Absolute asymmetric synthesis in enantioselective autocatalytic reaction networks: theoretical games, speculations on chemical evolution and perhaps a synthetic option.

DOI: 10.1002/chem.201404534

Review

& Absolute Asymmetric Synthesis

Absolute Asymmetric Synthesis in Enantioselective Autocatalytic Reaction Networks: Theoretical Games, Speculations on Chemical Evolution and perhaps a Synthetic Option Josep M. Rib ,*[a, b] Celia Blanco ,[c, d] Joaquim Crusats ,[a, b] Zoubir El-Hachemi ,[a, b] David Hochberg,[c] and Albert Moyano[a] Dedicated to the memory of Dr. Dagmar Vedrilla († 2014), a synthetic chemist who departs hating chemistry, but who loved this review

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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Review Abstract: The Soai reaction and the Viedma deracemization of racemic conglomerate crystal mixtures are experimental pieces of evidence of the ability of enantioselective autocatalytic coupled networks to yield absolute asymmetric synthesis. Thermodynamically open systems or systems with non-uniform energy distributions may lead to chiral final states and, in systems able to come into thermodynamic equilibrium with their surroundings, to kinetically controlled

absolute asymmetric synthesis. The understanding of network parameters and of the thermodynamic scenarios that may lead to spontaneous mirror symmetry breaking (SMSB) could assist in the development of new methods for asymmetric synthesis and enantioselective polymerizations (e.g., replicators), and to frame reasonable speculations on the origin of biological homochirality.

1. Introduction In a thermodynamically controlled transformation between or leading to an enantiomer pair (R, S) the chemical equilibrium ratio of the concentrations of the enantiomers is given by Equation (1): ½R DG ¼ expð Þ RT ½S

Table 1. Dependence of the enantiomeric excess (ee) on the free energy difference exerted by a chiral polarization on the enantiomers: thermodynamic control, Equation (1); kinetic control, Equation (2).

ð1Þ

In Equation (1), DG8 is the difference in free energy between the two enantiomers, which is zero in the absence of any discrimination arising from an enantiospecific interaction with a chiral nonracemic external agent, and expresses the fact that the equilibrium composition of a mixture of interconverting enantiomers is the racemic one. Enantiomeric ratios different from unity can be obtained, however, when a chiral polarization (chiral dopant, chiral media or a physical field’s chiral influence) exerts a diastereomeric discrimination upon the enantiomeric pair. However, only significant diastereomeric interactions can lead to enantiomeric excesses (ee) that are useful from the point of view of asymmetric synthesis (see Table 1).

[c] Dr. C. Blanco , Dr. D. Hochberg Department of Molecular Evolution Centro de Astrobiologa CSIC-INTA Ctra. Ajalvir km. 4, 28850 Torrejon de Ardoz, Madrid (Spain) [d] Dr. C. Blanco Present address: Department of Chemistry and Biochemistry University of California Santa Barbara, CA 93106-9510 (USA) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404534.

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1.0 1.1 1.5 3.0 10.0 100 500

0.0 4.8 20.0 50.0 81.8 98.0 99.6

0.00 0.24 1.01 2.74 5.74 11.49 15.50

ð2Þ

Notice that an analogous relationship applies to kinetic resolutions of the two enantiomers of a starting racemic mixture with a chiral resolution agent, because the ratio kR/kS gives the selectivity factor of the resolution and this depends only on the difference between the activation free energies for the reaction of each enantiomer with the resolution reagent. Advances in the field of the enantiocontrolled synthesis of chiral compounds have mainly focused, in the past 25 years, on asymmetric catalysis, which has generated an impressive arsenal of enantioselective synthetic methodologies.[2] In this context, the detection of nonlinear effects of (pre)catalyst enantiomeric excess on product enantioselectivity is the subject of much ongoing interest.[3] It is important to bear in mind, however, that the phenomenon of nonlinear effects in enantioselective catalysis does not necessarily imply a breakdown of the basic paradigms [Equations (1) and (2)] of asymmetric synthesis, since in most instances, it can be accounted for by the existence of dynamic equilibria between the monomeric catalyst and homochiral and heterochiral aggregates,[3c] by the establishment of diastereomeric associations of precata-

[b] Prof. J. M. Rib , Dr. J. Crusats , Dr. Z. El-Hachemi Department of Organic Chemistry University of Barcelona c. Mart I Franqus 1, 08028 Barcelona, Catalonia (Spain)

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DG8 or DDG [kJ mol1]

½R kR DDG6¼ ¼ ¼ expð Þ RT ½S kS

[a] Prof. J. M. Rib , Dr. J. Crusats , Dr. Z. El-Hachemi , Prof. A. Moyano Institute of Cosmos Science University of Barcelona (IEEC-UB) c. Mart I Franqus 1, 08028 Barcelona, Catalonia (Spain) E-mail: [email protected]

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ee [%] at 300 K

termining reaction steps have to be transformed into diastereomeric ones by the action of a chiral polarization. The enantiomeric ratio of the product [R]/[S] is given[1] by Equation (2), where kR and kS are the rate constants for the formation of R and S, respectively, and DDG is the free energy difference between the two transition states.

In the case of a kinetically controlled reaction leading to a chiral compound from achiral reagents (negligible backward reaction rates on the time scale of the bench experiment), the basic paradigm of asymmetric synthesis assumes that in order to obtain a nonracemic product, the corresponding pair of enantiomorphic transition states in the rate- and product-de-

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[R]/[S] at 300 K

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Review lytic species with different reactivities,[3a] or by the different solubility of the racemic crystals compared to the enantiopure crystals,[3d, e, h] processes for which the selectivity of the asymmetric catalysis step still obeys Equation (2). Some physical fields can establish a free energy difference between enantiomers [Eq. (1)] or between enantiomeric transition states [Eq. (2)].[4] However the number of such natural chiral fields is not large, and from the point of view of asymmetric synthesis, the resulting energy differences are exceedingly low. Notably, several of the reports on absolute asymmetric synthesis based on chiral effects of natural physical fields (see, for example, ref. [4b]) do not correspond to any scenario defined by Equations (1) and (2), but rather to the kinetically controlled selective destruction of one of the enantiomers. Therefore, absolute asymmetric synthesis,[5] understood as a reaction that, starting from achiral compounds or from racemic

mixtures, yields a reaction residue with natural optical activity, that is, a scalemic mixture, under the influence exerted by certain physical fields, has been considered as an intriguing but less interesting part of the subject of chiral induction in applied organic synthesis. This, in spite of the fact that the topic is of paramount importance for the understanding of the emergence of biological homochirality.[6] However, there is an increasing number of experimental examples[7–9] on the spontaneous emergence of chirality either in kinetically controlled transformations or in thermodynamically controlled scenarios [spontaneous mirror symmetry breaking (SMSB)][10] that correspond to true absolute asymmetric synthesis and that do not conform to the paradigms of asymmetric synthesis [Equations (1) and (2) and Table 1]. The Soai reaction[7] (Scheme 1) shows that enantioselective autocatalysis may lead, under an adequate experimental proce-

Celia Blanco de Torres defended her Ph.D thesis in physics from the Complutense University, Madrid in 2014 under the supervision of Dr. David Hochberg. She has worked on problems ranging from mirror symmetry breaking in chiral polymerization, in co-polymerization, in crystallization of glycine and alpha-amino acids at air–water interfaces, to templating effects, beta-sheet controlled copolymerization, chemical and chiral oscillations, chiral excursions, and more recently, on spontaneous mirror symmetry breaking in various models based on limited enantioselectivity, which under certain circumstances (out-of-equilibrium systems), provide an alternative to Frank’s classic model.

David Hochberg was born in Miami (USA) in 1957. He earned a B.A. in Physics in 1979 from the University of California, Berkeley and a Ph.D in Physics from the University of Chicago (1984). He is a founding member of the Centro de Astrobiologa (CSIC-INTA; Madrid) where he is a permanent research scientist, his research interests include symmetry breaking processes in the physics of complex systems, and spontaneous mirror symmetry breaking in chemical systems.

Albert Moyano was born (in 1955) and educated in Barcelona. He graduated with a degree in chemistry from the University of Barcelona (1978), where he also obtained a Ph. D. in Organic Chemistry, under the guidance of Prof. Flix Serratosa. After a postdoctoral position with Prof. Andrew E. Greene at the University in Grenoble (1985–1986), he returned to the University of Barcelona, where he has been a Professor of Organic Chemistry since 2003. His current research interests are centered on the development of new methods of organocatalytic asymmetric synthesis, and the study of asymmetric autocatalysis and of spontaneous symmetry-breaking processes.

Joaquim Crusats studied Chemistry at the University of Barcelona (1984–1989) where he received his Ph.D. degree in 1996 carrying out research in the laboratory of Prof. J. M. Rib. He then conducted research on the reactivity of porphyrins at Kyoto University (Japan) in the group of Prof. H. Ogoshi (1996–1997) as a joint EU/JSPS postdoctoral fellow. He became Assistant Professor at the Department of Physical Chemistry working with Prof. F. Sagus (2002–2004) in the field of selforganizing systems. He then rejoined the Department of Organic Chemistry under the Spanish Ramn y Cajal program (2004–2006) where he is currently an Associate Professor.

Josep M. Rib was born in Barcelona in 1940. His academic career has taken place entirely at the University of Barcelona, where he was a Full Professor of Organic Chemistry since 1989 and has been Emeritus since 2011. His research interests in chronological order from 1970 have been: natural products, oligopyrrole chemistry (reactivity and structure), polypyrroles as organic conducting polymers, selfassembly of amphiphilic porphyrins, supramolecular chirality, and spontaneous mirror symmetry breaking in chemical processes.

Zoubir El-Hachemi was born in Tangier (Morocco). From 1991 to 1995 he studied chemistry at the Ttouan University (Morocco). In 2002 he received his Ph.D. in Organic Chemistry under the supervision of Prof. Josep M. Rib, studying the self-assembly of porphyrins. From 2000 to 2007 he worked as an Assistant Professor in the Department of Organic Chemistry at the University of Barcelona. In 2008, he joined the Centro de Astrobiologa (CSIC-INTA; Madrid) in the group of Dr. S. Veintemillas-Verdaguer. His current interests include the effect of chiral polarization forces on processes that undergo chiral symmetry breaking.

