Periodic Reporting for period 1 - OleFluor (Carbyne transfer catalysis for C(sp2)–C(sp2) bond (radio)fluorinations)
Reporting period: 2021-08-01 to 2023-07-31
OleFluor focuses on developing a new and versatile method for making important carbon-fluor chemical bonds in drugs, which could lead to more efficient drug development and the synthesis of compounds that were previously hard to produce, to ultimately improve the availability of medical treatments for society.
The use of fluorine-containing drugs is now on the rise, and scientists have been working on new ways to create these bonds. Currently, they have two main approaches: one using pre-prepared molecules and the other using a type of carbon-hydrogen (C–H) bond as a starting point. However, because drugs come in many different shapes and sizes, no single method works for all of them.
Instead of the usual approaches, OleFluor wants to use a type of carbon-carbon double bond and a novel catalyst that performs carbyne transfer reactions. The main goal is to create a flexible process that can use various starting materials, including basic chemicals, fine-tuned molecules, and complex substances with specific types of bonds.
The specific project's objectives are summarized below, and in Figure 1:
1) The development of a new way to make a type of fluorinated molecule called "allylic fluorides" with the ability to control the structure of the molecules (chirality) and in a way that it can be used in the later stages of drug development.
2) Simplifying the currently complex process of making fluorinated versions of compounds that imitate biomolecules, which have medicinal properties.
3) Adapt this new method to use a specific source of fluorine called 18F, which has uses in medical imaging.
The use of fluorine-containing drugs is now on the rise, and scientists have been working on new ways to create these bonds. Currently, they have two main approaches: one using pre-prepared molecules and the other using a type of carbon-hydrogen (C–H) bond as a starting point. However, because drugs come in many different shapes and sizes, no single method works for all of them.
Instead of the usual approaches, OleFluor wants to use a type of carbon-carbon double bond and a novel catalyst that performs carbyne transfer reactions. The main goal is to create a flexible process that can use various starting materials, including basic chemicals, fine-tuned molecules, and complex substances with specific types of bonds.
The specific project's objectives are summarized below, and in Figure 1:
1) The development of a new way to make a type of fluorinated molecule called "allylic fluorides" with the ability to control the structure of the molecules (chirality) and in a way that it can be used in the later stages of drug development.
2) Simplifying the currently complex process of making fluorinated versions of compounds that imitate biomolecules, which have medicinal properties.
3) Adapt this new method to use a specific source of fluorine called 18F, which has uses in medical imaging.
As mentioned before, our process that involves using carbon double bonds, creates a type of chemical called an "allylic carbocation" from a catalyst called Rh-carbynoid. This carbocation then undergoes a reaction that adds fluorine atoms in a specific way. With this technique, we have successfully made 40 new fluorinated compounds in good to moderate amounts, and we also adapted this method to work with a 18F radionuclide with good success.
However, we encountered a challenge when trying to create chiral molecules, with a specific kind of shape. We could not control the shape of the molecule as we wanted, and it was eventually discovered during the investigation that it could be due to the formation of a flat allylic carbocationic species. This flat structure makes it difficult to predict how other chemicals will attach to it in a specific way.
We wondered if we could harness these transformations to make other useful substances like indenes and 1,3-dienes from a group of chemicals called vinylarenes. Indenes and 1,3-dienes are found in nature and are used in medicines, like indriline, dimetindene, and piperine. From the research on the new fluorination strategies, we developed a method that allows us to selectively create indenes and 1,3-dienes by adding just one carbon atom to the vinylarene molecules (Figure 2). This technique can be applied to make other similar compounds from various starting materials. We've successfully modified 63 different substances that are widely available to obtain the desired indenes and 1,3-dienes (regiodivergent), and we are currently preparing a manuscript to share our findings in a respected scientific journal.
Based on the challenges we faced on controlling the actual fluorinated molecule’s shape, we have been trying to understand how molecules with a certain shape interact with other chemicals. We wanted to understand why some reactions did not result in the creation of molecules with a specific shape, the so-called chirality. For example, when we were trying to make a compound called erythramine alkaloid, we found that the way molecules attached to the allylic carbocation did not depend on which side they came from. However, we made an exciting discovery by achieving a specific type of reaction where we could add a single carbon atom to a molecule in a way that retained its unique shape. This has the potential to provide new insights into how chemical reactions work. We have demonstrated this by performing the same type of reaction with other chemicals like sorbic acid and trans-3-hexene, compounds that serve as simplified models for more complex molecules. Our research suggests that a specific intermediate molecule must undergo a change before it reacts with another molecule in a unique way. This reaction generates a special molecule-pair, which is trapped in the solvent used in the experiment. This allows the second molecule to attach itself in a particular way, creating a chiral product. We're in the process of preparing a manuscript about this discovery, and we believe it will have a significant impact on our understanding of how specific enantioselective (that achieve chirality) chemical reactions occur.
