Effects In Asymmetric Catalysis Research Articles

Nonlinear Effects in Asymmetric Catalysis by Design: Concept, Synthesis, and Applications.

Asymmetric synthesis constitutes a key technology for the preparation of enantiomerically pure compounds as well as for the selective control of individual stereocenters in the synthesis of complex compounds. It is thus of extraordinary importance for the synthesis of chiral drugs, dietary supplements, flavors, and fragrances, as well as novel materials with tunable and reconfigurable chiroptical properties or the assembly of complex natural products. Typically, enantiomerically pure catalysts are used for this purpose. To prepare enantiomerically pure ligands or organocatalysts, one can make use of the natural chiral pool. Ligands and organocatalysts with an atropisomeric biphenyl and binaphthyl system have become popular, as they are configurationally stable and contain a C2-symmetric skeleton, which has been found to be particularly privileged. For catalysts with opposite configurations, both product enantiomers can be obtained. Configurationally flexible biphenyl systems initially appeared to be unsuitable for this purpose, as they racemize after successful enantiomer separation and thus are neither storable nor afford a reproducible enantioselectivity. However, there are strategies that exploit the dynamics of such ligands to stereoconvergently enrich one of the catalyst enantiomers. This can be achieved, for example, by coordinating an enantiomerically pure additive to a ligand-metal complex, which results in deracemization of the configurationally flexible biphenyl system, thereby enriching the thermodynamically preferred diastereomer. In this Account, we present our strategy to design stereochemically flexible catalysts that combine the properties of supramolecular recognition, stereoconvergent alignment, and catalysis. Such systems are capable to recognize the chirality of the target product, leading to an increase in enantioselectivity during asymmetric catalysis. We have systematically developed and investigated these smart catalyst systems and have found ways to specifically design and synthesize them for various applications. In addition to (i) reaction product-induced chiral amplification, we have developed systems with (ii) intermolecular and (iii) intramolecular recognition, and successfully applied them in asymmetric catalysis. Our results pave the way for new applications such as temperature-controlled enantioselectivity, controlled inversion of enantioselectivity with the same chirality of the recognition unit, generation of positive nonlinear effects, and targeted design of autocatalytic systems through dynamic formation of transient catalysts. Understanding such systems is of enormous importance for catalytic processes leading to symmetry breaking and amplification of small imbalances of enantiomers and offer a possible explanation of homochirality of biological systems. In addition, we are learning how to target supramolecular interactions to enhance enantioselectivities in asymmetric catalysis through secondary double stereocontrol. Configurationally flexible catalysts will enable future resource-efficient development of asymmetric syntheses, as enantioselectivities can be fully switched by stereoselective alignment of the stereochemically flexible ligand core on demand.

Non‐Linear Effects in Asymmetric Catalysis: Impact of Catalyst Precipitation

AbstractNon‐linear effects between the enantiomeric excesses of both the ligand and the product are ubiquitous phenomena in asymmetric catalysis, allowing asymmetric amplification (or depletion) and are widely used tools for mechanistic investigations. Non‐linear effects are caused by catalyst aggregation; however, the effect of catalyst precipitation on NLEs has not been systematically investigated to date, except in special cases such as ternary phase systems. In this article, we show through simulations and with several literature cases at hand how precipitation affects shape and amplitude of NLE curves. The limit of solubility of the homo‐ or heterochiral dimeric species causes broken‐shaped NLE curves or very pronounced NLEs even though the equilibria between the different species in solution are not favorable, at first sight. Peculiar features such as horizontal segments, inverse S‐shaped curves and a strong effect of total catalyst concentration are also observed. Overall, this study allows to get a better understanding of chiral catalytic systems and gives an outlook at other types of phase separation leading to NLEs.

Highlighting the DCO‐SCF 2020 Award Winners – A Valuable Collaboration with EurJOC

Highlighting the DCO‐SCF 2020 Award Winners – A Valuable Collaboration with EurJOC

Observation of hyperpositive non‐linear effect in catalytic asymmetric organozinc additions to aldehydes

Asymmetric amplification is a phenomenon that is believed to play a key role in the emergence of homochirality in life. In asymmetric catalysis, theoretical and experimental models have been investigated to provide an understanding of how chiral amplification is possible, in particular based on non-linear effects. Interestingly, it has been proposed a quarter century ago that chiral catalysts, when not enantiopure might even be more enantioselective than their enantiopure counterparts. We show here that such hyperpositive non-linear effect in asymmetric catalysis is indeed possible. An in-depth study into the underlying mechanism was carried out, and the scheme we derive differs from the previous proposed models.

