Stereochemical Outcome Research Articles

Access to fluorinated dienes through hydrofluorination of 2-En-4-ynoates.

The hydrofluorination of enynoates has been developed for the synthesis of fluorinated dienoates. Using a pyridinium tetrafluoroborate salt that is easily prepared on large scale, this approach enabled the direct conversion of these substrates to fluorinated targets through a vinyl cation mediated process. This approach was applied to a range of aryl-substituted enynoates to deliver the (Z)-configured products with high levels of stereo- and regioselectivity. Mechanistic studies were conducted to provide insights into the stereochemical outcome and reaction efficiency under different reaction conditions.

Diastereodivergence in catalytic asymmetric conjugate addition of carbon nucleophiles.

Catalytic asymmetric conjugate additions of carbon nucleophiles have emerged as a potent tool for constructing multi-stereogenic molecules with precise stereochemical control. This review explores the concept of diastereodivergence in such reactions, focusing on strategies to achieve selective access to diverse diastereomeric products upon carbon-carbon bond formation. Drawing from a rich array of examples, we delve into key approaches for controlling the stereochemical outcome of these transformations, including alteration of alkene geometry, fine-tuning of reaction parameters, synergistic catalysis, and isomerization of conjugate adducts. Additionally, we highlight the iterative strategies for conjugate additions, showcasing their potential for diastereodivergent synthesis of methyl-branched stereocenters in 1,3-relationships. By presenting a concentrated overview of this significant topic, this review aims to provide valuable insights into the design and execution of stereodivergent catalytic conjugate additions, offering new avenues for advancing stereoselective synthesis and structural diversity in organic synthesis.

Stereoselective 1,1'-glycosylation via reactivity tuning with protecting groups.

Chemical 1,1'-glycosylation for the synthesis of non-reducing disaccharides is complicated by the need to simultaneously control the stereochemistry at two anomeric centers. While considerable progress has been made in the synthesis of α,α-disaccharides, the assembly of 1,1'-β,β- and 1,1'-β,α-linked non-reducing sugars has received comparatively less attention. Many naturally occurring non-reducing disaccharides and their biologically active mimetics feature asymmetrically located functional groups at different positions on the two pyranose rings, highlighting the demand for reliable stereoselective methods to synthesize fully orthogonally protected 1,1'-conjugated sugars suitable for targeted functionalisation to create important biomolecules. By exploiting specific electronic and torsional effects imposed by protecting groups on both glycosyl donor and lactol acceptor molecules, we achieved highly stereoselective β,β- and β,α-1,1'-glycosylation and successfully synthesised a library of fully orthogonally protected β,β- and β,α-linked diglucosamines. Our approach is based on the premise that acceptor reactivity can greatly influence the stereochemical outcome of the glycosylation reaction. We show that the tailored choice of orthogonal protecting groups can alter the anomeric preferences in lactol acceptors, stabilising specific anomeric conformations, and that protecting group-driven modulation of lactol nucleophilicity is a useful tool to achieve stereoselective 1,1'-glycosidic bond formation. Structure-activity relationships have been established for a number of fully orthogonally protected glycosyl donor-lactol acceptor pairs, with a focus on optimizing lactol acceptor nucleophilicity to facilitate stereoselective 1,1'-β,β- and 1,1'-β,α-glycosylation on the acceptor side and enhance neighboring group-driven stereoselectivity on the donor side.

Selective Synthesis of Z-Michael Acceptors via Hydroalkylation of Conjugated Alkynes.

Hydroalkylation of terminal alkynes is a powerful approach to the synthesis of disubstituted alkenes. However, its application is largely unexplored in the synthesis of α,β-unsaturated carbonyls, which are common among synthetic intermediates and biologically active molecules. The thermodynamically less stable Z-isomers of activated alkenes have been particularly challenging to access because of their propensity for isomerization and the paucity of reliable Z-selective hydroalkylation methods. We developed a highly Z-selective silver-catalyzed hydroalkylation of terminal conjugated alkynes using alkyl boranes as coupling partners. The reaction allows access to (Z)-α,β-unsaturated esters, secondary and tertiary alkyl amides, aryl amides, and alkyl and aryl ketones and tolerates a wide range of functional groups. The reaction can be performed successfully in the presence of alkyl and aryl halides, esters, protected alcohols, and amines. The hydroalkylation involves the formation of an alkynylboronate complex followed by a 1,2-metalate shift. This sequence of steps mechanistically constrains the stereochemical outcome, which, together with mild reaction conditions, ensures high Z-selectivity.

