Achiral Substrates Research Articles

Iron- and Organo-Catalyzed Borrowing Hydrogen for the Stereoselective Construction of Tetrahydropyrans.

Stereocontrolled oxa-Michael additions are challenging, given the high reversibility of the process, which ultimately leads to racemization of the newly formed stereocenters. When iron-catalyzed borrowing hydrogen from allylic alcohols was combined with a stereocontrolled organocatalytic oxa-Michael addition, a wide array of chiral tetrahydropyrans were efficiently prepared. The reaction could be performed in a diastereoselective manner from pre-existing stereocenters or enantioselectively from achiral substrates. The key to success was the reactivity of the iron complex, which was selective for allylic alcohol dehydrogenation and irreversibly led the reaction to the final product.

Carbene organic catalytic planar enantioselective macrolactonization

Macrolactones exhibit distinct conformational and configurational properties and are widely found in natural products, medicines, and agrochemicals. Up to now, the major effort for macrolactonization is directed toward identifying suitable carboxylic acid/alcohol coupling reagents to address the challenges associated with macrocyclization, wherein the stereochemistry of products is usually controlled by the substrate’s inherent chirality. It remains largely unexplored in using catalysts to govern both macrolactone formation and stereochemical control. Here, we disclose a non-enzymatic organocatalytic approach to construct macrolactones bearing chiral planes from achiral substrates. Our strategy utilizes N-heterocyclic carbene (NHC) as a potent acylation catalyst that simultaneously mediates the macrocyclization and controls planar chirality during the catalytic process. Macrolactones varying in ring sizes from sixteen to twenty members are obtained with good-to-excellent yields and enantiomeric ratios. Our study shall open new avenues in accessing macrolactones with various stereogenic elements and ring structures by using readily available small-molecule catalysts.

Inherently chiral nor-heteracalixarenes: design and synthesis via enantioselective intramolecular Suzuki-Miyaura reaction.

There has been a recent upsurge in research aimed at synthesizing inherently chiral molecules devoid of point, axial, planar and helical chiralities. We present herein our design and enantioselective synthesis of a series of inherently chiral macrocycles. These compounds, termed nor-heteracalixaromatics, feature a biaryl bond that replaces one of the aryl-heteroatom-aryl linkages found in classic heteracalix[4]aromatics. Macrocyclization of linear achiral substrates via an intramolecular Suzuki-Miyaura cross-coupling reaction affords the 15-membered cyclophane without any chiral elements in high yields and enantioselectivities. Notably, the formation of the aryl-aryl bond does not induce axial chirality at the biaryl linkage. Instead, it restricts the free rotation of an aromatic ring located four bonds away, leading to the inherent chirality of the macrocycle. The intriguing chiroptical properties of these compounds made them promising platform for the development of CPL emitters.

Inducing Homochirality Through Intermediary Catalytic Species: A Stochastic Approach.

A new chiral amplification mechanism based on a stochastic approach is proposed. The mechanism includes five different chemical species, an achiral substrate (A), two chiral forms (L, D), and two intermediary species (LA, DA). The process occurs within a small, semipermeable compartment that can be diffusively coupled with the outside environment. The study considers two alternative primary sources for chiral species within the compartment, one chemical and the other diffusive. As a remarkable fact, the chiral amplification process occurs due to stochastic fluctuations of an intermediary catalytic species (LA, DA) produced in situ, given the interaction of the chiral species with the achiral substrate. The net process includes two different steps: the synthesis of the catalyst (LA and DA) and the catalytic production of new chiral species from the substrate. Stochastic simulations show that proper parameterization can induce a robust chiral state within the compartment regardless of whether the system is open or closed. We also show how an increase in the non-catalytic production of chiral species tends to negatively impact the homochirality degree of the system. By its conception, the proposed mechanism suggests a deeper connection with how most biochemical processes occur in living beings, a fact that could open new avenues for studying this fascinating phenomenon.

