New carbon reactivity rules for molecular editing

Project Information

CARBYNE

Grant agreement ID: 865554

DOI

10.3030/865554

EC signature date 18 December 2019

Start date 1 September 2020

End date 28 February 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 000 000,00

EU contribution

€ 2 000 000,00

Coordinated by

FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA
Spain

Periodic Reporting for period 3 - CARBYNE (New carbon reactivity rules for molecular editing)

Reporting period: 2023-09-01 to 2025-02-28

Summary of the context and overall objectives of the project

The art of organic synthesis and reaction discovery relies on logic-guided thought processes that often involve hypovalent carbon reactive species and their corresponding stabilized equivalent forms. However, not all of the possible carbon reactive intermediates and their reactivity rules have attracted the same attention by the synthetic community. This is mainly because of the perception of the lack of synthetic utility and importantly, because of the challenges associated with controlling its extreme reactivity and lack of efficient sources.

The major goal of this project is to develop the catalytic generation of conceptually-novel carbyne equivalents and related species, and to study their reactivity towards organic matter. The catalytic activation of designed sources will reveal new reactivity rules at carbon that have been missing, not only in the design and discovery of new chemical reactions, but also in their use to build molecular complexity. Our approach will rely on novel activation modes that unlock elusive and useful tools for molecular editing that may access molecular complexity faster and to new chemical space not possible to reach by current strategies. Such new methodologies will impact on drug and agrochemical design and in the way how complex molecules are made.

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

During this period, we have been able to test the high-risk/high-gain concepts and hypothesis described in the CARBYNE proposal. We are glad to say that some of those were successfully unveil and represent milestones in this project.


More than two-thirds of prescription drugs contain at least one chiral carbon centre. Such structural motifs are formed by carbon atoms substituted with four different chemical entities including other molecules or atoms. Their presence in drug candidates is linked with the success of transition from the discovery stage to clinical testing and to the market. Our CARBYNE project has been able to discover first-in-class methodologies able install chiral centers in medically relevant molecules using their prevalent C–H bonds.

On the other hand, the development of new tri-dimensional structural motifs rich in C–H bonds are known to improve the physicochemical properties of drug molecules, serve as functional group bioisosteres or provide entry to novel chemical and intellectual property space. We have discovered new methodologies able to reach structural motifs difficult or not possible to make by current approaches and we foresee that such motifs will have immediate use in drug discovery programmes of Pharmaceutical industries. We have published these works in top-tier journals such as Journal of the American Chemical Society or Angewandte Chemie International edition (see images uploaded).

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)

CARBYNE project is advancing a new reactivity platform for the transfer of monovalent carbons to organic matter. Key in our work is the generation of carbyne equivalents, reactive species never generated before, that shows completely new behaviours in the reactions with organic molecules. We are the pioneer and leading group discovering, developing, creating and questioning new science around the transfer of carbynes. Specifically, the type of bond activations performed are beyond the state-of-the-art in C–H and C–C bond activations.

Until the end of the project, it is expected to provide a palette of novel chemical reactivity and unique synthetic applications for the synthesis and functionalization of simple and complex molecules proposed in CARBYNE. More specifically, we will provide skeletal editing methods able to insert single-carbons in C–C bonds of organic molecules and provide a chemical space difficult or not possible to reach by current methodologies.

Such type of unexplored processes has witnessed a significant increase of interest over recent years, since are of high utility in the fields of drug/agrochemical discovery, chemical biology or material science. Skeletal editing processes were the skeleton of an organic molecule is modified may belong to the next paradigm shift in synthesis and our group is expected to be at the forefront of this exciting field.

Rh-catalyzed carbyne transfer to alkynes

Late-Stage Aryl C-H Bond Cyclopropenylation with Cyclopropenium Cations

Catalytic enantioselective monovalent carbon insertion of alkenes

Catalytic generation of Fischer-Type acyloxy Rh(II)-carbenes

A new multicomponent photocatalytic approach to diazo compounds