Chemical Science Blog

Researchers have shown that acid-catalysed condensations of aminobenzaldehydes with indole result in the formation of different products depending on whether the aminobenzaldehyde is primary or secondary.

Daniel Seidel’s group at Rutgers, The State University of New Jersey, found that N-methylbenzaldehyde reacts with indole to form neocryptolepine-related structures in a single step. Neocryptolepine (5) and its analogues are attractive targets for synthesis as they display promising antimalarial activity.

Conversely, primary benzaldehydes such as aminobenzaldehyde react under similar conditions to form quinolines (7). The mechanistic pathways leading to the formation of both indoles (5) and quinolines (7) are initially identical, with aminobenzaldehyde 1 condensing with indole 2 to form the corresponding azafulvenium ions (3), which undergo ring closure to yield tetracyclic products (4). At this point the mechanisms diverge; secondary systems (4a) undergo proton loss and oxidation to give neocryptolepine analogues (5), whilst primary systems (4b) undergo proton transfer to give products of type 6, which aromatise to form quinoline products (7) on ring opening.

The group made a range of both neocryptolepine analogues and quinoline systems in good to excellent yields, representing important scaffolds for medicinal chemistry.

Seidel’s Edge article is free to download. Let me know what you think of this work by leaving your comments below.

Posted on behalf of Alice E. Williamson, Chemical Science web writer.

Researchers from the University of Delaware have reported a total synthesis of hyacinthacine A2, an attractive target owing to its selective glycosidase inhibition and activity against HIV. 

Joseph Fox’s research group achieved the synthesis in less than ten steps from sucrose by designing and synthesising a functionalised 5-aza-cyclooctene system (1) that would undergo a novel transannular hydroamination, following stereocontrolled photoisomerisation.

The efficiency of the photoisomerisation process was improved by using a flow system that removes trans-isomers by selective complexation with silver salts, thereby enabling the cis-isomer of 1 to be recycled. Incorporation of a fused acetonide ring system in 1 imposed significant conformational constraints to favour formation of the desired trans-diastereosiomer 2 in good yield and in 8:1 diastereomeric ration following decomplexation from the silver salts.

Following separation of the major diasteroisomer of 2, and cleavage of both trifluoroacetyl and acetonide protecting groups, the corresponding ammonium salt was obtained. The planar chirality present in 2 was perfectly transferred in a transannular hydroamination to give the point chirality present in the natural product.

Find out more by downloading Professor Fox’s Chemical Science Edge article, which is free to access.

Posted on behalf of Alice E. Williamson, Chemical Science web writer.

Researchers in Australia have devised a new way to test how well drugs penetrate the low-oxygen core of solid tumours. ‘Hypoxic’ regions of tumours are notoriously difficult to target with drugs and the new work could help in the development of new compounds that can effectively reach these areas and efficiently kill the cells.

Tumours often grow faster than the blood vessels that supply them, and parts of the tumour therefore become starved of oxygen and grow slowly. This makes it difficult for drugs carried in the blood to reach these areas; furthermore many drugs rely on the rapid proliferation of cancer cells, so slowly growing ones are less susceptible.

One approach has been to develop ‘prodrugs’, which become toxic to the cell only upon entering the low-oxygen environment. Some of these are based upon cobalt(III) attached to a toxic ligand. In a hypoxic environment the cobalt is reduced to cobalt(II) and the ligand is released. However, there are currently no reliable ways either to visualise the hypoxic region of a tumour or to measure penetration of the drugs.

Now, Byung Kim, Trevor Hambley and Nicole Bryce at the University of Sydney have developed a three-dimensional model of a solid tumour with a hypoxic core that allows both the hypoxic region to be highlighted and the extent of penetration of prodrugs to be measured.

Scientists in the US have developed a sensitive and simple sensor that could be used to detect toxic gases occurring in urban areas.

Gases such as chlorine, sulfur dioxide and ammonia are toxic and are often emitted by industrial processes and agriculture. The gas molecule structures are small and simple, which makes them difficult to differentiate using sensors. Methods to detect such pollutants in urban environments thus require expensive equipment that has to be used in a laboratory.

Eric Kool and colleagues at Stanford University designed a sensor based on the structure of DNA, where base pairs were replaced with one of four fluorescing aromatic monomers. The DNA scaffold gave the sensor a stable structure where the monomers were stacked over each other. Using four sensing molecules in the structures produced a pattern of fluorescence outputs that could be used to differentiate between a mixture of toxic gases.

A combination of three structures could detect and differentiate between eight toxic gases

Read the full Chemistry World news story here

Link to journal Article
DNA polyfluorophores as highly diverse chemosensors of toxic gases
Chi-Kin Koo, Florent Samain, Nan Dai and Eric T. Kool
Chem. Sci., 2011, DOI: 10.1039/c1sc00301a