Enantioselective catalytic Strecker reaction on cyclic (Z)-aldimines in flow: reaction optimization and sustainability aspects

Catalytic enantioselective Strecker reactions on an achiral substrate using sub-stoichiometric amounts of a chiral catalyst represent an evolving key strategy for the effective synthesis of α-amino nitriles. We herein disclosed the set-up of a flow-based methodology for enantioselective Strecker, employing ethyl cyanoformate as a relatively safe cyanide source, a cinchona-based catalyst, and methanol as additive. A thorough exploration of key parameters allowed the identification of the most efficient reagent mixing mode, the optimum solvent for the flow synthesis, minimum catalyst loading, additive, temperature, and residence time. The newly developed method allows straightforward reaction channeling towards the fast and complete formation of the α-amino nitrile products, thus reducing the yield drop due to indolenine degradation during long-lasting batch-wise reactions. Moreover, we herein provide preliminary hints for sustainability, by proposing a simple procedure for catalyst recycling, thus opening the way for further optimization of the proposed methodology.Graphical

From a coenzyme-like mechanism to homochirality

Inspired in a coenzyme-like behavior, an alternative mechanism to induce homochirality within a small vesicle is proposed. The system includes six different chemical species: an achiral substrate A, the enantiomeric forms L and D, a coenzyme E and two intermediate catalytic forms LE and DE. Whereas the coenzyme and the intermediate catalytic forms are trapped within the vesicle, the substrate and the two enantiomeric forms are able to diffuse selectively across the vesicle boundary. Instead of using autocatalysis, the production of new enantiomers includes two different steps, the production of intermediate catalytic species (LE, DE) and the catalytic production of new enantiomers from the substrate. Using a suitable parameterization, we found that the chiral evolution of the system is highly dependent on the total amount of coenzyme within the vesicle, regardless of whether the surrounding membrane is permeable or not. However, the existence of large flows from the outside can destabilize the homochiral state inside the vesicle. In general, homochiral states tend to arise when the amount of coenzyme is quite low, a value that can vary according to the parametrization. On the other hand, the system tends to decrease the enantiomeric excess when the coenzyme levels are high enough. In general, the appearance of homochirality is conditioned by stochastic fluctuations in coenzyme levels within the vesicle, an effect that is gradually amplified throughout the entire process of enantiomer synthesis.

Total Synthesis of Hemerocallisamine I Paved by Gram-Scale Synthesis of (2S,4S)-4-Hydroxyglutamic Acid Lactone.

Total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is presented, both in racemic and enantiopure form. Our synthetic strategy involves (2S,4S)-4-hydroxyglutamic acid lactone as the key intermediate. Starting from an achiral substrate, the target stereogenic centers were introduced by means of crystallization-induced diastereomer transformation (CIDT) in a highly stereoselective fashion. A Maillard-type condensation was crucial to constructing the desired pyrrolic scaffold.

Noncentrosymmetric Lanthanide-Based MOF Materials Exhibiting Strong SHG Activity and NIR Luminescence of Er3+: Application in Nonlinear Optical Thermometry

Optically active luminescent materials based on lanthanide ions attract significant attention due to their unique spectroscopic properties, nonlinear optical activity, and the possibility of application as contactless sensors. Lanthanide metal-organic frameworks (Ln-MOFs) that exhibit strong second-harmonic generation (SHG) and are optically active in the NIR region are unexpectedly underrepresented. Moreover, such Ln-MOFs require ligands that are chiral and/or need multistep synthetic procedures. Here, we show that the NIR pulsed laser irradiation of the noncentrosymmetric, isostructural Ln-MOF materials (MOF-Er3+ (1) and codoped MOF-Yb3+/Er3+ (2)) that are constructed from simple, achiral organic substrates in a one-step procedure results in strong and tunable SHG activity. The SHG signals could be easily collected, exciting the materials in a broad NIR spectral range, from ≈800 to 1500 nm, resulting in the intense color of emission, observed in the entire visible spectral region. Moreover, upon excitation in the range of ≈900 to 1025 nm, the materials also exhibit the NIR luminescence of Er3+ ions, centered at ≈1550 nm. The use of a 975 nm pulse excitation allows simultaneous observations of the conventional NIR emission of Er3+ and the SHG signal, altogether tuned by the composition of the Ln-MOF materials. Taking the benefits of different thermal responses of the mentioned effects, we have developed a nonlinear optical thermometer based on lanthanide-MOF materials. In this system, the SHG signal decreases with temperature, whereas the NIR emission band of Er3+ slightly broadens, allowing ratiometric (Er3+ NIR 1550 nm/SHG 488 nm) temperature monitoring. Our study provides a groundwork for the rational design of readily available and self-monitoring NLO-active Ln-MOFs with the desired optical and electronic properties.

