Asymmetric Synthesis Research Articles

Tunable Thiazolium Carbenes for Enantioselective Radical Three-Component Dicarbofunctionalizations.

Asymmetric N-heterocyclic carbene (NHC) organocatalysis is a cornerstone of synthetic organic chemistry. The emerging concept of single-electron NHC catalysis broadened the scope of C-C bond-forming reactions, facilitating the synthesis of a variety of attractive racemic compounds. However, the development of effective and selective chiral NHC catalysts for asymmetric radical-mediated reactions has been challenging. In this report, we introduce a family of highly tunable chiral thiazolium carbenes with three distinct positions for broad electronic and steric modulation featuring bulky chiral flanking groups. We demonstrate the catalytic efficacy of these chiral carbenes in an enantioselective SET-type three-component acyl-difluoroalkylation of olefins using a broad range of aldehydes and difluoroalkyl bromides. This method provides straightforward access to a diverse set of β-difluoroalkylated α-chiral ketones (65 examples) with an up to 87% yield and excellent enantioselectivities of up to >99:1 er. The utility of this methodology is further outlined by enantio- and diastereoselective late-stage modifications of pharmaceutically relevant compounds and selective twofold orthogonal acyl-difluoroalkylations of linchpin reagents.

A recombinant L-threonine aldolase with high catalytic efficiency for the asymmetric synthesis of L-threo-phenylserine and L-threo-4-fluorophenylserine.

To develop robust variants of L-threonine aldolases (L-TAs), potent catalysts for synthesizing asymmetric β-hydroxy-α-amino acids, it is necessary to identify critical residues beyond the known active site residues. Through virtual screening, a neglected residue Asn305, was identified as critical for catalytic efficiency. Subsequent site-saturation mutagenesis led to a potent variant N305R which exhibited excellent conversions of 88%conv (87%de) and 80%conv (94%de) for the synthesis of L-threo-phenylserine and L-threo-4-fluorophenylserine respectively. This variant not only outperformed the template enzyme, but also represented a promising L-TA for synthesizing the two β-hydroxy-α-amino acids. It was suggested that Arg305 of the variant N305R generated strong cation-arene interaction and electrostatic force with the intermediates, leading to strengthened binding, enhanced L-threo favored orientation and wider entrance. Our work not only provided an excellent variant N305R, but also suggested the crucial function of a neglected residue Asn305, which offered valuable experiences for other L-TA studies.

Au]/[Ag]-Catalyzed Glycosidation of Ethynylcyclohexyl Glycosyl Carbonates Enables Direct Stereoselective Synthesis of 2-Azido-2-deoxy-β-mannopyranosides.

We describe the [Au]/[Ag]-catalyzed activation of ethynylcyclohexyl 2-azido-4,6-O-benzylidene mannosyl carbonates for β-mannosamine linkage preparation in high yield and selectivity in a temperature- and concentration-dependent manner. VT-NMR studies reveal an anomeric triflate intermediate generated in the absence of an acceptor alcohol that is stable up to -10 °C. The generality of the protocol was illustrated by successful application to a series of acceptors and by synthesis of a fully protected Streptococcus pneumoniae type 19F capsular trisaccharide.

Enantioselective Synthesis of Atropisomeric Tri‐Axis Naphthalenes via Diels–Alder Reaction and Dehydrative Aromatization of Isobenzofurans

Atropisomers with multiple stereogenic axes have attracted much attention due to their increasing significance in the fields of natural products, chiral materials, and drug discoveries. However, the catalytic stereoselective construction of axially chiral ring scaffolds with more than two axes on a single benzene ring remains a challenging task. Herein, we present an efficient method for synthesizing triaxially chiral polysubstituted naphthalene scaffolds via sequential Ni(II)‐catalyzed Diels–Alder reaction of isobenzofurans and TfOH‐promoted dehydrative aromatization reaction. Using 1,3‐biarylisobenzofurans and β‐aryl‐substituted α,β‐unsaturated N‐acyl pyrazoles as modular reaction partners, a series of naphthalenes with 1,3,4‐triaxes were synthesized with excellent enantioselectivities and diastereoselectivities. Furthermore, by attaching two pyrene chromophores to this novel triaxially chiral ring scaffold, a circularly polarized luminescence (CPL)‐active dye exhibiting a remarkable luminescence dissymmetry factor (glum = ‒0.019) and high fluorescence quantum efficiency (ØFL = 0.29) was obtained, highlighting the potential applications of atropisomers with multiple stereogenic axes in the design of chiroptical organic materials.

