mentioning

confidence: 99%

Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products

2017

View full text Add to dashboard Cite

The studies reported here were motivated by the desire to probe the extent to which benzynes, one of the classical reactive intermediates in organic chemistry, would react in discriminating fashion with benzyne trapping reagents that contain multiple functional groups and, accordingly, possible modes and sites of reactivity. We deemed that natural products comprise a palette of potential multifunctional compounds with which to address this question. We show that benzynes produced by the hexadehydro-Diels-Alder (HDDA) reaction react with many secondary metabolites with a high preference for one among several potential pathways. Examples demonstrating such selectivity include reactions with: phenolics, through dearomatizing ortho-substitution; alkaloids, through Hofmann-type elimination; tropolone and furan, through cycloaddition; and alkaloids, through three-component fragmentation-coupling reactions. We also demonstrate that the cinchona alkaloids quinidine and quinine give rise to products, some in as few as three steps, that enable subsequent and rapid access to structurally diverse, polyheterocyclic compounds. The results show that benzynes are quite discriminating in their reactivity—a trait perhaps not broadly appreciated.

show abstract

“…(B) Application of these rhodium carbenoid reactions towards other natural products results in similar observed selectivitles. 285 …”

Section: Figurementioning

confidence: 99%

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

2017

View full text Add to dashboard Cite

The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogs of natural products by this approach is then described as a quintessential “late-stage functionalization” exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this review is on the recent studies of non-enzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C–H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C–C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

show abstract

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

Cited by 124 publications

References 52 publications

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

Contact Info

Product

Resources

About