Periodic Reporting for period 1 - LateCPC (Late-stage C–H bond construction of cyclopropanes to impact drug discovery)
Okres sprawozdawczy: 2021-03-01 do 2023-02-28
The evaluation of the CPCs reactivity as electrophiles has been demonstrated principally with hard nucleophiles (RM, M = Li, MgBr, SnBu3, phosphide) and recently, the more stable trisaminocyclopropenyl cations found applications as photoelectrocatalysts, gene delivery promoters or catholytes for nonaqueous redox batteries. However, the full synthetic potential of cyclopropenyl cations has been underdeveloped and underappreciated by the synthetic community, perhaps due to the lack of general one-step processes for their synthesis. CPCs have the potential to be exploited as electrophilic reagents in the regio and stereoselective C–H bond functionalization of aromatic rings and to reach cyclopropenes which are direct precursors of one of the most important saturated carbocycles in drug discovery, the cyclopropane.
Novel and stable CPCs as well as C–H bond cyclopropenation are highly innovative and could have direct impact in human health, paving the way for the development of new bioactive compounds containing cyclopropenyl/cyclopropanyl moieties in a straightforward manner from APIs and drug intermediates.
Late CPC wants to develop the first general catalytic synthesis of cyclopropenyl cations from readily or commercially available alkynes and exploit them as electrophilic reagents for the first time in late-stage functionlization to impact medicinal chemistry.
The specific objectives of this programme include:
(1) The development of the first catalytic methodology for the synthesis of a previously elusive family of CPCs.
(2) The use of the new CPCs as electrophilic reagents in the regio- and chemoselective couplings with aromatic nucleophiles for the synthesis of valuable cyclopropenes.
(3) The development of the first late-stage electrophilic C–H bond cyclopropenation in complex natural products and drug molecules.
Moreover, we took advantage of the late-stage installation of the cyclopropene for further transformations into medicinally-relevant sp3-rich scaffolds, difficult or not possible to reach by current approaches.
This work has been published in the Journal of the American Chemical Society in open access and a second publication is almost ready to be submitted to Angewandte Chemie. In addition, the fellow presented part of this work in major International congress dedicated to Organic Chemistry & Drug disocvery.
In fact, by cooperating with Novartis (through a 3 months secondment), it was discovered that the introduction of cyclopropene ring onto drug molecules could improve their metabolic stability.
Being exposed to cutting-edge research in a world-class research institution has provided him exceptional opportunities for the development of his research experience, professional maturity, diversity, independence, and leadership qualities.
All these will help the fellow to be in an outstanding situation towards his next career step: to become an independent researcher in academy.