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

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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.

Catalytic Asymmetric C–N Bond Formation: Phosphine-Catalyzed Intra- and Intermolecular γ-Addition of Nitrogen Nucleophiles to Allenoates and Alkynoates

Rylan J. Lundgren, Ashraf Wilsily, Nicolas Marion, Cong Ma, Ying Kit Chung, and Gregory C. Fu
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201208957

fig2

A carbonyl group provides a pivot point for the functionalisation of its proximal positions – α and β. This can be demonstrated by the reactivity of classical enolates as α-functionalisation nucleophiles and Michael acceptors as β-functionalisation electrophiles, as well as their corresponding reactivities in enamine and imminium organocatalysis.

fig1

In a recent report Lundgren et al. have successfully demonstrated that γ-functionalisation of carbonyl compounds is also achievable, both intra- and inter- molecularly. Using a spirophospine ligand to induce stereoselectivity, the group has demonstrated the feasibility of asymmetric C-N bond formation with nitrogen nucleophiles and alkynoates or allenoates as electrophiles.

fig2

Investigating the scope of the reaction revealed that a good range of functional groups can be accommodated in either intramolecular reactions with alkynoates or intermolecular reactions with allenoates.

fig3

fig4

The process provides access to novel reactivity and it may even prove complementary to the classical α- and β- asymmetric functionalisation of carbonyl compounds. It would be interesting to see if a γ-, β-, α-cascade addition would be possible.

ChemDraw magic: shortcuts you know and the rest you don’t

We’re a bit late to this, but it really is essential viewing for anyone who uses ChemDraw software on a daily basis.

Pierre Morieux uses ChemDraw like most gamers play games: with lots of keyboard shortcuts and hotkeys. After being featured on In the Pipeline, Pierre has landed a job with ChemDraw publisher Perkin Elmer. Chemjobber has an interview with Pierre about his background and how he turned his skills to his advantage.

When you watch the video above, be ready to take notes.

Sequence-Specific Peptide Synthesis by an Artificial Small-Molecule Machine

Bartosz Lewandowski, Guillaume De Bo, John W. Ward, Marcus Papmeyer, Sonja Kuschel1, María J. Aldegunde, Philipp M. E. Gramlich, Dominik Heckmann, Stephen M. Goldup, Daniel M. D’Souza, Antony E. Fernandes, and David A. Leigh
Science
DOI: 10.1126/science.1229753

Chemical synthesis has advanced by an order of magnitude in the last two decades. So much so that the once groundbreaking field of natural product synthesis has become a relatively bland arena with occaisional highlights. Many synthetic chemists have turned their attention to far grander designs, passing over the mimicking of nature, and focusing their efforts on manipulating molecules ever more precisely.

Nowhere has this been demonstrated more clearly than in the development of complex molecular machines. Chemists have employed advances in synthesis to construct molecules that rotate in only one direction, walk along a track, and even change physical properties when irradiated with light. However, the field of nanotechnology has suffered from a lack of credibility in its creations: we have yet to make a molecular machine that does something useful.

This week, a report from Leigh and co-workers has taken a large step in addressing this problem, who in doing so have gone back to copying the functions of nature to inspire their designs.

Their machine mimics the function of the ribosome, taking amino acid building blocks in sequence and constructing a predefined peptide. This involes using two carefully interlocked molecules: a macrocycle with a thiolate-supporting arm and a ‘dock’ for amino acids; and a ‘track’, along which the macrocycle moves, that is functionalised at points with a defined set of amino acids. Once the machine is assembled, the macrocycle moves along the track cleaving the amino acid building blocks one at a time and docking them together in sequence. Once free of the track, the peptide can be removed from the macrocycle and isolated.

With such encouraging steps towards creating useful systems, it’s fascinating to think about what other uses this technology could be put to. The article is well worth reading to understand the chemical makeup of this machine and its function. (It’s unfortunately to complex to reproduce here.)