Asymmetric Synthesis Research Articles

TMSOTf Mediated Aminocyclization/[1,3]‐Sulfonyl Migration on N‐Homopropargyl Hydroxylamines for the Stereoselective Synthesis of 3‐Sulfonyl Cyclic Nitrones

TMSOTf‐mediated 5‐endo‐dig aminocyclization followed by N‐ to C‐[1,3]‐sulfonyl migration on N¬‐homopropargyl hydroxylamines gave diastereoselective access to trisubstituted 3‐sulfonyl cyclic nitrone (3‐sulfonyl pyrroline N‐oxide) derivatives. The synthetic utility of the 3‐sulfonyl cyclic nitrone products was demonstrated through the diastereoselective synthesis of the sulfonyl‐substituted nonaromatic N‐heterocycles such as N‐hydroxy pyrrolidine, pyrrolidine‐fused isoxazoline, and isoxazolidine derivatives.

Asymmetric Synthesis of Chiral Cyclopropanes from Vinyl Sulfoxonium Ylides Catalyzed by a Chiral-at-Metal Rh(III) Complex.

A chiral-at-metal Rh(III) complex-mediated [2+1] cyclization of vinyl sulfoxonium ylides with α,β-unsaturated 2,2-acylimidazoles has been demonstrated for the first time. This work provides a practical approach for assembling 1,2,3-trisubstituted chiral cyclopropane with alkyl structural units, which had advantages such as a wide range of substrates, good functional group tolerance, and mild reaction conditions. In addition, further amplification experiments and transformation of cycloaddition products were carried out to highlight the practicality of the method.

Asymmetric organocatalytic synthesis of chiral homoallylic amines.

In recent decades, the chiral allylation of imines emerged as a key methodology in the synthesis of alkaloids and natural products with 4-, 5- and 6-membered cyclic amine motifs. Initially reliant on stoichiometric reagents, synthetic chemists predominantly used N-substituted chiral imines, organometallic chiral reagents and achiral reagents with an equimolar chiral controller. However, recent years have witnessed the rise of asymmetric transition-metal catalysts and, importantly, organocatalytic allylation, reshaping the landscape of modern synthetic chemistry. This review explores the latest developments in the asymmetric allylation of imines, encompassing cutting-edge advances in hydrogen-bond catalysis and non-classical approaches. Furthermore, practical examples showcasing the application of these innovative methodologies in total synthesis are presented.

Spin Dynamics of Radical Pairs Using the Stochastic Schrödinger Equation in MolSpin.

The chemical reactivity of radical pairs is strongly influenced by the interactions of electronic and nuclear spins. A detailed understanding of these effects requires a quantum description of the spin dynamics that considers spin-dependent reaction rates, interactions with external magnetic fields, spin-spin interactions, and the loss of spin coherence caused by coupling to a fluctuating environment. Modeling real chemical and biochemical systems, which frequently involve radicals with multinuclear spin systems, poses a severe computational challenge. Here, we implement a method based on the stochastic Schrödinger equation in the software package MolSpin. Large electron-nuclear spin systems can be simulated efficiently, with asymmetric spin-selective recombination reactions, anisotropic hyperfine interactions, and nonzero exchange and dipolar couplings. Spin-relaxation can be modeled using the stochastic time-dependence of spin interactions determined by molecular dynamics and quantum chemical calculations or by allowing rate coefficients to be explicitly time-dependent. The flexibility afforded by this approach opens new avenues for exploring the effects of complex molecular motions on the spin dynamics of chemical transformations.

Improvement of bifunctional organocatalysts performance by water as an additive in the Michael addition of carbonyl compounds to maleimides

The diastereoselective Michael addition of ketones to maleimides using bifunctional organocatalysts presents a significat challenge. We developed a protocol in which the addition of 5 equivalents of water boosted the diastereoselectivity of six-membered ring ketones. However, the results were influenced by steric effects and varied outcomes were observed with different ring sizes of ketones and acyclic carbonyl compounds. The improvement in the asymmetric synthesis of succinimides due to water appears to be more related to hydrogen bonds at the interface rather than a water molecule embedded in the transition state. Additionally, we explored 3-substituted maleimides and found that only those with phenyl and phenylethynyl groups underwent the reaction. Finally, the desymmetrization of N-(2-tert-butylphenyl)maleimide generated the atropoisomer with good selectivity.

Enantiopure P-Chiral Secondary Phosphines (P*HRR') from the Catalytic Asymmetric Hydrogenation of P═C Bonds.

