Author Archives: paulm

Organotextile catalysis

Ji-Woong Lee, Thomas Mayer-Gall, Klaus Opwis, Choong Eui Song, Jochen Stefan Gutmann, and Benjamin List
Science
DOI: 10.1126/science.1242196

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I’ve written a research highlight for Nature Chemistry talking about Opwis’ and List’s recent paper on organotextile catalysis in Science. Take a look.

Catalytic cloth

Image credit: © 2013 American Association for the Advancement of Science

Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines

Sergey Pronin, Christopher Reiher, and Ryan Shenvi
Nature
DOI: 10.1038/nature12472

shenvi1

The bimolecular nucleophilic substitution (SN2) reaction is a well understood and widely used chemical transformation that allows a chemist to affect useful functional group interconversions or combine two molecules. A significant advantage of the SN2 reaction over the related (and often competitive) unimolecular nucleophilic substitution (SN1) reaction is that it provides predictable stereoinversion at the electrophilic carbon centre. SN2 processes do, however, suffer from a significant limitation: intolerance of tertiary electrophilic carbon atoms, where steric crowding inhibits the approach of the nucleophilic reacting partner. This drawback limits the stereochemical complexity of possible reaction substrates and the utility of nucleophilic substitution in the synthesis of challenging chiral molecules.

Now, a team of researchers from California led by Ryan Shenvi have developed a process that allows the stereochemical inversion of tertiary alcohols with nitrogen-based nucleophiles. The key reaction in their discover y involves Lewis-acid-catalyzed solvolysisof a tertiary alcohol derivative – trifluoroacetate or perfluoroalkanoate esters — in the presence of excess trimethylsilyl cyanide. Addition of the cyanide nucleophile to the carbocation of a postulated contact ion pair, generated by solvolysis, occurs with high enantioselectivity, giving tertiary isonitrile products in a remarkably simple transformation. The researchers compare this process to proposed biosynthetic pathways of nitrogen-based marine terpenoids, which are known to derive from the addition of inorganic cyanide to highly substituted carbon centres.

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As well as extending the scope of traditional SN2 processes, Lewis-acid-catalyzed solvolysis also provides complementary reactivity. Because the reaction is conceptually related to the SN1 reaction in the generation of a reactive carbocation in the contact ion pair, activated primary and secondary alcohols do not undergo solvolysis even over extended reaction times. The utility of the process was further demonstrated by converting the isonitrile products into various useful nitrogen-based compounds, such as amines, formamides and isothiocyanates.

The influence of steric crowding on this SN2-like reaction has not, however, been eliminated; branched tertiary alcohols react with lower stereoselectivity than minimally substituted analogues. Despite this, the reported transformation fills a gap in modern synthetic methodology and may lead to further developments in the synthesis of other stereo-defined tertiary-substituted compounds.

Organocatalytic C−H Bond Arylation of Aldehydes to Bis-heteroaryl Ketones

Qiao Yan Toh, Andrew McNally, Silvia Vera, Nico Erdmann and Matthew Gaunt
J. Am. Chem. Soc.
DOI: 10.1021/ja400051d

The synthesis of ketones bearing a diverse range of aryl and heteroaryl functionality is of great importance to the medicinal chemistry industry as they can be readily converted into structural motifs commonly found in medicinal agents.

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A novel approach to these scaffolds has been developed by Gaunt et al who exploit the inherent electrophilicity of diaryliodonium salts by using them to trap carbogenic nucleophiles to form carbon–aryl bonds. The driving force for this research is the lack of known methods for the preparation of bis-heteroaryl ketones. The authors set themselves the challenge of developing an organocatalytic method for the regioselective diaryl ketone formation which is tolerant of a broad range of hetreoaromatic nuclei derived from diaryliodonium salts and carbogenic nucleophiles. This was achieved by using a commercially available NHC-organocatalyst with DMAP as the base to form a nucleophilic enolate from the heteroaromatic aldehyde substrate. Subsequent trapping of this enolate by the heteroaryl iodonium salt gave the bis-heteroaryl ketone products in up to 91% isolated yield.

