Organoautocatalysis: Challenges for experiment and theory
© Tsogoeva; licensee BioMed Central Ltd. 2010
Received: 18 April 2010
Accepted: 18 August 2010
Published: 18 August 2010
Recent reports about enantioselective organoautocatalytic systems, in which small organic molecules assist in their own formation and under conservation of their absolute configuration, are discussed. This process, appearing as a natural extension to non-covalent enantioselective organocatalysis, seems analogous to template-directed self-replication, previously observed in simple organic molecules and holds implications for models on the origin of life.
The idea that molecules could make countless exact copies of themselves offers fascinating prospects in materials science and holds interesting implications for the origin of life on earth. Oparin was the first to realize the importance of self-replication for life processes [1, 2]. Self-replication appeared for a long time to be a sole domain of RNA and DNA molecules replicating via enzymatic pathways , until the pioneering studies of von Kiedrowski [4–7], who first demonstrated that oligonucleotides could self-replicate even non-enzymatically via template-directed autocatalysis. Self-replication has been also invoked as an integral part of systems chemistry [8, 9].
The finding has been much debated. Challenged by Menger et al. [12, 13], who argued that the rate enhancement is due to amide-catalysis and not due to template-autocatalysis, Rebek's interpretation of self-replication has been vindicated by Reinhoudt's group later . Since then, a few other scattered reports about self-replicating molecules have appeared in the literature [15–18].
The potential enantioselectivity of the self-replicating autocatalytic process was implied, but has not drawn particular attention at that time.
This mechanistic proposal has a high appeal, because it is resembling existing mechanistic concepts for classical non-covalent (enantioselective) organocatalysis [32, 33]. Further evidence supporting this idea was found by DFT computations, which allowed to locate the transition state structures for this transformation.
This mechanism, extended to account for the chirality of the template , provides a simple explanation for the observed chiral induction in the organoautocatalytic Mannich reaction: selective transition state structures (where the chiral product template catalyzes formation of new product molecules of the same absolute configuration) may yield homochiral dimers, while antiselective transition state structures (where the product template catalyzes formation of new product with opposite absolute configuration) may yield heterochiral dimers. For the Mannich reaction, the formation of homochiral dimers in the autocatalytic step was indeed found to be kinetically preferred, in accord with the observed enantioselectivity .
Furthermore, such organoautocatalytic reactions should involve merely linear autocatalysis (unlike to Soai's example) in the light of lacking coordination sites at a metal allowing to form multiple catalytic aggregates. Linear autocatalysis alone, though, cannot result in the observed asymmetric amplification .
Hence, to explain the unprecedented spontaneous mirror symmetry breaking observed in the Mannich reaction , Ribó and co-workers proposed the reversible exergonic formation of a heterochiral dimer of the product autocatalyst , resulting in mutual inhibition of autocatalyst formation through reduction of the antipode's concentration - in analogy to the seminal theoretical proposal of such spontaneous asymmetric amplification by Frank in 1953 . However, such thermodynamically stable dimers were not yet located computationally or observed experimentally for this reactive system. As an alternative, recycle kinetics, involving endergonic formation of labile heterochiral dimers which take part in closed reaction loops, was invoked recently to explain the observation of spontaneous mirror symmetry breaking in such formally closed reversible (homogenous) reactive systems [30, 37]. Non-equilibrium quasi-steady states might form temporarily in open subsystems of closed systems and with cyclic kinetics [37, 38]. A related theoretical model was also forwarded by Plasson and co-workers, wherein it was proposed that a non-spontaneous reactant recycling step could be driven through coupling to an external source of energy [39, 40]. This situation might apply to several biochemical reaction cycles, driven e.g. by hydrolysis of energy rich compounds.
The generality of asymmetric organoautocatalysis in various organic reactions is conceivable. It might be expected, that this phenomenon may be demonstrated for other reactions than the Mannich reaction in the near future.
Seemingly, presumably well-understood organic reactions appear to have much more complicated mechanisms, than previously expected. This poses a challenge for further mechanistic investigations of organoautocatalytic reactions, both experimentally and theoretically. Classical existing mechanistic concepts may not be sufficient to allow yet a full understanding of all the processes involved. There is no doubt, that the further insights gained will be of great value for the synthetic community both in research laboratories and in industry. A further related enticing prospect might be the deeper understanding of the fundamental question of biological homochirality.
The author gratefully acknowledge financial support from the Deutsche Forschungsgemeinschaft through SPP 1179 "Organocatalysis" and COST Action on Systems Chemistry CM0703.
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