We report the first bottleable enantiopure P-chiral secondary phosphines from the rhodium-catalyzed asymmetric hydrogenation of phosphaalkenes. Catalytic asymmetric hydrogenation, a reaction of broad academic and industrial importance for C═C, N═C, and O═C bonds, has not previously been reported for the P═C bond. The hydrogenation of ArP═CR2 (Ar = Mes, m-Xyl and TMOP; R = Ph, 4-C6H4F) affords four unprecedented P-stereogenic secondary phosphines in 76%-90% isolated yields with 91%-97% enantiomeric excess (ee). These isolable P-chiral secondary phosphines are configurationally stable indefinitely in the solid state and show only modest loss in ee when kept in solution for over a month at room temperature.

Stereoselective and site-divergent synthesis of C-glycosides.

Carbohydrates play important roles in medicinal chemistry and biochemistry. However, their synthesis relies on specially designed glycosyl donors, which are often unstable and require multi-step synthesis. Furthermore, the catalytic and stereoselective installation of arylated quaternary stereocentres on sugar rings remains a formidable challenge. Here we report a facile and versatile method for the synthesis of diverse C-R (where R is an aryl, heteroaryl, alkenyl, alkynyl or alkyl) glycosides from readily available and bench-stable 1-deoxyglycosides. The reaction proceeds under mild conditions and exhibits high stereoselectivity across a broad range of glycosyl units. This protocol can be used to synthesize challenging 2-deoxyglycosides, unprotected glycosides, non-classical glycosides and deuterated glycosides. We further developed the catalyst-controlled site-divergent functionalization of carbohydrates for the synthesis of various unexplored carbohydrates containing arylated quaternary stereocentres that are inaccessible by existing methods. The synthetic utility of this strategy is further demonstrated in the synthesis of pharmaceutically relevant molecules and carbohydrates.

Constructing Asymmetric Fe-Nb Diatomic Sites to Enhance ORR Activity and Durability.

Iron-nitrogen-carbon (Fe-N-C) materials have been identified as a promising class of platinum (Pt)-free catalysts for the oxygen reduction reaction (ORR). However, the dissolution and oxidation of Fe atoms severely restrict their long-term stability and performance. Modulating the active microstructure of Fe-N-C is a feasible strategy to enhance the ORR activity and stability. Compared with common 3d transition metals (Co, Ni, etc.), the 4d transition metal atom Nb has fewer d electrons and more unoccupied orbitals, which could potentially forge a more robust interaction with the Fe site to optimize the binding energy of the oxygen-containing intermediates while maintaining stability. Herein, an asymmetric Fe-Nb diatomic site catalyst (FeNb/c-SNC) was synthesized, which exhibited superior ORR performance and stability compared with those of Fe single-atom catalysts (SACs). The strong interaction within the Fe-Nb diatomic sites optimized the desorption energy of key intermediates (*OH), so that the adsorption energy of Fe-*OH approaches the apex of the volcano plot, thus exhibiting optimal ORR activity. More importantly, introducing Nb atoms could effectively strengthen the Fe-N bonding and suppress Fe demetalation, causing an outstanding stability. The zinc-air battery (ZAB) and hydroxide exchange membrane fuel cell (HEMFC) equipped with our FeNb/c-SNC could deliver high peak power densities of 314 mW cm-2 and 1.18 W cm-2, respectively. Notably, the stable operation time for ZAB and HEMFC increased by 9.1 and 5.8 times compared to Fe SACs, respectively. This research offers further insights into developing stable Fe-based atomic-level catalytic materials for the energy conversion process.

Mass transfer-enhanced platform for heterogeneous dual organocatalysis to boost yield and diastereoselectivity in enantioselective Michael/benzoin cascade reaction

Mass transfer limitation and tedious anchoring of multiple expensive chiral organocatalysts are the key bottlenecks in heterogeneous asymmetric cascade/tandem reactions, leading to high-cost processes with low catalytic performances. In this paper, two chiral organocatalysts, including (S)-diphenylprolinoltrimethylsilyl ether (ProTMS) and N-heterocyclic carbenes (NHC), are simultaneously immobilized to hollow mesoporous polystyrene nanospheres (HMPNs) in one-pot via Friedel-Crafts alkylation to afford supported dual organocatalysts (ProTMS&NHC@HMPNs) at low cost. The catalyst possesses the spherical morphology with a hollow interior and a thin mesopore-abundant shell, providing suitable environments for reactants to quickly access to the catalytic sites of NHC and ProTMS. The side reactions caused by limited mass transfer are effectively suppressed, and superior yields (70–92 %) and diastereoselectivities (dr = 3:120:1) to homogeneous catalysis are achieved in heterogeneous Michael/benzoin cascade reaction. Overall, the mass transfer-enhanced platform for efficient heterogeneous dual organocatalysis is developed to boost yield and diastereoselectivity in asymmetric cascade reactions.