Enantioselective Synthesis of Atropisomeric Tri-Axis Naphthalenes via Diels-Alder Reaction and Dehydrative Aromatization of Isobenzofurans.

Atropisomers with multiple stereogenic axes have attracted much attention due to their increasing significance in the fields of natural products, chiral materials, and drug discoveries. However, the catalytic stereoselective construction of axially chiral ring scaffolds with more than two axes on a single benzene ring remains a challenging task. Herein, we present an efficient method for synthesizing triaxially chiral polysubstituted naphthalene scaffolds via sequential Ni(II)-catalyzed Diels-Alder reaction of isobenzofurans and TfOH-promoted dehydrative aromatization reaction. Using 1,3-biarylisobenzofurans and β-aryl-substituted α,β-unsaturated N-acyl pyrazoles as modular reaction partners, a series of naphthalenes with 1,3,4-triaxes were synthesized with excellent enantioselectivities and diastereoselectivities. Furthermore, by attaching two pyrene chromophores to this novel triaxially chiral ring scaffold, a circularly polarized luminescence (CPL)-active dye exhibiting a remarkable luminescence dissymmetry factor (glum = ‒0.019) and high fluorescence quantum efficiency (ØFL = 0.29) was obtained, highlighting the potential applications of atropisomers with multiple stereogenic axes in the design of chiroptical organic materials.

A Quantitative Study of the Halogenophilic Nucleophilic Substitution (SN2X) Reaction and Chalcogenophilic Nucleophilic Substitution (SN2Ch) Reaction.

Halogenophilic nucleophilic substitution (SN2X) has a distinctly different reaction pathway compared to the bimolecular nucleophilic substitution reaction (SN2), but they can lead to the same reaction product. However, their differences can be distinguished by studying stereoselective reactions in which both reaction pathways are possible. Herein, we utilize the stereospecific nature of SN2 and the presence of a pro-chiral anion intermediate in SN2X to conduct a quantitative study in which both SN2 and SN2X reactions exist. We developed a procedure supported by kinetic simulations to measure the halogenophilic percentage (X%). We also developed a new parameter, relative halogenophilicity (H), to quantify the intrinsic characteristics of SN2X reactions and found it to correlate well with the Hammett and Mayr postulates. We studied the time dependency of X% under different reaction conditions, which led to the discovery of two new distinct mechanisms: chalcogenophilic nucleophilic substitution (SN2Ch) reaction and bromide-catalyzed dynamic kinetic resolution. The SN2 and SN2X reactions exhibit similar behavior from both thermodynamic and kinetic perspectives, suggesting that they occur to varying degrees in most of the reactions. Consequently, they are inherently linked and should not be considered in isolation.

Stereoselective Synthesis of Aliphatic α‐Amino Acids by Chemo‐Enzymatic Hydroamination‐Hydrodesulfurisation

Phenylalanine ammonia lyase (PAL) enzymes have been extensively exploited to produce differently substituted arylalanine analogues, but their use in the stereoselective synthesis of aliphatic fatty amino acids has never been addressed. In this work, a two‐step hydroamination‐hydrodesulfurisation process has been investigated for the production of aliphatic L‐α‐amino acids from thienylacrylic acids, easily accessible by condensation from the corresponding arylaldehyde. Wild‐type PALs from Planctomyces brasiliensis and Streptomyces rimosus were selected as the most promising candidates and improved by site‐directed mutagenesis, thus unlocking the hydroamination of a broad panel of 10 different thienylacrylic acids bearing aliphatic and aromatic substituents. The subsequent hydrodesulfurisation step, accomplished by means of inexpensive Raney nickel in mild conditions and aqueous medium, afforded the corresponding aliphatic α‐amino acids in 10‐63% overall isolated yield and perfect enantiopurity. This chemo‐enzymatic process represents the first example of aliphatic amino acid production using PALs, circumventing a major limitation of those biocatalysts.