Computer-aided directed evolution of l-threonine aldolase for asymmetric biocatalytic synthesis of a chloramphenicol intermediate

l-Threonine aldolases (LTAs) employing pyridoxal phosphate (PLP) as cofactor can convert low-cost achiral substrates glycine and aldehyde directly into valuable β-hydroxy-α-amino acids such as (2R,3S)-2-amino-3-hydroxy-3-(4-nitrophenyl) propanoic acid ((R,S)-AHNPA), which is utilized broadly as crucial chiral intermediates for bioactive compounds. However, LTAs’ stereospecificity towards the β carbon is rather moderate and their activity and stability at high substrate load is low, which limits their industrial application. Here, computer-aided directed evolution was applied to improve overall activity, selectivity and stability under desired process conditions of a l-threonine aldolase in the asymmetric synthesis of (R,S)-AHNPA. Selectivity and stability determining regions were computationally identified for structure-guided directed evolution of LTA-variants under efficient biocatalytic process conditions using 40% ethanol as cosolvent. We applied molecular modeling to rationalize selectivity improvement and design focused libraries targeting the substrate binding pocket, and we also used MD simulations in nonaqueous process environment as an effective and promising method to predict potential unstable loop regions near the tetramer interface which are hot-spots for cosolvent resistance. An excellent LTA variant EM-ALDO031 with 18 mutations was obtained, which showed ∼ 30-fold stability improvement in 40% ethanol and diastereoselectivity (de) raised from 31.5% to 85% through a three-phase evolution campaign. Our fast and efficient data-driven methodology utilizing a combination of experimental and computational tools enabled us to evolve an aldolase variant to achieve the target of 90% conversion at up to 150 g/L substrate load in 40% ethanol, enabling the biocatalytic production of β-hydroxy-α-amino acids from cheap achiral precursors at multi-ton scale.

A novel chiral fluorescence probe based on carbon dots-copper(II) system for ratio fluorescence detection of gatifloxacin

Up to now, compared to the well-developed researches on chiral nanomaterials, there are relatively few studies focused on chiral Carbon Dots (CDs). The chiral fluorescent probes have properties of high sensitivity and good selectivity, which have attracted extensive attention. Herein, we constructed a chiral fluorescent probe based on a chiral CDs-Copper (II) system, having high photostability and sensitivity, which had the fast dual response of ratiometric fluorescence and enhanced circular dichroism (CD) to gatifloxacin (GAT). This method displayed a linear range of 0.01877–105.1 μg mL−1 with the detection limit of 0.04995 μg mL−1 for GAT under the optimized parameters. It has advantages of good selectivity, wide linear range, convenience and speediness. It was successfully applied to the detection of GAT in serum with satisfactory results. At the same time, the interaction of the chiral probes with chiral or achiral substrates indicates that the chiral CDs as new chiral functional materials have great application potential.

Spontaneous mirror symmetry breaking in reaction-diffusion systems: ambivalent role of the achiral precursor.

The behaviour of a Frank-like chemical network model featuring autocatalytic production of chiral enantiomers from achiral reactants is studied numerically in 1D and 2D systems using fluctuating initial conditions and accounting for diffusion processes. Our results reveal that the achiral substrate concentration can play an ambivalent role. It is shown that when the achiral reactant concentration is maintained constant and homogeneous in 1D systems, global homochirality is not systematically reached when the size of the system or the achiral reactant concentration are increased. However, with a fixed concentration gradient, coexisting homochiral domains of opposite handedness are no longer observed and homogeneous homochirality, i.e. the presence of a single stable homochiral domain, is recovered. In 2D systems, reaching global homochirality is just a matter of time. This time is dramatically increased when insufficient or excessive amount of achiral reactant is used. An optimal amount of achiral material is observed to maximise the enantiomer production rates.

Asymmetric Synthesis of Indoline from Achiral Phthalimide Involving Crystallization-Induced Deracemization.

Asymmetric synthesis was performed by combining the photochemical reaction of an achiral substrate followed by crystallization-induced deracemization. The results indicated that a fused indoline produced by photochemical intramolecular δ-hydrogen abstraction and cyclization of N-(5-chloro-2-methylphenyl)phthalimide crystallized as a racemic conglomerate. Since this substrate has an aminal skeleton, racemization involving a ring-opening and ring-closing equilibrium process occurred under suitable conditions. Efficient racemization was observed in acetone containing a catalytic base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Crystallization-induced dynamic deracemization by Viedma ripening from racemic indoline was performed with an excellent enantioselectivity of 99 % ee. Furthermore, one-pot asymmetric synthesis of the indoline was achieved by the photochemical reaction of achiral phthalimide followed by continuous attrition-enhanced deracemization converging to 99 % ee of enantiomeric crystals. This is the first example of asymmetric expression and amplification by photochemical hydrogen abstraction and crystallization-induced dynamic deracemization.