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Scheme 1. Soai autocatalytic reaction.[7]

dure, to ee values close to 100 % even when starting from a nominally racemic mixture of product/catalyst. In the absence of any chiral polarization the “racemic outcome” corresponds to the set of a high number of batches with stochastic chiral sign distribution. This stochastic sign distribution of chiral signs can be transformed into a deterministic one under the action of a very weak chiral polarization, for example by cryptochiral additives such as 13C and 18O isotopic chiral compounds.[7e, f] Note that such “chiral inductions” in the Soai reaction cannot be explained by Equations (1) and (2) because of the spontaneous emergence of chirality and because the free energy differences for an effective chiral polarization is several orders of magnitude lower than those given by Equation (2) [Table 1]. The Soai reaction is a well-studied case but it is no longer the sole example of an experimental report on the spontaneous emergence of chirality in chemical transformations. Tsogoeva and co-workers described this phenomenon both in Mannich and aldol reactions (Scheme 2),[8] although the yields obtained do not meet the standards necessary for applied organic synthesis and further work would be necessary. The findings are of interest because they indicate that results similar to those of the Soai reaction may be obtained in other transformations implying the nucleophilic addition to a prochiral p carbon–heteroatom bond. The so-called Viedma deracemization (Scheme 3) is another well-established experimental realization of SMSB:[10] racemic conglomerate crystal mixtures of achiral or chiral compounds that undergo rapid racemization in solution deracemize by wet grinding[9a–e, h, i , k] or under the effect of temperature gradients.[9f, j, n–p] Apparently, the phenomenon does not seem to be related to a chemical reaction network, but in fact the Viedma deracemization can be actually described as a polymerization/depolymerization enantioselective autocatalytic network that includes the necessary stages for SMSB.[11]

Scheme 3. Viedma deracemization of a racemic conglomerate crystal mixture of an achiral or racemizing compound in solution. Mechanical grinding and spatio/temporal temperature gradients of solutions of crystals in contact with its saturated solution, leads to crystal mixtures with ee values mostly indistinguishable from homochirality. The graphic at the top shows the types of systems able to show Viedma deracemization. The graphic at the bottom depicts the experimental Viedma grinding procedure. Reproduced with permission from Ref. [9b].

These experimental instances of absolute asymmetric synthesis do not bear a direct relationship with the possible reactions that could have led to biologically significant chiral compounds. However, regarding the questions of the emergence of chirality during the chemical evolution on Earth, before the evolution of living systems, and the onset of biological homochirality, a full understanding of the conditions allowing SMSB in chemical synthesis is needed to develop any reasonable speculations on such central questions. We review here enantioselective autocatalytic systems that may lead to the emergence of chirality as a collective macroscopic phenomenon that determines that a chiral outcome can be more stable than a racemic one. In particular, we will see that in closed systems under a uniform temperature/ energy distribution and for relatively high exergonic transformations, one may obtain kinetically controlled absolute asymmetric syntheses, which are resilient to racemization. These reaction networks in open systems, that is, subjected to experimental constraints that do not allow the conditions for attaining Gibbs thermodynamic equilibrium, may lead to thermodynamically controlled absolute asymmetric synthesis. This occurs in the absence of any external chiral polarization, because the coupled reaction network is able to amplify the extremely low enantiomeric excess (ee), initiated by statistical fluctuations from the ideal racemic composition,[12, 13] to detectable ee values of stochastic sign distribution between experiments. However, weak chiral external polarizations may lead to a deterministic chiral sign.[14] Here we discuss how the transverse understanding of correlations between theoretical and experimental reports could lead to significant advances not only in the topic of the emergence of biological homochirality, but also in the development of new practical methodologies for asymmetric synthesis.

Scheme 2. Aldol and Mannich reactions reported[8] to show SMSB.

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Review 2. Thermodynamic scenario for spontaneous mirror symmetry breaking (SMSB) in chemical reactions

racemization. In this respect, perhaps the clue for understanding the emergence of biological homochirality is to assume Life’s enantioselective autocatalytic cycles as partial or “fossil remains” of the processes that led to the emergence of chirality in the course of prebiotic chemical evolution. The experimental proof for the understanding of all these points must arise from crucial experiments in absolute asymmetric synthesis, which, in addition, could be instrumental for the development of new methodologies in applied asymmetric synthesis. In this respect, the few recent pieces of evidence in absolute asymmetric synthesis in enantioselective autocatalytic reaction networks, need to be soundly correlated with the theory of SMSB. Thus, it is important to establish the necessary elements and trends of the reaction network architecture in its interactions with the surroundings for yielding absolute asymmetric synthesis. Importantly, since autocatalytic cycles are the accepted kernel for processes believed relevant for the emergence of life, the inclusion of enantioselectivity in such models could lead to a reasonable explanation for the emergence of biological homochirality.

The thermodynamic equilibrium state (maximum entropy and zero entropy production) for any reactive achiral system leading to chiral products, and in the absence of any chiral polarization, is the racemic mixture. However, equilibrium thermodynamics applies only to systems without state variable fluxes between the system and its surroundings, it therefore excludes common chemical scenarios such as those of closed systems showing permanent energy exchange with the surroundings or non-uniform temperature distributions, and open systems (matter exchange with the surroundings). These systems when near to their final state, can be studied within the framework of a reformulation of Gibbs thermodynamics for irreversible processes that assumes linear relationships between chemical rates and their driving forces (linear thermodynamics of irreversible processes):[15] the final state, that is, the “equilibrium” in these conditions, is the one that shows a minimum entropy production rate (dissipative system). In linear thermodynamics of irreversible processes, micro-reversibility constraints apply as in the case of Gibbs thermodynamics.[15] Therefore, at first glance it could seem that also in the case of linear thermodynamics of irreversible processes, any reaction system affording chiral products would lead to a racemic mixture. However, for some enantioselective autocatalytic networks, for specific values of the system parameters, the most stable final stationary state may be chiral, that is, one of two degenerate enantiomeric states (scalemic or homochiral).[16] Simulations of SMSB, such as the examples based on chemical kinetics discussed in this Review, may be open to criticism regarding the description of the early dynamic stages of the system,[17, 18] especially when the initial concentrations are very different from those of the final state, but not in terms of the description of the stability of the final state. The proposals for the emergence of chirality in chemical evolution are mostly based on reaction–diffusion processes, that is, under conditions of non-uniform distribution of matter, yielding dissipative spatio-temporal structures.[19] These chemical scenarios correspond to far from equilibrium conditions of high concentrations of species with low diffusion rates compared to their reaction rates, that is, to scenarios not following linear thermodynamics. Such reaction–diffusion scenarios do not suffice to describe the emergence of homochirality on Earth, that necessarily implies solution reaction scenarios: most of the reactions relevant to prebiotic chemical evolution on Earth should have occurred in water at low concentrations of reactants of low molecular weight, and thus they cannot lead to spatio/temporal dissipative structures.[20] A reasonable speculation on the emergence of homochirality in the chemical evolution on Earth must be able to justify the fact that homochiral or scalemic states, not racemic ones, are the most stable outcomes in solution chemistry. It is surely significant that in present day life racemization occurs when the network of chemical reactions is broken down (death), but that in a basal biological regime there is a chiral stationary state resilient to Chem. Eur. J. 2014, 20, 1 – 23

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2.1. Autocatalysis and enantioselective autocatalysis Autocatalysis: Autocatalyses are defined as reactions in which the reaction product catalyzes its own production and this contribution is higher than those of other non-autocatalytic reactions of the system.[21] It should be noted that this is not a mechanistic definition but a pure kinetic definition[21d] as described by Equation (3) (see Figure 1), d½Xi ¼ kðXÞXin þ f ðXÞ dt

ð3Þ

where X is the vector of all species concentrations contributing to the formation of compound xi, therefore the term k(X) is not necessarily a reaction rate constant because it also includes the effects of other species acting in the reaction mechanisms yielding the kinetic/dynamic autocatalytic signature. The first term in Equation (3), for n > 0, corresponds to an autocatalytic contribution and the effects of other species acting in the reaction mechanisms, yielding a kinetic/dynamic autocatalytic signature. The first term in Equation (3), for n > 0, corresponds to an autocatalytic contribution and the second term to the remainder of contributions to the concentration of xi. When the autocatalytic contribution dominates [k(X) @ f (X)] the dynamic change of xi displays, instead of the concave shape of common reactions such as those of the second term, an Sshaped growth due to the autocatalytic rate acceleration. The dynamic change expressed as the change of log[Xi] with time depends on n: convex shape for n < 1 and a concave one for n > 1 (see Figure 1).[21d] This transition from a concave to a convex shape expresses the selectivity of the autocatalysis. Only concave log[Xi] versus time shapes (values of n > 1) are able to lead to the selection of its final product over the other autocatalyses fed by the same starting compounds.[21b, 22, 23] Therefore, the dynamic signature, the expression of the value n (called here the autocatalytic order) defines the ability of the 5


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Review tions may also yield an autocatalytic evolution on Xi. This happens, for example, for the coupled reaction network given in Equation (6) (see Ref. [21d]). Ai þ C Ð M M Ð Xi þ E E Ð Xi

ð6Þ

Xi Ð C

Figure 1. Mechanistic, kinetic and dynamic descriptions of autocatalysis (AC) according to Plasson et al.[21d] (reproduced and adapted with permission from Ref. [21d]). The graphs correspond to the time evolution of a non-autocatalytic reaction (n = 0, red), and of autocatalytic reactions of order n = 1/2 (green), 1 (blue), 3/2 (dotted red), 2 (dotted green), and 3 (dotted blue). For the meaning of k(X) and f(X) see text.