Asymmetric Migratory Tsuji-Wacker Oxidation Enables the Enantioselective Synthesis of Hetero- and Isosteric Diarylmethanes.

Diarylmethanes play, in part, a pivotal role in the design of highly potent, chiral, nonracemic drugs whose bioactivity is typically affected by the substitution pattern of their arene units. In this context, certain arenes such as para-substituted benzenes or unsubstituted heteroarenes cause particular synthetic challenges, since such isosteric residues at the central methane carbon atom are typically indistinguishable for a chiral catalyst. Hence, the stereoselective incorporation of isosteric (hetero)arenes into chiral methane scaffolds requires the use of stoichiometrically differentiated building blocks, which is typically realized through preceding redox-modifying operations such as metalation or halogenation and thus associated with disadvantageous step- and redox-economic traits. As a counter-design, we report herein a generalized enantioselective synthesis of chiral diarylmethanes by means of an asymmetric migratory Tsuji-Wacker oxidation of simple stilbenes. The title protocol relies on the well-adjusted interplay of aerobic photoredox and selenium-π-acid catalysis to allow for the installation of a broad variety of arenes, including isosteric ones, into the methane core. Facial differentiation and regioselectivity are solely controlled by the selenium catalyst, which (a) renders the E/Z-configuration of the stilbene substrates inconsequential and (b) permits the stereodivergent synthesis of both product enantiomers from a single catalyst enantiomer, simply by employing constitutionally isomeric starting materials. Altogether, this multicatalytic platform offers the target structures with high levels of enantioselectivity in up to 97% ee, which has also been successfully exploited in expedited syntheses of antihistaminic (R)- and (S)-neobenodine.

Atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines via asymmetric multicomponent reaction.

Imidazo[1,2-a]pyridines are privileged heterocycles with diverse applications in medicinal chemistry; however, the catalytic asymmetric synthesis of these heterocyclic structures remains underexplored. Herein, we present an efficient and modular approach for the atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines via an asymmetric multicomponent reaction. By utilizing a chiral phosphoric acid catalyst, the Groebke-Blackburn-Bienaymé reaction involving various 6-aryl-2-aminopyridines, aldehydes, and isocyanides gave access to a wide range of imidazo[1,2-a]pyridine atropoisomers with high to excellent yields and enantioselectivities. Extensive control experiments underscored the pivotal role of the remote hydrogen bonding donor on the substrates in achieving high stereoselectivity for these reactions. The versatile derivatizations of these atropisomeric products, especially their role as an analog of NOBINs and their facile conversion into unique 6,6-spirocyclic products, further emphasize the merits of this methodology.

One-Pot, Three-Component Coupling Synthesis of [(Benzothiazol-2-ylamino)(aryl)methyl]isoquinolinols under Catalyst- and Solvent-Free Conditions

AbstractA one-pot, three-component coupling procedure has been developed for the synthesis of [(benzothiazol-2-ylamino)(aryl)methyl]isoquinolinols via the reaction of hydroxyisoquinolines, aryl/heteroaryl/aliphatic aldehydes with 2-aminobenzothiazoles under catalyst- and solvent-free conditions. The developed 2′-aminobenzothiazolomethylation procedure is suitable to execute even on a gram scale and has a broad scope. The 2′-aminobenzothiazolomethylated products (Betti bases) were formed through the initial nucleophilic C-attack of hydroxyisoquinolines on aldehydes to generate the ortho-quinone methide (o-QM) as an intermediate, followed by 1,4-aza-Michael addition of 2-aminobenzothiazoles. Betti bases have significance in medicinal chemistry due to their wide range of pharmacological applications and they are useful ligands and catalysts in asymmetric synthesis.

