Amplification of Chirality from Extremely Low to Greater than 99.5 % ee by Asymmetric Autocatalysis

Abstract

Biomolecules such as amino acids and sugars occur in Nature overwhelmingly as l and d enantiomers, respectively. The origins of chirality and the processes leading to high enantiomeric enrichment of organic compounds have been intriguing puzzles.[1] Several factors have been proposed as the origins of chirality of organic molecules.[2] However, the enantiomeric excesses (ee) of organic compounds induced by these factors have usually been very low (from 10 À4 to < 2 % ee). Circularly polarized light (CPL) induces very low selectivity (< 2 % ee) in asymmetric photosynthesis, [2a,b] photoisomerization, [2c] photoequilibration, [2d,e] and photolysis. [2f,g] Asymmetric adsorption on and desorption from chiral surfaces induce a tiny imbalance (< 2 % ee) in enantiomers.[2h±k] These very low levels of enantiomeric excess require an efficient method of amplification in order to explain the very high enantiomeric enrichment of organic compounds. A tiny imbalance in the enantiomeric composition of a sterically encumbered olefin induces the twist of a nematic phase into a cholesteric phase in liquid crystals.[2d]The positive nonlinear effect of asymmetric catalysis, discovered by Kagan et al., [3a] explains how a product can have a higher ee than the chiral catalyst required for its production. [3] However, the selectivity of the reaction remains low to moderate when the chirality level of the asymmetric catalyst employed is low. For example, the product was produced with only 36 % ee when a catalyst with 3 % ee was used.[3b] On the other hand, we reported asymmetric autocatalysis in which the chiral product acts as a chiral catalyst for its own production. [4] The chirality level of the initial catalyst with 0.3±2 % ee was enhanced to 87±88 % ee.[5] However, considering the much lower levels of chirality induced by a physical factor, [2l] it is a challenge to develop a method for ™amplifying chirality∫ starting from extremely small enantiomeric imbalances to give practically enantiomerically pure product.Herein we report efficient chirality amplification by a catalyst with as low as 10 À5 % ee to give practically enantiomerically pure (> 99.5 % ee) product in only three consecutive cycles. The product formed in situ with enhanced ee serves as an asymmetric autocatalyst for the further formation of itself with much higher ee.The initial asymmetric autocatalysts with very low levels of chirality were prepared carefully by adding calculated amounts of standardized solutions of (S)-and (R)-(2-alkynyl-5-pyrimidyl)alkanol 1 (> 99.5 % ee) [6] to racemic 1 (Scheme 1).[7] The enantiomeric enrichment of these two solutions was roughly 0.00005 % ee (i.e. enantiomeric ratio of ca. 50.000025:49.999975).[8] We found that the first asymmetric autocatalysis with (S)-1 of approximately 0.00005 % ee in the enantioselective addition of diisopropylzinc [9] to 2-alkynylpyrimidine-5-carbaldehyde 2 gave (S)-1 in 96 % yield with an enhanced selectivity of 57 % ee (Table 1, run 1). To take advantage of asymmetric autocatalysis, the (S)-1 o...

Mirror-symmetry breaking in the Soai reaction: A kinetic understanding

“…The catalyst chirality sign was systematically maintained until the initial concentration of the enantiomerically pure catalyst was as low as 10 Ϫ14 M. The threshold concentration depends on the parameter values; especially when k 0 increases the concentration threshold increases. This increase is due to the production of the opposite enantiomer by the uncatalyzed formation of R and S. Table 1 demonstrates strong chiral amplification analogous to that observed in the Soai reaction (24). It also indicates that the amplification strength depends on the k 2 ͞k 1 ratio, especially at very small initial ee.…”

“…Because of the relation between mirror-symmetry breaking and dimer formation rates and stabilities, it is likely that the structure of the aromatic part of the pyrimidine carbaldehydes is of essential importance not only for the amplification of ee but also for the occurrence of spontaneous symmetry breaking. For instance, there was no chiral amplification observed with ferrocenyl or 3-pyridyl carbaldehydes (35,36), whereas the amplification effects increased from 3-quinolyl to 5-pyrimidinyl and 2-methylpyrimidinyl to 2-alkynyl-5-pyrimidinyl carbaldehydes (12,24,37,38). Mirror-symmetry breaking has been observed only with the bulkiest alkynyl aldehydes.…”

“…However, reports using these approaches have not discussed the origin of the experimentally observed mirror-symmetry breaking so far. The purpose of this work is to analyze the foundation of mirror-symmetry breaking by focusing on closely related and more recently discovered properties of the Soai reaction such as astonishingly strong amplification starting from extremely small chiral imbalances (24) or the tremendous sensitivity of propagating the chirality sign starting with only a few thousand chiral molecules as an initiator (15). We will show that simple kinetic models are sufficient to understand the possible origin of these striking features.…”

Autosolvation: Architecture and Selection of Chiral Conformers in Alkylcobalt Carbonyl Molecular Clocks

“…The results presented in Figure 6, may represent an important hint in this direction. The possibility of obtaining high (almost quantitative) enantiomeric excesses initiated by even very small starting difference in the concentration of the enantiomeric product, or very low concentration of chiral auxiliary, have been demonstrated succesfully in the last few years [12][13][14][15][16][17][18][19][20][21][22][47][48][49][50][51]. The first chiral molecule formed at the very begining of an achiral-to-chiral reaction could have a particular role, if a sufficiently sensitive amplifying mechanism is available (as in the casae of the Soai-reaction) [52][53][54][55].…”

Natural Abundance Isotopic Chirality in the Reagents of the Soai Reaction

“…The Soai reaction shows extreme sensitivity towards the chiral induction exerted by even very low quantities both of the autocatalyst [16][17][18][19][20][21][22][23][24] and of added (enantiomerically pure or enriched) "foreign" chiral molecules [25][26][27][28][29][30][31]. It has also been proved experimentally that such inductor molecules may include enantiomers of simple chiral organic compounds with chirality due only to stable isotopic substitution [32][33][34][35][36][37][38][39].…”