Evidence of Asymmetric Autocatalysis in Organocatalytic Reactions

Abstract

Dedicated to Professor Lutz F. Tietze on the occasion of his 65th birthdayAsymmetric autocatalysis is the process of automultiplication of a chiral compound in which the chiral product acts as a chiral catalyst for its own formation.[1] Such reactions offer striking advantages as the chiral product does not need to be separated from the chiral catalyst and as no other chiral catalyst than the product itself is involved. Several examples are known, all of which involve organometallic reagents and are hence restricted to certain reaction types; [1][2][3] the most prominent of these is the Soai reaction for its ability to amplify a tiny initial enantiomeric excess of a chiral pyrimidyl alkanol in the presence of iPr 2 Zn to almost enantiomeric purity.[3c] A catalytic asymmetric autoinductive aldol reaction in the presence of Ti IV (binol) complexes was described by Szlosek and Figadre. [4] Whereas a purely organic specimen of product catalysis is known, such as the autocatalytic aldol reaction, [5] asymmetric examples of such reactions have not yet been reported.However, Sievers and von Kiedrowski described a template-based mechanism of autocatalytic self-replication of (naturally asymmetric) oligonucleotide strands.[6] Moreover, Bolm and co-workers cited a fully organocatalytic example of enantioselective autoinduction in the production of a chiral cyanhydrine, catalyzed by a cyclic dipeptide. The product and the external catalyst together form here a more efficient catalytic species, which resulted in higher ee values and yields. [7] These results led us to pose the question of whether the product alone could in principle act as an inductor of chirality and in any asymmetric organic reaction. Reversible reactions appear to be badly suited for such an undertaking, as racemization might occur by the reverse reaction. Additionally, if the reaction-accelerating feature of the product is poorly developed, competition with the "uncatalyzed" reaction further limits the achievable enantiomeric excesses.Herein, we demonstrate for the first time that even in quite ordinary (and reversible) asymmetric organic reactions (as opposed to reactions involving organometallic species) the chiral product alone could act as a catalyst with high stereoselectivity. As an example, we chose the asymmetric Mannich reaction [8] [Eq. (1)] under various reaction conditions. The choice fell on an example that allows for specific product-substrate interactions through hydrogen-bonded complexes of the product molecules with the prochiral substrate.First, we prepared the product catalyst with l-proline as external catalyst in 98 % ee (S) and with d-proline in 99 % ee (R) enantiomeric purity. [8,9] Experiments carried out under various conditions (different concentrations of educt; different solvents; different ee values, absolute configuration, and loadings of catalyst; variable temperatures and reaction times; see Table 1) revealed to our surprise that the product is formed in nearly the same enantiomeric purity as that of the initially added pr...

Cross‐Dehydrogenative Coupling Reactions by Transition‐Metal and Aminocatalysis for the Synthesis of Amino Acid Derivatives

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Enantioselective Synthesis of Arylglycine Derivatives by Asymmetric Addition of Arylboronic Acids to Imines

“…PMP-protected iminoester could be synthesized in one step and in high yield from ethyl glyoxylate. [41] The resulting products could be deprotected under mild conditions using CAN. Moreover, the PMP-protected iminoester are more stable than their corresponding imines such as tosylimine.…”

Life's Single Chirality: Origin of Symmetry Breaking in Biomolecules

“…Fully organic examples of asymmetric autocatalysis [51], which, similar to the Soai reaction, can also show the behavior of an absolute asymmetric synthesis, were first reported by Mauksch and Tsogoeva in 2007 [52]: an asymmetric Mannich-type product -a functionalized amino acid -was able to replicate itself and with the same absolute configuration (Figure 23.7). DFT (density functional theory) calculations showed that the formation of homochiral product dimers is kinetically preferred with respect to formation of heterochiral dimers in the autocatalytic steps [52].…”

“…DFT (density functional theory) calculations showed that the formation of homochiral product dimers is kinetically preferred with respect to formation of heterochiral dimers in the autocatalytic steps [52]. …”