mechanism of direct autocatalysis given by Equation (4). The discussion here is only centered on direct autocatalysis mechanisms as a reductionist approach of other possible, more involved autocatalytic mechanisms. Autocatalytic orders larger than unity are rare in solution chemistry, because the most simple case of Equation (4) (m = 1) is already a bimolecular reaction and molecularities higher than 2 for an elementary step in a reaction mechanism are unlikely. Determining path reaction rates of high molecularity ( 3) are expected to occur in the case of very high concentrations or in viscous media constituting reaction–diffusion systems leading to spatio/temporal structures that do not follow the mean field assumption of chemical kinetics. In this respect, the objective of the present discussion is devoted to absolute asymmetric synthesis in the mean field chemical kinetics assumption, and for reaction rates slower than the diffusion rates of the reacting species in solution. Enantioselective autocatalysis: In the case of enantioselective autocatalysis, we have two enantiomeric autocatalytic reactions, for example in the case of the transformation of an achiral compound A into the enantiomeric pair R/S through a direct autocatalysis mechanism [Eq. (7)]:

system for selectivity. Obviously for an autocatalytic reaction that takes place under experimental conditions able to achieve thermodynamic equilibrium conditions, the thermodynamically controlled output is that given by the ratios of the DG8 values, as in the case of other non-autocatalytic reactions, that is, either racemic or chiral-shifted in the case of permanent chiral induction. Previous reports on the selectivity of autocatalytic systems were based on mechanisms assuming an irreversible rate-determining step, that is, under the assumption of infinite ergocity, which has been the choice approximation in chemistry for analyzing kinetically controlled transformations. As we shall discuss below, in systems unable to achieve thermodynamic equilibrium with their surroundings, such a kinetic control is transformed into a thermodynamic control of the final stationary state. The most simple mechanistic expression of a system leading from a compound A to a reaction product X by autocatalysis is direct autocatalysis [Eq. (4)]. A þ mXi Ð ðm þ 1ÞXi

ð4Þ

This would account for the first term of Equation (3) and the non-autocatalytic background reaction (5), A Ð Xi

A þ mR Ð ðm þ 1ÞR

ð5Þ

A þ mS Ð ðm þ 1ÞS

for the more reasonable assumption of a contribution to the second term. In this case the autocatalysis order (n) is the same as the stoichiometry term (m) in Equation (4). For a bimolecular autocatalysis then m = n = 1, and the dynamics of log[Xi] will be a convex one (Figure 1), unable to survive in competition with other autocatalyses of the order of n > 1. The S-shaped plot of [Xi] versus time, which constitutes the dynamic signature of autocatalysis, is not only achieved by the direct autocatalysis reaction (4), but networks of coupled reac&

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The autocatalytic order depends on the molecularity of the rate-determining step and on its stoichiometry with respect to the other reactions of the network, and therefore fractional autocatalytic orders are possible. In fact most of the actual autocatalyses correspond to complex networks and not to the simple

ð7Þ

The more reasonable reactions competing with Equation (7), that is the contributions to the second term of Equation (3), are the non-autocatalytic background reactions (8) and the non-enantioselective autocatalyses, that for m = 1 are given by Equation (9). AÐR AÐS 6

ð8Þ



Review AþRÐRþS

the system, the racemic stationary state becomes metastable and the more stable final states are the two degenerate enantiomeric ones. This competition between two degenerate autocatalyses was called bistability in some previous reports,[24] using the systems biology terminology in the species selection topic. Notably, when such a SMSB occurs, the influence of a chiral polarization does not follow the selectivity ratios given by Equation (2). The ratio between the final products depends now on a more complex relationship than that of the ratio of rate constants between two elementary reactions, and it is much more sensitive to chiral inductions. An important point, with regards to the micro-reversibility constraints of linear thermodynamics is that the DG8 of reactions (7), (8), and (9), although corresponding to different reaction paths and mechanisms, must be the same.

ð9Þ

AþSÐRþS

Autocatalytic enantioselectivity implies the competition between the two degenerate autocatalyses of Equation (7). For an enantioselective autocatalysis of the order of n 1 no selectivity can occur by itself (see below for what occurs by the coupling with some specific reactions) between the two degenerate autocatalytic manifolds, and the reaction outcome cannot attain an ee higher than that of the initial conditions. This means that in the best case, either in open or in closed systems that are unable to achieve thermodynamic equilibrium with their surroundings, neither racemization nor ee amplification will be attained, and that in closed systems with a uniform temperature distribution the final output will be racemic, once thermodynamic equilibrium is achieved. Such systems can display the autocatalytic dynamic signature in the global production of chiral substances, even in the racemization when starting from a high initial ee, but not in the chiral amplification. For autocatalytic orders of n > 1 [in the case of the direct autocatalysis mechanism given in reaction (7) for n = m 2], for Gibbs thermodynamic equilibrium conditions, the final state must be necessarily racemic, but for relatively highly exergonic transformations, kinetically controlled amplification of chirality may be possible. In such cases the kinetic signature of autocatalyses will be observed in the amplification of the ee. Such reaction networks in closed systems may show chiral excursions before reaching thermodynamic equilibrium (transformation in an isolated system). However, such systems may show SMSB (final ee ¼ 6 0) in closed systems having a non-uniform distribution of temperature/energy or in open systems, that is, in systems that cannot reach thermodynamic equilibrium with their surroundings. This occurs because for specific parameters of

2.1.1. Ability of enantioselective autocatalysis for the amplification of chirality in closed and in open systems Some previous reports (for example, Ref. [25]) had assumed that the emergence of biological homochirality could be explained by an enantioselective autocatalytic transformation such as that in reaction (7) of the order m = 1. However, such an autocatalysis, when not coupled to a heterochiral reaction between product/catalysts (see below), cannot amplify any initial ee either in closed nor in open systems. Enantioselective autocatalysis of the order of n > 1, that is, for m 2 in the case of the direct mechanism of reaction (7), may lead to temporary chiral amplifications in closed systems. Obviously these amplifications correspond to kinetically controlled processes, whose outcomes depend on the initial concentrations of products/ catalysts, and the time frame in which the systems are not racemic increases with the exergocity of the transformation. Nu-

Figure 2. Evolution of the species concentration and of the ee in the case of the enantioselective autocatalysis reaction (7) in closed systems (kea = 1: kea = 1 104) [a) m = 1; b) m = 2; c) m = 4] accompanied by a much slower non-autocatalytic transformation reaction (8) (kna = 1 105 : kna = 109). Initial concentrations: [A]0 = 1 m; two columns on the left) high initial concentration of products/catalysts and high ee: [R]0 = 0.10 m, [S]0 = 0.11 m; two columns on the right) high initial concentrations of products/catalysts and very low ee: [R]0 = 0.1 m, [S]0 = ([R]0 + 1 1014) m. Chem. Eur. J. 2014, 20, 1 – 23

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Review mass. This is because this final state is the more stable state merical simulation examples of this are shown in Figure 2 for for these system parameters and experimental conditions.[27] a relatively high exergonic transformation (ki/k-i = 10 000: at 1 300 K, DG8 22 kJ mol ): following direct enantioselective auMicro-flow chemistry, recently introduced in synthetic methodtocatalysis reaction (7) and for several orders of m [Figure 2 a, ologies, allows the experimental implementation of open flow m = 1; Figure 2 b, m = 2; Figure 2 c, m = 4]. The examples conditions at the bench, as exemplified in the simulation of assume the presence of a much slower non-autocatalytic transFigure 4. In the example of Figure 4, the SMSB corresponding formation (8). When under the initial conditions the concentrato the final steady state would be achieved after approximately tion and the initial ee of products/catalysts are not very low, seven days and a consumption of 12 mmol of both A and B. the autocatalysis of the order m = 1 is only able to maintain However, the continuous production (94 % yield and ee > 99 %) the initial ee during a certain time (Figure 2, two left-hand colof the final state would also be achieved when the initial conumns).[26] However, autocatalyses of higher order may show in ditions correspond to the reactor primed at the concentrations of the final stationary state. In spite of the fact that a continuclosed systems temporary chiral amplifications. At initial condious flow reaction can be of interest for applied organic synthetions of significant concentration of products/catalysts sis, it is not quite adequate for the analysis of autocatalysis in (Figure 2 two right-hand columns) the magnitude of the chiral biological cyclic reaction networks,[28] which are based on low amplification is similar in all the range of possible initial ee values; that is, for a very low initial ee the final ee remains in exergonic auto-reproductive cycles driven by external reagents, the very small ee range (see the two right-hand columns in that is, on the compartmentalization of reactions and surFigure 2). When starting at low concentrations of products/catrounding interactions through selective membranes. alysts, the initial autocatalytic reaction rate can be slower than It is worth noting that enantioselective autocatalysis of such that of the non-enantioselective transformation (8), so that inihigh molecularities able to lead to SMSB are unlikely to be reatial racemization dominates upon a possible amplification sonable reactions in the framework of linear thermodynamics. effect of reaction (7) (see Figure 3). In summary, high order autocatalyses are of low interest, even theoretically, as candidates for absolute asymmetric synthesis. The reaction networks capable of showing kinetically controlled huge chiral amplifications in closed systems when they are in an open flow may lead to a ther- Figure 3. Example of the system in Figure 2 b (m = 2) when starting at very low concentrations of products/catafor statistical fluctuations from the ideal racemic composition: modynamically controlled final lysts and an10ee below the values expected [R]0 = 1 10 m, [S]0 = ([R]0 + 1 1022) m. Under these initial conditions simulating the initial conditions of the abchiral state, that is, to absolute sence of final products at chiral statistical fluctuations,[18] fast racemization occurs before achieving the transforasymmetric synthesis (SMSB). mation of A. Similar results are obtained for the systems in Figure 2 a and 2c (m = 1 and 4, respectively). Figure 4 shows a simulation of this for the case of an open flow reactor scenario (constant input of a solution of the initial reaction product and the same volume output of reaction mixture) for an enantioselective autocatalysis of the order of m = 2 in an addition reaction between two achiral compounds (A and B) creating a stereogenic center. After a relatively long induction time, due to the low rate of high order autocatalysis in the initial absence or low concentrations of products/catalysts, a chiral non-racemic state is obtained. Notably, the final concentrations, Figure 4. Open flow simulation of SMSB for an enantioselective autocatalysis of the order of m = 2 (a trimolecular that is, the final state although order reaction!). A final chiral stationary state, close to homochirality, is obtained once the reactor is primed. The time to achieve this depends on the initial ee: in the example it corresponds to an initial ee below the range of stationary, are the same for any the chiral fluctuations about the ideal racemic composition.[18] Reaction parameters are: k1 = 1 105, initial concentrations when start- km1 = 1 1010, k2 = 10, km2 = 1 104. Initial conditions in the reactor: [A]o = [B]o = 0.1 mol L1; [R]o = 1 1010 ; ing with the same total chemical [L]o = [R]o + 1 1022. &

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Review Asymmetric autocatalytic reactions are scarce and probably none of them are of the order > 1, or of an equivalent order for other autocatalytic mechanisms, able to lead to the selection of one of the two enantiomeric manifolds, therefore a SMSB due exclusively to an “isolated” autocatalytic reaction probably does not exist.