Enantioselective S‐Alkylation of Sulfenamides by Phase‐Transfer Catalysis

AbstractA general phase‐transfer catalyst (PTC) mediated enantioselective alkylation of N‐acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at −40 °C. With these key parameters, enantiomeric ratios up to 97.5 : 2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S‐(hetero)aryl and branched and unbranched S‐alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever‐increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free‐NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)‐sulfoximine stereoisomer.

Cu-Catalyzed Asymmetric Synthesis of γ-Amino Alcohols Featuring Tertiary Carbon Stereocenters.

Alkyne-functionalized oxetanes are presented as versatile substrates that in combination with amine reagents can be transformed into structurally diverse, chiral γ-amino alcohols featuring a tetrasubstituted tertiary stereocenter under Cu catalysis. Control experiments demonstrate the privileged nature of these oxetane precursors in terms of yield and asymmetric induction levels in the developed protocol, and postsynthetic modifications offer an easy way to access more advanced synthons.

Biocatalytic Desymmetrization for the Atroposelective Synthesis of Axially Chiral Biaryls Using an Engineered Imine Reductase.

The enzymatic atroposelective synthesis of biaryl compounds is relatively rare, despite considerable attention received by biocatalysis in academic and industrial sectors. Imine reductases (IREDs) are an important class of enzymes that have been applied in the asymmetric synthesis of chiral amine building blocks. In this work, two IREDs (IR140 and IR189) were identified to catalyze the efficient desymmetrization of biaryls utilizing various amine donors. Further protein engineering enabled the identification of variants (IR189 M8-M9 and IR189 M13-M14) that are able to catalyze the formation of both (R) and (S) atropisomers in excellent yields and atroposelectivities for up to 24 examples (up to 99% ee and yield). The absolute configuration and rotational barriers were confirmed, and the reactions were readily enlarged to allow isolation of the atropisomeric products in 99% ee and 82% isolated yields. The optically pure biaryl amines were further derivatized into various synthetically useful atropisomers. To shed light on the molecular recognition mechanisms, molecular dynamics (MD) simulations were performed, offering plausible explanations for the improved atroposelectivities and enzymatic activities. The current strategy expands the scope of IRED-catalyzed synthesis of axially chiral biaryl amines, contributing significantly to the field of atroposelective biocatalysis.

A General Enantioselective α-Alkyl Amino Acid Derivatives Synthesis Enabled by Cobalt-Catalyzed Reductive Addition.

Enantioenriched unnatural amino acids represent a prevalent motif in organic chemistry, with profound applications in biochemistry, medicinal chemistry, and materials science. Herein, we report a cobalt-catalyzed aza-Barbier reaction of dehydroglycines with unactivated alkyl halides to afford unnatural α-amino esters with high enantioselectivity. This catalytic reductive alkylative addition protocol circumvents the use of moisture-, air-sensitive organometallic reagents, and stoichiometric chiral auxiliaries, enabling the conversion of a variety of primary, secondary, and even tertiary unactivated alkyl halides to α-alkyl-amino esters under mild conditions, thus leading to broad functional group tolerance. The expedient access to biologically active motifs demonstrates the practicality of this protocol by reducing the number of synthetic steps and enhancing the reaction efficiency.

Catalytic Asymmetric Cycloadditions of Cyclic Sulfamidate Imines: Straightforward Access to Chiral N‐Heterocycles

AbstractChiral N‐heterocyclic compounds are key structures in natural compounds and pharmaceuticals, and they serve as essential building blocks of functional materials. Catalytic asymmetric cycloaddition reactions represent one of the most efficient synthetic strategies for constructing optically active heterocycles. Cyclic sulfamidate imines have recently come to be extensively studied and widely utilized in both organocatalytic and transition metal‐catalyzed asymmetric cycloadditions, where they have been shown to provide various N‐fused‐heterocycles and spiro‐cycles exhibiting high efficiencies with excellent stereoselectivities. This review highlights recent advancements in catalytic asymmetric cycloadditions of cyclic sulfamidate imines for the stereoselective synthesis of biologically active sulfamidate‐containing heterocycles since 2012 while focusing on the diverse reactivities of cyclic sulfamidate imines and the mechanisms of chiral induction in catalysis.

Conformational Analysis and Organocatalytic Activity of Helical Stapled Peptides Containing α-Carbocyclic α,α-Disubstituted α-Amino Acids.

Conformational freedom-restricted peptides, such as stapled peptides, play a crucial role in the advancement of functional peptide development. We synthesized stapled octapeptides using α-carbocyclic α,α-disubstituted α-amino acids, particularly 3-allyloxy-1-aminocyclopentane-1-carboxylic acid, as the crosslink motifs. The organocatalytic capabilities of the synthesized stapled peptides were assessed in an asymmetric nucleophilic epoxidation reaction because the catalytic activities are known to be proportional to α-helicity. Despite incorporating side-chain crosslinks, the enantioselectivities of the epoxidation reaction catalyzed by stapled octapeptides were found to be comparable to those obtained using unstapled peptides. Interestingly, the stapled peptides using α-carbocyclic α,α-disubstituted α-amino acids demonstrated higher reactivities and stereoselectivities (up to 99% ee) compared to stapled peptides derived from (S)-α-(4-pentenyl)alanine, a commonly used motif for stapled peptides. These differences could be attributed to the increased α-helicity of the former stapled peptide in contrast to the latter, as evidenced by the X-ray crystallographic structures of their N-tert-butoxycarbonyl derivatives.

