Elsevier

Tetrahedron: Asymmetry

Volume 23, Issue 24, 31 December 2012, Pages 1663-1669
Tetrahedron: Asymmetry

Insights into the spontaneous emergence of enantioselectivity in an asymmetric Mannich reaction carried out without external catalyst

https://doi.org/10.1016/j.tetasy.2012.10.021Get rights and content

Abstract

ESI-MS, chiral HPLC, time-resolved 1H NMR and optical rotation measurements were performed to gain insights into the nature of spontaneous mirror symmetry breaking in the catalyst-free Mannich reaction of PMP protected α-iminoethylglyoxylate with hydroxyacetone. Spontaneous temporary generation of enantiomeric excesses of up to 7.4% in the major syn diastereomer is reproducibly observed in aqueous phosphate buffers, starting from achiral conditions. The syn-product ee values for both enantiomers [(2S,3S) and (2R,3R)], although not with stochastic distribution, have been observed with no clear preference for either enantiomer.

Introduction

The origin of biomolecular homochirality, that is that only one enantiomeric form of amino acids dominates in Nature, still belongs to one of the most profound conundrums in science.1, 2, 3, 4, 5, 6, 7, 8 Could the (R)/(S) symmetry of biomolecules have become broken spontaneously? One of the main dogmas of asymmetric synthesis has it that enantioselective reactions always give racemic products in the absence of chiral inductors such as chiral catalysts, auxiliaries, solvents or circularly polarized light.9, 10, 11 This partly explains the sensation caused by Soai’s report in 1995 on the dramatic spontaneous asymmetric amplification in the irreversible alkylation reaction of pyrimidine carbaldehydes with diisopropyl zinc.12 At completion, the reaction produces a dominance of either the (R)- or (S)-product in the reaction mixture, depending on an initial accidental and miniscule enantiomeric imbalance. It has been disclosed that autocatalytically active homochiral dimers of the product seem to be mainly responsible for the symmetry breaking effect.13, 14, 15, 16

The possibility of spontaneous autoamplification of ee in chemical reactions has already been the focus of several theoretical investigations.17, 18, 19, 20, 21, 22, 23, 24, 25 The first proposal of a mathematical mechanism for the spontaneous emergence of enantiomeric excess through enantioselective autocatalysis in conjunction with mutual inhibition of enantiomers was made by Charles Frank in 1953.26 Symmetry breaking by spontaneous deracemisation of chiral conglomerates has also been reported.27, 28, 29

In this process, autocatalysis was again proposed to be involved in the crystallization.30 Very recently, the spontaneous generation of a chiral surplus was implied in the theoretical study of the product assisted hemiacetal formation of acetone with trihaloacetaldehydes.31

Self-replication processes of products have been studied earlier, involving oligomeric nucleotide molecules and β-sheet peptides.32, 33 Even before the Soai reaction was discovered, it was suggested that an enantioselective autocatalytic reaction in conjunction with a positive non-linear effect of catalyst versus product ee should lead to spontaneous asymmetric amplification.34

In 2007, it was reported that in the product assisted asymmetric Mannich reaction35 of PMP protected α-iminoethylglyoxylate with acetone, a spontaneously generated product enantiomeric excess of 9.4% can be observed with 31% yield after four days reaction time – even when the initial reaction mixture is achiral or racemic (Scheme 1a).36 This result has indicated that seemingly well-known37 organic reactions might have much more complicated mechanisms than was previously assumed. In order to study this process further, we decided to use hydroxyacetone as the donor (Scheme 1b), instead of acetone, because of the higher reactivity of the former, and hence, the expectation of reduced reaction times.

Herein we report our results on the reaction kinetics of this transformation using 1H NMR studies, which show an induction period of product formation thus evidencing the involvement of an autoinductive process. Based on ESI-MS measurements and 1H NMR studies, we propose the in situ formation of an organic base, a diamine side product, which could assist in the enolate formation from the ketone. Furthermore, polarimetry was used to monitor the variation of the optical rotations during the reaction. It is also shown that optical rotation emerges spontaneously and temporarily at the beginning of the reaction.

Section snippets

Results and discussion

Firstly, the reaction of PMP protected α-iminoethylglyoxylate with hydroxyacetone (Scheme 1b)37 was studied under various conditions (solvent, temperature, reactant concentration) and without any external catalyst. The results are summarized in Table 1. The diastereoselectivity is almost the same (84:16 to 89:11 dr, entries 1–14) under most of the studied conditions and for the investigated reaction times, except for the results in aqueous conditions (in phosphate buffer) measured after 1 h

Conclusion

In conclusion, we have gained further insights into an asymmetric Mannich reaction, carried out without external catalyst, and which is capable of generating small ee values spontaneously in the early stages of the reaction. Without resorting to the particular physics of a non-equilibrium steady state,39, 40 the spontaneous asymmetric amplification in the Mannich reaction could be understood from two basic assumptions in accord with the well-known Frank mechanism of spontaneous asymmetric

General

Solvents were purified by standard procedures and distilled prior to use. Reagents obtained from commercial sources were used without further purification. TLC chromatography was performed on precoated aluminium silica gel ALUGRAM SIL G/UV254 plates (Macherey, Nagel & Co.). Flash chromatography was performed using silica gel ACROS 60 Å, (particle size 0.035–0.070 mm). 1H NMR spectra were recorded in CDCl3 with Bruker Avance 300 or 400. Enantioselectivities were determined by chiral HPLC analysis

Acknowledgments

We gratefully acknowledge generous financial support from the Deutsche Forschungsgemeinschaft and COST Action on Systems Chemistry CM0703. We thank Dr. Michael Mauksch for stimulating discussions. We further thank C. Placht, H. Maid, Professor Dr. W. Bauer for time-resolved 1H NMR measurements; Dr. J. Einsiedel, W. Donaubauer, M. Dzialach for ESI-MS and LC–MS spectra.

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