Product Enantioselectivity Research Articles

Innovative Approach to Chiral Polyurethanes: Asymmetric Copolymerization with Isocyanates.

The introduction of nitrogen-containing functional groups to chiral polymer backbones enables the tailoring of physical properties and offers opportunities for further post-polymerization modification. However, the substrate scope of such polymers is extremely limited because monomers having nitrogen-containing groups can change coordination state with respect to the metal centers, thus decreasing the activity and enantioselectivity and even poisoning the catalyst completely. In this paper, we report our attempts to carry out the asymmetric copolymerization of meso-epoxide with highly reactive isocyanates. In particular, we found that biphenol-linked bimetallic Co(III) complexes with multiple chiral centers are very efficient in catalyzing this asymmetric copolymerization reaction, affording optically active polyurethanes with a completely alternating nature and a high enantioselectivity of up to 94% ee. Crucially, we identified that the steric hindrance at the phenolate ortho position of the ligand strongly influences the catalytic activity and product enantioselectivity. In addition, density functional theory calculations revealed that the highly sterically bulky substituents change the mechanism from bimetallic to monometallic, and result in the unexpected inversion of the chiral induction direction. Moreover, the high stereoregularity of the produced polyurethanes enhances their thermal stability. This study offers a versatile methodology for the synthesis of chiral polymers containing nitrogen functionalities.

Innovative Approach to Chiral Polyurethanes: Asymmetric Copolymerization with Isocyanates

AbstractThe introduction of nitrogen‐containing functional groups to chiral polymer backbones enables the tailoring of physical properties and offers opportunities for further post‐polymerization modification. However, the substrate scope of such polymers is extremely limited because monomers having nitrogen‐containing groups can change coordination state with respect to the metal centers, thus decreasing the activity and enantioselectivity and even poisoning the catalyst completely. In this paper, we report our attempts to carry out the asymmetric copolymerization of meso‐epoxide with highly reactive isocyanates. In particular, we found that biphenol‐linked bimetallic Co(III) complexes with multiple chiral centers are very efficient in catalyzing this asymmetric copolymerization reaction, affording optically active polyurethanes with a completely alternating nature and a high enantioselectivity of up to 94 % ee. Crucially, we identified that the steric hindrance at the phenolate ortho position of the ligand strongly influences the catalytic activity and product enantioselectivity. In addition, density functional theory calculations revealed that the highly sterically bulky substituents change the mechanism from bimetallic to monometallic, and result in the unexpected inversion of the chiral induction direction. Moreover, the high stereoregularity of the produced polyurethanes enhances their thermal stability, and they can be selectively decomposed into oxazolidinones. This study offers a versatile methodology for the synthesis of chiral polymers containing nitrogen functionalities.

Is Reaction Acceleration of Microdroplet Chemistry Favorable to Controlling the Enantioselectivity?

Microdroplet chemistry has been proven to amazingly accelerate many chemical and biological reactions in the past 2 decades. Current microdroplet accelerated reactions are predominantly symmetric synthetic but minorly asymmetric synthetic reactions, where stereoselectivity is scarcely concerned. This study selected unimolecular and bimolecular reactions, multicomponent Passerini reactions, and enzymatic ketone reduction as the model reactions to illustrate whether reaction acceleration of microdroplet chemistry is favorable to retaining a chiral center and controlling the enantioselectivity or not. The results illustrated that microdroplet chemistry did not disrupt pre-existing stereogenic centers in chiral starting materials during reactions but did harm to stereospecificity in asymmetric catalysis by chiral catalysts and chiral organic ligands with the exclusion of enzymatic reactions. Our preliminary study reminds us of more cautions to the product enantioselectivity when conducting asymmetric catalysis in microdroplets. We also hope this study may promote more valuable further research on the stereoselectivity of microdroplet chemistry.

Synthesis of cyclodextrin derivatives for enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate.