Stereoselective synthesis of naturally-occurring γ-lactones through photoredox catalysis

Stereoselective synthesis of naturally-occurring γ-lactones through photoredox catalysis

A Stereoselective Synthesis of a Novel α,β-Unsaturated Imine-Benzodiazepine through Condensation Reaction, Crystal Structure, and DFT Calculations.

The stereoisomers (E)-2,2-dimethyl-4-(4-subsitutedstyryl)-2,3-dihydro-1H-[1,5]-benzodiazepine 3(a-d) were synthesized via the condensation reaction of 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (BZD) 1 with the benzaldehyde derivatives 2(a-d) in ethanol. The chemical structure of the prepared products was confirmed by NMR (1H and 13C), HRMS, and X-ray analysis of the crystal structure 3d. The condensation reaction was examined using DFT calculations at the theoretical level of B3LYP/6-31G(d) to elucidate the chemo-, regio-, and stereoselectivity and the reaction mechanism of the produced isomer. Furthermore, we identified each reagent's reactive sites by the measurement of the reactivity indices. We also looked at how the electron-withdrawing groups (EWGs) of various aldehydes affected the reaction's mechanism and the stability of products 3(a-d).

Enamine Acylation Enabled Desymmetrization of Malonic Esters.

Asymmetric enamine alkylation represents a powerful tool for stereoselective C-C bond formation; in contrast, the development of enantioselective enamine acylation remains elusive. Here, we report that a chiral phosphoric acid can render an in-situ-formed enamine to undergo a stereoselective intramolecular α-carbon acylation, providing an alternative approach for the synthesis of useful pyrrolinones and indolinones bearing tetrasubstituted stereocenters. Utilizing an effective integration of the desymmetrization strategy and bifunctional organocatalysis, the first example of enantioselective enamine acylation is achieved by employing readily available aminomalonic esters and cyclic ketones. Instead of reactive and moisture-sensitive acyl chlorides, common esters with low electrophilicity were successfully used as efficient acylating reagents via hydrogen bonding interactions. The utility is demonstrated in the concise and enantioselective synthesis of (+)-LipidGreen I and II. Experimental studies and DFT calculations establish the reaction pathway and the origin of stereocontrol.

Synthesis of α-Aminonitriles via Ammonium-Catalyzed Reactions of Aminoacetonitrile.

α-Aminonitriles are not only broadly useful building blocks but also structural motifs in bioactive molecules. The Strecker reaction is one of the most widely used methods for α-aminonitrile synthesis. However, a severe drawback in Strecker reactions is the required use of a stoichiometric amount of toxic cyanation reagents. Thus, the development of a greener and widely applicable method for the synthesis of aminonitriles from readily available starting materials presents an important yet unmet challenge. We developed a general and new method for the synthesis of aminonitriles from readily available aminoacetonitrile. This method utilized off-the-shelf ammonium salts as catalysts, tolerated air and moisture, and avoided the use of cyanation reagents, which rendered it a greener alternative to the widely practiced Strecker reaction approach. We further illustrated that chiral ammonium-catalyzed asymmetric reactions of N-arylidene aminoacetonitriles could provide chiral α-tertiary and α-quaternary aminonitriles and α-aminonitriles bearing two continuous stereocenters.

Asymmetric Synthesis of Chiral Calix[4]arenes with Both Inherent and Axial Chirality via Cobalt-Catalyzed Enantioselective Intermolecular C-H Annulation.

Inherently chiral calixarenes have garnered significant attention due to their distinctive properties, yet the development of efficient catalytic asymmetric synthesis methods remains a critical challenge. Herein, we report the asymmetric synthesis of calix[4]arenes featuring inherent or both inherent and axial chirality via a cobalt-catalyzed C-H activation/annulation strategy in high yield with excellent enantio- and diastereoselectivity (up to > 99% ee and > 20:1 dr). Electrooxidation was also suitable for this transformation to obviate the sacrificial metal oxidants, underscoring the environmentally friendly potential of this approach. A key octahedral cobaltacycle intermediate was synthesized and characterized, providing valuable insights into the mode of enantio- and diastereocontrol of this protocol. Noteworthy photoluminescence quantum yields of up to 0.94 were measured, underscoring the potential of these compounds in the domain of organic fluorescent materials.