Hyperpositive nonlinear effects in asymmetric catalysis

Asymmetric amplification is a curious phenomenon that is believed to play a key role in the emergence of biological homochirality, and thus of life itself. In asymmetric catalysis, it is achieved via positive nonlinear effects, which allow high product enantiomeric excesses with a non-enantiopure catalyst. However, it has also been proposed that non-enantiopure catalysts may be even more enantioselective than their enantiopure counterparts, although such a case has never been experimentally observed so far. Here, we present an example of such a hyperpositive nonlinear effect in asymmetric catalysis. We found that addition of dialkylzinc reagents to benzaldehyde gave higher product enantiomeric excesses with only partially resolved chiral N-benzyl-ephedrine ligands. A mechanistic study was carried out and our results point towards a two-component catalysis, where mononuclear as well as aggregated catalysts are in equilibrium and in competition. These results introduce an unprecedented class of asymmetric amplification in enantioselective catalysis. Nonlinear effects in catalysis have been shown to allow for asymmetric amplification. Here the authors report a particularly intriguing case whereby a catalytic asymmetric reaction gives a significantly higher product e.e. when run with a non-enantiopure catalyst compared to the enantiopure version.

Dynamic Nonlinear Effects in Asymmetric Catalysis

For three decades, “conventional” nonlinear effects in asymmetric catalysis, commonly becoming apparent as a nonproportional relationship between the enantiomeric purity of the chiral catalyst and ...

Autoamplification‐Enhanced Oxidative Kinetic Resolution of sec‐Alcohols and Alkyl Mandelates, and its Kinetic Model

AbstractIn this contribution, the new dynamic nonlinear effect in asymmetric catalysis is discussed, manifesting itself in the oxidative kinetic resolution (OKR) of racemic secondary benzylic alcohols and alkyl mandelates with H2O2 in the presence of chiral Mn‐based catalyst, with the apparent selectivity factor (krel) of the resolution being nonconstant over the reaction course. Typically, the initial growth of krel is changed into decay at high conversions. In this contribution, we demonstrate the oxidative kinetic resolution of various substrates bearing sec‐alcoholic moieties, with the krel varying in different manners with increasing substrate conversion. We also present the predictive kinetic model of OKR with participation of asymmetric autoamplification. The influence of substrate and catalyst structure, as well as solvents and additives, on the behavior of krel variation, is discussed.

Principles for designing an achiral receptor promoting asymmetric autocatalysis with amplification of chirality

The idea that an achiral receptor can promote asymmetric autocatalysis with amplification of chirality is presented and discussed in the light of two models, dubbed ACM1 and ACM2, corresponding to the autocatalytic versions of the classical Kagan and Noyori models for non-linear effects in asymmetric catalysis. The chiral amplifications produced by the two models have been investigated. The results suggest that an achiral receptor working according to the ACM1 model presents distinct advantages over the ACM2 counterpart, both in terms of elegance of design and performance.

Non-linear Effects in Asymmetric Catalysis: Whys and Wherefores

AbstractIt is argued that the titled non-linear effects (NLE) may arise whenever the order of the reaction in the chiral catalyst in greater than 1. In a fundamental departure from previous approaches, this is mathematically elaborated for the second order case. (NLE may also be observed if the chiral catalyst forms non-reacting dimers in a competing equilibrium; practically, however, this implies the in situ resolution of the catalyst.) The amplification of enantiomeric excess by NLE implies a relative (although modest) reduction in the entropy of mixing. The consequent increase in free energy apparently indicates a non-equilibrium process. It is suggested, based on arguments involving the chemical potential, that kinetically-controlled reactions lead to a state of “quasi-equilibrium”: in this, although overall equilibrium is attained, the product-spread is far from equilibrium. Thus, both the linear and NLE cases of chiral catalysis represent departures from equilibrium (which requires that the product e.e. = 0). Interesting similarities exist with models of non-equilibrium systems, the NLE cases apparently being analogs of open systems just after the bifurcation point has been crossed.

