Homochirality asymmetric amplification

Tanaka reported the synthesis of (/ )-muscone (10) by an enantioselective conjugate addition of chiral alkoxydimethylcuprate, which was prepared from chiral ercdo-3-[(l-methylpyrrol-2-yl)methylamino]-l,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (9), methyllithium, and copper iodide (Scheme 9.7) [16]. In this reaction, convex deviation from a linear correlation was observed when the chiral ligand had a higher enantiopurity. This positive NLE was probably induced by the formation of a reactive homochiral dinuclear copper complex to give (R)-muscone. Rossitter also observed asymmetric amplification in a copper-catalyzed conjugate addition of methyl-... 

As described in the preceding sections, asymmetric amplification is generally a consequence of the formation of aggregates (i.e., dimers or oligomers that are homochiral or heterochiral) of a chiral catalyst. However, even a racemic catalyst can be used as a chiral catalyst with the aid of chiral additives (a simple model consisting of dimers is depicted in Scheme 9.17). If a chiral additive (R)-B is selectively associated with (S)-A in the racemic catalyst, the remaining (R)-A could operate as the chiral monomer catalyst (asymmetric deactivation). Conversely, the chiral additive (/ )-B can be selectively associated with (/ )-A in racemic catalyst to generate an active dimeric catalyst (asymmetric activation). 

In order to achieve an amplification of chirality, it requires that/> 1. If P = 0 (no meso catalyst) or g = 1 (same reactivity of meso and homochiral catalysts), then/= 1. The condition/> 1 is achieved for 1 + p > 1 + g ), or g < 1. Thus the necessary condition for asymmetric amplification in the above model is for the heterochiral or meso catalyst to be less reactive than the homochiral catalyst. If the meso catalyst is more reactive, then/< 1, and hence a negative nonlinear effect is observed. The size of the asymmetric amplification is regulated by the value off, which increases as K does. The more meso catalyst (of the lowest possible reactivity) there is, the higher will be eeproduct. This is well illustrated by computed curves in Scheme 11. The variation of eeproduct with eeaux is represented for various values of g (the relative reactivity of the meso complex) with K = 4 (corresponding to a statistical distribution of ligands Scheme 11, top). The variation in the relative amounts of the three complexes with eeaux is also represented for a statistical distribution of ligands (Scheme 11, bottom). 

One of the most exciting and recently emerging areas in asymmetric synthesis is asymmetric amplification. This topic has extraordinarily broad implications from mechanistic insights provided by non-linear effects to the enhancement of enantiomeric composition of important compounds to new hypotheses for the origin of biomolecular homochirality. The final chapter by Henri Kagan and David Fenwick provides a thorough and insightful analysis of the basic principles of asymmetric amplification and illustrations of some of the more important applications in synthesis. 

The mechanism of the polyleucine-catalyzed epoxidation is still under investigation [74]. Kinetic studies indicate that the reaction proceeds via the reversible addition of chalcone to a polyleucine-bound hydroperoxide [75]. Recent discussions have included studies of asymmetric amplification polyleucine derived from non-enantiopure amino acid shows highly amplified epoxide enantiomeric excess, and the results fit a mathematical model requiring the active catalyst to have five terminal homochiral residues, as rationalized by molecular modeling studies [76]. 

The remarkable features of macromolecules and the necessity to create functional macromolecules as an integral part of hving organisms provides clues to how complete homochirality might have been achieved and stabihzed. Homochirality is even suggested as an inevitable outcome during the evolution of such functional macromolecules (54). Still, processes of asymmetric amplification as discussed above could have helped to provide a pool of enantiomerically enriched building blocks that made the evolution of homochiral macromolecules much more feasible. 

These schemes have been frequently suggested [105-107] as possible mechanisms to achieve the chirally pure starting point for prebiotic molecular evolution toward our present homochiral biopolymers. Demonstrably successftd amplification mechanisms are the spontaneous resolution of enantiomeric mixtures under race-mizing conditions, [509 lattice-controlled solid-state asymmetric reactions, [108] and other autocatalytic processes. [103, 104] Other experimentally successful mechanisms that have been proposed for chirality amplification are those involving kinetic resolutions [109] enantioselective occlusions of enantiomers on opposite crystal faces, [110] and lyotropic liquid crystals. [Ill] These systems are interesting in themselves but are not of direct prebiotic relevance because of their limited scope and the specialized experimental conditions needed for their implementation. 

We describe highly enantioselective asymmetric autocatalysis with amplification of chirality and asymmetric autocatalysis initiated by chiral triggers. Asymmetric autocatalysis correlates between the origin of chirality and the homochirality of organic compounds. We also describe spontaneous absolute asymmetric synthesis in combination with asymmetric autocatalysis. 

Keywords Asymmetric autocatalysis Amplification of chirality Pyrimidyl alkanol Automultiplication Origin of homochirality... 

It was soon recognized that in specific cases of asymmetric synthesis the relation between the ee of a chiral auxiliary and the ee of the product can deviate from linearity [17,18,72 - 74]. These so-called nonlinear effects (NLE) in asymmetric synthesis, in which the achievable eeprod becomes higher than the eeaux> represent chiral amplification while the opposite case represents chiral depletion. A variety of NLE have been found in asymmetric syntheses involving the interaction between organometallic compounds and chiral ligands to form enantioselective catalysts [74]. NLE reflect the complexity of the reaction mechanism involved and are usually caused by the association between chiral molecules during the course of the reaction. This leads to the formation of diastereoisomeric species (e.g., homochiral and heterochiral dimers) with possibly different relative quantities due to distinct kinetics of formation and thermodynamic stabilities, and also because of different catalytic activities. 

The above examples demonstrate that mirror symmetry breaking by self-assembly of non-chiral molecules into chiral architectures is indeed a feasible process. However, in order to preserve the handedness and amplify the stochastically-generated chirality, it is imperative to couple such chance events with efficient sequential autocatalytic processes. We refer now to several experimental systems that illustrate the occurrence of such scenarios. We shall allude in particular to systems undergoing amplification via non-linear asymmetric catalysis processes, via the formation of 2-D and 3-D crystalline systems and amplification of homochiral bio-like polymers in general and oligopeptides in particular. 

Asymmetric photochemistry is intensively discussed as one of the possibilities for the origin of the observed homochirality of amino acids and saccharides in biological systems. There is no doubt that also in natural environments cpl exists and may create an enantiomeric excess in a photoreaction, but according to all knowledge, there must be an amplification mechanism, which has not yet been safely detected. 

Thus, the origin of homochirality of biomolecules might have involved the inherently achiral nucleotide base cytosine. In conjunction with the subsequent amplification of chirality by asymmetric autocatalysis, spontaneously formed chiral crystals of achiral cytosine acted as an origin of homochirality in biomolecules. The structure of cytosine indicates that the Nl-atom may be prochiral (marked by an asterisk in Fig. 3.5). In contrast, uracil and adenosine do not have asymmetric atoms. It remains unknown whether the distantly related structure of guanine can... 

Asymmetric autocatalysis with amplification of chirality is a very efficient method of asymmetric catalysis. One of the implications is that the existence of a chemical reaction has been shown in which very slight bias of chirality can be amplified significantly to reach almost enantiopure. The reaction has been employed for the study on the origins of homochirality and on the chiral discrimination. We describe how we find the reaction and the recent aspects of asymmetric autocatalysis. 

---