Photochemical cascade reactions by merging organo- and iridium catalysis: A stereocontrolled entry to molecular complexity.

Project Information

PHOTO ORGANO-Ir CAT

Grant agreement ID: 795793

DOI

10.3030/795793

Project closed

EC signature date 6 March 2018

Start date 1 April 2018

End date 31 March 2020

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 158 121,60

EU contribution

€ 158 121,60

Coordinated by

FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA
Spain

Periodic Reporting for period 1 - PHOTO ORGANO-Ir CAT (Photochemical cascade reactions by merging organo- and iridium catalysis: A stereocontrolled entry to molecular complexity.)

Reporting period: 2018-04-01 to 2020-03-31

Summary of the context and overall objectives of the project

The requirement for drug discovery to facilitate the identification of successful lead candidates has challenged synthetic chemists to develop innovative strategies to rapidly generate screening collections of chiral molecules. Recently, the application of asymmetric aminocatalysis to cascade reactions has addressed this target enabling extraordinary levels of sophistication and stereocontrol, while fulfilling the requirements for both atom and step economy. Because of the rapid progress achieved, the general perception is that it would be difficult to further expand the synthetic potential of the aminocatalytic cascade approach. However, recent works from the host’s laboratories demonstrate that, by exploiting the photochemical activity of organocatalytic intermediates, light irradiation unlocks reaction pathways unavailable in the ground-state domain. In particular, by bringing a catalytically generated iminium ion to an electronically excited state, it is possible to perform β-functionalisations of enals not achievable under thermal control. This project seeks to capitalise upon this novel reactivity to further expand the synthetic potential of the organocatalytic cascade technique, by providing new opportunities for reaction invention. We planned to accomplish this by exploiting the photochemistry of iminium ions in processes that synergistically combine enamine chemistry with transition metal catalysis, thus merging, for the first time, tandem organo-metal catalysis with asymmetric photoreactions.

The specific objectives were the following:

1. Design and optimise cascade reactions that take advantage of the unprecedented reactivity enabled by the photo-activation of iminium ions and exploit it in synergistic enamine/transition metal catalytic processes.
2. Functionalize and modify the compounds obtained using the above methodologies to access previously elusive natural-product-inspired architectures.
3. Evaluate the biological activity of the analogue libraries generated through bioassays and, eventually, modify and improve the most promising leads via fine modification of the previous structures

Research endeavours that the project have produced:

1. A novel photochemical asymmetric protocol that converts raw materials into value-added synthetic building blocks, by exploiting the reactivity of chiral organocatalytic intermediates (iminium ions) under visible-light irradiation.
2. A further unprecedented asymmetric photochemical protocol, which is currently under investigation.
3. Five written contributions, including scientific papers and outreach publications.

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

At the outset of our investigations, the feasibility of the design plan was tested for an asymmetric photochemical protocol combining iminium ion photochemistry and iridium catalysed allylic substitution. Unfortunately, no suitable conditions to enable the postulated reactivity were found, due to the occurrence of competing side reactivity. Nevertheless, in depth investigation of these competing pathways leaded to the development of two novel asymmetric photochemical processes, one of which cannot be currently disclosed due to confidentiality reasons. Regarding the other project, the unconventional reactivity of excited-state iminium ion intermediates has been exploited to activate unfunctionalised feedstock materials, and convert them into enantioenriched synthetic building blocks. Using this strategy, toluene and its derivative, copiously obtained during the naphtha catalytic reformation process, can be directly functionalised to obtain valuable aldehyde products. The synthetic potential of this method has been showcased by the direct derivatisation of densely functionalised substrates ad pharmaceutical agents. Remarkably, this protocol realise, for the first time, a fully organocatalytic asymmetric C-H functionalisation process on toluene and related compounds. The results within this line of research have found publication on a top-level peer-reviewed journal (The Journal of the American Chemical Society), have been highlighted on a scientific magazine (Synfacts) and, more recently, they have been released on an open-access project dissemination vehicle (The Project Repository Journal). Following these contribution, diverse photochemical protocols exploiting the photoactivity of iminium ion intermediates have been conceived, which are currently under development within our research group. Besides experimental contributions, Dr. Crisenza has co-authorised a comprehensive review (Angewandte Chemie), a comment contribution (Nature Communications) and a perspective article (The Journal of the American Chemical Society), all promoting the use of photochemical methods in research settings. These, along with all the scientific outcomes within the PHOTO ORGANO-Ir CAT project, have been advertised on social media (Twitter).

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)

Work within the project disclosed the very first fully-organocatalytic protocol to enable the asymmetric and direct C-H functionalisation of commonly-used feedstocks, such as toluene and its derivatives. Previous methods had to rely on either the pre-functionalisation of the starting materials or the use of transition metal catalysts. Here, this has been achieved by using non-toxic organic compounds and visible light, as the sole energy source. This strategy stands out as a sustainable platform to re-valorise highly-abundant raw materials, by converting them into stereodefined synthetic precursors. These can be employed to manufacture libraries of target compounds for pharmaceutical and agrochemical testing. Moreover, we demonstrated that our strategy can serve as a mean for the efficient derivatisation of drug cores, with potential applications in the ADME-tox (absorption, distribution, metabolism, excretion, and toxicology) modification/evaluation of existing lead candidates. By disseminating the results of this project, we aimed at advertising to both the scientific community and the general public the potential of photochemical methods in providing more sustainable solutions to chemical synthesis and research.
Furthermore, investigations and scientific outcomes within PHOTO ORGANO-Ir CAT deeply impacted both the professional and personal growth of Dr. Crisenza. During the project the researcher has broadened his knowledge over previously unexplored fields, such as radical reactivity and photochemistry. This exposed him to new challenges and settings, ultimately, strengthening his resilience as a scientist. On the other hand, during the time of the project, Dr. Crisenza has refined his science communication ability and mentoring skills, and acquired consistent managerial experience (leading research projects, recruiting interviews and involvement in journal peer-review process). All of these skills will be extremely beneficial for Dr. Crisenza to attain his career goal, which is to become an established top level independent investigator and lecturer in chemistry.

Project Summary