Non-linear Effects in Asymmetric Catalysis: Whys and Wherefores

It is argued that the titled non-linear effects (NLE) may arise whenever the order of the reaction in the chiral catalyst in greater than 1. In a fundamental departure from previous approaches, this is mathematically elaborated for the second order case. (NLE may also be observed if the chiral catalyst forms non-reacting dimers in a competing equilibrium; practically, however, this implies the in situ resolution of the catalyst.) The amplification of enantiomeric excess by NLE implies a relative (although modest) reduction in the entropy of mixing. The consequent increase in free energy apparently indicates a non-equilibrium process. It is suggested, based on arguments involving the chemical potential, that kinetically-controlled reactions lead to a state of “quasi-equilibrium”: in this, although overall equilibrium is attained, the product-spread is far from equilibrium. Thus, both the linear and NLE cases of chiral catalysis represent departures from equilibrium (which requires that the product e.e. = 0). Interesting similarities exist with models of non-equilibrium systems, the NLE cases apparently being analogs of open systems just after the bifurcation point has been crossed.

ChemInform Abstract: Kinetic Aspects of Nonlinear Effects in Asymmetric Catalysis

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Nonlinear Effects in Asymmetric Catalysis

There is a need for the preparation of enantiomerically pure compounds for various applications. An efficient approach to achieve this goal is asymmetric catalysis. The chiral catalyst is usually prepared from a chiral auxiliary, which itself is derived from a natural product or by resolution of a racemic precursor. The use of non-enantiopure chiral auxiliaries in asymmetric catalysis seems unattractive to preparative chemists, since the anticipated enantiomeric excess (ee) of the reaction product should be proportional to the ee value of the chiral auxiliary (linearity). In fact, some deviation from linearity may arise. Such nonlinear effects can be rich in mechanistic information and can be synthetically useful (asymmetric amplification). This Review documents the advances made during the last decade in the use of nonlinear effects in the area of organometallic and organic catalysis.

Equilibrium of Homochiral Oligomerization of a Mixture of Enantiomers. Its Relevance to Nonlinear Effects in Asymmetric Catalysis

The origin of nonlinear effects (no proportionality between enantiomeric excess (ee) of chiral auxiliary and ee of product) is first summarized in general terms, underlining the importance of the presence of molecular species bearing several moieties deriving from the chiral auxiliary. The presence of a heterochiral species, produced from enantioimpure chiral auxiliaries, usually explains well the deviation to linearity, especially asymmetric amplification. In this article it is shown that the absence of a heterochiral species is not incompatible with an asymmetric amplification. The demonstration has been done on a simple model, the equilibrium of homochiral dimerization. The monomers R and S being in equilibrium with the dimers R(2) and S(2), it was possible to calculate ee(monomer) and ee(dimer) as a function of the initial concentration and the initial ee of the monomer. The asymmetric amplification can be quite substantial for the dimer, while asymmetric depletion characterizes the residual monomers. Similar conclusions apply to homochiral tri- and tetramerizations. The extension to irreversible reactions was briefly analyzed as well as the use of these results.

Non‐Linear Effects in Asymmetric Catalysis

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Ligand and substrate π-stacking interaction controlled enantioselectivity in the asymmetric aziridination

Both the steric hindrance and the electronic effect are important factors for controlling the enantioselectivity in asymmetric catalysis. The substituent-dependent enantioselectivity in the asymmetric aziridination of chalcones catalyzed by 1,8-anthracene-linked bis-oxazoline (AnBOX) was rationalized to the π-stacking interaction between the ligand backbone and substrates and primarily confirmed by the use of bulky substrates and catalysts without aromatic backbones. The results provide important information for designing novel ligands and for understanding the influence of the electronic effect in asymmetric catalysis.

Energy-Resolved Collision-Induced Dissociation Cross Sections of 2:1 Bis-oxazoline Copper Complexes. Nonbonded Interactions and Nonlinear Effects

Absolute ligand binding energies are determined for the 2:1 complexes of bis-oxazoline ligands and Cu(I) in the gas phase by the fitting of energy-resolved collision-induced dissociation cross sections. The complexes were chosen for their occurrence in asymmetric catalysis for which the phenomenon of nonlinear effects is explained by differences in stability for homochiral and heterochiral complexes. Pseudo-enantiomeric ligands are used so that mass spectrometric measurements can be employed. The measurements find that the sterically similar, but electronically different, isopropyl versus phenyl substituents lead to a different stability ordering of the homo- versus heterochiral complexes, which then leads to the prediction of nonlinear effects in asymmetric catalysis by the complexes with isopropyl-substituted ligands. The origin of the difference in stability order is found in noncovalent interactions between the phenyl groups on the ligands, which are poorly described by DFT calculations.

