Asymmetric Carbonyl Research Articles

Unmasking the reverse catalytic activity of 'ene'-reductases for asymmetric carbonyl desaturation.

Carbonyl desaturation is a fundamental reaction widely practised in organic synthesis. While numerous methods have been developed to expand the scope of this important transformation, most of them necessitate multi-step protocols or suffer from the use of high loadings of metal or strong oxidizing conditions. Moreover, approaches that can achieve precise stereochemical control of the desaturation process are extremely rare. Here we report a biocatalytic platform for desymmetrizing desaturation of cyclohexanones to generate diverse cyclohexenones bearing a remote quaternary stereogenic centre, by reengineering 'ene'-reductases to efficiently mediate dehydrogenation, the reverse process of their native activity. This 'ene'-reductase-based desaturation system operates under mild conditions with air as the terminal oxidant, tolerates oxidation-sensitive or metal-incompatible functional groups and, more importantly, exhibits unparalleled stereoselectivity compared with those achieved with small-molecule catalysts. Mechanistic investigations suggest that the reaction proceeded through α-deprotonation followed by a rate-determining β-hydride transfer.

Quaternary Chiral Phthalides Enabled by Dirhodium(II)/Phosphine Catalyzed Asymmetric Carbonyl Addition Cascade.

The catalytic asymmetric synthesis of chiral phthalides has garnered considerable interest. However, the construction of phthalides with a chiral quaternary carbon stereocenter still remains challenging. In this study, we developed a new strategy toward catalytic asymmetric synthesis of chiral 3,3-disubstituted phthalides via a dirhodium(II)/phosphine-catalyzed carbonyl addition cascade, yielding phthalides with up to 97% ee values. The reaction proceeded through dirhodium(II)/phosphine-catalyzed asymmetric carbonyl addition of arylboronic acids to isoquinoline-1,3,4(2H)-triones, followed by base-mediated ring contraction.

Enantioconvergent synthesis of axially chiral amides enabled by Pd-catalyzed dynamic kinetic asymmetric aminocarbonylation

Atropisomeric biaryls bearing carbonyl groups have attracted increasing attention due to their prevalence in diverse bioactive molecules and crucial role as efficient organo-catalysts or ligands in asymmetric transformations. However, their preparation often involves tedious multiple steps, and the direct synthesis via asymmetric carbonylation has scarcely been investigated. Herein, we report an efficient palladium-catalyzed enantioconvergent aminocarbonylation of racemic heterobiaryl triflates with amines via dynamic kinetic asymmetric transformation (DyKAT). This protocol features a broad substrate scope and excellent compatibility for rapid construction of axially chiral amides in good to high yields with excellent enantioselectivities. Detailed mechanistic investigations discover that the base can impede the intramolecular hydrogen bond-assisted axis rotation of the products, thus allowing for the success to achieve high enantioselectivity. Moreover, the achieved axially chiral heterobiaryl amides can be directly utilized as N,N,N-pincer ligands in copper-catalyzed enantioselective formation of C(sp3)-N and C(sp3)-P bonds.

Approaches for constraining uncertainty and degeneracy in geometry reconstruction of molecules from simulated Coulomb explosion data

Coulomb explosion imaging (CEI) data, consisting of atomic ion momenta, resulting from a rapid (few fs) ionization event, is typically recorded as a first step in the generation of a single molecule geometry measurement or the production of a ‘molecular movie’ that watches the evolution of an excited state geometry in time. Deriving a reliable geometry from this data is a crucial and challenging step, as unique solutions may not exist. In this work, we start by simulating the geometries of a molecule, which is out of equilibrium, the asymmetric carbonyl sulfide (OCS) molecule. We generate momentum data resulting from six-fold ionization and investigate two methods to reconstruct geometries. The first method is a look-up table, which is simple in principle but shows limitations in terms of accuracy and ability to identify multiple ‘degenerate’ solutions. The second is a new method using nonlinear constrained optimization, which shows potential for scalability to higher dimension. We investigate the possibility of identifying problematic geometry regions where different degenerate geometries can not be distinguished.

