Henry

The first quarter century: The Buchwald–Hartwig amination enables the formation of C(sp²)−N bonds through the Pd‐catalyzed coupling of (hetero)aryl halides and pseudohalides with amines. This Minireview discusses the development of this methodology over the past 25 years, including highlights of some of the most recent applications.

Abstract

The Pd‐catalyzed coupling of aryl (pseudo)halides and amines is one of the most powerful approaches for the formation of C(sp²)−N bonds. The pioneering reports from Migita and subsequently Buchwald and Hartwig on the coupling of aminostannanes and aryl bromides rapidly evolved into general and practical tin‐free protocols with broad substrate scope, which led to the establishment of what is now known as the Buchwald–Hartwig amination. This Minireview summarizes the evolution of this cross‐coupling reaction over the course of the past 25 years and illustrates some of the most recent applications of this well‐established methodology.

Site-selective functionalizations of C–H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures1-4. Towards this goal, developing strategies to activate C–H bonds that are distal from a functional group is essential4-6. In this context, distinguishing remote C–H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C–H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukemia agent, and hydrocinnamic acid substrates.

Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development.

 

 

Here’s a caution from a new paper out of Manchester. The group had been synthesizing inhibitors of PARG (poly-ADP ribose glycohydrolase), an enzyme involved in DNA repair. The general chemotype is shown at right, but there are a number of variations. That fluorine is a new addition, though. The corresponding cyclopropylmethyl series came from their earlier paper, but they found that the series wasn’t particularly stable to metabolic oxidation. The major metabolites proved to be the primary sulfonamides in each case, suggesting that oxidation of the cyclopropylmethyl itself (which would be most likely at the methyl carbon) was the problem. Indeed, fluorination as shown increased the microsomal stability substantially (difluorination decreased the affinity for the PARG target itself, and deuteration, interestingly, had no real effect).

So far, so good. But trouble hit when the compounds were dosed in mice – there were obvious signs of toxicity, and deaths at the higher doses. This had never been seen with the earlier compounds, and dosing a fluoromethyl analog that had significantly reduced PARG potency showed the same effects. The trouble was noted at around the five-hour point, and only after oral dosing. Necropsy showed obvious signs of liver damage, which fits with that observation as well.

That all adds up to off-target tox brought on by metabolic activation of the fluoromethylcyclopropyl group. What the active species might be is not clear yet, nor is the specific liver target. But these observations alone are enough to flag that modification as a serious potential problem, which is the whole reason this new paper was published. Monofluoroalkyls can be a little odd – terminal monofluoroalkanes get cleaved down to fluoroacetic acid, for example, which is toxicological bad news. And fluorobenzyls (monofluoromethyl aryls) are reactive as electrophiles, despite the fluorocarbon reputation for stability. But this appears to be something different from either of those cases.

It’s true that this may vary according to the rest of the molecule, but just seeing it show up this strongly in one series is cause for concern. And since cyclopropyl groups and fluorinated methyls are both pretty common motifs in medicinal chemistry, it’s important to realize that the combination could be bad news. A quick Reaxys search of the fluoromethylcyclopropylsulfonamide side chain gave 183 hits, but those are all from two patents filed by the Manchester group themselves.  But if you search for the corresponding amide, you also pick up a couple of compounds from Gilead as IRAK-4 inhibitors. The amine is a perfectly reasonable-looking building block, and it would be a good thing if it did not spread through the med-chem literature without people knowing that there may be a red flag attached to it.

Catalytic deracemization of chiral allenes by sensitized excitation with visible light

Catalytic deracemization of chiral allenes by sensitized excitation with visible light, Published online: 12 December 2018; doi:10.1038/s41586-018-0755-1

Photochemical deracemization through irradiation with visible light in the presence of a chiral sensitizer enables the direct formation of single enantiomers from a racemic mixture of the same compound.

The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform using a chemical programming language which formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, Nytol, rufinamide, and sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.

A protein functionalization platform based on selective reactions at methionine residues

A protein functionalization platform based on selective reactions at methionine residues, Published online: 15 October 2018; doi:10.1038/s41586-018-0608-y

This methionine-selective functionalization strategy uses hypervalent iodine reagents to introduce new groups via the formation of a sulfonium intermediate, which can then undergo further visible-light-mediated reactions to form a diverse range of protein conjugates.

Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation

Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation, Published online: 26 September 2018; doi:10.1038/s41586-018-0537-9

Complex tertiary alkylamines are prepared in one step from readily available amines, carbonyls and alkenes, via the visible-light-mediated reduction of in-situ-generated iminium ions to form alkyl-substituted α-amino radicals.

Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron–induced variants of this reaction class have proven particularly useful in the formation of C(sp²)–C(sp³) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method’s tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.

Machine learning methods are becoming integral to scientific inquiry in numerous disciplines. Here we demonstrate that machine learning can be used to predict the performance of a synthetic reaction in multidimensional chemical space using data obtained via high-throughput experimentation. We created scripts to compute and extract atomic, molecular, and vibrational descriptors for the components of a palladium-catalyzed Buchwald-Hartwig cross-coupling of aryl halides with 4-methylaniline in the presence of various potentially inhibitory additives. Using these descriptors as inputs and reaction yield as output, we show that a random forest algorithm provides significantly improved predictive performance over linear regression analysis. The random forest model was also successfully applied to sparse training sets and out-of-sample prediction, suggesting its value in facilitating adoption of synthetic methodology.

Abstract