R þ S Ð RS

When this meso-dimer can revert to the monomers in the treatment of the reaction crude, the total ee (eetotal) will decrease but not the reaction yield. Figure 5 compares the same closed systems of Figure 2 when they are coupled to a mutual inhibition reaction (12) faster than the enantioselective autocatalysis (7). Now the systems, also for values below the critical value of the autocatalytic order able to amplify chirality (m 1 for reaction (7)), may yield high ee values when starting from initial ee values initiated by the statistical fluctuations of the racemic composition. The examples of Figure 5 indicate that such a system would lead to a kinetically controlled absolute asymmetric synthesis of potential practical use in synthesis: this is not only due to the huge chiral amplifications—from chiral statistical fluctuations to significant ee values—but also because the timeframe of the high ee is longer than in the absence of reaction (12). In summary, the principal characteristics of this kinetically controlled chiral amplification, due the metastability of the racemic state compared to the two degenerate chiral states, are:

2.2. Effect of the coupling of enantioselective autocatalysis with a heterochiral reaction between products/catalysts: The inhibition stage The enantioselective autocatalysis of low order [0 < n 1, that is m = 1 in the case of reaction (7)] cannot yield, by itself, any chiral amplification. However, when coupled to a heterochiral reaction between products/catalysts leading to a decrease of the racemic composition,[29] it may lead to absolute asymmetric synthesis: kinetically controlled in closed systems and thermodynamically controlled in open systems, or in closed systems with non-uniform temperature/energy/matter distribution. In spite of the lack of mathematical proof and theoretical studies on the effect of such coupling with an inhibition stage, they very probably transform the dynamic signature of log[ee] to a convex one (Figure 1). We can classify the inhibition stages in two types. The Frank mutual inhibition[30] (10) and the limited enantioselective inhibition (LES):[14e, 31, 32] in Frank mutual inhibition (10), the reaction between the two enantiomers of product/catalyst leads to an achiral addition product (P), which leads to a decrease in the racemic composition of the system and the increase of the ee value. When this occurs at a rate faster than the enantioselective autocatalysis, a cooperative effect occurs in the amplification of the initial ee value. In the LES model the racemic composition decreases thanks to the different total rates of the enantiomeric reactions (11) [M is an achiral compound] when ee > 0: RþSÐP

a) High ee values are obtained when starting with chiral fluctuations from the ideal racemic composition: increases of 15 orders of magnitude in the examples of Figure 5 a and Figure 5 b. Notably, when the contribution of the achiral dimer is taken into account, the total ee (eetotal) decreases, but it remains in the same temporal range of ee values. b) Highly autocatalytic orders at low concentration of products/catalysts in closed systems cannot lead to these huge kinetic chiral “amplifications” at low initial ee values (Figure 5 c, right), because the autocatalytic reaction rate is much slower than the racemization of the system by the contributions of the second term of Equation (3), for example the reaction shown in Figure 4 c (m = 4: two right-hand columns). In actual systems the statistical fluctuations of chirality will most likely be too fast to be “detected” when the absolute rate of the enantioselective autocatalysis is very low. c) The “amplified” ee value remains constant, at the level of the experimental detection, for a relatively long time. This chiral window is larger when the exergocity of the transformation increases and when the non-autocatalytic reaction (8) is much slower than reaction (7). Notably, for a weakly exergonic transformation this timeframe will be too narrow for any practical application in asymmetric synthesis, and in the case of very high exergocities, the chiral window would be in the range of geological time scales. d) A similar effect is observed when the simulations maintain the ideal racemic composition but the rate constants for the two enantiomers are slightly different. This simulates the effect of asymmetric inductions, such as those of chiral media, chiral doping or chiral physical fields in the case of the strict absence of any statistical fluctuation of chirality. The effect of such chiral inductions is already detected for

ð10Þ

SþRÐRþM

ð11Þ

RþSÐSþM

2.2.1. Frank mutual inhibition The so-called Frank network[30] is composed of an enantioselective autocatalysis, of the order n = 1, coupled to a reaction of mutual inhibition such as that given in Equation (10). The original report assumes totally “irreversible” reactions,[33] that is, infinite exergocity, which for a closed system in the frame of the microreversibility principle would lead to a kinetically controlled absolute asymmetric synthesis. Later reports[28, 34] recognized how the Frank network, for reactions showing non-zero reverse reaction rates, may also yield in open systems a thermodynamically controlled absolute asymmetric synthesis (SMSB). We consider here that the achiral product of the Frank inhibition stage [P in reaction (10)] is the heterochiral (meso) dimer: Chem. Eur. J. 2014, 20, 1 – 23

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ð12Þ

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Figure 5. Simulations in a closed system of the same examples as in Figure 2 [a) m = 1; b) m = 2; c) m = 4] when coupled to the mutual inhibition reaction (12) (ki = 1 104 : kmi = 10). Initial concentration [A]0 = 1.00 m. Two left-hand columns) high initial concentrations and high ee of products/catalyst [R]0 = 0.10 m, [S]0 = 0.11 m. Two right-hand columns) the case of simulation of absence of products/catalysts and chiral statistical fluctuations from the ideal racemic composition:[19] [R]0 = 1 1010 m, [S]0 = ([R]0 + 1 1022) m. The total ee (eetotal) refers to the ee calculated when the separation method allows one to revert the dimer RS of reaction (10) to the monomeric enantiomers. See Ref. [34] for details. The examples correspond to a moderately exergonic reaction (DG8 23 kJ mol1 at 300 K).

DDG values many orders of magnitude smaller than those necessary for the classical chiral inductions (Table 1). In fact, the difference in reaction rate constants for yielding chiral amplifications such as those of Figure 4 a and 4 b correspond to DDG values similar to those expected for the DG8 differences between enantiomers induced by the parity violation of the weak force in the formation of atomic nuclei.[36] In our opinion, the effect of moderately fast statistical fluctuations from the ideal racemic composition gains the upper hand over such exceedingly low energy differences between enantiomers.

Figure 6 compares, for such an open system, the effect of the mutual inhibition stage on the reaction outcome of a direct enantioselective autocatalysis (7) of the order m = 1: the examples refer to initial conditions simulating the absence of products/catalysts and an ee value of the order of the statistical fluctuations. As discussed above, in the case of the absence of the mutual inhibition reaction (12), no chiral amplification will occur: the final stationary state is racemic for any given set of system parameters (Figure 6, left). By contrast, in the case of the Frank system (Figure 6, right), the final stationary state may be chiral, but compared to the kinetically con-

Figure 6. Comparison of the effect of a Frank mutual inhibition in an enantioselective autocatalysis of the order of m = 1 in an open flow system. In the absence of the mutual inhibition reaction, racemization occurs for any initial ee (left-hand graphics). In the case of the coupled reaction network with a Frank mutual inhibition reaction (right-hand graphics), the final state may be chiral and with an ee experimentally indistinguishable from the homochiral composition. Such a final chiral state is obtained independently of the initial ee (for the same total chemical mass!). Reaction parameters are: k1 = 1 105, km1 = 1 1010, k2 = 10, km2 = 1 104, k3 = 1 104, km3 = 10. Initial conditions in the reactor: [A]o = [B]o = 0.1 mol L1; [R]o = 1 1010 ; [L]o = [R]o + 1 1022.

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Review surely more complex.[38] The analysis of this kind of models in coupled reaction networks is necessary to establish the relative contributions of the possible reactions in the system dynamics, that is, to the different contributions to Equation (3), a task that should be carried out prior to the examination of the reaction mechanisms. Several authors have summarized the principal trends of the Soai reaction (see for example Ref. [38e]). In what follows, we emphasize those characteristics that suggest that the Soai reaction can be described as a Frank-like reaction network taking place in a closed system giving rise to a kinetically controlled absolute asymmetric synthesis.

trolled chiral state obtained in closed systems (Figure 5), in the open system a thermodynamically controlled absolute asymmetric synthesis (SMSB) takes place. In this case, as expected for a final stable state of the system, the same final composition is obtained for any initial reagent and product concentrations (for the same total chemical mass!). In a Frank reaction network in an open flow system it is also possible to achieve SMSB for a low exergonic reaction: for example a similar system such as that of Figure 6 (right) showing the same forward rate constants but with k1/km1 = k2/km2 = 100, a state of similar final ee is obtained, but obviously in lower yield. In the Frank system of Figure 6 (right) the chiral stationary regime is achieved after three days and a consumption of 6 mmol of reactant ( 60 mL of solution), and the final stable regime yields compound S in 97 % yield and an ee > 99.98 % at a rate of 1.7 mmol per day. With respect to potential synthetic applications of such an open system, it is worth pointing out that the same yield and ee are obtained from t = 0 when the reactor solution is primed to the same initial concentrations as those of the final stationary state. In the case of the Frank system with mutual inhibition (12), we should assume in fact that the homochiral dimer is also formed to some extent [Eq. (13)]. 2R Ð R2

a) The relatively low ee values obtained in a single batch operation indicate that the efficiency of the system is decreased by the significant contribution of reactions such as the non-enantioselective autocatalysis (9) and the homochiral dimerization (13). b) The addition of a dialkylzinc species to a carbonyl group to give the zinc alkoxide is a highly exergonic transformation, that is it must lead to kinetically controlled outcomes. This occurs for most nucleophilic additions of organometallic compounds to the carbon–heteroatom double bond. On the other hand, the rate of the uncatalyzed addition of dialkylzinc is very low, so that the backward reaction of the non-catalyzed reaction (8) does not contribute significantly to the racemization. The asymmetric autocatalytic reaction (7) can overcome the deleterious contribution of the background reaction (8) in the second term of Equation (3). c) The non-enantioselective autocatalysis (9) is slower than the enantioselective one, but it plays a significant contribution in the formation of the final products, that is, it decreases the ability of the system to amplify chirality. d) The catalytic species is a chiral oligomer of the Zn alkoxide, and the enantioselective autocatalysis is more complex than that of a direct autocatalysis (7). The heterochiral dimerization of the catalysts could constitute the mutual inhibition stage. However, several experimental and theoretical reports point towards the similar stability of the homochiral and the heterochiral oligomer catalysts, which, in turn, implies an inefficient mutual inhibition stage.