Exploring Mycolactone—The Unique Causative Toxin of Buruli Ulcer: Biosynthetic, Synthetic Pathways, Biomarker for Diagnosis, and Therapeutic Potential

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of action of these polyketides as well as their therapeutic potential. The synthetic work has largely been driven by the desire to afford researchers enough (≥100 mg) of the pure toxins for systematic biological studies toward understanding their very high biological activities. The review focuses on pioneering studies of Kishi which elaborate first-, second-, and third-generation approaches to the synthesis of mycolactones A/B. The three generations focused on the construction of the key intermediates required for the mycolactone synthesis. Synthesis of the first generation involves assignment of the relative and absolute stereochemistry of the mycolactones A and B. This was accomplished by employing a linear series of 17 chemical steps (1.3% overall yield) using the mycolactone core. The second generation significantly improved the first generation in three ways: (1) by optimizing the selection of protecting groups; (2) by removing needless protecting group adjustments; and (3) by enhancing the stereoselectivity and overall synthetic efficiency. Though the synthetic route to the mycolactone core was longer than the first generation, the overall yield was significantly higher (8.8%). The third-generation total synthesis was specifically aimed at an efficient, scalable, stereoselective, and shorter synthesis of mycolactone. The synthesis of the mycolactone core was achieved in 14 linear chemical steps with 19% overall yield. Furthermore, a modular synthetic approach where diverse analogues of mycolactone A/B were synthesized via a cascade of catalytic and/or asymmetric reactions as well as several Pd-catalyzed key steps coupled with hydroboration reactions were reviewed. In addition, the review discusses how mycolactone is employed in the diagnosis of Buruli ulcer with emphasis on detection methods of mass spectrometry, immunological assays, RNA aptamer techniques, and fluorescent-thin layer chromatography (f-TLC) methods as diagnostic tools. We examined studies of the structure–activity relationship (SAR) of various analogues of mycolactone. The paper highlights the multiple biological consequences associated with mycolactone such as skin ulceration, host immunomodulation, and analgesia. These effects are attributed to various proposed mechanisms of actions including Wiskott–Aldrich Syndrome protein (WASP)/neural Wiskott–Aldrich Syndrome protein (N-WASP) inhibition, Sec61 translocon inhibition, angiotensin II type 2 receptor (AT2R) inhibition, and inhibition of mTOR. The possible application of novel mycolactone analogues produced based on SAR investigations as therapeutic agents for the treatment of inflammatory disorders and inflammatory pain are discussed. Additionally, their therapeutic potential as anti-viral and anti-cancer agents have also been addressed.

Organocatalyzed Enantioselective Double Dearomatization of Tricyclic Phenols and Alkoxybenzenes.

To advance more efficient dearomatization approaches, we present herein an organocatalyzed asymmetric double dearomatization reaction of tricyclic phenols and alkoxybenzenes by leveraging a novel steric hindrance-regulated dearomatization strategy for nonfunctionalized phenols. This protocol allows the efficient synthesis of structurally complex polycyclic diketones with four tertiary carbon centers under mild conditions while also showcasing the potential of multiple dearomatizations for building intricate molecular frameworks from simple starting materials.

Copper-Catalyzed Asymmetric C(sp3)-H Benzylation: Stereoselective Synthesis of Unnatural Aromatic Amino Acids.

The general synthesis of chiral unnatural aromatic amino acids has rarely been reported. We herein describe a visible light-promoted copper-catalyzed enantioselective C(sp3)-H benzylation of glycine derivatives. The method demonstrated compatibility in coupling various N-hydroxyphthalimide (NHP) esters derived from aromatic acids with glycine derivatives, providing a general protocol for synthesizing analogues of phenylalanine, tryptophan, and tyrosine. This protocol features mild conditions, high enantioselectivity, excellent functional group tolerance, and important impacts on the development of peptide drugs.

