Absolute Asymmetric Synthesis in Enantioselective Autocatalytic Reaction Networks: Theoretical Games,Speculations on Chemical Evolution and Perhaps a Synthetic Option

The Soai reaction and the Viedma deracemization of racemic conglomerate crystal mixtures are experimental pieces of evidence of the ability of enantioselective autocatalytic coupled networks to yield absolute asymmetric synthesis. Thermodynamically open systems or systems with non‐uniform energy distributions may lead to chiral final states and, in systems able to come into thermodynamic equilibrium with their surroundings, to kinetically controlled absolute asymmetric synthesis. The understanding of network parameters and of the thermodynamic scenarios that may lead to spontaneous mirror symmetry breaking (SMSB) could assist in the development of new methods for asymmetric synthesis and enantioselective polymerizations (e.g., replicators), and to frame reasonable speculations on the origin of biological homochirality.     

The Viedma Deracemization of Racemic Conglomerate Mixtures as a Paradigm of Spontaneous Mirror Symmetry Breaking in Aggregation and Polymerization

Simulations of a chemical kinetics model, based on the free‐energy relationships of classical primary nucleation theory, show that the deracemization phenomenon in systems of achiral or fast racemizing compounds yielding enantiopure crystals as the more stable solid phase is a true spontaneous mirror symmetry breaking process (SMSB). That is, the achievement of a stationary chiral state is more stable than the racemic one. The model translates the free‐energy relationships determined by the existence of a critical size cluster to a chemical kinetics model, in which the consideration of forward and backward reaction rate constants avoids the misuse of network parameters that violate thermodynamic constraints (microreversibility principle), which would lead to apparent in silico SMSB. The model provides qualitative agreement for deracemizations by mechanical attrition of visible crystals, as well as for those obtained under temperature gradients. The analysis of the effect of the system parameters to obtain a SMSB scenario shows that the network possesses the principal characteristics of SMSB networks: 1) an enantioselective autocatalytic stage, corresponding to the non‐linear kinetics of enantioselective (homochiral) cluster‐to‐cluster growth, and 2) the mutual inhibition step originating in the backward flow of chiral clusters towards smaller achiral clusters, or even to a racemizing monomer. The application of such a SMSB kinetic model to enantioselective polymerizations and to chiral biopolymers is discussed.     

Frank Model and Spontaneous Emergence of Chirality in Closed Systems

In a closed system an irreversible enantioselective autocatalysis coupled to a mutual inhibition reaction, corresponding to a fast and low exergonic formation of the heterochiral dimer which reverts to the monomers in the final reaction work‐up, yields absolute asymmetric synthesis even in the absence of chiral polarizations. This is due to the very high chiral amplifications of the initial small statistical deviations from the ideal racemic composition. Moreover, this system is sensitive to very small chiral polarizations (energy differences between transition states below the mJ mol^?1 range). This behaviour can also be observed in reversible exergonic reactions, because the racemization time scale is substantially longer than that of the transformation of the initial reagents. The effect of the presence of other reactions likely to occur (i.e. non‐catalytic transformations, non‐enantioselective catalysis and homodimer formation) is discussed. Even if these decrease the sensitivity of the network in several chemical scenarios, the emergence of kinetically controlled spontaneous symmetry breaking is not hindered. These features, together with the response of the system to a sequential reaction procedure, suggest that a similar type of network is at the heart of the Soai reaction.     

Engineering Chiral Catalysts through Asymmetric Activation and Super High Throughput Screening (SHTS)

A conceptually new strategy for asymmetric catalysis, namely asymmetric activation, in which a chiral activator selectively activates one enantiomer of a racemic chiral catalyst, and a highly efficient screening system for finding the most effective catalysts, namely super high throughput screening (SHTS), by which the reaction can be conducted in parallel and the ee% of the product is allowed to determine within minutes, are summarized in the present account. It is reasonable to believe that SHTS technique combined with asymmetric activation or deactivation principle will provide a very powerful methodology for finding the new catalysts and the best catalyst tuning for asymmetric reactions.     

Spontaneous Chiral Symmetry Breaking for Finite Systems

Theoretical clues are desirable to help uncover the origin of bio‐homochirality in life, as well as the mechanisms for the asymmetric production of functional chiral substances. Here, an open‐to‐matter reaction network based on a model proposed by Plasson et al. is studied. In the extended model, the statistical fluctuations lead the system to break chiral symmetry autonomously, that is, without any initial enantiomeric excess or external influence. In the stability diagrams, we observe regions of parameter space that correspond to racemic, homochiral, chiral oscillatory, and, to our knowledge, for the first time in a chiral model, chaotic regimes. The dependencies of the final concentrations of chiral substances on the parameters are determined analytically and discussed for both the racemic and homochiral regimes.     

