Investigating Asymmetric Catalytic Dihalocyclopropanation

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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.