Studies on the Stereoselective Synthesis of Sacubitril via a Chiral Amine Transfer Approach.

We present a comprehensive account of our efforts directed towards the synthesis of sacubitril, a neprilysin inhibitor used in combination with valsartan and marketed as Entresto™. Our initial approach to the formal synthesis of sacubitril employed a chiral pool strategy, utilizing (S)-pyroglutamic acid as a key building block and Cu(I)-mediated Csp2-Csp3 cross-coupling as a key transformation. Further investigations led to the development of chiral amine transfer (CAT) reagents-based stereoselective synthesis. This involved the E-selective construction of γ-ylidene-butenolide from readily available biphenyl bromide and 4-pentynoic acid, the conversion of this butenolide to its ene-lactam using chiral amine, and substrate-controlled diastereoselective reduction of ene-lactam using Et3SiH or Pd/C, H2 (overall chiral amine transfer) as key transformations. Antipodal lactam intermediates were synthesized using corresponding chiral amines, and the stereochemical outcomes during the ene-lactam reduction with Et3SiH were rationalized by DFT studies.

Stereo-Differentiating Asymmetric Rh(I)-Catalyzed Pauson-Khand Reaction: A DFT-Informed Approach to Thapsigargin Stereoisomers.

We report a stereo-differentiating dynamic kinetic asymmetric Rh(I)-catalyzed Pauson-Khand reaction, which provides access to an array of thapsigargin stereoisomers. Using catalyst-control, a consistent stereochemical outcome is achieved at C2─for both matched and mismatched cases─regardless of the allene-yne C8 stereochemistry. The stereochemical configuration for all stereoisomers was assigned by comparing experimental vibrational circular dichroism (VCD) and 13C NMR to DFT-computed spectra. DFT calculations of the transition-state structures corroborate experimentally observed stereoselectivity and identify key stabilizing and destabilizing interactions between the chiral ligand and allene-yne PKR substrates. The robust nature of our catalyst-ligand system places the total synthesis of thapsigargin and its stereoisomeric analogues within reach.

Mechanism of C-3 Acyl Neighboring Group Participation in Mannuronic Acid Glycosyl Donors.

One of the main challenges in oligosaccharide synthesis is the stereoselective introduction of the glycosidic bond. In order to understand and control glycosylation reactions, thorough mechanistic studies are required. Reaction intermediates found by NMR spectroscopy often cannot explain the glycosylation's stereochemical outcome. Hence, reactions may proceed through low-abundance reaction intermediates that are difficult to detect, according to a Curtin-Hammett scenario. We have previously observed that manno-type sugars can engage in C-3 acyl neighboring group participation. Herein, we report the detection of glycosyl dioxanium ions that result from C-3 neighboring group participation in mannuronic acid donors. Using a suite of exchange NMR techniques, we were able to dissect the kinetics of the conformational ring-flip that precedes C-3 acyl participation and the participation event itself in various manno-type sugars. Hence, this study provides a complete picture of mannosyl dioxanium ion formation.

Surface Decoration of Cellulose With Trifluoromethylphenyl Substituted Thiourea: A Robust Hydrogen-Bonding Catalyst in Conjunction With L-Proline for the Asymmetric Direct Mannich Reaction.

Cellulose is one of the most abundant biopolymers in nature. Despite being the subject of research in various fields, it is not as famous as chitosan in catalyst design. Herein, a novel thiourea-functionalized cellulose (CTU-6) was synthesized as a robust hydrogen bonding catalyst with the degree of substitution (DS) of 0.84. CTU-6 was characterized using Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), x-ray powder diffraction (XRD), proton nuclear magnetic resonance spectroscopy (1HNMR), solid-state cross-polarization magic angle spinning carbon-13 nuclear magnetic resonance (CP/MAS 13C-NMR), thermal gravimetric analysis (TGA) and elementel analysis. CTU-6 catalyzed the direct asymmetric Mannich reaction between acetone, aniline, and various aromatic aldehydes in cooperation with L-proline. The reaction exhibited excellent enantioselectivity, achieving up to 98% enantiomeric excess (ee) at room temperature. Incorporating trifluoromethylphenyl-substituted thiourea into the cellulose framework leverages its ability to form hydrogen bonds, thereby enabling precise control over the asymmetric induction. This study highlights the potential of cellulose-based catalysts in advancing asymmetric synthesis and their versatility in various organic reactions in cooperation with small chiral ligands. This synergy not only facilitates the efficient catalytic process but also improves the stereochemical outcomes of the reactions. This method underscores the importance of utilizing renewable and versatile cellulose materials in combination with chiral auxiliaries to achieve high levels of enantioselectivity.