Enantiomerically Pure Helical Bilayer Nanographenes: A Straightforward Chemical Approach.

The semiconductor properties of nanosized graphene fragments, known as molecular nanographenes, position them as exceptional candidates for next-generation optoelectronics. In addition to their remarkable optical and electronic features, chiral nanographenes exhibit high dissymmetry factors in circular dichroism and circularly polarized luminescence measurements. However, the synthesis of enantiomerically pure nanographenes remains a significant challenge. Typically, these materials are synthesized in their racemic form, followed by separation of the enantiomers using high-performance liquid chromatography (HPLC). While effective, this method often requires expensive instrumentation, extensive optimization of separation conditions, and typically yields analytical quantities of the desired samples. An alternative approach is the enantioselective synthesis of chiral molecular nanographenes; however, to date, only two examples have been documented in the literature. In this work, we present a straightforward chemical method for the chiral resolution of helical bilayer nanographenes. This approach enables the effective and scalable preparation of enantiomerically pure nanographenes while avoiding the need for HPLC. The incorporation of a BINOL core into the polyarene precursor facilitates the separation of diastereomers through esterification with enantiomerically pure camphorsulfonyl chloride. Following the separation of the diastereomers by standard chromatographic column, the hydrolysis of the camphorsulfonyl group yields enantiomerically pure nanographene precursors. The subsequent graphitization, achieved through the Scholl reaction, occurs in an enantiospecific manner and with the concomitant formation of a furan ring and a heterohelicene moiety. The absolute configurations of the final enantiomers, P-oxa[9]HBNG and M-oxa[9]HBNG, have been determined using X-ray diffraction. Additionally, electrochemical, photophysical, and chiroptical properties have been thoroughly evaluated.

Diversity-Oriented Synthesis of Spirooxindoles via Asymmetric Organocatalytic Regiodivergent Cascade Reactions.

A regiodivergent strategy for the asymmetric diversity-oriented synthesis of spirooxindoles via organocatalytic cascade reactions is developed. Two regioselective pathways can be precisely controlled with different aminocatalysts in the reaction of 2-hydroxycinnamaldehydes and β,β-disubstituted 3-alkylidene oxindoles. The cascade vinylogous Michael/oxa-Michael/aldol reactions gave spiro-bridged oxindoles bearing two adjacent quaternary stereocenters, while the cascade oxa-Michael/Michael reactions gave spirooxindoles. Moreover, during the synthetic application studies, an acid-catalyzed rearrangement of spiro-bridged oxindoles was found to yield biologically important 3-alkylidene oxindoles.

Highly Enantioselective Synthesis of 3,3-Diarylpropyl Amines and 4-Aryl Tetrahydroquinolines via Ir-Catalyzed Asymmetric Hydrogenation.

Chiral nitrogen-containing compounds are crucial for the chemical, pharmaceutical, and agrochemical industries. Nevertheless, the synthesis of certain valuable scaffolds remains underdeveloped due to the vast chemical space available. In this work, we present a diastereoselective methodology for synthesizing 3,3-diarylallyl phthalimides, which, following iridium-catalyzed asymmetric hydrogenation using Ir-UbaPHOX, yield 3,3-diarylpropyl amines with high enantioselectivity (98-99% ee). The importance of alkene purity to achieve high enantioselectivity is discussed. The synthetic utility of the chiral propylamines obtained is demonstrated through the preparation of medicinally useful bioactive compounds like the drugs tolterodine and tolpropamine and 4-aryl tetrahydroquinolines. This strategy enables the synthesis of these compounds with the highest enantioselectivity reported to date.