Pd-catalyzed asymmetric carbonyl alkynylation: Synthesis of axial chiral ynones

Ynones are important skeletons in bioactive molecules and valuable building blocks for organic synthesis, thus great efforts have been devoted to their preparation. While, introducing prochiral substrates to construct ynones bearing a chiral framework is unrealized to date. Herein, we reported the first example of Pd/SOP-catalyzed asymmetric carbonylative alkynylation via a non-classical carbonylative Sonogashira-type approach (acyl-Pd(II) species generated from nucleophiles). By using cyclic diaryliodonium salts as prochiral substrates, various axial chiral ynones with good functional group tolerance (39 examples), satisfied yields (71%-96%) and excellent enantioselectivities (generally 94%-99% ee) were produced. Synthesis of bioactive compounds, scale-up experiment and useful transformations were also conducted to demonstrate the utility of this process.

Confronting the Challenge of Asymmetric Carbonyl Addition to Sterically Bulky Isatins: Upgrading Dirhodium(II)/Biphosphine Catalytic System

Catalytic asymmetric addition of arylboronic acids to ketones is a powerful transformation for directly delivering chiral tertiary alcohols. However, there is no successful example of enantioselective addition to steric bulky isatins, which contain bulky substituent at the 4-position. To confront this challenge, in this work a dirhodium/(BTFM-Garphos) system was developed that showed extremely high activity and stereoselectivity, and the reactions were usually finished within a few minutes.

Carbonyl Allylation and Crotylation: Historical Perspective, Relevance to Polyketide Synthesis, and Evolution of Enantioselective Ruthenium-Catalyzed Hydrogen Auto-Transfer Processes.

The evolution of methods for carbonyl allylation and crotylation of alcohol proelectrophiles culminating in the design of iodide-bound ruthenium-JOSIPHOS catalysts is prefaced by a brief historical perspective on asymmetric carbonyl allylation and its relevance to polyketide construction. Using gaseous allene or butadiene as precursors to allyl- or crotylruthenium nucleophiles, respectively, new capabilities for carbonyl allylation and crotylation have been unlocked, including stereo- and site-selective methods for the allylation and crotylation of 1,3-diols and related polyols.

Chiral Pyridoxal–Gold Rush in Asymmetric Carbonyl Catalysis

Chiral Pyridoxal–Gold Rush in Asymmetric Carbonyl Catalysis

Vibrational relaxation by methylated xanthines in solution: Insights from 2D IR spectroscopy and calculations.

Two-dimensional infrared (2D IR) spectroscopy, infrared pump-infrared probe spectroscopy, and density functional theory calculations were used to study vibrational relaxation by ring and carbonyl stretching modes in a series of methylated xanthine derivatives in acetonitrile and deuterium oxide (heavy water). Isotropic signals from the excited symmetric and asymmetric carbonyl stretch modes decay biexponentially in both solvents. Coherent energy transfer between the symmetric and asymmetric carbonyl stretching modes gives rise to a quantum beat in the time-dependent anisotropy signals. The damping time of the coherent oscillation agrees with the fast decay component of the carbonyl bleach recovery signals, indicating that this time constant reflects intramolecular vibrational redistribution (IVR) to other solute modes. Despite their similar frequencies, the excited ring modes decay monoexponentially with a time constant that matches the slow decay component of the carbonyl modes. The slow decay times, which are faster in heavy water than in acetonitrile, approximately match the ones observed in previous UV pump-IR probe measurements on the same compounds. The slow component is assigned to intermolecular energy transfer to solvent bath modes from low-frequency solute modes, which are populated by IVR and are anharmonically coupled to the carbonyl and ring stretch modes. 2D IR measurements indicate that the carbonyl stretching modes are weakly coupled to the delocalized ring modes, resulting in slow exchange that cannot explain the common solvent-dependence. IVR is suggested to occur at different rates for the carbonyl vs ring modes due to differences in mode-specific couplings and not to differences in the density of accessible states.

Nickel-Catalyzed Asymmetric Hydroaryloxy- and Hydroalkoxycarbonylation of Cyclopropenes.

The asymmetric Reppe carbonylation reactions provide a straightforward access to α-chiral carbonyl compounds. The reported paradigms predominantly adopted precious palladium as the catalyst. Here we report a nickel-catalyzed asymmetric carbonylation of cyclopropenes with phenyl formate and CO/ROH, respectively. This asymmetrical synthetic protocol features high atom economy, good functional group tolerance, which rapidly constructs polysubstituted cyclopropanecarboxylic derivatives with excellent diastereo- and enantioselectivity. The synthetic utility is demonstrated by facile conversion of the chiral products into bioactive molecules such as (-)-Tranylcypromine and (-)-Lemborexant.

