Investigating Asymmetric Catalytic Dihalocyclopropanation

Lead Research Organisation: University of Nottingham
Department Name: Sch of Chemistry


Note: in this summary the footnotes, shown in square brackets thus [a] etc.., are only for lay scientific readers. Those with an academic chemistry background should ignore them.

2012 is the 150th anniversary of the reaction of chloroform (CHCl3) with sodium hydroxide. This reaction is a versatile source of the carbene CCl2, that readily undergoes cyclopropanation with alkenes [a]. Unfortunately, despite 60 years of 'modern' research attempting to 'entrap' free CCl2 (or its cousins CF2 and CBr2), or to release them in suitable chiral [b] environments, absolutely no success has been realised in selective chiral addition of CX2 units to one of the two faces of prochiral alkenes [c]. There is a general belief that such reactions are 'impossible' due to the exceptionally high reactivity of free CX2 compared to any of its derivatives. The lack of a suitable catalytic asymmetric reaction is highly regrettable as the derived chiral cyclopropanes often have biological activity, that is intimately dependent on their chiral 'shape'. There is a pressing need to overturn this established dogma by finding an alternative approach to using indiscriminate 'CX2' carbenes in these reactions - by attaining a fundamental new mechanism that avoids them completely. Hints in the primary literate indicate that this is a way forward - the immediate precursors to 'CX2' are CX3- anions and these have appreciable lifetimes and suitable reactivity to certain alkenes. Under appropriate catalysis these anions add to electron deficient alkenes [d] faster than free CX2 is formed or direct cyclopropanation of such alkenes. Our research will focus on designing new catalytic cycles whereby CX3- or CX2(LeavingGroup)- anions undergo conjugate addition to electron deficient alkenes leading to an intermediate that loses the leaving group generating the cyclopropane indirectly [e]. This approach has not been attempted before, for dihalocyclopropanation, but there are sufficient clues in the literature to show it is valid idea. If this mechanism can be turned into a very efficient process, with suitable chiral derivatives, then new routes for effective asymmetric dihalocyclopropanation will become available to pharmaceutical chemistry [f].

[a] A carbene is a carbon atom with only 2 attached substituents (as opposed to the normal 4). Cyclopropanation is the formation of 3-membered rings (in this case from CCl2 and a derivative of CH2=CH2).
[b] Chiral objects are related as non super imposable mirror images - your hands are a good example. Many drug molecules are chiral and the two mirror images can have profoundly different effects, e.g. one mirror image of Ethambutol cures TB, the other causes blindness.
[c] A substituted alkene (e.g. RCH=CH2) has two equivalent surfaces to its central pi (=) bond. Reaction at one with CX2 generates the opposite mirror image to the other; controlling this is very challenging.
[d] An alkene as in [c] were the R group removes electron density from the central pi (=) bond.
[e] A 'leaving group' is part of the molecule that can be easily displaced. Addition of CX3- (or indeed, many other anions) to the terminus of an electron deficient alkene.
[f] Pharmaceutical chemistry is the use of chemistry to produce 'drug' molecules primerily for human health.

Planned Impact

The absence of any effective chemical catalytic method to prepare enantiomerically enriched dihalocyclopropance means that, should an effective catalytic method be developed, that access to previouly unattainable chiral derivatives will become available. Over 2400 patents describe dihalogenocyclopropanes in the SciFinder database while Reaxys describe >600 pages of data related to cyclopropane biological data. Of over 45000 compounds in these two databases, at a conservative estimate, <1% have ever been prepared in an enantiomerically enriched form. An ability to dihalocyclopropanate even a small sub-set of the potential alkene precursors planned in our research would be significant.

Who will benefit from this research?
All chemists interested in the preparation and use of dihalocyclopropane cores for further synthesis/application. Immediate applications in insecticides, enzyme inhibitors and other bio-medical uses already exist in crop, animal and human health companies both in the UK and globally. In the longer term applications for organic materials and organic electronics can be envisaged - the lack of suitable general asymmetric catalytic processes has disfavoured their use.

How will they benefit from this research?
This grant sets itself the tough challenge of overturning established dogma in a quite mature area - there is simply not an effective chemical process to deliver these molecule with high (well indeed any) enantioselectivity at present. The history of asymmetric catalysis tells us that the establishment of a new efficient process breeds a legion of applications (cf. Asymmetric epoxidation, dihydroxylation, enamine/iminium organocatalysis, etc.). A new dihalocyclopropanation paradigm would place the UK at the leading edge of a new global economic sector enhancing quality of life, health and creative output in this niche. The aim of our application is not that this can be achieved in a single bound but to show that conjugate addition of polyhalomethyl anions is a viable way to reactivate an area which has practically become an academic 'no go zone'. The translation of initial fundamental results into application might well take 5 years post project. The staff working on this project will also have long-term impact as normally postdoctoral co-workers from my group have entered the European chemical employment sector with some becoming academics in their own right.
Description Access to a reagent, Me3SiCCl3, that can act as a nucleaophilic souce of trichloromethyl anions for conjugate addition has been developed. We found at the end of the grant that we could also prepare Me3SiCCl2Br and that is a good reagent for dichlorocyclopropnation (no enantioselective version possible) - a 'hot paper' in Chem. Eur. J. (Chem. Eur. J. 2016, 22, 7609-7616).
Exploitation Route The reagents have become used and commercially available, see:
Sectors Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology

Description The compound TMSCCl2X (X = Br, Cl) has been sold in small amounts (through Key Organics; and
Sector Other
Impact Types Economic

Title Efficient route to TMSCCl3, TMSCCl2Br 
Description Efficient route to previously poorly prepared TMSCCl3, TMSCCl2Br 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Reagent being used based on citations, we have also commercialized these reagents with Key Organics Ltd see: and 
Description Key Organics Ltd 
Organisation Key Organics Ltd
Country United Kingdom 
Sector Private 
PI Contribution Use of DABAL-Me3 at scale and commercial sale at scale.
Collaborator Contribution Advice 'open innovation' partnership with ourselves and Aesica
Start Year 2012
Description University of Cádiz 
Organisation University of Cadiz
Country Spain 
Sector Academic/University 
PI Contribution We have been informally collaborating with Dr Maria Jesus Duran Pena since 2015 on identifying new methods for cyclopropanes and their use.
Collaborator Contribution Dr Maria Jesus Duran Pena, was able to visit the UK on a Fellowship and contributed to a publication (Chem. Eur. J. 2016, 22, 7609-7616). We hope to repeat this.
Impact Chem. Eur. J. 2016, 22, 7609-7616
Start Year 2015