Final Report Summary - ALKENESTOAMINOACIDS (Organic synthesis for chemical biology: enantioselective synthesis of α-amino acids from terminal alkenes using gold catalysis and investigation into the selective functionalisation of proteins)
For the outgoing phase of my IOF, I worked in the group of Prof. F. Dean Toste at the University of California Berkeley, investigating the application of a novel strategy for asymmetric catalysis based on chiral anion phase-transfer catalysis, employing chiral phosphate catalysts.
One of the key strategies envisioned for enantioselective induction in the IOF project proposal was the use of chiral counterions with gold metal catalysts as previously developed in the Toste group (Science, 2007, 317, 496-499), with the intention of asymmetrically functionalising alkenes. However, between the submission of the proposal and commencement of work on the project, the group of Prof. Toste made an exciting breakthrough in discovering that chiral counterions can be used in the absence of a metal catalyst to enable highly enantioselective electrophilic functionalisation (specifically fluorination) of alkenes (Science, 2011, 334, 1681-1684).
In accordance with the novelty of this exciting new area of research in which the precious metal is no longer required, we envisaged that the goals of the project may be more effectively met using these new insights and thus the use of gold to enable to enantioselective catalysis may be unnecessary. Such an advance would make the chemistry developed more sustainable, economical and likely to be adopted by the wider community. Particularly, the introduction of fluorine into small organic molecules is of great interest for two reasons: firstly due to the positive impact on pharmacokinetic properties which it generally confers in pharmaceutical molecules and secondly due to the use of 18F radiolabelling in medical imaging. For these reasons, the development of new ways to introduce fluorine will have a profound influence on a number of aspects of medicine. The initial proof-of-concept was made around the time of my arrival in the group and since that time I have played a leading role in exploring the possibilities of this versatile methodology. I have developed an highly asymmetric fluorination of ketone-derived enamides (J. Am. Chem. Soc, May 2012) as well as related aldehyde derived enamides (Angew. Chem. Int. Ed., August 2012), both giving versatile α-fluoro imine precursors to medicinally important β-fluoroamines. I also took the leading role in authoring a review discussing the emerging area of asymmetric catalysis utilising chiral anions (Nature Chem., July 2012). I subsequently developed a highly enantioselective fluorinative dearomatisation of simple phenols (J. Am. Chem. Soc, Jan 2013). This type of direct dearomatization is highly challenging in an asymmetric sense and holds promise for synthesis of fluorinated natural product analogues, as demonstrated in our publication. Furthermore, phenols bearing pendant electron-rich alkenes were discovered to undergo fluorination/elimination to give allylic fluorides with high enantioselectivity (Proc. Natl. Acad. Sci. USA, August 2013). I have extended the methodology to encompass asymmetric α-fluorination of simple ketones, which is a challenging but potentially highly useful transformation for asymmetric fluorination. This was made possible by the use of two chiral catalytic cycles working in harmony – an enamine catalysis cycle and a chiral anion phase-transfer catalysis cycle. With the enantiomers of the two catalysts matched very high enantiomeric excesses were able to be obtained (J. Am. Chem. Soc, March 2014). Most recently, I have coauthered a comprehensive invited review on asymmetric fluorination with several colleagues, currently under review (Chem. Rev., Late 2014). My work has also been featured in a patent relating to chiral anion-phase transfer catalysis as a general method for asymmetric fluorination (WO 2013/096971). I have presented my work at four conferences (three oral and one poster presentation). In the return phase of the fellowship, my work has been aiming at transferring expertise and knowledge gained from the outgoing phase of the fellowship back to the host institution, and fostering strong links between the University of Cambridge and the University of California, Berkeley via the host groups. To this end, very encouraging results have been obtained when applying asymmetric catalysis to the delivery of aromatic groups to a number of scaffolds. This was chemistry originally developed in Prof. Matthew Gaunt’s group in a racemic sense. Expertise gained in the outgoing phase has been applied to this area and the results obtained are not yet ready for public disclosure but will hopefully be in the not too distant future.
