Efficient, Flexible Synthesis of Molecules with Tailored Shapes: from Photo-switchable Helices to anti-Cancer Compounds

Project Information

FRESCO

Grant agreement ID: 670668

DOI

10.3030/670668

Project closed

EC signature date 15 June 2015

Start date 1 October 2015

End date 31 March 2021

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 436 379,00

EU contribution

€ 2 436 379,00

Coordinated by

UNIVERSITY OF BRISTOL
United Kingdom

Periodic Reporting for period 4 - FRESCO (Efficient, Flexible Synthesis of Molecules with Tailored Shapes: from Photo-switchable Helices to anti-Cancer Compounds)

Reporting period: 2020-04-01 to 2021-03-31

Summary of the context and overall objectives of the project

The creation of new molecular entities and subsequent exploitation of their properties is central to a broad spectrum of research disciplines from medicine to materials but progress has been limited by the difficulties associated with chemical synthesis. There are many tools available in synthesis and we have focused on exploiting the chemistry of boron to facilitate this endeavour. Boron is an unusual element in that it is normally has three groups around it but this makes it vulnerable to attack by a fourth group since most elements (e.g. carbon) like to have 4 groups around them However, once it has 4 groups it readily expels one of them to go back to three groups – its behaviour makes it rather schizophrenic. This feature is exploited in a fundamentally new strategy, which has the potential to revolutionise how we conduct complex organic synthesis. By adding a fourth group that has an adjacent leaving group attached, one of the three groups on boron migrates expelling the leaving group creating a new C–C bond. C–C bond formation is fundamental to organic synthesis. In so doing, it generates a new organo-boron compound which can react again and again multiple times making complex organic synthesis easier than before.

To realise this strategy, we need to develop new ways of introducing boron into molecules (introductory phase), a family of reagents which react with the organoboron compound effecting chain growth (growth phase), and new methods to transform the carbon-boron bond into other functional groups (termination phase). This will enable complex molecules to be made more easily.

In addition we seek to use the precise control of stereochemistry that this methodology enables to create molecules with tailored shape, be they helical or linear. By doing this we will be able to create molecules with substituents hanging from the main chain at precise positions and they will be used to dock and disrupt certain protein-protein interactions involved in cancers.

The methodology is also being used to target natural products which are members of the polyketide family since many of them have profound anti-bacterial/anti-inflammatory and anti-cancer properties.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

So far, we have made good progress on the objectives. We have discovered new ways of introducing boron into molecules: we have been able to convert common functional groups found in nature (carboxylic acids and C-H bonds) and convert them into boronic esters and have been able to take an alkene and adds the elements of H and B across it.
For the growth phase we have expanded the family of reagents that can be used and this enables a greater diversity of structures to be made.
In the termination phase we have found new ways of converting boron into aromatic groups and other functional groups.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Significant progress has been achieved beyond the state-of-the-art, e.g. in the conversion of a carboxylic acids and C-H bonds into boronic esters. We have also converted other common functional groups e.g. amines and alcohols into boronic esters as this allows a greater diversity of building blocks to be used in our assembly line synthesis chemistry.
We have made a highly unusual observation that that the helicity of a molecule is affected by its chain length: even numbered carbon chains adopt a perfect helical structure which alternates from right to left handed helices with increasing size and odd number carbon chains do not adopt a single low energy conformation but are rather random. We are trying to understand this phenomenon and then we will see if we can control it.
In collaboration with computational chemists, we have developed a computer program that is able to predict the shape of complex molecules which we plan to use to create molecules which can interact with protein surfaces and therefore disrupt detrimental protein-protein interactions involved in cancers.

image of high and low control of helical chains depending on chain length