Spontaneous asymmetric synthesis

Abstract The addition of diisopropylzinc to prochiral pyrimidine carbaldehydes (Soai reaction) is the only known example of spontaneous asymmetric synthesis in organic chemistry. It serves as a model system for the spontaneous occurrence of chiral asymmetry from achiral initial conditions. This review describes the possible kinetic origin of specific experimental features of this reaction. It is shown that generic kinetic models, including enantioselective autocatalysis and mutual inhibition between the enantiomers,... 

Spontaneous asymmetric synthesis has been envisaged by theoretical models for more than 50 years [1-7]. This process features the generation and amplification of optical activity during the course of a chemical reaction. It stands in contrast to asymmetric procedures, such as stoichiometric resolution, conglomerate crystallization, or chiral chromatography, in which the optical activity can be increased but no additional chiral product is formed [8]. It is also different from classical asymmetric synthesis, in which new chiral product is obtained but the resulting enantiomeric excess (ee) is usually less than or, at most, equal to that of the chiral initiator or catalyst1. 

The first experimental invention of spontaneous asymmetric synthesis was achieved only a little more than a decade ago in an organic reaction system by Soai and coworkers [9-15]. The Soai reaction (Scheme 1) comprises the addition of diisopropylzinc to prochiral pyrimidine carbaldehydes yielding isopropylzinc alkoxides that, after hydrolysis, are usually converted into stable chiral pyrimidyl alkanols. 

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]. 

Scheme 2. (a) Model for spontaneous asymmetric synthesis according to Frank [12]. (b) Deactivation of the catal3ttically active chiral product. 

Frank F.C. (1953) On spontaneous asymmetric synthesis, Biochim. Biophys. Acta 11,459-463. 

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. Shibata, T Kowata, Y. Asymmetric Synthesis of Enantioenriched Alkanol by Spontaneous Asymmetric Synthesis. Jap. Kokai Tokkyo Koho 1997, 9-268179. 

Frank, F. C. Spontaneous Asymmetric Synthesis. Biochim. Biophys. Acta 1953, 11, 459-463. 

Meanwhile, we noticed a short review by Wynberg in the same year on asymmetric autocatalysis [22]. He introduced the theoretical paper of Frank [23] on spontaneous asymmetric synthesis. He explained that no experimental realization of asymmetric autocatalysis had ever been achieved. He also described the potential difficulties to realize asymmetric autocatalysis (1) chiral product should have the catalytic activity for producing itself, (2) asymmetric autocatalyst of certain absolute configuration should induce the same absolute configuration of the product, and (3) enantiomeric excess of the product should not decrease because the repeated... 

Spontaneous Asymmetric Synthesis - Asymmetric Amplification in Autocatalysis... 

In 1953, Frank developed a mathematical model showing that spontaneous asymmetric synthesis is theoretically possible (21). If the chiral product of a catalytic reaction would act as a catalyst for its own formation and at the same time suppress the formation of its enantiomer, a basically enantiopirre product could be formed from near-racemic starling materials. About forty years later, Soai and coworkers provided the first experimental proof for this concept of asymmetric autocatalysis with the alkylation of pyrimidyl aldehydes with diallgrlzinc reagents (Figure 1) (22). 

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