Photochemical methods are increasingly being used in organic synthesis. They are especially useful for preparing many compounds that are not readily accessible through thermal or enzymatic reactions. The supramolecular strategy has proved highly promising in recent years for manipulating the stereochemical outcome of chiral photoreactions through relatively strong and long-lasting noncovalent interactions in both ground and excited states. Among the numerous chiral photochemical reactions, photocyclodimerization of 2-anthracenecarboxylate (AC) is the most comprehensively studied supramolecular chiral photoreaction and has essentially become a benchmark reaction for evaluating supramolecular photochirogenesis. Cyclodextrin (CD) derivatives were the earliest and are the most widely applied chiral host for mediating photoreactions. Herein, we use CD-mediated photocyclodimerization of AC as an example to introduce the operation process of supramolecular chiral photoreactions. The protocol includes the following contents: (i) the preparation, purification and characterization of β-CD derivatives; (ii) methods for investigating the host-guest inclusion behavior between AC and β-CD derivatives; (iii) the photochemical reaction operation flow under different solvent and temperature conditions; (iv) chiral high-performance liquid chromatography (HPLC) analyses of the product distribution and enantioselectivity. The protocol is introduced by using representative examples of the synthesis of β-CD derivatives and the manipulation of environmental factors that give excellent regio- and enantioselectivities in the photocyclodimerization of AC. The synthesis and purification of β-CD derivatives require 3-5 d of work. The photoirradiation of AC with β-CD derivatives can be done within 1 h. The product analysis requires 5 h.

Determinants of Selectivity for the Formation of Monocyclic and Bicyclic Products in Monoterpene Synthases

Monoterpene synthases (MTSs) catalyze the initial committed step in the biosynthesis of monoterpenes. MTSs control challenging reactions that involve highly reactive carbocations through exquisite steric and electrostatic confinement, in some cases with remarkable product specificity and enantioselectivity. Using two well-characterized MTSs as models, (4S)-(−)-limonene synthase (LMNS) and (+)-bornyl diphosphate synthase (BPPS), we implemented an iterative approach that involves comparative atomistic simulations and experimental testing of wild-type enzymes and thirty-six variants to identify the mechanistic underpinnings of selectivity. Free energy simulations indicate that a common reaction intermediate, the α-terpinyl cation (ATC), preferentially adopts one of two different conformations in LMNS and BPPS, thus leading to the formation of monocyclic monoterpenes in the former and bicyclic products in the latter. An assessment of the ATC binding free energy in LMNS, BPPS, and variants revealed that nonbonded interactions with active site residues explain the propensity of the ATC to assume a favored conformation that is consistent with the experimentally determined reaction outcome. The free energy of the ATC in different environments (active sites of LMNS, BPPS, and variants) correlates strongly with the ratio of monocyclic to bicyclic products in model MTSs.

Isothiourea-Catalyzed Enantioselective Michael Addition of Malonates to α,β-Unsaturated Aryl Esters

An enantioselective Michael addition of malonates to α,β-unsaturated para-nitrophenyl esters was achieved using the Lewis basic isothiourea HyperBTM, giving excellent levels of product enantioselectivity (up to >99:1 enantiomeric ratio) in good yields and with complete regioselectivity (>20:1 regioselectivity ratio) in the presence of alternative (phenyl ketone and ethyl ester) Michael acceptors. Density functional theory calculations indicate that N-acylation is rate-limiting. This constitutes a rare example of a highly enantioselective addition of simple, readily available malonates to α,β-unsaturated esters.

Catalytic Asymmetric Strecker Reaction of Ketoimines with Potassium Cyanide

AbstractA catalytic asymmetric Strecker reaction of ketoimines with potassium cyanide (KCN) is developed. Control experiments reveal the involvement of a retro‐Strecker reaction, which inevitably decreases the product yield and enantioselectivity. The use of a protic additive in combination with a chiral 1,2,3‐triazolium ion as a catalyst allows for the highly efficient and enantioselective cyanide addition to various ketoimines.

Supramolecular Enantiodifferentiating Photocyclodimerization of 2-Anthracenecarboxylic Acid Mediated by Bridged β-Cyclodextrins: Critical Effects of the Host Structure, pH and Co-Solvents.

