New methods for bicyclo[1.1.1]pentane synthesis and functionalization
Lead Research Organisation:
University of Oxford
Abstract
This project falls within the EPSRC Synthetic Organic Chemistry research area.
Bioisosteres are important tools for the design of pharmaceutical drug candidates, offering improved physicochemical profiles whilst maintaining biological activity. Di-substituted bicyclo[1.1.1]pentanes (BCPs) act as a three dimensional spacer units in drug design, and are often used as a substitute for 1,4-substituted arenes, tert-butyl groups and alkynyl groups. While it is questionable whether the BCP motif is truly 'isosteric', it nonetheless has been shown to impart attractive properties such as metabolic stability, aqueous solubility and membrane permeability over the parent arene-containing compound. BCPs are typically accessed through strain relief addition reactions to tricyclo[1.1.1]pentane (TCP). Carbon/halogen-substituted BCPs have been synthesised through insertion into C-X bonds, although the methods used usually suffer from harsh reaction conditions or poor functional group tolerance. Our group has demonstrated a mild method to achieve carbon/halogen-substituted BCP's via atom-transfer radical addition (ATRA) reactions with TCP. The formation of heteroatom-substituted BCPs is less established than the C-substituted analogues, often requiring multiple steps. The focus of this research will be to form hetero-iodo-BCP compounds via one step ATRA cascades. In our preliminary work, we have successfully achieved ATRA reactions of nitrogen centred radicals with TCP to give halo-amino-BCP products, but optimisation to reduce the formation of unwanted side products and to improve reaction yield is required. We will establish reaction scope by varying the substituents of our starting material and by using alternative nitrogen centred radicals, this will provide access to a wide range of desirable BCP containing derivatives. Another area of investigation would be the addition of other heteroatoms across TCP; while TCP has been previously reacted with disulfides, diselenides, and thiols and phosphoranyl radicals to give hetero-BCP compounds, many opportunities are available for expansion of this scope. Exploration of ATRA reaction with sulfonyl radicals would be an attractive starting point. Iodo-BCP products can be functionalised classically through lithium-halogen exchange; but perhaps more usefully by radical re-generation or cross coupling methods to give hetero-carbon substituted BCPs analogous to the parent arene compounds. We have demonstrated that iodo-BCPs can be re-subjected to the reaction conditions to re-initiate the reactive intermediate; it would therefore be attractive to incorporate a third component to our ATRA reaction, and head towards currently unachieved multi-component ATRA couplings across TCP to give hetero-carbon-substituted BCPs. Finally, it would be interesting to apply the developed methodology to drug analogues, showcasing the utility of this work. Biological testing of these products is also of interest. In summary, the work proposed in this project will contribute knowledge of radical-initiated strain relief reactions, achieving access to new 3D templates which will be of interest to the medicinal and agrochemical communities.
Bioisosteres are important tools for the design of pharmaceutical drug candidates, offering improved physicochemical profiles whilst maintaining biological activity. Di-substituted bicyclo[1.1.1]pentanes (BCPs) act as a three dimensional spacer units in drug design, and are often used as a substitute for 1,4-substituted arenes, tert-butyl groups and alkynyl groups. While it is questionable whether the BCP motif is truly 'isosteric', it nonetheless has been shown to impart attractive properties such as metabolic stability, aqueous solubility and membrane permeability over the parent arene-containing compound. BCPs are typically accessed through strain relief addition reactions to tricyclo[1.1.1]pentane (TCP). Carbon/halogen-substituted BCPs have been synthesised through insertion into C-X bonds, although the methods used usually suffer from harsh reaction conditions or poor functional group tolerance. Our group has demonstrated a mild method to achieve carbon/halogen-substituted BCP's via atom-transfer radical addition (ATRA) reactions with TCP. The formation of heteroatom-substituted BCPs is less established than the C-substituted analogues, often requiring multiple steps. The focus of this research will be to form hetero-iodo-BCP compounds via one step ATRA cascades. In our preliminary work, we have successfully achieved ATRA reactions of nitrogen centred radicals with TCP to give halo-amino-BCP products, but optimisation to reduce the formation of unwanted side products and to improve reaction yield is required. We will establish reaction scope by varying the substituents of our starting material and by using alternative nitrogen centred radicals, this will provide access to a wide range of desirable BCP containing derivatives. Another area of investigation would be the addition of other heteroatoms across TCP; while TCP has been previously reacted with disulfides, diselenides, and thiols and phosphoranyl radicals to give hetero-BCP compounds, many opportunities are available for expansion of this scope. Exploration of ATRA reaction with sulfonyl radicals would be an attractive starting point. Iodo-BCP products can be functionalised classically through lithium-halogen exchange; but perhaps more usefully by radical re-generation or cross coupling methods to give hetero-carbon substituted BCPs analogous to the parent arene compounds. We have demonstrated that iodo-BCPs can be re-subjected to the reaction conditions to re-initiate the reactive intermediate; it would therefore be attractive to incorporate a third component to our ATRA reaction, and head towards currently unachieved multi-component ATRA couplings across TCP to give hetero-carbon-substituted BCPs. Finally, it would be interesting to apply the developed methodology to drug analogues, showcasing the utility of this work. Biological testing of these products is also of interest. In summary, the work proposed in this project will contribute knowledge of radical-initiated strain relief reactions, achieving access to new 3D templates which will be of interest to the medicinal and agrochemical communities.
Organisations
People |
ORCID iD |
| Edward Anderson (Primary Supervisor) | |
| Helena Pickford (Student) |
| Description | Photoredox catalysis has transformed the landscape of radical-based synthetic chemistry. Additions of radicals generated through photoredox catalysis to carbon-carbon p bonds are well-established; however, this approach has yet to be applied to the functionalization of carbon-carbon s-bonds. Here, we report the first such use of photoredox catalysis to promote the addition of organic halides to the carbocycle [1.1.1]-propellane; the product bicyclo[1.1.1]pentanes (BCPs) are motifs of high importance in the pharmaceutical industry and in materials chemistry. Showing broad substrate scope and functional group tolerance, this methodology results in the first examples of bicyclopentylation of sp2 carbon-halogen bonds to access (hetero)arylated BCPs, as well as the functionalization of nonstabilized sp3 radicals. Substrates containing alkene acceptors allow the single-step construction of polycyclic bicyclopentane products through unprecedented atom transfer radical cyclization cascades, while the potential to accelerate drug discovery is demonstrated through late-stage bicyclopentylations of natural productlike and druglike molecules. Mechanistic investigations demonstrate the importance of the photocatalyst in this chemistry and provide insight into the balance of radical stability and strain relief in the reaction cycle. |
| Exploitation Route | The published work demonstrates facile access to iodo-bicyclo[1.1.1]pentanes and has been applied to a range of substrates including the late stage functionalization of drug compounds. The iodo-BCPs have potential for further functionalization. The work if of interest to the pharmaceutical and agrochemical industries. Additionally the novel methodology is of interest to research chemist in related fields. |
| Sectors | Chemicals,Education,Pharmaceuticals and Medical Biotechnology |
| URL | https://pubs.acs.org/doi/10.1021/acscatal.9b03190 |