微反应器中的不对称光化学反应

化学反应的手性诱导一直备受化学家的关注,虽然不对称热化学合成和手性技术已经取得了巨大的进展,但不对称光化学反应的研究远远没有取得相应的成功.激发态寿命短、活化能低是导致其对映选择性低的主要原因.最新的研究表明,采用含手性空间或经手性修饰的微环境可以使光化学反应的立体选择性大大提高.本文针对这一热点问题,综述在微反应器中进行不对称光化学反应的研究进展.     

Nickel(II)‐Catalyzed Asymmetric Propargyl [2,3] Wittig Rearrangement of Oxindole Derivatives: A Chiral Amplification Effect

A highly enantioselective [2,3] Wittig rearrangement of oxindole derivatives was realized by using a chiral N,N′‐dioxide/Ni^II complex as the catalyst under mild reaction conditions. A strong chiral amplification effect was observed, and allowed access to chiral 3‐hydroxy 3‐substituted oxindoles bearing allenyl groups in high yields and enantioselectivities (up to 92 % ee) by using a ligand with only 15 % ee. A reasonable explanation was given based on the experimental investigations and X‐ray crystal structures of enantiomerically pure and racemic catalysts. Moreover, the first catalytic kinetic resolution of racemic oxindole derivatives by a [2,3] Wittig rearrangement was realized with high efficiency and stereoselectivity.     

Vicinal Difunctionalization of Alkenes with Iodine(III) Reagents and Catalysts

Hypervalent iodine(III) reagents have been known for over a century, and their reaction profile is still actively investigated. Recent years have seen impressive improvements in the area of alkene difunctionalization reactions, where new methodologies have become available. Especially chiral non‐racemic hypervalent iodine(III) reagents and catalysts have emerged as versatile tools for the realization of important enantioselective transformations.     

Enantioselective decarboxylation of beta-keto esters with Pd/amino alcohol systems: successive metal catalysis and organocatalysis

The kinetics and mechanisms of one-pot cascade reactions of racemic beta-keto esters to give chiral ketones in the presence of Pd/C-chiral amino alcohol catalyst systems were studied. Transformation of 2-methyl-1-tetralone-2-carboxylic acid benzyl ester (1) into 2-methyl-1-tetralone (4) in the presence of Pd/C and cinchona alkaloids or ephedrine was chosen as a model reaction. After the first reaction step, the Pd-catalysed debenzylation of 1 to afford the corresponding beta-keto acid (2), there are two possible reaction routes that may be catalysed by the chiral amino alcohol in solution or by Pd(0) sites on the metal surface in cooperation with the adsorbed amino alcohol. The reaction intermediate 2 was synthesized, and the kinetics of decarboxylation were followed by NMR, UV and IR spectroscopy. The studies revealed that the role of Pd is to trigger the reaction series by deprotection of 1. The subsequent dominant reaction route from the racemic beta-keto acid 2 to the chiral ketone 4 is catalysed by the chiral amino alcohol in the liquid phase. It is shown that kinetic resolution of the diastereomeric salt of rac-2 and the chiral amino alcohol plays a key role in the enantioselection. High enantioselectivity necessitates an amino alcohol/rac-2 ratio of at least 2. A high ratio favours the formation of 1:1 amino alcohol/acid diastereomeric complexes, and the second amino alcohol molecule may be responsible for the enantioselective protonation of 2 in the diastereomeric complex.     

A Complex Reaction Network Model for Spontaneous Mirror Symmetry Breaking in Viedma Deracemizations

Attrition-enhanced chiral symmetry breaking in crystals, known as Viedma deracemization, is a promising method for converting racemic solid phases into enantiomerically pure ones under non-equilibrium conditions. However, many aspects of this process remain unclear. In this study, we present a new investigation into Viedma deracemization using a comprehensive kinetic rate equation continuous model based on classical primary nucleation theory, crystal growth, and Ostwald ripening. Our approach employs a fully microreversible kinetic scheme with a size-dependent solubility following the Gibbs–Thomson rule. To validate our model, we use data from a real NaClO₃ deracemization experiment. After parametrization, the model shows spontaneous mirror symmetry breaking (SMSB) under grinding. Additionally, we identify a bifurcation scenario with a lower and upper limit of the grinding intensity that leads to deracemization, including a minimum deracemization time within this window. Furthermore, this model uncovers that SMSB is caused by multiple instances of concealed high-order autocatalysis. Our findings provide new insights into attrition-enhanced deracemization and its potential applications in chiral molecule synthesis and understanding biological homochirality.     