Front Cover Picture: Synthesis of Enantioenriched Amines by Iron‐Catalysed Amination of Alcohols Employing at Least One Achiral Substrate (Adv. Synth. Catal. 24/2021)

The Front Cover Picture, designed by Anastasiia Afanasenko, illustrates the methodology for the synthesis of enantioenriched amines by the direct Fe-catalysed coupling of amines with alcohols through the borrowing hydrogen strategy, while at least one of these substrates is achiral. As in the well-known “The Tortoise and the Hare” fable by Aesop, tortoise – stands for chiral amine – won the race retaining the stereochemical integrity in the final product, whereas beta-branched enantioenriched primary alcohol – depicts by the hare – lost the competition due to its racemization that led to the partial loss of the chirality in the target amine. Details can be found in the Research Article by Katalin Barta and collaborators (G. Bottari, A. Afanasenko, A. A. Castillo-Garcia, B. L. Feringa, K. Barta, Adv. Synth. Catal. 2021, 363, 5436–5442; DOI: 10.1002/adsc.202100231).

Synthesis of Enantioenriched Amines by Iron‐Catalysed Amination of Alcohols Employing at Least One Achiral Substrate

AbstractThe synthesis of a broad range of enantioenriched amines by the direct Fe‐catalysed coupling of amines with alcohols through the borrowing hydrogen strategy, while at least one of these substrates is achiral is reported. When starting from α‐chiral amines and achiral alcohols, a wide range of enantioenriched amine products, including N‐heterocyclic moieties can be obtained with complete retention of stereochemistry and the power of this method is demonstrated in the one‐step synthesis of known pharmaceuticals from commercially available, simple enantiopure primary amines and achiral alcohols. It was also found that the use of β‐branched enantioenriched primary alcohols and achiral amines as reaction partners leads to a partial loss of stereochemical integrity in the final product, however, a systematic optimization enabled partial retention of enantiopurity and possible parameters effecting for racemization were identified.magnified image

DFT Mechanism Studies: Biomimetic 1,4-NADH Chemoselective, Co-factor Regeneration with [Cp*Rh(bpy)H]+, in Tandem with the Biocatalysis Pathways of a Core Model of the (HLADH)-Zn(II) Mediated Enzyme, in the Enantioselective Reduction of Achiral Ketones to Chiral S-Alcohols

Quantum Chemical (QC) calculations, utilizing Density Functional Theory (DFT), were performed to investigate the mechanistic aspects of the chemoselective catalyzed reaction of [Cp*Rh(bpy)H]+ with the biomimetic NAD+ analogues, N-benzylnicotinamide triflate, 1, and β-nicotinamide ribose-5′-methyl phosphate, 2, in the conversion to their 1,4-NADH analogues, 1,4-dihydro-N-benzylnicotinamide, 4, and β-1,4-dihydronicotinamide-5′-ribose methyl phosphate, 5. This reaction was in tandem with the 1,4-NADH dependent HLADH-Zn(II)-catalyzed reduction of achiral ketones to chiral S-alcohols. The [Cp*Rh(bpy)H]+ complex, and not its equilibrium tautomer, [η4-Cp*HRh(bpy)]+, was found to control the hydride transfer during the biomimetic NAD+/1,4-NADH conversion, through the non-covalent interactions of the biomimetic co-factors with [Cp*Rh(bpy)H]+. The thermodynamics and kinetics for the chiral reduction of the Zn(II) bound ketones, 2-pentanone and 4-phenyl-2-butanone, with co-factor, 4, catalyzed by Zn(SCH3)2(Imidazole), a core model of the Zn(II)-based catalytic center of HLADH, was also investigated by the evaluation of two possible reaction pathways: (1) formation of a ZnH from the C4-H hydride transfer of co-factor, 4, followed by reaction of the postulated ZnH with the bound 2-pentanone or 4-phenyl-2-butanone substrate, and (2), the direct C4-H transfer to the bound achiral ketone substrates, to provide the dominant chiral alcohols, S-2-pentanol or S-4-phenyl-2-butanol. The latter pathway was found most viable, and DFT calculations also revealed an essential η2-coordination of the 5,6 double bond of co-factor, 4, to the HLADH-Zn(II) metal ion center, upon imidazole decomplexation, providing an asymmetric differentiation of S-η2-5,6-1,4-NADH-Zn(II) binding. A proposed new paradigm for the Zn(II)'s non-innocent role in the HLADH-Zn(II) biocatalysis reduction mechanism, for enantioselective hydride transfer to a Zn(II) bound ketone, providing S-alcohols.