Nickel‐Catalyzed Asymmetric Hydroaryloxy‐ and Hydroalkoxycarbonylation of Cyclopropenes

The asymmetric Reppe carbonylation reactions provide a straightforward access to α-chiral carbonyl compounds. The reported paradigms predominantly adopted precious palladium as the catalyst. Here we report a nickel-catalyzed asymmetric carbonylation of cyclopropenes with phenyl formate and CO/ROH, respectively. This asymmetrical synthetic protocol features high atom economy, good functional group tolerance, which rapidly constructs polysubstituted cyclopropanecarboxylic derivatives with excellent diastereo- and enantioselectivity. The synthetic utility is demonstrated by facile conversion of the chiral products into bioactive molecules such as (−)-Tranylcypromine and (−)-Lemborexant.

Acrylic acid conformers and their interactions with dibutyl ether

Fourier Transform Infrared spectra of pure acrylic acid (ARA), dibutyl ether, and their binary solutions at various acid concentrations have been recorded. Density functional theory calculations on ARA monomers and dimers have been carried out. In addition to the cis–cis and trans–trans dimers, cis–trans dimers also exist in liquid acid. The dimer ring formed by carboxyl group has an asymmetry. The experimental asymmetric and symmetric hydroxyl and carbonyl stretching bands have been assigned. Shifts suffered by the absorption bands in binary solutions have been analyzed in view of the formation of heteromolecular hydrogen bonds.

Stereo- and Site-Selective Conversion of Primary Alcohols to Allylic Alcohols via Ruthenium-Catalyzed Hydrogen Auto-Transfer Mediated by 2-Butyne.

The first enantioselective ruthenium-catalyzed carbonyl vinylations via hydrogen autotransfer are described. Using a ruthenium-JOSIPHOS catalyst, primary alcohols 2a-2m and 2-butyne 1a are converted to chiral allylic alcohols 3a-3m with excellent levels of absolute stereocontrol. Notably, 1°,2°-1,3-diols participate in site-selective C-C coupling, enabling asymmetric carbonyl vinylation beyond premetalated reagents, exogenous reductants, or hydroxyl protecting groups. Using 2-propanol as a reductant, aldehydes dehydro-2a, 2l participate in highly enantioselective 2-butyne-mediated vinylation under otherwise identical reaction conditions. Regio-, stereo-, and site-selective vinylations mediated by 2-pentyne 1b to form adducts 3n, 3o, and epi-3o also are described. The tiglyl alcohol motif obtained upon butyne-mediated vinylation, which is itself found in diverse secondary metabolites, may be converted to commonly encountered polyketide stereodiads, -triads, and -tetrads, as demonstrated by the formation of adducts 4a-4d. The collective mechanistic studies, including deuterium labeling experiments, corroborate a catalytic cycle involving alcohol dehydrogenation to form a transient aldehyde and a ruthenium hydride, which engages in alkyne hydrometalation to form a nucleophilic vinylruthenium species that enacts carbonyl addition. A stereochemical model for carbonyl addition invoking formyl CH···I[Ru] and CH···O≡C[Ru] hydrogen bonds is proposed based on prior calculations and crystallographic data.

Palladium-Catalyzed Asymmetric Dearomative Carbonylation of Indoles.

Herein, we disclose a strategy for the asymmetric dearomatization of N-arylacyl indoles via a palladium-catalyzed tandem Heck/carbonylation, leading to an array of indoline-3-carboxylates bearing vicinal C2-aza-quaternary and C3 tertiary stereocenters in high yields and excellent enantio- and diastereoselectivities. This study is an important advance in the field of asymmetric carbonylation and enantioselective dearomatization reactions.

Confronting the Challenging Asymmetric Carbonyl 1,2-Addition Using Vinyl Heteroarene Pronucleophiles: Ligand-Controlled Regiodivergent Processes through a Dearomatized Allyl-Cu Species.

