Asymmetric synthesis Autocatalytic

Another achievement in recent asymmetric reaction study is the so-called chiral autocatalysis—where the product itself catalyzes its own asymmetric synthesis. In this process, the chiral catalyst and the products are the same in an asymmetric autocatalytic reaction. The separation of chiral catalyst from the product is not required, because the product itself is the catalyst. Starting from an optically active product with very low ee, this process allows the formation of a product with high ee values.106,114... 

In the absence of any chiral factors, the probability of the formation of S- and 77-enantiomers is 1 to 1. However, the numbers of the resulting two enantiomers are not exactly the same in almost all cases. Mislow197 described the inevitability of small enantiomeric enrichment in absolute asymmetric synthesis. According to the statistics, it is expected that a fluctuation in the ratio of the S- and 77-enantiomers becomes more and more likely as the numbers in the enantiomer mixture become smaller198. Thus, if the asymmetric autocatalysis is initiated without adding any chiral substance, small fluctuations of enantiomers produced in the initial stage could be enhanced by consecutive asymmetric autocatalytic reaction of pyrimidyl alkanol with amplification of chirality. 

During classical asymmetric synthesis, the amplitude of these fluctuations are expected to decrease during the course of the reaction because more and more chiral molecules are formed and eeeXp declines. However, in the presence of chiral autocatalysis, the small ee caused by such fluctuations can be amplified. In such cases, the system is likely to be most sensitive in the initial stage of reaction when the concentration of chiral molecules is still small. If the autocatalytic species are concentrated they can be either in a racemic or optically active state but if they are highly diluted, as at the beginning of the reaction, statistical fluctuations can become significant so that the state... 

Unlike conventional asymmetric synthesis, asymmetric autocatalytic reaction does not require the use of any chiral catalyst of different structure... 

The cpl-induced asymmetry in photoreactions as described in Sec. B. of this chapter is not very pronounced. In order to obtain ees in excess of a few percent, photodestruction must be chosen and most of the reactant material must be sacrificed. Therefore amplification mechanisms for all types of cpl-induced asymmetric photoreactions would be highly desirable. Autocatalysis, i.e., an asymmetric synthesis where a chiral product acts as a catalyst for its own production [128], and autoinduction, i.e., the stimulation of a chiral catalyst by a chiral product [44,129], are options. Autocatalytic systems that will tilt to one enantiomeric side were introduced by Frank [130] and Seelig [131]. 

The non-equivalence of enantiomers through the spontaneous breaking of mirror-symmetry in nature is amplified by asymmetric autocatalytic reaction [34], e.g. Frank s spontaneous asymmetric synthesis [35, 36] (Fig. 7-8). Alberts and Wyn-berg have reported in enantioselective autoinduction that chiral lithium alkoxide products may be involved in the reaction to increase the enantioselectivity (Eq. (7.9)) [37]. The product % ee however does not exceed the level of catalyst % ee. In asymmetric hydrocyanation catalyzed by cyclic dipeptides, the (Si-cyanohydrin product complexes with the cyclic peptide to increase the enantioselectivity in the (S)-cyanohydrin product, the reaction going up to 95.8% ee (Eq. (7.10)) [38]. In the presence of achiral amine, (/ )-l-phenylpropan-l-ol catalyzed carbonyl-addition reaction of diethylzinc has been reported to show lower % ee than that of the catalyst employed [39]. 

The absolute asymmetric synthesis described above is a stochastic process, as the probabihty of obtaining either a left- or a right-handed crystal, in different experiments, is identical. At the authors laboratories, attempts have been made to extend the absolute asymmetric synthesis into autocatalytic cycles, where the presence of a product formed in a given enantiomorphous crystal could induce -by ensuing fresh crystallizations cycles comprising crystallization/dissolution - the formation of crystals of the same handedness as in the first crystal formed by chance. In this way, the handedness generated in the first stochastic experiment would be both preserved and efficiently proliferated in the ensuing fresh crystallization experiments (Scheme 8.7). 

Scheme 8.7 Schematics of an absolute asymmetric synthesis by autocatalytic cycles of crystallization coupled with reaction, where the presence of a product formed in a given enantiomorphous crystal could inhibit the formation of its parent crystals in ensuing fresh crystallization cycles leading to the formation of crystals of the opposite handedness.