With the IOF providing a great vehicle to develop a strong track record to provide the basis for an academic career within the EU, I have been successful in securing a Royal Society University Research Fellowship to commence independent research at the University of Cambridge, from October 2014.
One of the key strategies envisioned for enantioselective induction in the IOF project proposal was the use of chiral counterions with gold metal catalysts as previously developed in the Toste group (Science, 2007, 317, 496-499), with the intention of asymmetrically functionalising alkenes. However, between the submission of the proposal and commencement of work on the project, the group of Prof. Toste made an exciting breakthrough in discovering that chiral counterions can be used in the absence of a metal catalyst to enable highly enantioselective electrophilic functionalisation (specifically fluorination) of alkenes (Science, 2011, 334, 1681-1684).
In accordance with the novelty of this exciting new area of research in which the precious metal is no longer required, we envisaged that the goals of the project may be more effectively met using these new insights and thus the use of gold to enable to enantioselective catalysis may be unnecessary. Such an advance would make the chemistry developed more sustainable, economical and likely to be adopted by the wider community. Particularly, the introduction of fluorine into small organic molecules is of great interest for two reasons: firstly due to the positive impact on pharmacokinetic properties which it generally confers in pharmaceutical molecules and secondly due to the use of 18F radiolabelling in medical imaging. For these reasons, the development of new ways to introduce fluorine will have a profound influence on a number of aspects of medicine. The initial proof-of-concept was made around the time of my arrival in the group and since that time I have played a leading role in exploring the possibilities of this versatile methodology. I have developed an highly asymmetric fluorination of ketone-derived enamides (J. Am. Chem. Soc, May 2012) as well as related aldehyde derived enamides (Angew. Chem. Int. Ed., August 2012), both giving versatile α-fluoro imine precursors to medicinally important β-fluoroamines. I also took the leading role in authoring a review discussing the emerging area of asymmetric catalysis utilising chiral anions (Nature Chem., July 2012). I subsequently developed a highly enantioselective fluorinative dearomatisation of simple phenols (J. Am. Chem. Soc, Jan 2013). This type of direct dearomatization is highly challenging in an asymmetric sense and holds promise for synthesis of fluorinated natural product analogues, as demonstrated in our publication. Furthermore, phenols bearing pendant electron-rich alkenes were discovered to undergo fluorination/elimination to give allylic fluorides with high enantioselectivity (Proc. Natl. Acad. Sci. USA, August 2013). I have extended the methodology to encompass asymmetric α-fluorination of simple ketones, which is a challenging but potentially highly useful transformation for asymmetric fluorination. This was made possible by the use of two chiral catalytic cycles working in harmony – an enamine catalysis cycle and a chiral anion phase-transfer catalysis cycle. With the enantiomers of the two catalysts matched very high enantiomeric excesses were able to be obtained (J. Am. Chem. Soc, March 2014). Most recently, I have coauthered a comprehensive invited review on asymmetric fluorination with several colleagues, currently under review (Chem. Rev., Late 2014). My work has also been featured in a patent relating to chiral anion-phase transfer catalysis as a general method for asymmetric fluorination (WO 2013/096971). I have presented my work at four conferences (three oral and one poster presentation). In the return phase of the fellowship, my work has been aiming at transferring expertise and knowledge gained from the outgoing phase of the fellowship back to the host institution, and fostering strong links between the University of Cambridge and the University of California, Berkeley via the host groups. To this end, very encouraging results have been obtained when applying asymmetric catalysis to the delivery of aromatic groups to a number of scaffolds. This was chemistry originally developed in Prof. Matthew Gaunt’s group in a racemic sense. Expertise gained in the outgoing phase has been applied to this area and the results obtained are not yet ready for public disclosure but will hopefully be in the not too distant future.
With the IOF providing a great vehicle to develop a strong track record to provide the basis for an academic career within the EU, I have been successful in securing a Royal Society University Research Fellowship to commence independent research at the University of Cambridge, from October 2014.