ð13Þ

2S Ð S2

This latter reaction decreases the concentration of the catalysts but it does not change significantly the ee value of the monomeric catalysts. Nevertheless, it decreases the ability of the system to achieve an absolute asymmetric synthesis, because it decreases the contribution of the first term of Equation (3).[35] Furthermore, when the equilibrium constant for reaction (13) is higher than that of the heterochiral dimer, the role of reaction (12) in the reaction network is no longer effective. The simplest Frank-like network is that of reactions (7) + (12), but in real systems it ought to be assumed that reactions (8), (9), and (13) will also be present to some extent. These latter reactions have a deleterious role in the efficiency of system for absolute asymmetric synthesis, by virtue of the increase of the second term of Equation (3) and in the role of reaction (13) in its first term. Nevertheless, in the case of a relatively high exergonic transformation, such a system is able to lead to kinetically controlled absolute asymmetric synthesis,[35] and in an open system such as that shown in Figure 6 (right), it would lead to a true SMSB. In the following we discuss this for the case of the Soai reaction.

In our opinion, optimizations of the experimental conditions of the Soai reaction with the objective of reducing the contribution of reactions of the type (9) and (13) could lead to high ee values in a single batch reaction. However, this is likely to be a lengthy and cumbersome task. In this respect, it should be noted that only after patient work, could Soai’s group find the right conditions leading to the stochastic distribution of chiral signs of the product/catalyst when the reaction is run in the nominal absence of any chiral species. Without such effort, the dramatic character of absolute asymmetric synthesis, that is, that of the instability of the racemic final state, would have remained unknown and the Soai reaction would be simply classified as an enantioselective autocatalysis showing nonlinear amplification effects.

The Soai reaction: An experimental example of kinetic controlled absolute asymmetric synthesis of a Frank-like network The Soai reaction (Scheme 1) corresponds to a kinetically controlled absolute asymmetric synthesis that can be rationalized within the framework of a Frank-like network.[35, 37] Here we discuss the possible reactions forming the Soai reaction network, that is, a reductionistic model without consideration of more specific details of the reaction mechanism that are Chem. Eur. J. 2014, 20, 1 – 23

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Review which in addition to the reactions necessary for SMSB [reaction (7) of the order m = 1 and mutual inhibition (12)] shows a much slower non-autocatalytic reaction (8) and significant contributions of non-enantioselective autocatalysis (9) and homochiral dimerization (13). The same network simulated for a closed system, following the successive batch procedure, yields a kinetically controlled absolute asymmetric synthesis of similar ee after 4–5 successive batch additions (see Ref. [35]). 2.2.2. Limited enantioselectivity (LES) inhibition The inhibition stage of a Frank-like network assumes an enantiomeric discrimination in favor of the heterochiral interactions (DG8homo DG8hetero). Whereby the so-called limited enantioselectivity (LES) model that avoids such a constraint has been proposed.[14e, 30, 31] The inhibition stage is that of the reactions given in Equation (14).

Figure 7. Common procedure in the Soai reaction to achieve high final ee values. Reproduced with permission form Ref. [7b].

SþR!AþR

The Soai reaction requires an experimental procedure of successive batches starting at the same initial concentrations of reactants but using the final reaction mixture obtained in the previous batch (see Figure 7).[7] This implies successive increases of volume and chemical mass, or reduction of the reaction mass, which limits the practical use of the synthetic procedure. However, as has been pointed by Plasson and co-workers,[29] such a procedure is in fact an approximation to running the reaction in an open system. Therefore, the Soai reaction is a first candidate for absolute asymmetric synthesis in flow chemistry. Figure 8 shows an open flow simulation of the Soai reaction,

RþS!AþS

ð14Þ

Notably, reaction (14) is the backward path of the non-enantioselective autocatalysis (9). Therefore the coupling of reaction (9) to an enantioselective autocatalysis may lead to a mathematical SMSB. However, in a closed system the stability analysis of LES has demonstrated that the system parameters yielding such a SMSB can occur only through violations of the micro-reversibility principle.[31] The stability analysis of LES shows that SMSB can only occur when the rate of the backward reaction in (9) is faster than the backward reaction of the enantioselective autocatalysis (7); however, for autocatalytic exponential growth the forward reaction in (7) must be faster than that for (9), that is, reactions (7) and (9) should show different DG8, and this implies a violation of the micro-reversibility principle. In summary, in closed systems or in open systems of simple architectures, such as those of the examples of Figure 5, Figure 6, and Figure 8, kinetically or thermodynamically controlled absolute asymmetric synthesis based on a LES network are not possible. Nevertheless, recent reports show that in open systems of adequate architecture (for example cyclic and semipermeable to some reacting Figure 8. Simulation of the behavior in an open flow system of a possible network for the Soai reaction. The species) and in closed systems system leads to SMSB despite the significant contributions of the non-enantioselective autocatalysis and of the homochiral dimerization reactions. Yield and eetotal are calculated by assuming, and such as occurs in the Soai rewith non-uniform distribution of action, that in the separation method the oligomers of products/catalysts revert back to the monomeric species temperature and reacting spe5 10 4 6 (R and S). Reaction parameters are : k1 = 1 10 , km1 = 1 10 , k2 = 10, km2 = 1 10 , k3 = 0.1, km3 = 1 10 , cies (reaction compartmentalizak4 = 1 106, km4 = 1 103, k5 = 1 106, km5 = 1 102. Initial conditions in the reactor: [A]o = [B]o = 0.1 mol L1; tion at different temperatures), [R]o = 1 1010 ; [S]o = [R]o + 1 1022. &

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Review LES networks may also lead to thermodynamically controlled absolute asymmetric synthesis.[39] This SMSB is discussed in Sections 3.1. and 3.2.

talized in different temperature regions, with reaction (7) being located in the lower temperature compartment.[39c] The system corresponds basically to that shown in Scheme 4: there is continuous matter transfer between the two temperature regions, with the enantioselective autocatalysis (7) compartmentalized

3. Network architectures By “network architecture” we understand the specific ordering of the interactions of the system and the coupling of the reaction network with its surroundings. The simplest case of a system not able to establish thermodynamic equilibrium with its surroundings is a system with homogeneous distribution of chemicals showing a permanent temperature gradient. However, when the corresponding rate constants are simply those following the Arrhenius equation (Eyring theory) for chemical reactions, the micro-reversibility constraints, which determine the final formation of the racemic state, will remain unchanged. However, in the case that the external energy input is an energy uptake of only some of the chemical species of the system (for example, photochemically) the final state will lead to an “equilibrium” of the chemical transformation corresponding to a steady state (photo-stationary) of minimum entropy production. In the case of such a non-uniform temperature/energy distribution, SMSB may be possible in closed systems if such a specific energy is supplied to the adequate species of the reaction network. Notably, avoiding the conditions that can lead to thermodynamic equilibrium of the system with its surroundings does not in itself suffice for achieving SMSB, because although the final outcome will be a stationary state, it will not be necessarily chiral. In summary, for the design, search, and understanding of enantioselective autocatalytic reaction networks yielding SMSB, in addition to the reaction network and the kinetic and chemical parameters of the system, it is also important to take into account the interactions of the enantioselective autocatalysis and the inhibition stages (LES or Frank-like) with the system’s surroundings. Examples of this are discussed in the following Sections.

Scheme 4. System with permanently different temperature regions and compartmentalized enantio- and non-enantioselective autocatalysis able to lead to SMSB. For a simulation in which the autocatalytic processes are promoted by racemic pro-catalysts, see the Supporting Information.

in the low temperature region and the non-enantioselective autocatalysis (9) in the higher temperature one. This allows one to fulfill the general condition for SMSB in the LES model,[31] that is, that the backward reaction of (9) must have, and without violation of the micro-reversibility principle, a rate constant higher than that of the backward reaction of (7), and with the opposite trend holding for the forward reaction rates. A reasonable chemical scenario for this model can be imagined by assuming that the autocatalytic reactions (7) and (9) are promoted by immobilized catalysts located in different temperature regions (see the Supporting Information). The high temperature differences needed for such a SMSB model exclude its use in applied organic synthesis: the solvent must remain fluid (liquid or critical phases) at all the temperatures of the system, and this can be only achieved under very high pressure conditions. Nevertheless, with regards to abiotic chemistry, such uncommon experimental constraints fit those assumed for the Archean/Hadean ocean hydrothermal vents, which are scenarios of current interest for justifying the primordial stages of life’s evolution on Earth. The enantioselectivity for a transformation like reaction (7) can be obtained by the stereochemical effect of an external chiral catalyst, and several phyllosilicates are chiral. Note that for this mechanism, the external chiral catalyst acts in a racemic composition.[40] It is also worth noting that, in agreement with the required dependence of catalytic activities with the temperature, the phyllosilicate structure in water may be different depending on the temperature, and that enantioselectivity is expected to be lower at high temperatures. This means that the same type of material could exhibit a chiral structure at the low temperature