There are many speculations on the origin of chirality of biosystems. Most interesting for the self assembly of reproducing catalytic systems are theories on the amplification of enantiomeric excess. Frankl proposed a general mechanism for spontaneous asymmetric synthesis. He showed that if the production of living molecules of life is rare and, hence, slow compared with their rate of multiplication, the whole Earth is likely to be extensively populated with the progeny of the first event before another appears. A living entity is defined as one able to reproduce its own kind. Frank showed that a simple and sufficient life model is a chemical substance which is a catalyst for its own production (hence, autocatalytic) and an anticatalyst for the production of its optical enantiomers. 

Soai K, Hayase T, Shimada C, Isobe K (1994) Catalytic asymmetric synthesis of chiral diol, bis[2-(l-hydroxyalkyl)phenyl]ether, an asymmetric autocatalytic reaction. Tetrahedron Asymmetry 5 789-792... 

Natta, G. (1963) From the stereospecific polymerization to the asymmetric autocatalytic synthesis of macromolecules, Nobel Lecture, 12 December, 1963. 

Direct asymmetric autocatalysis amplified the slight excess of one enantiomer, leading to the enantiopure compound by reaction with diisopropylzinc. It is widely accepted that enantiomerically enriched products must form from achiral precursors merely because of statistical fluctuations. Usually, however, enantiomeric enrichment by fluctuations is very low. Thus, an amplification process of enantiomeric enrichment is required. Detailed kinetic analysis revealed that autocatalysis and inhibition are the major players in asymmetric autocatalytic synthesis. It turned out that tetramers serve as catalyst in the Soai reaction. The transition state for the Soai reaction implicates two molecules of pyrimidine alcohols or alcoxides as the dimeric catalysts and one molecule of prochiral aldehyde substrate (Buono and Blackmond 2003). Further kinetic studies using different ratios of substrate and reagent showed that a tetramer template is used. 

In the context of asymmetric cyanhydrin synthesis applying q cZo-peptide 50 as catalyst Danda and coworkers studied the positive influence of lowered viscosity of the reaction mixture on enantioselectivity and the asymmetric autocatalytic properties of the reaction system.During the following years other groups carried out further computational and mechanistic... 

Furthermore, the absolute asymmetric syntheses have been extended for reactions taking place in solution, where chiral supramolecular clusters are formed as intermediate templates. In particular, consideration should be given to the remarkable absolute autocatalytic Soai reaction in the synthesis of alcohols, where minute enantiomeric fluctuations are ampHfied from achiral reactants into products of single handedness [100, 101]. Tsogoeva and Mauksch reported absolute asymmetric transformations in the Mannish and aldol condensation reactions [102-104]. The same authors also proposed that similar spontaneous... 

A related asymmetric autocatalytic reaction (addition of a lithium acetylide to a trifluoromethyl ketone catalysed by product) has been applied to the synthesis of a... 

Nobelprize.org (1972) Giulio Natta - Nobel lecture From the stereospecific polymerization to the asymmetric autocatalytic synthesis of macromolecules. In Nobel lectures, chemistry 1963-1970. Elsevier, Amsterdam, http //www.nobelprize.org/nobel prizes/chemistry/laure ates/1963/natta-lecture.pdf. Accessed 7 July 2013... 

Shibata T, Choji K, Moiioka H, Hayase T, Soai K (1996) Highly enantioselective synthesis of a chiral 3-qninolyl alkanol by an asymmetric autocatalytic reaction. Chem Commun 751—752. doi 10.1039/CC9960000751... 

Shibata T, Mraioka H, Tanji S, Hayase T, KodakaY, Soai K(1996) Enantioselective synthesis of chiral 5-carbamoyl-3-pyridyl alcohols by asymmetric autocatalytic reaction. Tetrahedron Lett 37 8783-8786. doi 10.1016/S0040 39(96)02031-X... 

Other FRET-based applications include its use in a high throughput screening assay to identify novel G-quadruplex binding ligands, to monitor protein synthesis using a fluorescently-labelled tRNA, to monitor the asymmetric degradation of siRNA, and in a DNA detection assay based on autocatalytic hybridisation of DNA. " ... 

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