However, we encountered a challenge when trying to create chiral molecules, with a specific kind of shape. We could not control the shape of the molecule as we wanted, and it was eventually discovered during the investigation that it could be due to the formation of a flat allylic carbocationic species. This flat structure makes it difficult to predict how other chemicals will attach to it in a specific way.
We wondered if we could harness these transformations to make other useful substances like indenes and 1,3-dienes from a group of chemicals called vinylarenes. Indenes and 1,3-dienes are found in nature and are used in medicines, like indriline, dimetindene, and piperine. From the research on the new fluorination strategies, we developed a method that allows us to selectively create indenes and 1,3-dienes by adding just one carbon atom to the vinylarene molecules (Figure 2). This technique can be applied to make other similar compounds from various starting materials. We've successfully modified 63 different substances that are widely available to obtain the desired indenes and 1,3-dienes (regiodivergent), and we are currently preparing a manuscript to share our findings in a respected scientific journal.
Based on the challenges we faced on controlling the actual fluorinated molecule’s shape, we have been trying to understand how molecules with a certain shape interact with other chemicals. We wanted to understand why some reactions did not result in the creation of molecules with a specific shape, the so-called chirality. For example, when we were trying to make a compound called erythramine alkaloid, we found that the way molecules attached to the allylic carbocation did not depend on which side they came from. However, we made an exciting discovery by achieving a specific type of reaction where we could add a single carbon atom to a molecule in a way that retained its unique shape. This has the potential to provide new insights into how chemical reactions work. We have demonstrated this by performing the same type of reaction with other chemicals like sorbic acid and trans-3-hexene, compounds that serve as simplified models for more complex molecules. Our research suggests that a specific intermediate molecule must undergo a change before it reacts with another molecule in a unique way. This reaction generates a special molecule-pair, which is trapped in the solvent used in the experiment. This allows the second molecule to attach itself in a particular way, creating a chiral product. We're in the process of preparing a manuscript about this discovery, and we believe it will have a significant impact on our understanding of how specific enantioselective (that achieve chirality) chemical reactions occur.
• Precise Fluorination: Researchers developed a method to add fluorine atoms to specific parts of molecules with high precision. They created 40 new compounds using this method, including some derived from natural products and drugs. Although in some cases the shape of the resulting molecules could not be controlled, the method allowed to incorporate also radioactive fluorine. The development of the 18F compounds could be further developed into a product, generating opportunities in the health industry and raise awareness in the unsolved research gap between synthetic chemists and radiochemists in accessing radiochemical compounds.
• Adapted Compound Synthesis: Scientists found a way to transform certain chemicals into valuable compounds known as indenes and 1,3-dienes. These compounds are important in nature and medicines. They believe this method can be extended to create similar compounds from various starting materials. The results may lead to building an alternative platform to synthesize these substrates in the long term, giving new tools to synthetic chemists to provide the health industry with more affordable compounds.
• Controlling Chemical Shape: Researchers achieved a breakthrough in understanding the control of the shape of molecules during certain reactions. They created molecules with specific shapes, which is crucial for producing particular types of compounds. They are preparing to publish their findings, which could have a significant impact on our understanding of chemical reactions in the academic field.
• Adapted Compound Synthesis: Scientists found a way to transform certain chemicals into valuable compounds known as indenes and 1,3-dienes. These compounds are important in nature and medicines. They believe this method can be extended to create similar compounds from various starting materials. The results may lead to building an alternative platform to synthesize these substrates in the long term, giving new tools to synthetic chemists to provide the health industry with more affordable compounds.
• Controlling Chemical Shape: Researchers achieved a breakthrough in understanding the control of the shape of molecules during certain reactions. They created molecules with specific shapes, which is crucial for producing particular types of compounds. They are preparing to publish their findings, which could have a significant impact on our understanding of chemical reactions in the academic field.