Deracemization of compounds possessing a sec-alcohol or -amino group through a cyclic oxidation–reduction sequence: a kinetic treatment

Deracemization of compounds bearing a chiral sec-hydroxy or -amino group can be achieved in a one-pot reaction via a novel process consisting of a cyclic oxidation–reduction sequence. Thus, in the first step, one enantiomer from the racemic starting material (R+S) is enantioselectively oxidized forming an achiral intermediate product (P, a ketone or imine, respectively). In the second step, the latter is non-selectively reduced to give again R+S in racemic form. Cyclic repetition of this oxidation–reduction sequence leads to an overall chiral inversion of the faster reacting enantiomer from the racemic starting material to yield the slower reacting enantiomer as the final product in a theoretical 100% chemical and enantiomeric yield. Mathematical treatment of the kinetics of this `cyclo-process' allowed the estimation of the practical feasibility at hand of two crucial parameters: (i) the maximal obtainable enantiomeric excess and (ii) the number of cycles required (expressed as theoretical turnover) to reach equilibrium. A computer program for analysis and optimization of such processes was developed, which is available via the Internet.     

手性磷酸在不对称反应中的应用

手性磷酸催化剂因其在不对称催化反应中表现出的高效、高对映选择性而受到人们越来越多的关注.含1,1'-联二萘酚(BINOL)骨架的手性磷酸类催化剂已被广泛用于亚胺的不对称氢转移、Friedel-Crafts反应和Mannich反应等许多重要的有机合成反应.手性磷酸具有同时提供质子和接受质子的双功能作用,因此可以同时活化两个反应底物.含BINOL骨架的手性磷酸可以通过改变BINOL骨架3,3'-位上的取代基调控空间位阻和手性磷酸的酸性,因此可以调节反应的对映选择性.为了合理地设计新的手性磷酸催化剂,扩大其应用范围,最近人们对手性磷酸不对称催化反应机理进行了初步的理论计算研究并取得了显著进展.综述了手性磷酸在不对称反应中的部分研究工作,尤其是理论研究领域的最新成果.     

Dynamic processes in the copper-catalyzed substitution of chiral allylic acetates leading to loss of chiral information

Copper-catalyzed alpha-substitution of enantiomerically pure secondary allylic esters with Grignard reagents was studied with the aim to find conditions that give racemic products. It was observed that the degree of chiral transfer is strongly dependent on the temperature. The loss of chiral information is consistent with an equilibration of the Cu(III)(allyl) intermediates prior to product formation. Equilibration of the reaction intermediates is of importance for a possible development of a dynamic kinetic asymmetric transformation (DYKAT) process, in which a chiral catalyst is used to produce an optically active product from a racemic substrate, by means of a dynamic equilibrium of the diastereomeric reaction intermediates.     

Enantio and diastereoselective addition of phenylacetylene to racemic α-chloroketones

In this report, we have presented the first diastereoselective addition of phenylacetylene to chiral racemic chloroketones. The addition is controlled by the reactivity of the chloroketones that allowed the stereoselective reaction to be performed at -20 °C. Chiral racemic chloroketones are used in the reaction. By carefully controlling the temperature and the reaction time we were able to isolate the corresponding products in moderate yields and with good, simple and predictable facial stereoselection. Our reaction is a rare example of the use of chiral ketones in an enantioselective alkynylation reaction and opens new perspectives for the formation of chiral quaternary stereocenters.     

Chiral N-heterocyclic carbene catalyzed, enantioselective oxodiene Diels-Alder reactions with low catalyst loadings

Chiral N-heterocyclic carbene (NHC) catalyzed redox reactions of racemic alpha-chloroaldehydes lead to the generation of chiral enolates suitable for highly enantioselective inverse-electron-demand 1-oxodiene Diels-Alder reactions. Significantly, these reactions proceed under mild, operationally friendly reaction conditions (EtOAc, room temperature, 2-8 h) using less than 1 mol % of a chiral N-mesityl triazolium salt as the precatalyst. A broad array of densely functionalized dihydropyran-2-ones bearing either aliphatic or aromatic substiutents are formed in excellent yields and exceptional enantioselectivities from readily available reactants. Stereochemical mismatching between the racemic starting materials and the chiral catalyst is avoided by rapid epimerization of the chloroaldehydes under the reaction conditions.     

Asymmetric cross-benzoin condensation promoted by a chiral triazolium precatalyst bearing a pyridine moiety

Cross-benzoin condensation catalyzed by NHC, prepared from chiral triazolium salts bearing a pyridine ring, afforded α-hydroxy ketones with reasonable chemical yields and enantioselectivities. A wide range of aliphatic and aromatic aldehydes were successfully used in the reaction.     