Kinetic Rationalization of Nonlinear Effects in Asymmetric Catalysis Based on Phase Behavior

Kinetic Rationalization of Nonlinear Effects in Asymmetric Catalysis Based on Phase Behavior

Kinetic Rationalization of Nonlinear Effects in Asymmetric Catalysis Based on Phase Behavior

Mit Prolin als einem „kinetischen Konglomerat“ lässt sich sowohl der früher beobachtete nichtlineare Effekt in prolinkatalysierten Aldolreaktionen als auch die später beobachtete Linearität ohne Widerspruch mit dem derzeit akzeptierten Ein-Prolin-Reaktionsmechanismus erklären. Es ist wichtig, zwischen Gleichgewichts- und Kinetikeffekten in heterogenen Systemen zu unterscheiden – und diese physikalischen Einflüsse von nichtlinearen Effekten wirklich chemischen Ursprungs zu trennen. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2006/z602521_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Ligand Anatomy: Probing Remote Substituent Effects in Asymmetric Catalysis through NMR and Kinetic Analysis

A series of structurally related beta-amino alcohols only differing in the steric bulk of a remote alkoxy group exhibit striking differences in kinetic behavior when used as ligands in the asymmetric diethylzinc addition to benzaldehyde (R = Trityl, much more active). A combination of NMR titration studies and kinetic analysis allows the quantitative decomposition of the remote substituent effect into a lower dimerization constant of the active species and a much faster ethyl addition step.

Direct Asymmetric Intermolecular Aldol Reactions Catalyzed by Amino Acids and Small Peptides

We would like to point out an error of omission of a citation and present an accurate definition of eutectic in reference [29] in our paper (DOI: 10.1002/chem.200501639; submitted: December 29, 2005, published online: April 25, 2005). We were remiss not to state that the concept relating eutectics of amino acids to nonlinear effects in asymmetric catalysis had previously been presented at the Erdtman Lecture at KTH Stockholm by Prof. D. G. Blackmond on November 29, 2005. This work is now published (see M. Klussmann, H. Iwamura, S. P. Matthew, D. H. Wells, U. Pandya, A. Armstrong, D. G. Blackmond, Nature 2006, 441, 621; submitted November 21, 2005). We fully agree that the Blackmond group was the first to introduce this concept. Our discussion implied that we measured the eutectics of valine and alanine in this work, which we did not. We would like to clarify the definition of a eutectic with respect to these scalemic amino acid systems. We stated that the eutectic point is the point at which all three phases, (R)-amino acid, (S)-amino acid and DMSO can exist simultaneously. We are grateful to Prof. Donna Blackmond for providing us with the correct definition of a eutectic in the context of these amino acid systems: In an isothermal, three-component system at equilibrium consisting of (R)-amino acid, (S)-amino acid, and solvent, containing two distinct solid phases and one solution phase, the eutectic composition is dictated by the phase rule and is described as a point on the phase diagram where three separate phases intersect. The phase rule also dictates that the solution composition at the eutectic is fixed in this case and hence this composition is identical for any given (R)- and (S)-enantiomeric composition employed. The ee [%] for the (S)-alanine-catalyzed reaction in water given in Table 3, entry 17, should read 0 % ee and not 67 % ee. Editorial Note: D. G. Blackmond and co-workers transmitted their experimental observations prior to A. Cordova et al. The data in the paper by Cordova and co-workers describing nonlinear effects at higher alanine and valine concentrations were obtained during the week December 1–6, 2005. In addition, the experimental data presented in Figure 2 in the paper by Cordova and co-workers (showing striking asymmetric amplification in an asymmetric aldol reaction using scalemic serine as catalyst) were acquired on December 5, 2005. The Nature paper by Blackmond and co-workers referenced above represents, to our knowledge, the first measurement of eutectic points of free amino acids that form racemic compounds and the first comprehensive interpretation of nonlinear effects in asymmetric catalysis using acyclic amino acids as catalysts.