Periodic Reporting for period 1 - LateCPC (Late-stage C–H bond construction of cyclopropanes to impact drug discovery)
Période du rapport: 2021-03-01 au 2023-02-28
The cyclopropenyl cation (CPC) is the smallest member of the Hückel aromatic systems. This type of aromatic cations with two π-electrons delocalized over three 2p orbitals are known to have considerable thermodynamic stability, despite of their molecular strain. Current synthetic strategies, developed between 1950s and 1980s, rely on multistep sequences to generate a cyclopropene precursor that leads to the CPC upon (pseudo)halide, nitrile or hydride abstraction with strong Lewis acid or Brønsted acid. Those methods show severe limitations in the scope with regards to efficiency and structural diversity. To date, synthetic methods based on a catalytic platform that reaches CPCs in one step are unknown.
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.
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.
We disclosed a new class of aromatic cyclopropenium cations (CPCs) using a one-step Rh-catalyzed process that combines readily available alkynes and hypervalent iodine reagents as cationic carbyne sources. Such CPCs were suitable reagents for the development of a late-stage electrophilic C–H bond cyclopropenylation of simple aromatics, densely-functionalized drug molecules, natural products and fluorescent dyes that occurred with excellent regio-, site- & chemoselectivity.
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.
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.
The methodology developed wihtin this project allowed the first catalytic one-step synthesis of cyclopropenium cations (CPCs) with readily available alkynes and hypervalent iodine reagents as carbyne sources. Late stage construction of cyclopropene/cyclopropane rings using C−H bonds of drug molecules or drug leads via CPC is new and highly innovative within drug discovery and may impact the way of how cyclopropane-based drugs will be made in the near future.
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.
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.