Autocatalytic Enantiomerisation at the Crystal Surface in Deracemisation of Scalemic Conglomerates

Deracemisation of racemic or scalemic conglomerates of intrinsically chiral compounds appears to be a promising method of chiral resolution. By combining the established methods of asymmetric synthesis and the physical process of crystal growth, we were able to achieve a complete deracemisation (with 100 % ee) of an asymmetric Mannich product conglomerate—vigorously stirred in its saturated solution—from a starting enantiomeric excess value of 15.8 % in the presence of pyrrolidine (8 mol %) as an achiral catalyst for the CC bond‐forming reaction. Strong activation of this deracemisation process was observed on mild isothermal heating to only 40 °C, resulting in dramatic acceleration by a factor of about 20 with respect to the results obtained at room temperature. Despite the fact that the racemisation half‐life time of the nearly enantiopure Mannich product (with 99 % ee) in the homogenous solution at the reaction temperature is eight days, the deracemisation process took only hours in a small‐scale experiment. This apparent paradox is explained by a proposed rapid enantiomerisation at the crystal/solution interface, which was corroborated by a ¹³C labelling experiment that confirmed the involvement of rapid enantiomerisation. Frequent monitoring of the solution‐phase ee of the slowly racemising compound further revealed that the minor enantiomer dominated in solution, supporting an explanation based on a kinetic model. A generalisation of the process of “aymmetric autocatalysis” (resulting in automultiplication of chiral products in homogenous media) to encompass heterogeneous systems is also suggested.     

Solvent- and temperature-dependent functionalisation of enantioenriched aziridines

A highly stereo‐ and regioselective functionalisation of chiral non‐racemic aziridines is reported. By starting from a parent enantioenriched aziridine and finely tuning the reaction conditions, it is possible to address the regio‐ and stereoselectivity of the lithiation/electrophile trapping sequence, thereby allowing the preparation of highly enantioenriched functionalised aziridines. From chiral N‐alkyl trans‐2,3‐diphenylaziridines (S,S)‐ 1 a , b , two differently configured chiral aziridinyllithiums could be generated (trans‐ 1 a , b‐Li in toluene and cis‐ 1 a , b‐Li in THF), thus disclosing a solvent‐dependent reactivity that is useful for the synthesis of chiral tri‐substituted aziridines with different stereochemistry. In contrast, chiral aziridine (S,S)‐ 1 c showed a temperature‐dependent reactivity to give chiral ortho‐lithiated aziridine 1 c‐ ortho ‐Li at ?78 °C and α‐lithiated aziridine 1 c‐α‐Li at 0 °C. Both lithiated intermediates react with electrophiles to give enantioenriched ortho‐ and α‐functionalised aziridines. The reaction of all the lithiated aziridines with carbonyl compounds furnished useful chiral hydroxyalkylated derivatives, the stereochemistry of which was ascertained by X‐ray and NMR spectroscopic analysis. The usefulness of chiral non‐racemic functionalised aziridines has been demonstrated by reductive ring‐opening reactions furnishing chiral amines that bear quaternary stereogenic centres and chiral 1,2‐, 1,3‐ and 1,5‐aminoalcohols. It is remarkable that the solvent‐dependent reactivity observed with (S,S)‐ 1 a , b permits the preparation of both the enantiomers of amines ( 11 and ent‐ 11 ) and 1,2‐aminoalcohols ( 13 and ent‐ 13 ) starting from the same parent aziridine. Interestingly, for the first time, a configurationally stable chiral α‐lithiated aziridine ( 1 c‐α‐Li ) has been generated at 0 °C. In addition, ortho‐hydroxyalkylated aziridines have been easily converted into chiral aminoalkyl phthalans, which are useful building blocks in medicinal chemistry.     

Enantiospecific synthesis of vicinal stereogenic tertiary and quaternary centers by combination of configurationally-trapped radical pairs in crystalline solids

[reaction: see text] Photochemical irradiation of crystalline (2R,4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-butanone 1 led to highly efficient decarbonylation reactions. Experiments with optically pure and racemic crystals showed that the intermediate radical pairs undergo a highly diastereo- and enantiospecific radical-radical combination that leads to the formation of two adjacent stereogenic centers in good chemical yield and with high chemical control. Reactions with chiral crystals occurred with quantitative enantiomeric yields and >95% diastereomeric yields.     

Structurally diverse second-generation [2.2]paracyclophane ketimines with planar and central chirality: syntheses, structural determination, and evaluation for asymmetric catalysis

A set of 20 novel [2.2]paracyclophane ketimines with planar and central chirality has been synthesized from enantiomerically pure and racemic 5-acyl-4-hydroxy[2.2]paracyclophane and alpha-branched chiral amines. Their X-ray structures were determined to elucidate the three-dimensional structures and the absolute configuration. The ketimines were used as catalysts in the asymmetric 1,2-addition reactions of diethylzinc with substituted benzaldehydes to furnish chiral alcohols in up to 95 % ee.