The selective reductive coupling of vinyl heteroarenes with aldehydes and ketones represents a versatile approach for the rapid construction of enantiomerically enriched secondary and tertiary alcohols, respectively. Herein, we demonstrate a CuH-catalyzed regiodivergent coupling of vinyl heteroarenes with carbonyl-containing electrophiles, in which the selectivity is controlled by the ancillary ligand. This approach leverages an in situ generated benzyl- or dearomatized allyl-Cu intermediate, yielding either the dearomatized or exocyclic addition products, respectively. The method exhibits excellent regio-, diastereo-, and enantioselectivity and tolerates a range of common functional groups and heterocycles. The dearomative pathway allows direct access to a variety of functionalized saturated heterocyclic structures. The reaction mechanism was probed using a combination of experimental and computational approach. Density functional theory studies suggest that the ligand-controlled regioselectivity results from the C-H/π interaction and steric repulsion in transition states, leading to the major and minor regioisomers, respectively. Hydrocupration of vinyl heteroarene pronucleophile is the enantiodetermining step, whereas the diastereoselectivity is enforced by steric interactions between the benzylic or allyl-Cu intermediate and carbonyl-containing substrates in a six-membered cyclic transition state.

Molecular Field Analysis Using Computational-Screening Data in Asymmetric N-Heterocyclic Carbene-Copper Catalysis toward Data-Driven In Silico Catalyst Optimization

Abstract A molecular-field-based regression analysis using computational screening data for N-heterocyclic carbene (NHC)-Cu-catalyzed asymmetric carbonyl additions of a silylboronate to aldehydes is reported. A computational screening was performed to collect enantioselectivity data (ΔΔG‡: energy differences between the transition states leading to each enantiomer) via transition-state (TS) calculations using density functional theory (DFT) methods. A molecular field analysis (MFA) was carried out using the obtained calculated ΔΔG‡ values and TS structures (30 samples in total). Important structural information for enantioselectivity extracted by the MFA was visualized on the TS structures, which provided insight into an asymmetric induction mechanism. Based on the obtained information, chiral NHC ligands were designed, which showed improved enantioselectivity in these carbonyl additions (designed ligands: up to 96% ee, initial training samples: up to 73% ee).

Atroposelective carbonylation of aryl iodides with amides: facile synthesis of enantioenriched cyclic and acyclic amides

An unprecedented palladium-catalyzed asymmetric carbonylation of ArI with carbon monoxide (CO) to expand a class of atroposelective cyclic and acyclic amides in good yields with high enantioselectivities has been reported.

An Improved Process for Synthesis of (S)-Duloxetine Hydrochloride Involving Enzymatic Asymmetric Carbonyl Reduction on a Novel Ketoamine

(S)-Duloxetine hydrochloride 1 is a medication used to treat major depressive disorder, generalized anxiety disorder, fibromyalgia and neuropathic pain (Figure 1). 1 , 2 Due to its versatility in d...

Aureobasidium subglaciale F134 is a bifunctional whole-cell biocatalyst for Baeyer–Villiger oxidation or selective carbonyl reduction controllable by temperature

The microbial production of either ester/lactones or enantio-enriched alcohols through Baeyer–Villiger oxidation or stereoselective reduction of ketones, respectively, is possible by using whole cells of A. subglaciale F134 as a bifunctional biocatalyst. The chemoselective pattern of acetophenone biotransformation catalyzed by these cells can be regulated through reaction temperature, directing the reaction either towards oxidation or reduction products. The Baeyer–Villiger oxidation activity of A. subglaciale F134 whole cells is particularly dependent on reaction temperature. Acetophenone was transformed efficiently to phenol via the primary Baeyer–Villiger product phenyl acetate at 20 °C after 48 h with 100% conversion. In contrast, at 35 °C, enantio-enriched ( S )-1-phenylethanol was obtained as the sole product with 64% conversion and 89% ee . In addition, A. subglaciale F134 cells also catalyze the selective reduction of various structurally different aldehydes and ketones to alcohols with 40% to 100% yield, indicating broad substrate spectrum and good enantioselectivity in relevant cases. Our study provides a bifunctional biocatalyst system that can be used in Baeyer–Villiger oxidation as well as in asymmetric carbonyl reduction, setting the stage for future work concerning the identification and isolation of the respective enzymes.

Catalytic Asymmetric Carbonylation of Prochiral Sulfonamides via C–H Desymmetrization

An enantioselective oxidative C–H/N–H carbonylation process was developed in this work. A bimetallic Pd/Cu-based catalyst system was found to catalyze enantioselective C(sp2)–H carbonylation of prochiral arylsulfonamides via desymmetrization process in the presence of mono-N-protected amino acid ligands. This reaction provides a facile strategy to the stereoselective construction of the lactam-type products, such as isoindoline-1-ones and isoquinoline-1-ones, in good yields and enantioselectivities under balloon pressure with the mixture of CO/O2. The reaction mechanism was rationalized by using density functional theory (DFT) study.