Final Report Summary - DIAZOFREE (Efficient Synthesis of N-Heterocycles using Ynamides as Diazo Equivalents)
This project was intended to explore the viability of developing a new strategy to construct classes of molecules called N-heterocycles which are important as they are widely encountered within pharmaceuticals, agrochemicals and naturally occurring bioactive materials. The type of structure and the functional groups attached around it greatly affect their function and so the ability to make such molecules in a general and straightforward manner is important to further progress those areas of society which depend on.
Metal carbenes are privileged reactive intermediates in organic chemistry which are used to access extraordinarily important reactivity patterns not possible by others means, such as cyclopropanation, ylide formation or insertion reactions. However, the traditional approach to prepare these important species involves the use of diazo compounds. These N-heterocyle precursors are lengthy to prepare, producing much waste material, limit the types of structures that can be made as a result and are hazardous due their toxicity and explosive nature.
In this project we have developed a novel, general and mild strategy to access to a great diversity of N-heterocycles, widely present in bioactive natural products, pharmaceuticals and agrochemicals, that avoids the use of diazo compounds but accesses similar reactive species. Based on the recent discovery by our group which demonstrates that ynamides, under gold catalysis and in the presence of a suitable oxidant, provide direct access to -amido carbene intermediates, we proposed to expand the scope of this initial discovery to achieve a robust strategy which could solve the limitations present in the already known transformations. This methodology overcomes the limitations and drawbacks associated with conventional transformations which suffered from compatibility, generality and safety issues, providing the chemical community with a new tool to readily access to a wide range of valuable structural motifs.
In this study we have developed a novel gold-catalysed intermolecular oxidative-cyclisation sequence of ynamides, involving presumably -amido gold carbenoids as intermediates, which has allowed us to come to identical reaction modes to those known for diazo compounds bypassing the disadvantages associated with the use of such functionality. The value of our methodology has been demonstrated with the development of four different reaction modes and the preparation of six distinct N-heterocyclic frameworks.
The initial stage of the project was to assess our initial hypothesis proving that ynamides under gold catalysis and in the presence of an external nucleophilic oxidant were suitable substrates to generate the desired N-heterocycles. After testing our hypothesis the second stage of the project was to optimize the transformation to render it an effective and general process. A third stage was to demonstrate the scope of the reaction showing its applicability in more complex substrates than the one that was previously used for its optimization. These three stages were repeated for each different reaction modes that were developed.
The generality of our developed methodology has prompted us to apply it to the synthesis of complex natural products and a core component of a bioactive alkaloid has been prepared as a result. Novel compounds prepared in this project are being tested for activity against a number of disease targets.
In addition, the course of the proposed project has allowed us to discover and develop unexpected reaction modes of the gold-catalyzed chemistry of ynamides. The catalytic system we have optimised has also revealed to be very effective in promoting the cycloisomerization of eneynamides. This transformation has proven to be very general and has shown a different and complementary scope respect to the previously known isomerization pathways of eneyne systems.
From an individual point of view the Research Fellow has received an important training which will be very useful for his future career. He has acquired a deep intellectual knowledge in organometallic and catalytic chemistry and has obtained practical skills in performing parallel synthesis, catalytic reactions, reaction screening, Schlenk techniques and in the preparation of catalyst species. This project has also allowed him to improve his experience in modern analytical methods, in particular mass spectometry, X-Ray single crystal analysis and NMR spectrospcopy for structural confirmation and elucidation. His participation in the supervision of undergraduate and graduate students has provided him with leadership qualities and has enhanced his capabilities to work and communicate in English. The participation in international meetings and in the internal group meetings has also improved his knowledge transfer skills.
As a conclusion, from this project we have been able to achieved the objectives we proposed in our application. We have demonstrated our initial hypothesis which stated that ynamides under gold catalysis are suitable substrates to prepare a wide range of N-heterocycles via the participation of -amido carbenes as intermediates, providing a readily alternative to the use of hazardous diazo compounds. The novel methodology has been applied successfully to access four different reaction modes which cover six distinct structural motifs showing a general scope in all of them. We have successfully applied the developed strategy to construct the core structure of a complex natural product and the unexpected reaction pathways has allowed us to developed additional reaction modes. As a result of this work the Research Fellow has acquired a strong intellectual knowledge and practical skills which have allowed him to consolidate his future career.