Copper-Catalyzed Asymmetric Tertiary Radical Cyanation for the Synthesis of Chiral Tetrasubstituted Monofluoroacyl Nitriles.

The construction of chiral tetrasubstituted α-fluoro-α-cyano carbonyl compounds remains a key challenge in synthetic organic chemistry because of their popularity in multiple disciplines. In this paper, we report the copper-catalyzed asymmetric fluorinated tertiary radical cyanation reaction of cyclic α-iodo-α-fluoroindanones with TMSCN to achieve chiral nitriles with carbon-fluorine quaternary stereogenic centers. Thus, an array of optically active tetrasubstituted monofluoroacyl nitriles were synthesized with high reaction efficiency and excellent enantioselectivities (up to 91% yield, 99% ee). Moreover, mechanistic investigations, including experiments, were conducted to clarify the reaction pathway and stereochemical outcomes.

Bulk Stereoselective Cationic Polymerization of Vinyl Ethers by the Coordination of ZrCl4 with Tunable Spirocyclic Phosphoric Acids.

Control over stereochemistry in poly(vinyl ether)s leads to a notable change in their physical properties, yet remains a grand challenge. Here, we demonstrate the bulk stereoselective cationic polymerization of vinyl ethers using ZrCl4 coordinated with a spirocyclic phosphoric acid (SPA). The widely variable substituents in SPAs exert a profound impact on the stereochemical and activity outcome of the polymerization: the % m of poly(vinyl ether)s linearly increases with the Hammett substituent constant (σ) of SPAs; the catalytic activity increases with the σ; the large steric hindrance groups lead to decreased polymerization activity. Mechanism studies suggest that the coordination of ZrCl4 with three equivalents of SPAs generates the chiral complex. The complex can abstract chlorine from the initiator/chain end to form the chiral ion pair allowing the selective facial addition of incoming monomers. The catalyst system features characteristics of no solvent, low loads, high tacticity control, high monomer scope, and recyclability.

Bulk stereoselective cationic polymerization of vinyl ethers by the coordination of ZrCl4 with tunable spirocyclic phosphoric acids

Control over stereochemistry in poly(vinyl ether)s leads to a notable change in their physical properties, yet remains a grand challenge. Here, we demonstrate the bulk stereoselective cationic polymerization of vinyl ethers using ZrCl4 coordinated with a spirocyclic phosphoric acid (SPA). The widely variable substituents in SPAs exert a profound impact on the stereochemical and activity outcome of the polymerization: the % m of poly(vinyl ether)s linearly increases with the Hammett substituent constant (σ) of SPAs; the catalytic activity increases with the σ; the large steric hindrance groups lead to decreased polymerization activity. Mechanism studies suggest that the coordination of ZrCl4 with three equivalents of SPAs generates the chiral complex. The complex can abstract chlorine from the initiator/chain end to form the chiral ion pair allowing the selective facial addition of incoming monomers. The catalyst system features characteristics of no solvent, low loads, high tacticity control, high monomer scope, and recyclability.

Diastereoselective Substitution Reactions of Acyclic Acetals Controlled by Remote Participation of an Acyloxy Group.

A remote carbonyl group up to six atoms away from the acetal group can induce 1,2-asymmetric induction in nucleophilic substitution reactions of acyclic acetals. Isolation of a cyclic carbonate under Lewis acidic conditions and computational studies suggested that the remote carbonyl group participated through the formation of a cyclic dioxocarbenium ion intermediate. The stereochemical outcomes depended on the size of the alkyl substituent and that of the nucleophile employed.