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The broad scope of this transformation was illustrated with a variety of aryl and heteroaryl aldehydes. More interestingly, however, Gaunt and co-workers have shown that the use of a non-symmetrical diaryliodonium salts is tolerated in excellent selectivity.
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Non-symmetrical diaryliodonium salts are more economical as they are prepared with only one equivalent of the transferring group. Out of a number of non-symmetrical diaryliodonium salts screened, a uracil-pyridine salt displayed the best selectivity with the desired bis-heteroaryl ketone isolated with no evidence of the undesired ketone identifiable in the crude 1H NMR.

Finally, to further illustrate the utility of this methodology, the Gaunt research team demonstrated that a bis-heteroaryl ketone could be readily converted into enantioenriched amines by an Ellman imine formation and subsequent reaction with methylmagnesium bromide to give an α-tertiary amine in high yield and enantiopurity after cleavage of the chiral auxiliary.

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Welcome to Stuart L, a new contributor to the cascade

We’re delighted to welcome a new contributor to the Chemistry Cascade – Stuart Leckie.

Stuart is a synthetic organic chemist whose main interest is in catalytic asymmetric transformations, although currently he has been side-tracked by a desire to save the planet and is working on the development of sustainable cross-coupling reactions.

He completed a Ph.D. looking at novel applications of NHCs and isothioureas as Lewis base organocatalysts and he is also interested in all things involving samarium diiodide, especially it’s application in total synthesis.

Blog Syn sheds light on IBX oxidation

Blog Syn – the site publishing crowdsourced verification of synthetic procedures – is only 3 investigations old but is already showing signs of maturing into a valuable resource for the synthetic community.

Their 3rd investigation into the reliability of IBX oxidations of arylmethanes detailed some disappointing results in attempts to repeat published procedures. To their credit, the (high profile) authors of the original work engaged the contributors in a discussion of the variables in the experimental procedures.

In a follow-up post to the discussion, the Blog Syn contributors propose that the active species in the oxidation is actually a hydrated version of the IBX oxidant and that the presence of water is critical in the reaction.

This is fascinating stuff. The site had come under some heavy criticism recently for questioning peer-reviewed results without subjecting itself to the same process. But here’s the real beauty of a community-based discussion – we can all learn something new, and maybe even improve our understanding of chemistry.

Blog Syn #003A – Secret Ingredient

Uncovering alkenes: complex products from all-carbon substrates

alkenerev1

Molecules containing simple alkene functionality are attractive substrates in synthesis. Carbon-carbon double bonds are relatively stable groups, lacking polarisation, they can be carried through synthetic processes involving acid, base, mildly oxidative and reductive conditions. But, the availability of the π-electrons for reaction embodies remarkable potential for constructing substituted contiguous stereocentres and the possibility of introducing complex functionality to an all-carbon system.

In recent years, functionalisation of unactivated alkenes has blossomed with developments in robust metal-catalysed processes and new oxidating agents. In the last few weeks several reports of new alkene functionalisations have been published that cover many aspects of this broad area, and show the diverse utility of alkenes in synthesis.

Hayashi and co-workers have published an elegant cyclising difunctionalisation of dienes.[1] The process is an iridium-catalysed C-H activation of cyclic aryl N-sulfonyl ketimines and gives spirocyclic aminoindane scaffolds with high diastereoselectivity.

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We’ve already discussed an asymmetric cyclising aminofluorination reaction carried out by a chiral hypervalent iodine fluoride oxidant.[2] The reaction is endo-selective and prepares fluoropiperidine-based systems. Extension of the reaction to a racemic intermolecular process with styrene substrates was also demonstrated.