See Webpages at: http://www.birmingham.ac.uk/research/activity/chemistry/Davies/index.aspx(opens in new window)
Metal carbenes are privileged reactive intermediates in organic chemistry which are used to access extraordinarily important reactivity patterns not possible by others means, such as cyclopropanation, ylide formation or insertion reactions. However, the traditional approach to prepare these important species involves the use of diazo compounds. These N-heterocyle precursors are lengthy to prepare, producing much waste material, limit the types of structures that can be made as a result and are hazardous due their toxicity and explosive nature.
In this project we have developed a novel, general and mild strategy to access to a great diversity of N-heterocycles, widely present in bioactive natural products, pharmaceuticals and agrochemicals, that avoids the use of diazo compounds but accesses similar reactive species. Based on the recent discovery by our group which demonstrates that ynamides, under gold catalysis and in the presence of a suitable oxidant, provide direct access to -amido carbene intermediates, we proposed to expand the scope of this initial discovery to achieve a robust strategy which could solve the limitations present in the already known transformations. This methodology overcomes the limitations and drawbacks associated with conventional transformations which suffered from compatibility, generality and safety issues, providing the chemical community with a new tool to readily access to a wide range of valuable structural motifs.
In this study we have developed a novel gold-catalysed intermolecular oxidative-cyclisation sequence of ynamides, involving presumably -amido gold carbenoids as intermediates, which has allowed us to come to identical reaction modes to those known for diazo compounds bypassing the disadvantages associated with the use of such functionality. The value of our methodology has been demonstrated with the development of four different reaction modes and the preparation of six distinct N-heterocyclic frameworks.
The initial stage of the project was to assess our initial hypothesis proving that ynamides under gold catalysis and in the presence of an external nucleophilic oxidant were suitable substrates to generate the desired N-heterocycles. After testing our hypothesis the second stage of the project was to optimize the transformation to render it an effective and general process. A third stage was to demonstrate the scope of the reaction showing its applicability in more complex substrates than the one that was previously used for its optimization. These three stages were repeated for each different reaction modes that were developed.
The generality of our developed methodology has prompted us to apply it to the synthesis of complex natural products and a core component of a bioactive alkaloid has been prepared as a result. Novel compounds prepared in this project are being tested for activity against a number of disease targets.
In addition, the course of the proposed project has allowed us to discover and develop unexpected reaction modes of the gold-catalyzed chemistry of ynamides. The catalytic system we have optimised has also revealed to be very effective in promoting the cycloisomerization of eneynamides. This transformation has proven to be very general and has shown a different and complementary scope respect to the previously known isomerization pathways of eneyne systems.
From an individual point of view the Research Fellow has received an important training which will be very useful for his future career. He has acquired a deep intellectual knowledge in organometallic and catalytic chemistry and has obtained practical skills in performing parallel synthesis, catalytic reactions, reaction screening, Schlenk techniques and in the preparation of catalyst species. This project has also allowed him to improve his experience in modern analytical methods, in particular mass spectometry, X-Ray single crystal analysis and NMR spectrospcopy for structural confirmation and elucidation. His participation in the supervision of undergraduate and graduate students has provided him with leadership qualities and has enhanced his capabilities to work and communicate in English. The participation in international meetings and in the internal group meetings has also improved his knowledge transfer skills.
As a conclusion, from this project we have been able to achieved the objectives we proposed in our application. We have demonstrated our initial hypothesis which stated that ynamides under gold catalysis are suitable substrates to prepare a wide range of N-heterocycles via the participation of -amido carbenes as intermediates, providing a readily alternative to the use of hazardous diazo compounds. The novel methodology has been applied successfully to access four different reaction modes which cover six distinct structural motifs showing a general scope in all of them. We have successfully applied the developed strategy to construct the core structure of a complex natural product and the unexpected reaction pathways has allowed us to developed additional reaction modes. As a result of this work the Research Fellow has acquired a strong intellectual knowledge and practical skills which have allowed him to consolidate his future career.
See Webpages at: http://www.birmingham.ac.uk/research/activity/chemistry/Davies/index.aspx(opens in new window)