Matthew H. Todd

Gold-Catalysis: Reactions of Organogold Compounds with Electrophiles

Different arylgold(i), one alkynylgold(i), and one vinylgold(i) triphenylphosphane complexes were subjected to electrophilic halogenation reagents. With N-chlorosuccinimid, N-bromosuccinimid, and N-iodosuccinimid as well as the Barluenga reagent, selectively halogenated compounds were obtained. Trifluoroacetic acid, as a source of protons, leads to a clean protodeauration. With N-fluorobenzenesulfonimide or Selectfluor, exclusively a homocoupling was observed. For the precursor of the vinylgold(i) complex, a similar oxidative coupling could be induced by gold(iii) chloride. Reactions with silicon or tin electrophiles failed.

Open science is a research accelerator

An open-source approach to the problem of producing an off-patent drug in enantiopure form serves as an example of how academic and industrial researchers can join forces to make new scientific discoveries that could have a huge impact on human health.

Computer-aided organic synthesis

It is tempting for those in the field of organic synthesis to liken the process of retrosynthesis to a game of chess. That the world chess champion was recently defeated by a computer leads us to think that perhaps new and powerful computing methods could be applied to synthetic problems. Here the analogy between synthesis and chess is outlined. Achievements in the 35-year history of computer-aided synthetic design are described, followed by some more recent developments.

A Click Fluorophore Sensor that Can Distinguish CuII and HgII via Selective Anion‐Induced Demetallation

A cyclam-based fluorescent sensor featuring a novel triazole pendant arm has been synthesised using click chemistry. The sensor is highly responsive to both Cu(II) and Hg(II) in neutral aqueous solution and displays excellent selectivity in the presence of various competing metal ions in 50-fold excess. The addition of specific anions such as I(-) and S(2)O(3)(2-) causes a complete revival of fluorescence only in the case of Hg(II), providing a simple and effective method for distinguishing solutions containing Cu(II), Hg(II) or a mixture of both ions, even in doped seawater samples. X-ray crystal structures of both the Hg(II) sensor complex and a model Cu(II) complex show that pendant triazole coordination occurs through the central nitrogen atom (N2), providing to the best of our knowledge the first reported examples of this unusual coordination mode in macrocycles. Fluorescence, mass spectrometry and (1)H NMR experiments reveal that the mechanism of anion-induced fluorescence revival involves either displacement of pendant coordination or complete removal of the Hg(II) from the macrocycle, depending on the anion.

An oxidative carbon–carbon bond-forming reaction proceeds via an isolable iminium ion

The mechanism of our previously reported DDQ-mediated oxidative C–C bond-forming reaction is investigated. We are able to trap and characterize an iminium ion intermediate with X-ray crystallography, elemental analysis, and solid-state NMR spectroscopy; to our knowledge this is the first time this putative intermediate ion has been directly observed in such cross-dehydrogenative couplings (CDCs). The intermediate can be reacted with a range of nucleo-philes, including a malonate that is not amenable to a one-pot reaction protocol.

Asymmetric autocatalysis: product recruitment for the increase in the chiral environment (PRICE).

Asymmetric catalytic reactions are possible via efficient transfer of the chiral environment of a reaction to the transition state. In theory any asymmetric structure may contribute to this, including the product of the reaction itself. For product influence to be significant, a nonlinear effect needs to operate, whereby one diastereomer of the product/catalyst assists the reaction, and the other does not. When these conditions are satisfied, we obtain an asymmetric autocatalytic reaction in which the enantiomeric excess of a compound (that is both product and catalyst) actually increases as the reaction iterates. It is only recently that we have seen reports of such processes. Of particular interest are Soais reports of the alkylation of aromatic heterocycles. Such reactions, aside from their inherent interest, may offer clues into the origins of asymmetric molecular replication that predated the origin of life.

Resolution of praziquantel.

Background Praziquantel remains the drug of choice for the worldwide treatment and control of schistosomiasis. The drug is synthesized and administered as a racemate. Use of the pure active enantiomer would be desirable since the inactive enantiomer is associated with side effects and is responsible for the extremely bitter taste of the pill. Methodology/Principal Findings We have identified two resolution approaches toward the production of praziquantel as a single enantiomer. One approach starts with commercially available praziquantel and involves a hydrolysis to an intermediate amine, which is resolved with a derivative of tartaric acid. This method was discovered through an open collaboration on the internet. The second method, identified by a contract research organisation, employs a different intermediate that may be resolved with tartaric acid itself. Conclusions/Significance Both resolution procedures identified show promise for the large-scale, economically viable production of praziquantel as a single enantiomer for a low price. Additionally, they may be employed by laboratories for the production of smaller amounts of enantiopure drug for research purposes that should be useful in, for example, elucidation of the drugs mechanism of action.

Studies on the Synthesis, Characterisation and Reactivity of Aromatic Diboronic Acids

Abstract The synthesis and characterisation of 1,3- and 1,4-phenyl diboronic acids are described, and the palladium-catalysed couplings between 1,4-phenyl diboronic acid and a number of aryl iodides is reported.

A Kernel for Open Source Drug Discovery in Tropical Diseases

Background Conventional patent-based drug development incentives work badly for the developing world, where commercial markets are usually small to non-existent. For this reason, the past decade has seen extensive experimentation with alternative R&D institutions ranging from private–public partnerships to development prizes. Despite extensive discussion, however, one of the most promising avenues—open source drug discovery—has remained elusive. We argue that the stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. Historically, open source software collaborations have almost never succeeded without such “kernels”. Methodology/Principal Findings Here, we use a computational pipeline for: (i) comparative structure modeling of target proteins, (ii) predicting the localization of ligand binding sites on their surfaces, and (iii) assessing the similarity of the predicted ligands to known drugs. Our kernel currently contains 143 and 297 protein targets from ten pathogen genomes that are predicted to bind a known drug or a molecule similar to a known drug, respectively. The kernel provides a source of potential drug targets and drug candidates around which an online open source community can nucleate. Using NMR spectroscopy, we have experimentally tested our predictions for two of these targets, confirming one and invalidating the other. Conclusions/Significance The TDI kernel, which is being offered under the Creative Commons attribution share-alike license for free and unrestricted use, can be accessed on the World Wide Web at http://www.tropicaldisease.org. We hope that the kernel will facilitate collaborative efforts towards the discovery of new drugs against parasites that cause tropical diseases.

Open source drug discovery – A limited tutorial

SUMMARY Open science is a new concept for the practice of experimental laboratory-based research, such as drug discovery. The authors have recently gained experience in how to run such projects and here describe some straightforward steps others may wish to take towards more openness in their own research programmes. Existing and inexpensive online tools can solve many challenges, while some psychological barriers to the free sharing of all data and ideas are more substantial.