3.1. Closed systems with non-uniform temperature distribution Frank-like networks [composed by reactions (7) + (12) + (8)] of a highly exergonic transformation in a closed system with nonuniform temperature distribution do not exhibit a different behavior from those taking place at a uniform temperature distribution, that is, only a kinetically controlled absolute asymmetric synthesis may be obtained for exergonic reactions, as in the case of a uniform temperature distribution.[39a, b] This is so because the dependence of the reaction rate constants on the temperature and their ratios between forward and backward transformations are given by the Arrhenius and Helmholtz equations: the final outcome will be the same one as that resulting from the weighted average of the temperature sites and gradients in the system. However, it has been recently shown that LES may lead to thermodynamic controlled SMSB in a closed system with a non-uniform temperature distribution when the enantioselective autocatalysis (7) and the nonenantioselective autocatalysis (9) are individually compartmenChem. Eur. J. 2014, 20, 1 – 23

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Review region [promoting reaction (7)] and an achiral structure at the higher temperature [promoting reaction (9)]. The more significant result of this LES model is that SMSB occurs below a critical concentration value,[39a, b] that is, SMSB can occur at extremely high dilutions of reactants. To the best of our knowledge, this is in contrast to all previous Frank-like models of SMSB, where a critical chemical mass value determines the lower mass limit where SMSB may be obtained. Notice that high dilutions correspond to a realistic scenario for chemical evolution, where organic compounds from astrophysical origin are present in high diversity but in low concentrations.[41]

The results from the numerical simulations and stability analysis of these cycles show that SMSB may occur, both for Frank and for LES, for chemically reasonable system parameters. Cycles able to lead to SMSB, such as those in Scheme 4, can be also designed when, instead of an external reagent, a specific energy is given to the inhibition stage, for example photochemically (photostationary state). In some previous reports, in similar Frank-like cycles, such a specific energy input to only some species of the system was called “species activation”.[43] Figure 9 shows a numerical simulation of SMSB in a LES network [(7) + (16) + (8)] of the type of Scheme 5. In this example,

3.2. Cyclic Networks Frank-like networks in open systems[29] are well understood from a theoretical point of view but most of these systems are too complex for solving analytically the corresponding (linearized) differential equation systems needed for a stability analysis.[42] Recently, the stability analyses of SMSB in Frank and in LES cycles with an inhibition stage [reactions (14) and (15) respectively] reverting to the initial compound (A), have been reported.[39c] In particular, the reaction of products/catalysts with a reagent (X/Y) of constant X input and Y output (see Scheme 5) were studied.[39c] X þ S þ R Ð Y þ 2A

Figure 9. SMSB in LES for a non-exergonic transformation in an enantioselective autocatalytic cycle open to an external reagent X/Y (fixed at constant concentration simulates the constant input of X and the constant selective output of Y) that drives the inhibition stage towards the initial achiral compound A (adapted with permission from Ref. [39c]). Reaction parameters: k1 = km1 = 1 104, kea = kea = 10, kmi2 = 100, kmi2 = 5000. Initial conditions: [A]o = 0.1 mol L1, [R]o = 1 1010 ; [S]o = [R]o + 1 1022.

ð15Þ

a thermodynamically controlled absolute asymmetric synthesis is obtained in spite of the fact that the transformation from A ð16Þ to R or S is non-exergonic.[39c] The inhibition stage drives the XþSþRÐYþAþS cycle flow in the direction towards the initial achiral compound. In a related system, but with a Frank inhibition stage The autocatalytic cycle, being driven by the incoming and (15), SMSB was obtained for similar system parameters. outgoing of reagents X/Y, shows a directional flow of matter. As an example of a possible role of such cycles in prebiotic chemistry, a speculative cycle composed of a Strecker a-amino acid synthesis, a Strecker amino acid oxidative degradation has been proposed.[39c] SMSB was simulated by assuming the role of a racemic mediator/catalyst promoting enantioselective autocatalysis, either in the imino nitrile formation or at the amino acid hydrolysis. With respect to chemical evolution the significant point of the network architecture of autocatalytic cycles, such as those of Scheme 4, is their analogy to autocatalytic pre-metabolic cycles.[28] This would supScheme 5. Autocatalytic cyclic systems capable of yielding thermodynamically controlled SMSB (adapted with permission from Ref. [39c]). The same type of cycle able to yield port the idea of a correlation between the emerSMSB can be obtained for the two types of inhibition stage (Frank-like or LES). Solid gence of metabolic cycles and the emergence of chirarrows indicate the net flow direction in the cycle but each reaction path has a finite ality. In cycles of the type of Scheme 5 (see for exambackward reaction rate constant (reaction equations that proceed from right to left) in ple Figure 9), SMSB may occur for non-exergonic agreement with the constraints imposed by microreversibility. XþSþRÐYþAþR

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Review transformations as some of the reactions implied in metabolic cycles.[28d] Furthermore, the interaction with an external reagent as X/Y mediated by membranes is a characteristic of cellular compartmentalization. 3.3. Spontaneous mirror symmetry breaking in polymerizations Chirality is probably a necessary condition for sustaining life because of its strong relation to self-reproduction and enzymatic processes. This would imply that the conceivable ancestors of polypeptides and polynucleotides should have been already homochiral to be able to drive primordial life-like processes.[6] In this respect, modern abiogenic theories on the emergence of biological homochirality—life arising from enantio-riched compounds—are substituting previous biotic theories based on the selection between racemic primordial life systems.[6, 44] In the evolution from simple achiral compounds to homochiral enantiopure primordial life systems, a progressive increase of ee is the more reasonable assumption.[14e] In abiogenic theories, biopolymer homochirality could have arisen by polymerization from a pool of enantiopure building blocks or from enantioselective polymerizations showing SMSB. In summary, it is reasonable to speculate on prebiotic Earth scenarios of enantioselective polymerization networks capable of showing SMSB. Such polymerizations would be able to transfer chirality, to amplify it, and to be resilient to racemizations. In view of this, the search for polymerizations capable of showing absolute asymmetric synthesis is a central point in the topic of biological homochirality. All speculations on the emergence of chirality in polymerizations must first take into account the question of biopolymer stereoregularity. Early discussions on the topic were confronted with the low probability of obtaining racemic mixtures of isotactic peptides from a pool of racemic a-amino acids when assuming random monomer-to-polymer growth. However, in the last few years, several reports have shown that the formation of homochiral chains may be a favored process because of the preferential formation of a-helix and b-sheet structures which require isotacticity.[45] This not only drives polymerization towards the isotactic diastereoisomer but also justifies why the same tacticity is obtained for chains with different a-amino acid residues. The experimental results of some of these reports strongly suggest that stereoregular growth occurs as a consequence of cooperative template effects occurring above a critical size oligomer. It is worth noting that these cooperative effects can lead to autocatalytic kinetics for the polymer growth.[21, 46] Notably, autocatalytic cycles are common scenarios in theoretical and experimental reports for replicators and for the stereoselective growth of peptides and polynucleotides (see for example Scheme 6).[47] In all these autocatalytic cycles (and already in the seminal work by Eigen and Schuster[47a]) although enantioselectivity is not discussed it is implicitly assumed: the assumption of homochiral autocatalytic polymerization cycles implies that its enantiomeric counterpart can exist. Therefore, such an abiotic polymerization scenario could explain not only stereoregularity but also SMSB generated by Chem. Eur. J. 2014, 20, 1 – 23

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Scheme 6. Enantioselective autocatalytic cycle examples. Left) Eigen–Schuster theoretical hypercycle as a basis for reproductive and evolutive biological systems (homochirality implicitly assumed): reproduced with permission from Ref. [47a]. Right) Ghadiri experimental report on the stereoselective formation of a racemic mixture of homochiral peptides (TLL + TDD), compared to the diastereomeric mixture (TLD + TDL), by the enantioselective template effect of the final peptide on an initial racemic mixture of oligopeptides: reproduced with permission from Ref. [47e].

autocatalytic processes. Perhaps the present enantiopure autocatalytic cycles are the remains of the abiotic enantioselective processes that led to biological homochirality. The first attempt to describe an enantioselective autocatalytic growth coupled to an inhibition stage was made by Sanders on the basis of a Frank-like model based on an autocatalytic homochiral growth and a heterochiral cross inhibition.[48] The Sanders model has been the basis of several reports on similar polymerization networks.[49] Stability analyses of SMSB on these systems are not easy to carry out, but some simulations in closed systems on the stereoselectivity of the homochiral growth and of the consequences of template mechanisms are being reported (see for example Ref. [50]). 3.3.1. The Viedma deracemization as a model for Spontaneous mirror symmetry breaking in enantioselective polymerizations The Viedma deracemization[9, 11] occurs in systems of one chemical component (either an achiral or chiral compound undergoing fast racemization) that crystallizes as a racemic conglomerate, that is, as a racemic mixture of enantiomorphic crystals. The experimental conditions are those of a racemic crystal mixture in its saturated solution subject to grinding or temperature gradients. Some early reports had classified the Viedma phenomenon as a kinetically controlled process, but later ones have described it as a thermodynamically controlled process as a consequence of Ostwald ripening (higher stability of bigger crystals compared to the smaller ones due to surface energy differences). A discussion on the different models[9, 11, 51, 52] proposed to justify Viedma deracemization is beyond the scope of this Review. Here we discuss, in relation with the topic of this Review, the general scenario that describes the Viedma phenomenon as a thermodynamic absolute asymmetric synthesis under experimental conditions that prevent the system from reaching thermodynamic equilibrium.[11] The characteristics of 15


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Viedma deracemization than in standard crystallizations, because the supersaturation value is maintained constant over time (via grinding), in contrast with its rapid decay in common crystallizations.

i)