Several sulfoxide- and sulfone-bridged β-cyclodextrin (CD) dimers were synthesized for mediating the enantiodifferentiating [4+4] photocyclodimerization of 2-anthracenecarboxylic acid (AC). The complexation behavior of these chiral hosts with AC was investigated by UV-vis, circular dichroism, fluorescence, and NMR spectroscopies and certified the formation of 1 : 1 and 1 : 2 host-guest complexes. The product distribution and enantioselectivity of the photoreaction turned out to be a critical function of the chemical structure of bridged CDs. Comparing to the sulfur-bridged 2AX -3GX β-CD dimer 7, the conversion of the photolyzes with sulfoxide-bridged was significantly improved, and the ee of cyclodimer 2 was remarkably increased from -82.8% with 7 to -96.7% with the sulfoxide-bridged 2AX -3GX β-CD dimer 8. The relative yields and ee values of the slipped cyclodimers 5 and 6 were greatly enhanced in the presence of 6 M CsCl. The reaction selectivity is susceptible to the pH variation of the aqueous buffer solution, demonstrating that the supramolecular photochirogenesis is controlled by multidimensional factors, including the chemical structure of the chiral host, solvent, and pH conditions.

Semi‐Rational Engineering of Toluene Dioxygenase from Pseudomonas putida F1 towards Oxyfunctionalization of Bicyclic Aromatics

AbstractToluene dioxygenase (TDO) from Pseudomonas putida F1 was engineered towards the oxyfunctionalization of bicyclic substrates. Single and double mutant libraries addressing 27 different positions, located at the active site and entrance channel were generated. In total, 176 different variants were tested employing the substrates naphthalene, 1,2,3,4‐tetrahydroquinoline, and 2‐phenylpyridine. Introduced mutations in positions M220, A223 and F366, exhibited major influences in terms of product formation, chemo‐, regio‐ and enantioselectivity. By semi‐rational evolution, we lighted up the TDO capability to convert bulkier substrates than its natural substrate, at unprecedented reported conversions. Thus, the most active TDO variants were applied to biocatalytic oxyfunctionalizations of 1,2,3,4‐tetrahydroquinoline, and 2‐phenylpyridine, enabling the production of substantial amounts of (+)‐(R)‐1,2,3,4‐tetrahydroquinoline‐4‐ol (71% isolated yield, 94% ee) and (+)‐(1S,2R)‐3‐(pyridin‐2‐yl)cyclohexa‐3,5‐diene‐1,2‐diol (60% isolated yield, 98% ee), respectively. Here, we provide a set of novel TDO‐based biocatalysts useful for the preparation of oxyfunctionalized bicyclic scaffolds, which are valuable to perform downstream synthetic processes.magnified image

Asymmetric Hetero-Michael Additions to α,β-Unsaturated Carboxylic Acids by Multifunctional Boronic Acid Catalysts

Several direct asymmetric Michael additions to α,β-unsaturated carboxylic acids with integrated catalysts comprising chiral bifunctional thiourea and arylboronic acid were developed. First, the asymmetric aza-Michael addition of hydroxylamine derivatives efficiently afforded a variety of optically active β-amino acid derivatives. Furthermore, upon detailed investigation of the reaction, tetrahedral borate complexes, comprising two carboxylate molecules, were found to serve as reaction intermediates. Based on this observation, a drastic improvement in product enantioselectivity was achieved upon benzoic acid addition. Second, on merely changing the solvent, the asymmetric thia-Michael addition of arylthiols afforded both enantiomers of the adducts, which are important building blocks for biologically active compounds.

Insights into the Chiral Phosphoric Acid-Catalyzed Dynamic Kinetic Asymmetric Hydroamination of Racemic Allenes: An Allyl Carbocation/Phosphate Pair Mechanism.

Computational studies of chiral phosphoric acid (CPA)-catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes show that the reaction proceeds through a catalytic asymmetric model involving a highly reactive π-allylic carbocationic intermediate, generated from a racemic allene through an intermolecular proton transfer mediated by CPA, which also results in a high E/Z selectivity. Moreover, the distortion-interaction, atom in molecule, and electrostatic interaction analyses and space-filling models are employed on the basis of the DyKAH catalyzed by (S)-A5 (reaction 1) or (R)-A2 (reaction 2) to explain the high enantioselectivity and the controlling effects of SPINOL scaffolds on the signs of enantioselectivity. Our calculations indicate that the enantioselectivity of reactions 1 and 2 can be mainly ascribed to the favorable noncovalent interactions within the stronger chiral electrostatic environment created by the phosphoric acid in the preferential transition states. Finally, the effect of (S/R)-SPINOL-based CPAs on the signs of enantioselectivity can be explained by the different combination modes of substrates into the chiral binding pocket of the catalyst controlled by the chirality of SPINOL backbones. Overall, the new insights into the reaction rationalize the outcome and these key factors that affect the product enantioselectivity are important to guide the DyKAHs.

Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts.

The regio- and stereoselective addition of C(1)-ammonium enolates – generated in situ from aryl esters and the isothiourea catalyst (R)-BTM – to pyridinium salts bearing an electron withdrawing substituent in the 3-position allows the synthesis of a range of enantioenriched 1,4-dihydropyridines. This represents the first organocatalytic approach to pyridine dearomatisation using pronucleophiles at the carboxylic acid oxidation level. Optimisation studies revealed a significant solvent dependency upon product enantioselectivity, with only toluene providing significant asymmetric induction. Using DABCO as a base also proved beneficial for product enantioselectivity, while investigations into the nature of the counterion showed that co-ordinating bromide or chloride substrates led to higher product er than the corresponding tetrafluoroborate or hexafluorophosphate. The scope and limitations of this process are developed, with enantioselective addition to 3-cyano- or 3-sulfonylpyridinium salts giving the corresponding 1,4-dihydropyridines (15 examples, up to 95 : 5 dr and 98 : 2 er).

Isothiourea‐Catalyzed Atropselective Acylation of Biaryl Phenols via Sequential Desymmetrization/Kinetic Resolution

AbstractAxially chiral phenols are attractive targets in organic synthesis. This motif is central to many natural products and widely used as precursors to, or directly, as chiral ligands and catalysts. Despite their utility few simple catalytic methods are available for their synthesis in high enantiopurity. Herein the atropselective acylation of a range of symmetric biaryl diols is investigated using isothiourea catalysis. Studies on a model biaryl diol substrate shows that the high product er observed in the process is a result of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with a second chiroablative kinetic resolution. Extension of this process to a range of substrates, including a challenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples, up to 98:2 er), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate. Computation has been used to understand the factors that lead to high enantiocontrol in this process, with maintenance of planarity to maximize a 1,5‐S⋅⋅⋅O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.

Isothiourea-Catalyzed Atropselective Acylation of Biaryl Phenols via Sequential Desymmetrization/Kinetic Resolution.

Axially chiral phenols are attractive targets in organic synthesis. This motif is central to many natural products and widely used as precursors to, or directly, as chiral ligands and catalysts. Despite their utility few simple catalytic methods are available for their synthesis in high enantiopurity. Herein the atropselective acylation of a range of symmetric biaryl diols is investigated using isothiourea catalysis. Studies on a model biaryl diol substrate shows that the high product er observed in the process is a result of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with a second chiroablative kinetic resolution. Extension of this process to a range of substrates, including a challenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples, up to 98:2 er), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate. Computation has been used to understand the factors that lead to high enantiocontrol in this process, with maintenance of planarity to maximize a 1,5-S⋅⋅⋅O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.

Using Choline Chloride-Based DESs as Co-Solvent for 3,5-Bis(trifluoromethyl) Acetophenone Bioreduction with Rhodococcus erythropolis XS1012

(S)-3,5-Bistrifluoromethylphenyl ethanol((S)-BTPE) is a key pharmaceutical intermediate of the NK-1 receptor antagonist. The asymmetric bioreduction of 3,5-bis(trifluoromethyl) acetophenone (BTAP) to (S)-BTPE using Rhodococcus erythropolis XS1012 has been established in a phosphate buffer system. To overcome the problem of unsatisfactory yields at high substrate concentration, deep eutectic solvents (DESs) have been introduced to the buffer system. After screening 13 kinds of choline chloride-based DESs, [choline chloride][urea] ([ChCl][U]) showed great influence on the cell activity and significantly increased the cell membrane permeability. Subsequently, some major parameters for this reaction were determined. A remarkable (S)-BTPE yield of 91.9% was gained at 150 mM substrate concentration under optimized reaction conditions with >99.9% product enantioselectivity. Compared to reduction in a buffer system, the developed [ChCl][U]-containing system increased the yield from 82.6% to 91.9%. It maintains a yield of 80.7% with the substrate concentration up to 300 mM, compared to only 63.0% in buffer system. This study demonstrated that [ChCl][U] is a feasible co-solvent to improve the bioreduction process.