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In a similar example of intermolecular alkene difunctionalisation, Zhang reports aminocyanation and diamination of (predominantly) styrene substrates.[3] The principle reagent for functionalisation is NFSI (N-fluorobenzenesulfonimide), which aminates the terminal end of the double bond. Subsequent reaction with TMSCN gives the aminonitrile product. Alternatively, an alkylnitrile may be used to give the Ritter product of the second addition.

alkenerev4

The authors suggest a copper(I)-catalysed radical mechanism, generating a carbon-centered radical intermediate after amination by •N(SO2Ph)2. This reaction gives some idea of the kind of complex functionality that can be introduced to all-carbon alkene substrates by oxidative processes.

Hydrofunctionalisation of alkenes doesn’t provide the same high degree of complexity as oxidative difunctionalisation processes, but reactions in this category do offer a great deal of diversity in synthetic options while still providing regio- and stereocontrol of sp3 carbon centres. A report from Qing and co-workers describes a general and high yielding hydrotrifluoromethylation of unactivated alkenes.[4] Trifluoromethyl groups are useful moieties in pharmaceutical development of lead compounds. The group apply the method to a wide scope of unactivated alkene substrates showing tolerance to many other functionalities.

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Hartwig’s group in Berkeley have developed an asymmetric hydroheteroarylation of bicycloalkenes.[5] The reaction is catalysed by an iridium DTBM-Segphos complex and tolerates various heteroaromatic coupling partners.

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Alkenes offer chemists widely available, stable and highly tolerant substrates for synthesis. Careful application of modern reactions allows the uncovering of diverse and complex functionality from a carbon-carbon double bond, and new developments provide ever more effective methods for the preparation of desirable adducts.

References:
1. DOI: 10.1021/ja311968d
2. DOI: 10.1002/anie.201208471
3. DOI: 10.1002/anie.201209142
4. DOI: 10.1002/anie.201208971
5. DOI: 10.1021/ja312360c

A paramagnetic/diamagnetic molecular switch

Fraser Stoddart’s group have reported a catenane molecule that can be oxidised to a stable paramagnetic radical state. The oxidation states of the molecule are easily configurable, so this structure has significant potential for use in data storage on the molecular level.

From the Chemistry World article:

The key to the stability of the new radical compound is the mechanical bond that links the two macrocycles, forcing the charged species to remain close. And that proximity means that the molecule never oxidises to a fully charged species but stops at the paramagnetic species •7+. That, says Barnes, is because the molecule is trying to minimise the charge in the centre where the two catenanes link. ‘The charged units have no choice but to interact with one another,’ explains Barnes, so it holds on to that remaining electron to reduce the charge repulsion.

But while the •7+ species is paramagnetic, all the other charged species are diamagnetic, as the electrons spins pair. Using cyclic voltammetry it is possible to quickly switch between the paramagnetic and diamagnetic states by adding and removing electrons. And it is this simple switching that could be the key to a potential application of the material: memory storage.

DOI: 10.1126/science.1228429

A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products

Robert W. Huigens III, Karen C. Morrison, Robert W. Hicklin, Timothy A. Flood Jr, Michelle F. Richter and Paul J. Hergenrother
Nature Chem.
DOI: 10.1038/nchem.1549

To synthetic chemists, natural products are generally viewed as end-points in synthetic projects (or occasionally as tools, such as ligands or catalysts). Rarely, are complex natural products considered as launching-off points in the synthesis of other interesting molecules. A recent report takes this rather unusual approach by applying the principles of diversity oriented synthesis (DOS) in preparing a series of molecules with drug-like molecular properties.

The authors take three widely available natural products and carry out numerous derivatisations and transformations to give 49 dissimilar molecular scaffolds, a process they dub ‘compexity-to-diversity’ (CtD). A few examples are shown below.

hergenrother1

These molecules are presented as exemplifying a new approach to preparing drug-like molecules. They are analysed in characteristics typical of drug molecules and compared with a common screening library of 150,000 molecules.

In terms of diversity, these molecules display considerable structural dissimilarity (established by calculating Tanimoto coefficients for each pair of molecules), even within derivatives of the same natural product.