The experimental conditions (specific energy input only to visible crystals or non-uniform temperature distribution) are such that, in the framework of linear thermodynamics of irreversible processes, they lead necessarily to a final stationary state. According to the large number of experimental reports on the topic, it is easier to achieve a chiral final state than a racemic one. Therefore, the results agree with a bifurcation scenario of racemic instability leading to one of the two degenerate final chiral states. ii) As a consequence of the irreversible crystal grinding and the higher solubility of the smaller crystals, a final stationary state of crystal size distribution and continuous recycling of matter, from the solids to the solution and from the solution to the solids, is achieved. iii) Once the grinding has stopped, or a uniform temperature distribution is achieved, the system returns to conditions capable of leading to thermodynamic equilibrium. However, now this does not imply racemization: the scalemic (near to 100 % ee) crystal mixture cannot racemize, because the system is composed of a unique chemical compound and three phases, solution and two enantiomorphic solid phases.[51b] Notably, this is the expected ideal behavior for such a system: that is, a homochiral or a scalemic mixture of crystals of similar size in its saturated solution does not racemize.[51b, 53] The main arguments[11] that support the classification of the Viedma deracemization as a SMSB reaction in the framework of linear thermodynamics of irreversible processes are:

Bimolecular order in the cluster-to-cluster agglomeration would not suffice for SMSB, and all the simulations indicate that cross-inhibition, as expected for a Frank-like network, does not play a role in this SMSB, but that there is an inhibition stage consisting of the endergonic first steps of the two enantiomeric manifolds connected through the monomer:[11] the less populated enantiomeric manifold attempts to balance the concentration of clusters below the critical size with that of the majority manifold at the expense of its homochiral clusters above the critical size.[54] The significance for understanding the physical chemistry basis of the Viedma phenomenon is its extrapolation to SMSB in peptide and biopolymer polymerizations. For example, the experimental Gadhiri transformation[47e] of Scheme 6 (right) may be transformed into a SMSB system if the following features could be incorporated into the process (see Scheme 7):

Scheme 7. Description of a polymerization/depolymerization system, based on the same scenario as the Viedma deracemization, which could lead to SMSB. The lysis stage in the Viedma deracemization corresponds to the mechanical grinding of big crystals. Adapted and reproduced with permission from Ref. [11].

a) The DG8 of the aggregation process is described by the crystallization models in supersaturated solutions that define the critical size cluster given by the supersaturation value.[11, 51v] This determines both a cooperative exergonic aggregation after the critical size cluster and an endergonic aggregation before it. Scheme 7 (left) shows such a free energy profile in supersaturated solutions. This DG8 pattern is similar to that of cooperative polymerizations above a oligomer size capable of showing template or self-replicating behavior.[46] b) The enantioselective autocatalysis in the Viedma deracemization is given by a homochiral cluster-to-cluster growth mechanism.[11] This cluster-to-cluster aggregation (agglomeration) mechanism plays a more significant role in the &

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i) polymerization starts from an achiral or racemizing monomer and the first polymerization steps are both non-stereoselective (random) and weakly endergonic; ii) the final oligomer resulting for the template replication is depolymerized to some extent by an “external” reagent towards the homochiral oligomers which are the building blocks of the template mechanism. This depolymerization would play the role of the mechanical force of grinding of the Viedma deracemization, or that of the external reagent driving the autocatalytic cycles discussed in Section 3.2. For specific system parameters the racemic state would be destabilized and a chiral final state could be obtained.

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Review 3.3.2. Other scenarios for spontaneous mirror symmetry breaking in crystallizations and self-assembly aggregations

to attribute such phenomena to the intrinsically asymmetric nature of our Universe.[61] Other previous reports can also be explained through mixed scenarios. For example: i) in the Kondepudi experiments[57] it cannot be ruled out that the powerful ability for chiral amplification in the Viedma deracemization is not acting during the time range of the supersaturation before saturation is achieved; ii) there are SMSB reports concerning highly concentrated solutions leading to high ee, such as those of the eruptionlike crystallization of supersaturated boiling solutions[9j] and the crystallizations of supercooled viscous melts,[9m,p, 62] where perhaps the Viedma SMSB mechanism coexists with the formation of spatio-temporal inhomogeneous distributions governed by far from equilibrium nonlinear thermodynamics. Several organic materials obtained by self-assembly of achiral building blocks, when doped with a chiral compound, yield chiral aggregates.[63] In liquid thermotropic crystals, this has been mostly interpreted as the formation of a diastereomeric phase, or structure, for example going from an achiral nematic phase to a chiral cholesteric one. However, for many self-assembling materials, the formation of chiral particles (see for example Ref. [64]) or chiral domains, in the case of surfaces and layered structures,[65] is also observed in the absence of chiral polarizations and the effect of the chiral dopant is that leading to a high chiral bias or to domain homochirality. This would belong to scenarios similar to those discussed above in the crystallization of an achiral or racemizing compound yielding racemic conglomerates. In summary, all these points suggest that the same effects as those discussed for the crystallization of racemic conglomerates from achiral compounds, also occur in the self-assembly of soft matter. Another topic related to absolute asymmetric synthesis is that of chiral effects in supra- and macromolecular aggregates.[66] The paradigm is Green’s sergeant-and-soldiers principle, where a mesogen chiral center is able to “amplify” macromolecular helicity to many other sites supporting achiral substituents.[67] Notably, this involves a cooperative mechanism inside the chemical species. However, there is a lack of studies on the effect of external chiral polarizations upon such systems. In this respect there are some dramatic examples of supramolecular species not only sensitive to chiral molecular doping (down-to-up chiral effect) but also to the chiral forces originated by stirring flows in an up-to-down chiral induction (see works cited in the reviews of Ref. [68]). When these aggregates show elongated shapes, they may be aligned/oriented in laminar flows; that is, imperfect mixing[69] dominates over Brownian dynamics and dynamic separation, stereoselective, even enantioselective effects have been reported. Obviously, these reports belong to mixed scenarios implying successive or parallel stages and paths following kinetic and thermodynamically controlled transformations where autocatalytic enantioselective growth coupled to inhibition stages can lead to the spontaneous emergence of chirality. In spite of the interest of this topic, a detailed discussion of this subject lies outside the specific scope of this Review.

Absolute asymmetric transformations can also occur in competition or as part of successive stages showing distinct chiral effects, from chiral processes governed by nonlinear thermodynamics scenarios to simple chirality transfer. Well-known examples are found in the crystallization of achiral or of racemizing compounds yielding racemic conglomerates, that is, in the same systems that may show SMSB (Viedma deracemization). These previously reported chiral effects are: 3.3.2.1. Kinetic control: High ee values for the solid phase have been reported for chiral racemic compounds in solution by the slow growth of an initial Adam crystal (necessarily homochiral!), or of a few initial nuclei, and the replenishment of the enantiomer concentration by the solution equilibrium. This is the so-called “total spontaneous resolution of enantiomers”, based on the selective crystallization of one enantiomer nourished by displacing the enantiomer solution equilibrium.[55] The coupling of this to a diastereoselective reaction is used in asymmetric synthesis (see for example Ref. [56]). 3.3.2.2. Autocatalytic growth without chiral amplification: Kondepudi and co-workers reported on apparently homochiral crystal mixtures obtained by crystallization under strong stirring.[57] This yields crystal mixtures of high ee on a shorter time scale than the former case (3.3.2.1.). These results are a consequence of the formation of a first Adam crystal and its autocatalytic growth because stirring erodes the crystals forming new nucleation sites (autocatalytic secondary nucleation mechanisms) of the same chiral sign.[58] 3.3.2.3. Scenarios with inhomogeneous distribution of chemical species (i.e. for which the mean field assumption of chemical kinetics does not hold): The formation of the first insoluble crystallite occurs generally by the heterogeneous nucleation mechanism. This implies an inhomogeneous spatial distribution of small clusters around the nucleation particle. Therefore, at this stage of the crystallization, the mean field assumption of chemical kinetics cannot be applied: the formation in supersaturated solutions of the first Adam crystal occurs under a spatio/temporal inhomogeneous distribution of chemical species, probably governed by nonlinear thermodynamics. In the case of chiral crystals, a chiral contaminant particle acting as a heterogeneous nucleation center may select the chiral sign of the first insoluble crystals. Notably, this could be also acting in the case of 3.3.2.1. and 3.3.2.2. In the former scenarios a) and b) when such a mechanism is also acting, a non-stochastic distribution of chiral signs between experiments will be found. 3.3.3. Mixed scenarios The last scenario (3.3.2.3.) of chiral induction at the primary nucleation stage, when followed by 3.3.2.1. or 3.3.2.2., is the explanation of many historical and recent reports.[59] Such reports are common in the literature, despite the drawback that the possible chiral contaminants have not been identified.[60] In such cases some authors have succumbed to the temptation Chem. Eur. J. 2014, 20, 1 – 23

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metastable state towards one of the two stable degenerate chiral states. Here chirality emerges in the system as a macroscopic collective phenomenon and a stochastic distribution of chiral signs between experiments will occur: only a large number of experiments can reestablish the racemic “composition” determined by the law of large numbers. However, under SMSB conditions, very weak chiral polarizations or very low initial chiral biases suffice to transform the perfect bifurcation into an imperfect one, that is, the same final chiral sign will be obtained in each experiment. Notice that both “true” as well as “false” chiral polarizations, in the sense defined by Barron and co-workers,[5b, 70] can yield a deterministic final chiral sign. The energy difference between enantioselective paths to transform the stochastic distribution of chiral signs into a deterministic one may be orders of magnitude lower than the energy values required to achieve significant chiral inductions in common asymmetric synthesis. These low chiral polarizations do not change significantly the final absolute ee value, and the principal effect of such “chiral inductions” is to select one of the two chiral branches. Therefore, because the system, in the absence of any permanent chiral polarization, already leads to a chiral state of similar ee, and in order to avoid misunderstandings with classical chiral asymmetric inductions, it is more appropriate to call the polarizations operating in these types of autocatalytic emergence of chirality as a chiral sign selection instead of chiral induction. Enantioselective autocatalysis by itself must show an autocatalytic order high enough: that is, m > 1 for the examples of autocatalysis with direct reaction mechanisms discussed here, to show SMSB. In spite of the fact that absolute asymmetric synthesis can be achieved by autocatalytic mechanisms of

4.1. Theory versus synthesis Enantioselective autocatalytic networks may yield absolute asymmetric synthesis under micro-reversibility constraints, that is, in common solution chemistry scenarios, as a consequence of the fact that the racemic state is unstable or metastable. This contradicts the old axiom in asymmetric chemistry that, when starting from achiral compounds or racemic mixtures, in the absence of any chiral induction, the final outcome must be necessarily a racemic mixture. In the case that the system in which the reaction takes place can evolve to thermodynamic equilibrium with its surroundings, absolute asymmetric synthetic can only be kinetically controlled (i.e. the temporary formation of a nonracemic outcome). For relatively high exergonic reactions (i.e. in the case of the Soai reaction), this can be of potential application in asymmetric synthesis. In the case that the system cannot achieve conditions of thermodynamic equilibrium with its surroundings, a thermodynamically controlled absolute asymmetric synthesis is possible (i.e. a final nonracemic state of minimum entropy production) also for non-exergonic reactions, as in the case of the Viedma deracemization. See the summary of this in Scheme 8. It is worth noting that the selectivity in autocatalyses, that is, the survival of a specific species, is achieved in specific reaction networks but only for specific parameters of the system, which also include the chemical mass of the reacting system. In agreement with the descriptions of bifurcation scenarios,[14] under conditions of SMSB, chiral statistical fluctuations from the ideal racemic composition suffice to drive the racemic

Scheme 8. Summary of the ability of enantioselective autocatalysis for absolute asymmetric synthesis under microreversibility constraints.