Copper-Catalyzed Enantioselective Radical 1,4-Difunctionalization of 1,3-Enynes.

Chiral allenes are important structural motifs frequently found in natural products, pharmaceuticals, and other organic compounds. Asymmetric 1,4-difunctionalization of 1,3-enynes is a promising strategy to construct axial chirality and produce substituted chiral allenes from achiral substrates. However, the previous state of the art in 1,4-difunctionalization of 1,3-enynes focused on the allenyl anion pathway. Because of this, only electrophiles can be introduced into the allene backbones in the second functionalization step, consequently limiting the reaction and allene product types. The development of asymmetric 1,4-difunctionalization of 1,3-enynes via a radical pathway would complement previous methods and support expansion of the toolbox for the synthesis of asymmetric allenes. Herein, we report the first radical enantioselective allene formation via a group transfer pathway in the context of copper-catalyzed radical 1,4-difunctionalization of 1,3-enynes. This method addresses a longstanding unsolved problem in asymmetric radical chemistry, provides an important strategy for stereocontrol with free allenyl radicals, and offers a novel approach to the valuable, but previously inaccessible, chiral allenes. This work should shed light on asymmetric radical reactions and may lead to other enantioselective group transfer reactions.

Asymmetric Transformation Driven by Confinement and Self-Release in Single-Layered Porous Nanosheets.

Reported here is the use of single-layered, chiral porous sheets with induced pore chirality for repeatable asymmetric transformations and self-separation without the need for chiral catalysts or chiral auxiliaries. The asymmetric induction is driven by chiral fixation of absorbed achiral substrates inside the chiral pores for transformation into enantiopure products with enantioselectivities of greater than 99 % ee. When the conversion is completed, the products are spontaneously separated out of the pores, enabling the porous sheets to perform repeated cycles of converting achiral substrates into chiral products for release without compromising pore performance. Confinement of achiral substrates into two-dimensional chiral porous materials provides access to a highly efficient alternative to current asymmetric synthesis methodologies.

Asymmetric Transformation Driven by Confinement and Self‐Release in Single‐Layered Porous Nanosheets

AbstractReported here is the use of single‐layered, chiral porous sheets with induced pore chirality for repeatable asymmetric transformations and self‐separation without the need for chiral catalysts or chiral auxiliaries. The asymmetric induction is driven by chiral fixation of absorbed achiral substrates inside the chiral pores for transformation into enantiopure products with enantioselectivities of greater than 99 % ee. When the conversion is completed, the products are spontaneously separated out of the pores, enabling the porous sheets to perform repeated cycles of converting achiral substrates into chiral products for release without compromising pore performance. Confinement of achiral substrates into two‐dimensional chiral porous materials provides access to a highly efficient alternative to current asymmetric synthesis methodologies.

Diastereoselective Spirocyclization of Benzoxazines with Nitroalkenes via Rhodium-Catalyzed C–H Functionalization/Annulation Cascade under Mild Conditions

A Rh(III)-catalyzed [3 + 2] annulation of benzoxazines with nitroolefins that proceeds via redox-neutral C-H functionalization has been demonstrated, leading to the novel class of spirocycles in a single step. The construction of three continuous stereogenic centers has been achieved starting from easily accessible achiral substrates in an atom-efficient manner under mild reaction conditions. A broad range of pharmaceutically relevant nitro substituted spirocyclic 2,3-dihydro-1,4-benzoxazine derivatives has been synthesized in good to excellent yields with high diastereoselectivity.

Encoding Chiral Molecular Information in Metal Structures.

The concept of encoding molecular information in bulk metals has been proposed over the past decade. The structure of various types of molecules, including enantiomers, can be imprinted in achiral substrates. Typically, to encode metals with chiral information, several approaches, based on chemical and electrochemical concepts, can be used. In this Minireview, recent achievements with respect to the development of such materials are discussed, including the entrapment of chiral biomolecules in metals, the chiral imprinting of metals, as well as the combination of imprinting with nanostructuring. The features and potential applications of these designer materials, such as chirooptical properties, enantioselective adsorption and separation, as well as their use for asymmetric synthesis will be presented. This will illustrate that the development of molecularly encoded metal structures opens up very interesting perspectives, especially in the frame of chiral technologies.