Catalytic Asymmetric Synthesis of Inherently Chiral Eight‐Membered O‐Heterocycles through Cross‐[4+4] Cycloaddition of Quinone Methides

AbstractInherently chiral eight‐membered rings embedded in tetraphenylene derivatives and hetero‐analogues exhibit unique properties and allow diverse applications. A conceptually viable and straightforward approach to these frameworks is [4+4] cycloaddition, which still remains elusive. Herein, we describe the stereoselective cross‐[4+4] cycloaddition of quinone methides (QMs), leading to the formation of oxa‐analogues of tetraphenylene with exceptional chemo‐, diastereo‐, and enantioselectivity. The structures of these novel rigid eight‐membered O‐heterocycles were explored by single‐crystal X‐ray diffraction, and their stereochemical stability was elaborated through both density functional theory (DFT) calculations and thermal racemization experiments. The developed methodology exhibited broad substrate scope and the resulting cross‐[4+4] cycloadducts could be readily transformed into valuable chiral building blocks. Our findings expand the library of inherently chiral medium‐sized rings and also contribute to the advancement of asymmetric cross‐[4+4] cycloadditions of quinone methides.

Asymmetric Synthesis, Structure Determination, and Biologic Evaluation of Isomers of TLAM as PFK1 Inhibitors

Asymmetric Synthesis, Structure Determination, and Biologic Evaluation of Isomers of TLAM as PFK1 Inhibitors

Cooperative Catalysis in Stereoselective O- and N-Glycosylations with Glycosyl Trichloroacetimidates Mediated by Singly Protonated Phenanthrolinium Salt and Trichloroacetamide.

The development of small-molecule catalysts that can effectively activate both reacting partners simultaneously represents a pivotal pursuit in advancing the field of stereoselective glycosylation reactions. We report herein the development of the singly protonated form of readily available phenanthroline as an effective cooperative catalyst that facilitates the coupling of a wide variety of aliphatic alcohols, phenols, and aromatic amines with α-glycosyl trichloroacetimidate donors. The glycosylation reaction likely proceeds via an SN2-like mechanism, generating β-selective glycoside products. The developed protocol provides access to O- and N-glycosides in good yields with excellent levels of β-selectivity and enables late-stage functionalization of O- and N-glycosides via cross-coupling reactions. Importantly, this method exhibits excellent β-selectivity that is unattainable through a C2-O-acyl neighboring group participation strategy, especially in the case of glycosyl donors already containing a C2 heteroatom or sugar unit. Kinetic studies demonstrate that the byproduct trichloroacetamide group plays a previously undiscovered pivotal role in influencing the reactivity and selectivity of the reaction. A proposed mechanism involving simultaneous activation of the glycosyl donor and acceptor by the singly protonated phenanthrolinium salt catalyst with the assistance of the trichloroacetamide group is supported by kinetic analysis and preliminary computational studies. This cooperative catalysis process involves four consecutive hydrogen bond interactions. The first interaction occurs between the carbonyl oxygen of the trichloroacetamide group and the hydroxyl group of alcohol nucleophile (C═O···HO). The second involves the trichloroacetamide-NH2 forming a hydrogen bond with the nitrogen atom of the phenanthroline (NH···N). The third involves the donor trichloroacetimidate (═NH) engaging in a hydrogen bond interaction with the phenanthrolinium-NH (NH···N═H). Lastly, the protonated trichloroacetimidate-NH2 forms a hydrogen bond with the fluorine atom of the tetrafluoroborate ion.

Difluoroenoxysilanes in Catalytic Asymmetric Allylic Alkylation.

An allylic substitution with difluoroenoxysilanes as the nucleophile is accomplished for the enantioselective synthesis of α-allylic α,α-difluoroketones. With racemic branched allylic alcohols as the easily accessible allylic electrophile, this branched-selective and enantioconvergent allylic alkylation reaction is catalyzed by an Ir(I)/(P,olefin) complex and overcomes the low nucleophilicity of difluoroenoxysilanes to furnish β-chiral α,α-difluoroketones in moderate to good yields with high enantioselectivity (up to >99.9:0.1 er).