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Review high molecularity, they correspond to unreasonable reaction mechanisms. However, the autocatalytic dynamic signature capable of selecting the survival of one of the enantiomers can be achieved for an enantioselective autocatalysis of the order lower than the critical value (m = 1 for the examples discussed here) when it is coupled to a heterochiral reaction between product/catalysts leading to a decrease of the racemic composition (Frank-like models), or to an increase of the ee value (LES-like model). The main handicap for the design of absolute asymmetric synthesis based on enantioselective autocatalyses is that such reactions are very rare. However, the study of the coupling of such inhibition stages to well-known enantioselective autocatalysis of replicators of low order[21] could lead to dramatic experiments in absolute asymmetric synthesis. The reaction network and system architecture, in their relationships with the surroundings, is a necessary element in the design of experiments leading to absolute asymmetric synthesis. In this respect, bench work in open systems by using flow chemistry is nowadays an accessible methodology.[71] Therefore, reactions, that in closed systems lead to kinetically controlled absolute asymmetric synthesis as in the case of the Soai reaction, would be transformed in open flow systems into thermodynamically controlled asymmetric synthesis. Micro-flow synthesis seems to be an adequate tool to study the complex dynamics and kinetics of autocatalytic coupled reaction networks such as those discussed here: the different continuous outcomes obtained when starting from different initial conditions would allow one to identify the different reactions that compose the enantioselective autocatalysis and mutual inhibition stages, and to distinguish between the reactions forming part of the SMSB kernel and those secondary ones that have a deleterious effect on the SMSB kernel efficiency. In our opinion only after knowing this, does it make sense to discuss the mechanisms and stereochemical arguments of the individual reactions forming part of such reaction networks. In this respect, nowadays the study of the dynamics and kinetics of complex reaction networks leading to a macroscopic answer of complex reaction networks is at a stage such as was the study of mechanisms of fundamental organic chemistry reactions in the middle of the 20th century. Only after accurate kinetics studies in structurally similar chemical families was it possible to infer the more adequate reaction mechanisms of simple transformations,[72] and very probably only after the study of the dynamics of such complex reaction networks, will a description of the mechanisms of the reactions composing them be possible.

tive autocatalysis could lead not only to the precursors of the metabolic and self-reproducing cycles, but also to the simultaneous emergence of biological homochirality. However, the molecularity order of the autocatalysis implied in enantioselective autocatalytic transformations (template reactions and replicators mimicking molecular biological processes) is too low for destabilizing the racemic outcome, that is, to select one of the two enantiomeric autocatalytic manifolds. Therefore, the experiments on absolute asymmetric synthesis of oligomers, of interest in biological chemistry, should be directed not only to the search for enantioselective autocatalysis, but also to the study of their coupling with inhibition stages capable of destabilizing the racemic state. Perhaps such inhibition stages could be inferred from the actual paths of metabolic and self-reproducing cycles. The experimental study on replicators and template autocatalytic systems showing enantioselectivity could lead to absolute asymmetric synthesis implying peptide and oligonucleotide polymerizations. Despite the lack of specific experimental examples, the mystery surrounding the question of biological homochirality is slowly becoming clearer. It is worth noting that these speculations are not concerned with the emergence of chirality in reactions at astrophysical scenarios, which clearly imply nonlinear thermodynamics arguments, but rather with Earth’s evolution. In this respect, the massive arrival to Earth of basic chiral organic compounds[73] with some ee bias would determine the final chiral sign (chiral sign selection) of the absolute asymmetric synthesis of the enantioselective autocatalytic reaction networks discussed here. Notably, without such autocatalytic reaction networks capable of leading to SMSB, and in spite of a high initial ee, racemization would finally occur. A speculative conclusion of all this is that the dilemma between racemization and deracemization could be the selection path in abiotic chemistry towards primordial Life systems.

Acknowledgement Financial support by MINECO (Projects CTQ2013-47401-C2-1/2P) is gratefully acknowledged. The work forms part of the COST Actions CM0905 Organocatalysis (A.M.) and CM1304 Systems Chemistry (D.H. and J.M.R.). Keywords: asymmetric synthesis · autocatalysis · chirality · coupled reactions · flow chemistry [1] a) K. Mislow, Einfhrung in die Stereochemie, Verlag Chemie, Weinheim, 1967, pp. 114 – 115; b) E. Eliel, S. H. Wilen, Stereochemistry of organic compounds, Wiley, New York, 1994. [2] a) Comprehensive Asymmetric Catalysis, Vol 3.(Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999; b) Comprehensive Asymmetric Catalysis: Supplements I and II, (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 2004; c) Catalytic Asymmetric Synthesis, 3rd ed., (Ed.: I. Ojima). Wiley, Hoboken, 2010; d) Catalysis in Asymmetric Synthesis, 2nd ed., (Eds.: V. Caprio, J. Williams), Wiley, Hoboken, 2009; e) Comprehensive Chirality, (Eds.: E. M. Carreira, H. Yamamoto), Elsevier Science, Oxford, 2012; f) Comprehensive Enantioselective Organocatalysis, Vol. 3 (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2013. [3] a) D. Guillaneux, S.-H. Zhao, O. Samuel, D. Rainford, H. B. Kagan, J. Am. Chem. Soc. 1994, 116, 9430 – 9439; b) C. Girard, H. B. Kagan, Angew.

4.2. Emergence of chirality in chemical evolution A model of increasing interest for the abiotic stage of chemical evolution on Earth is that of pre-metabolic autocatalytic cycles.[28] The reaction networks discussed here, leading to final stationary states in network architectures unable to achieve thermodynamic equilibrium with the surroundings, share characteristics with basic life processes related to polymerization and self-replication.[47] Therefore, it is a reasonable hypothesis to assume that the presence in such scenarios of enantioselecChem. Eur. J. 2014, 20, 1 – 23

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Review

REVIEW & Absolute Asymmetric Synthesis

Network solutions: The theoretical reports on the destabilization of racemic outcomes and chiral amplifications generated in enantioselective autocatalysis are discussed in relationship to experimental absolute asymmetric synthesis and with regard to speculations on the origin of biological homochirality and chemical evolution on Earth.

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J. M. Rib ,* C. Blanco , J. Crusats , Z. El-Hachemi , D. Hochberg, A. Moyano && – && Absolute Asymmetric Synthesis in Enantioselective Autocatalytic Reaction Networks: Theoretical Games, Speculations on Chemical Evolution and perhaps a Synthetic Option

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Grip on complexity in chemical reaction networks.

Translated chemical reaction networks.

Catalytic enantioselective synthesis of planar-chiral cyclic amides based on a Pd-catalyzed asymmetric allylic substitution reaction.

Absolute asymmetric synthesis of a tetrahedral silver complex.

Asymmetric Synthesis of Functionalized Tetrasubstituted α-Aminophosphonates through Enantioselective Aza-Henry Reaction of Phosphorylated Ketimines.

Speculations on the evolution of awareness.

Asymmetric synthesis of fortucine and reassignment of its absolute configuration.

Asymmetric Evolutionary Games.

Speculations on the origin and evolution of metabolism.

A fully synthetic and biochemically validated phosphatidyl inositol-3-phosphate hapten via asymmetric synthesis and native chemical ligation.

Stochastic flux analysis of chemical reaction networks.

Chemical reaction networks: Colour by number.

Speculations on the evolution of the genetic code.

Bicyclic Guanidine Catalyzed Asymmetric Tandem Isomerization Intramolecular-Diels-Alder Reaction: The First Catalytic Enantioselective Total Synthesis of (+)-alpha-Yohimbine.

Asymmetric synthesis of chiral dihydrothiopyrans via an organocatalytic enantioselective formal thio [3 + 3] cycloaddition reaction with binucleophilic bisketone thioethers.

Interaction of β-cyclodextrin as catalyst with acetophenone in asymmetric reaction: a theoretical survey.

Asymmetric Total Synthesis of (-)-Englerin A through Catalytic Diastereo- and Enantioselective Carbonyl Ylide Cycloaddition.

A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines.

Chemical evolutionary games.

An enantioselective synthesis and the absolute configuration of natural pumiliotoxin-C.

Asymmetric triple relay catalysis: enantioselective synthesis of spirocyclic indolines through a one-pot process featuring an asymmetric 6π electrocyclization.

Asymmetric synthesis of α-chiral hydroxyalkylphosphines by a catalytic enantioselective reduction of acylphosphines.

An Enantioselective Synthesis of the ABD Tricycle for (-)-Phomactin A Featuring Rawal's Asymmetric Diels-Alder Cycloaddition.

Autocatalytic reaction fronts inside a porous medium of glass spheres.