- Open Access
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.
- Oparin AI: The Origin of Life. Rabochii, Moscow; 1924.Google Scholar
- Orgel LE: Molecular replication. Nature 1992, 358: 203–209. 10.1038/358203a0View ArticleGoogle Scholar
- Joyce GF: RNA evolution and the origins of life. Nature 1989, 338: 217–224. 10.1038/338217a0View ArticleGoogle Scholar
- von Kiedrowski G: A Self-Replicating Hexadeoxynucleotide. Angew Chem Int Ed 1986, 25: 932–935.View ArticleGoogle Scholar
- von Kiedrowski G: Templates, autocatalysis and molecular replication. Pure Appl Chem 1996, 68: 2145–2152. 10.1351/pac199668112145Google Scholar
- Sievers D, von Kiedrowski G: Self-replication of complementary nucleotide-based oligomers. Nature 1994, 369: 221–224. 10.1038/369221a0View ArticleGoogle Scholar
- Patzke V, von Kiedrowski G: Self-replicating systems. ARKIVOC 2007, 5: 293–310.Google Scholar
- Ludlow RF, Otto S: Systems Chemistry. Chem Soc Rev 2008, 37: 101–108. 10.1039/b611921mView ArticleGoogle Scholar
- Peyrelans JJP, Otto S: Recent highlights in systems chemistry. Curr Opin Chem Biol 2009, 13: 705–713. 10.1016/j.cbpa.2009.08.006View ArticleGoogle Scholar
- Tjivikua T, Ballester P, Rebek J Jr: Small molecule self-replication. J Am Chem Soc 1990, 112: 1249–1250. 10.1021/ja00159a057View ArticleGoogle Scholar
- Nowick JS, Feng Q, Tjivikua T, Ballester P, Rebek J Jr: Kinetic studies and modeling of a self-replicating system. J Am Chem Soc 1991, 113: 8831–8839. 10.1021/ja00023a036View ArticleGoogle Scholar
- Menger FM, Eliseev AV, Khanjin NA: "A self-replicating system": new experimental data and a new mechanistic interpretation. J Am Chem Soc 1994, 116: 3613–3614. 10.1021/ja00087a063View ArticleGoogle Scholar
- Menger FM, Eliseev AV, Khanjin NA, Sherrod MJ: Evidence for an alternative mechanism to a previously proposed self-replicating system. J Org Chem 1995, 60: 2870–2878. 10.1021/jo00114a043View ArticleGoogle Scholar
- Reinhoudt DN, Rudkevich DM, de Jong F: Kinetic analysis of the Rebek self-replicating system: is there a controversy? J Am Chem Soc 1996, 118: 6880–6889. 10.1021/ja960324gView ArticleGoogle Scholar
- Lee DH, Granja JR, Martinez JA, Severin K, Ghadiri MR: A self-replicating peptide. Nature 1996, 382: 525–528. 10.1038/382525a0View ArticleGoogle Scholar
- Quayle J, Slawin A, Philp D: A structurally simple minimal self-replicating system. Tetrahedron Lett 2002, 43: 7229–7233. 10.1016/S0040-4039(02)01613-1View ArticleGoogle Scholar
- Rubinov B, Wagner N, Rapaport H, Askhenasi G: Self-replicating amphiphilic β-sheet peptides. Angew Chem Int Ed 2009, 48: 6683–6686. 10.1002/anie.200902790View ArticleGoogle Scholar
- Li T, Nicolaou KC: Chemical self-replication of palindromic duplex DNA. Nature 1994, 369: 218–221. 10.1038/369218a0View ArticleGoogle Scholar
- Alberts AH, Wynberg H: The role of the product in carbon-carbon bond formation: stoichiometric and catalytic enantioselective autoinduction. J Am Chem Soc 1989, 111: 7265–7266. 10.1021/ja00200a059View ArticleGoogle Scholar
- Soai K, Niwa S, Hori H: Asymmetric self-catalytic reaction. Self-production of chiral 1-(3-pyridyl)alkanols as chiral self-catalysts in the enantioselective addition of dialkylzinc reagents to pyridine-3-carbaldehyde. J Chem Soc Chem Commun 1990, 982–983. 10.1039/c39900000982Google Scholar
- Soai K, Shibata T, Morioka H, Choji K: Asymmetric autocatalysis and amplification of enantiomeric excess of a chiral molecule. Nature 1995, 378: 767–768. 10.1038/378767a0View ArticleGoogle Scholar
- Shibata T, Morioka H, Hayase T, Choji K, Soai K: Highly enantioselective catalytic asymmetric automultiplication of chiral pyrimidyl alcohol. J Am Chem Soc 1996, 118: 471–472. 10.1021/ja953066gView ArticleGoogle Scholar
- Soai K, Shibata T, Sato I: Enantioselective automultiplication of chiral molecules by asymmetric autocatalysis. Acc Chem Res 2000, 33: 382–390. 10.1021/ar9900820View ArticleGoogle Scholar