The Origins of the Stereoselectivity and Enantioswitch in the Rare‐Earth‐Catalyzed Michael Addition: A Computational Study

AbstractThe general strategy for forming an opposite enantiomeric product from an asymmetric reaction involves using the opposite enantiomeric catalyst. For the Michael addition of 4‐substituted‐5‐pyrazolones (1) to 1,4‐dicarbonyl but‐2‐enes (2) catalyzed by rare earth with the chiral N,N′‐dioxide derivative ligand (L), the product enantioselectivity was switched only by changing the rare earth from Sc to Y. To understand the mechanism, we investigated the reaction energy profile using the density functional theory combined with the automated reaction path search method. The enantioselectivity on 1 was determined by the coordination structure of the pre‐reaction complex. The pre‐reaction complex of the Sc system was ScL(OTf)1, where only the Si‐face attack of 2 was blocked. Conversely, the pre‐reaction complex of the Y system had one more triflate anion, (YL(OTf)21), which stabilized the different coordination structure, where only the Re‐face attack of 2 was blocked. The origin of the diastereoselectivity was also investigated based on the transition states (TSs) of the C−C bond formation. The orientation of 2 at the TSs was fixed because of the proton transfer, which destabilized the TS affording the minor diastereomer.

Enantiodivergent α-Amino C-H Fluoroalkylation Catalyzed by Engineered Cytochrome P450s.

The introduction of fluoroalkyl groups into organic compounds can significantly alter pharmacological characteristics. One enabling but underexplored approach for the installation of fluoroalkyl groups is selective C( sp3)-H functionalization due to the ubiquity of C-H bonds in organic molecules. We have engineered heme enzymes that can insert fluoroalkyl carbene intermediates into α-amino C( sp3)-H bonds and enable enantiodivergent synthesis of fluoroalkyl-containing molecules. Using directed evolution, we engineered cytochrome P450 enzymes to catalyze this abiological reaction under mild conditions with total turnovers (TTN) up to 4070 and enantiomeric excess (ee) up to 99%. The iron-heme catalyst is fully genetically encoded and configurable by directed evolution so that just a few mutations to the enzyme completely inverted product enantioselectivity. These catalysts provide a powerful method for synthesis of chiral organofluorine molecules that is currently not possible with small-molecule catalysts.

Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas.

Carboxylic acids and their corresponding carboxylate anions are generally utilized as Brønsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH2 to α,β-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Brønsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.

Structural insight into the catalytic mechanism of a cis-epoxysuccinate hydrolase producing enantiomerically pure d(−)-tartaric acid

Crystal structure determination and mutagenesis analysis of a cis-epoxysuccinate hydrolase which produces enantiomerically pure d(-)-tartaric acids revealed a zinc ion and essential residues in the stereoselective mechanism for the catalytic reaction of the small mirror symmetric substrate.

Catalyst Optimisation for Asymmetric Synthesis by Ligand Chirality Element Addition: A Perspective on Stereochemical Cooperativity.

The concept of matched and mismatched stereochemical pairings has been utilised extensively in organic synthesis, with the cooperativity resulting from the former enabling many reactions to proceed with high stereoselectivity. This approach was first developed to improve the diastereoselectivity of a reaction by matching the configuration of an enantiopure reagent or catalyst with the configuration of an enantiopure substrate. It has been extended to the asymmetric transformation of prochiral substrates controlled by reagents and catalysts containing two or more stereogenic centres. Matched and mismatched pairings may again be identified, with the former resulting in higher product enantioselectivity. This Minireview examines stereochemical pairings within catalysts generated from the combination of a metal with an enantiopure ligand; specifically examples in which the ligand diastereoisomers examined for cooperativity are formally the result of the addition of a chiral element to an existing enantiopure ligand. Comparison of all three ligands in each of the fifty-six examples examined reveals that, in the majority of cases, the added element of chirality increases and decreases the enantioselectivity with respect to the parent ligand. The iterative application of this effect offers a potentially powerful method for catalyst optimisation for use in asymmetric synthesis.