The CtD molecules display superior lipophilicity (average ClogP = 2.90) compared with the screening collection (average ClogP = 3.99), with over 60% of CtD molecules in the optimal logP range of 0 to 4. Similarly, the CtD library also displays a far higher fraction of sp3 character than the screening compounds, a property indicating a high degree of 3D structure and correlated with enhanced aqueous solubility.

The authors argue that molecular complexity is advantageous in drug-like molecules as more complex molecules might bind their targets more specifically. They point to the number of stereogenic centres the molecule contains as a surrogate for molecular complexity and show that their CtD molecules contain far more stereocentres than the compounds in the screening collection.

Despite demonstrating clear drug-like properties (particularly ClogP), the molecules have not been analysed in another significant property indicative of the likelihood of observing drug-like behaviour: molecular weight. While molecular complexity offers the possibility of tighter target binding, it also decreases the chances of observing binding in any given target site. This is correlated with molecular weight, where it is estimated that each heavy atom added to the molecule increases the number of potential structures by a factor of 10.1 The chances of finding hit molecules is increased when screening molecules with lower molecular weight (due to better sampling of chemical space), albeit with potentially weaker binding (cf. fragment-based design).

The six CtD molecules displayed above lie in the molecular weight range of 353 to 505, outside of the optimal range of 200 to 350 for lead compounds, though within the boundaries of the Lipinski rule of 5 for drug-like molecules.

This approach is, of course, not limited to the derivatisation of the natural products or classes presented within this paper, but that similar structural modifications may be carried out on any readily available complex molecules to prepare diverse structures with drug-like properties.

1. A. Nadin, C. Hattotuwagama, I. Churcher Angew. Chem. Int. Ed. 2012, 51, 1114 and references 27-29 therein.

What we’ve been reading

Each week we post a list of articles we’ve been reading and found interesting but haven’t been able to feature individually.

The Isolation of [Pd{OC(O)H}(H)(NHC)(PR3)] and Its Role in Alkene and Alkyne Reductions Using Formic Acid
Julie Broggi, Václav Jurčík, Olivier Songis, Albert Poater, Luigi Cavallo, Alexandra M. Z. Slawin, and Catherine S. J. Cazin
J. Am. Chem. Soc. DOI: 10.1021/ja311087c

Simplifying Nickel(0) Catalysis: An Air-Stable Nickel Precatalyst for the Internally Selective Benzylation of Terminal Alkenes
Eric A. Standley and Timothy F. Jamison
J. Am. Chem. Soc. DOI: 10.1021/ja3116718

Ni-Catalyzed Direct Carboxylation of Benzyl Halides with CO2
Thierry León , Arkaitz Correa , and Ruben Martin
J. Am. Chem. Soc. DOI: 10.1021/ja311045f

Free-Radical-Mediated [2 + 2 + 1] Cycloaddition of Acetylenes, Amidines, and CO Leading to Five-Membered α,β-Unsaturated Lactams
Takahide Fukuyama , Nao Nakashima , Takuma Okada , and Ilhyong Ryu
J. Am. Chem. Soc. DOI:10.1021/ja312654q

Carbofluorination via a palladium-catalyzed cascade reaction
Marie-Gabrielle Braun , Matthew H. Katcher and Abigail G. Doyle
Chem. Sci. DOI: 10.1039/C2SC22198E

The role of organometallic copper(III) complexes in homogeneous catalysis
Alicia Casitas and Xavi Ribas
Chem. Sci. DOI: 10.1039/C3SC21818J

‘Square’ four-stranded DNA structure found in cells

A Paper in Nature Chemistry this week reports the first observation of a G-quadruplex structure of DNA in cells. Nature News has a summary of the discovery that hints at the possibility that these DNA structures may have important biological functions.

A G-quadruplex comprises four guanines from different places along a G-rich strand held together by a special type of hydrogen bonding to form a compact square structure that interrupts the DNA helix.

In a paper published online today in Nature Chemistry, researchers led by Shankar Balasubramanian at the University of Cambridge, UK, provide strong evidence that G-quadruplexes do occur in cells.

For those without subscription access, the Nature Chemistry paper is available for free for the rest of this week.