- Mislow K: Absolute asymmetric synthesis: A commentary. Collect Czech Chem Commun 2003, 68: 849–863. 10.1135/cccc20030849View ArticleGoogle Scholar
- Puchot C, Samuel O, Dunach E, Zhao S, Agami C: Nonlinear Effects in Asymmetric Synthesis. J Am Chem Soc 1986, 108: 2353–2357. 10.1021/ja00269a036View ArticleGoogle Scholar
- Blackmond DG, McMillan CR, Ramdeehul S, Schrom A, Brown JM: Origins of asymmetric amplification in autocatalytic alkylzinc additions. J Am Chem Soc 2001, 123: 10103–10104. 10.1021/ja0165133View ArticleGoogle Scholar
- Buono FG, Blackmond DG: Kinetic evidence for a tetrameric transition state in the asymmetric autocatalytic alkylation of pyrimidyl aldehydes. J Am Chem Soc 2003, 125: 8978–8979. 10.1021/ja034705nView ArticleGoogle Scholar
- Schiaffino L, Ercolani G: Amplification of chirality and Enantioselectivity in the asymmetric autocatalytic Soai reaction. ChemPhysChem 2009, 10: 2508–2515. 10.1002/cphc.200900369View ArticleGoogle Scholar
- Mauksch M, Tsogoeva SB, Martynova IM, Wei S: Evidence of Asymmetric Autocatalysis in Organocatalytic Reactions. Angew Chem Int Ed 2007, 46: 393–396. 10.1002/anie.200603517View ArticleGoogle Scholar
- Mauksch M, Tsogoeva SB, Martynova IM, Wei S: Demonstration of spontaneous chiral symmetry breaking in asymmetric Mannich and aldol reactions. Chirality 2007, 19: 816–825. 10.1002/chir.20474View ArticleGoogle Scholar
- Mauksch M, Wei S, Freund M, Zamfir A, Tsogoeva SB: Spontaneous mirror symmetry breaking in the aldol reaction and its potential relevance in prebiotic chemistry. Orig Life Evol Biosp 2010, 40: 79–91. 10.1007/s11084-009-9177-2View ArticleGoogle Scholar
- Etzenbach-Effers K, Berkessel A: Noncovalent Organocatalysis Based on Hydrogen Bonding: Elucidation of Reaction Paths by Computational Methods. Topics Curr Chem 2009, 291: 1–27. full_textView ArticleGoogle Scholar
- Prins LJ, Reinhoudt DN, Timmerman P: Noncovalent Synthesis Using Hydrogen Bonding. Angew Chem Int Ed 2001, 40: 2382–2426. Publisher Full Text 10.1002/1521-3773(20010702)40:13<2382::AID-ANIE2382>3.0.CO;2-GView ArticleGoogle Scholar
- Hochstim AR: Nonlinear mathematical models for the origin of asymmetry in biological molecules. Orig Life Evol Biosph 1975, 6: 317–366. 10.1007/BF01130337View ArticleGoogle Scholar
- Crusats J, Hochberg D, Moyano A, Ribó JM: Frank model and spontaneous emergence of chirality in closed systems. ChemPhysChem 2009, 10: 2123–2131. 10.1002/cphc.200900181View ArticleGoogle Scholar
- Frank CF: On spontaneous asymmetric synthesis. Biochim Biophys Acta 1953, 11: 459–463. 10.1016/0006-3002(53)90082-1View ArticleGoogle Scholar
- Mauksch M, Tsogoeva SB: Spontaneous emergence of homochirality via coherently coupled antagonistic and reversible reaction cycles. ChemPhysChem 2008, 9: 2359–2372. 10.1002/cphc.200800226View ArticleGoogle Scholar
- Qian H: Open-System Nonequilibrium Steady State: Statistical Thermodynamics, Fluctuations, and Chemical Oscillations. J Phys Chem B 2006, 110: 15063–15074. 10.1021/jp061858zView ArticleGoogle Scholar
- Plasson R, Bersini H, Commeyras A: Recycling Frank: Spontaneous emergence of homochirality in noncatalytic systems. Proc Natl Acad Sci 2004, 101: 16733–16738. 10.1073/pnas.0405293101View ArticleGoogle Scholar
- Plasson R: Energetic and entropic analysis of mirror symmetry breaking processes in recycled microreversible chemical systems. J Phys Chem B 2009, 113: 3477–3490. 10.1021/jp803807pView ArticleGoogle Scholar
- Amedjkouh M, Brandberg M: Asymmetric autocatalytic Mannich reaction in the presence of water and its implication in prebiotic chemistry. Chem Commun 2008, 3043–3045. 10.1039/b804142nGoogle Scholar
- Wang X, Zhang Y, Tan H, Wang Y, Han P, Wang DZ: Enantioselective Organocatalytic Mannich Reactions with Autocatalysts and Their Mimics. J Org Chem 2010, 75: 2403–2406. 10.1021/jo902500bView ArticleGoogle Scholar
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