Base‐Promoted Diastereoselective Addition of 2‐Aryloxy‐2‐Fluoroketones to N‐(tert‐Butylsulfinyl)Imines

AbstractThe asymmetric construction of a quaternary fluorine‐containing stereogenic carboncenter is highly valuable for the development of fluoroine‐containing bioactive molecules. Herein, a base‐promoted, diastereoselective Mannich‐type reaction of 2‐aryloxy‐2‐fluoroketones with N‐(tert‐butylsulfinyl)imines has been developed. A number of the addition products featuring a fluorinated quaternary stereocarbon centre and a β‐fluoroamine structural motif have been readily obtained in good yields with moderate to good diastereoselectivities. The absolute configuration of the major diasteromer was determined by X‐ray crystallography analysis, and a closed transition‐state mode was proposed to explain the stereochemical outcome of this reaction. In addition, the addition product was efficiently converted into a α‑fluoro‐β‐amino alcohol through desulfinylation followed by reduction of the carbonyl group.

(E)-2-Benzylidenecyclanones: Part XX-Reaction of Cyclic Chalcone Analogs with Cellular Thiols: Unexpected Increased Reactivity of 4-Chromanone- Compared to 1-Tetralone Analogs in Thia-Michael Reactions.

In vitro relative cytotoxicity (IC50 (IIb)/IC50 (IIIb) of (E)-3-(4'-methylbenzylidene)-4-chromanone (IIIb) towards human Molt 4/C8 and CEM T-lymphocytes showed a >50-fold increase in comparison to those of the respective tetralone derivative (IIb). On the other hand, such an increase was not observed in the analogous 4-OCH3 (IIc and IIIc) derivatives. In order to study whether thiol reactivity-as a possible basis of the mechanism of action-correlates with the observed cytotoxicities, the kinetics of the non-enzyme catalyzed reactions with reduced glutathione (GSH) and N-acetylcysteine (NAC) of IIIb and IIIc were investigated. The reactivity of the compounds and the stereochemical outcome of the reactions were evaluated using high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Molecular modeling calculations were performed to rationalize the unexpectedly higher thiol reactivity of the chromanones (III) compared to the carbocyclic analog tetralones (II). The results indicate the possible role of spontaneous thiol reactivity of compounds III in their recorded biological effects.

Escape from Flatland: Stereoselective Synthesis of Hexa‐aryl Borazines and their sp²‐Based 3D Architectures

Borazine and its derivatives can be considered critical doping units for engineering hybrid C(sp2)‐based molecules with tailored optoelectronic properties. Herein, we report the first synthesis of hexaarylborazines that, bearing ortho‐substituted aryl moieties, extend three‐dimensionally. Using a one‐pot protocol, we first form an electrophilic chloroborazole and then react it with an aryl lithium (ArLi). By selecting the appropriate ortho‐substituent, we can guide the ArLi to add to the BN‐core in a specific way, ultimately controlling the stereochemical outcome of the three‐substitution reaction. Rationalization of the stereochemical model through computational analysis allowed us to show that when aryl lithium nucleophiles bearing rigid long‐range ortho‐substituents are used, i.e., stiff substituents. The ortho‐substituent shields its side of the electrophilic B3N3 core, biasing the incoming ArLi to add anti at each addition step, forming the final tri‐aryl borazine exclusively as cc‐isomer. Leveraging this stereoselective approach, prototypical multichromophoric borazine derivatives were prepared, and we showcased how the stereochemical arrangement of these chromophores distinctly influences their redox behavior. This methodology paves the way for previously inaccessible borazines to serve as privileged precursors to transcend the conventional bidimensionality associated with graphenoid systems and pioneer the construction of new forms of three‐dimensional C(sp2)‐based architectures.

Escape from Flatland: Stereoselective Synthesis of Hexa-aryl Borazines and their sp²-Based 3D Architectures.

Borazine and its derivatives can be considered critical doping units for engineering hybrid C(sp2)-based molecules with tailored optoelectronic properties. Herein, we report the first synthesis ofhexaarylborazines that, bearingortho-substituted aryl moieties, extend three-dimensionally.Using a one-pot protocol, we first form an electrophilic chloroborazole and then react it with an aryl lithium (ArLi). By selecting the appropriateortho-substituent, we can guide the ArLi to add to the BN-core in a specific way, ultimately controlling the stereochemical outcome of the three-substitution reaction. Rationalization of the stereochemical model through computational analysis allowed us to show thatwhen aryl lithium nucleophiles bearing rigid long-rangeortho-substituentsare used,i.e.,stiff substituents. Theortho-substituent shields its side of the electrophilic B3N3core, biasing the incoming ArLi to addantiat each addition step, forming the final tri-aryl borazine exclusively ascc-isomer.Leveraging this stereoselective approach, prototypical multichromophoric borazine derivatives were prepared, and we showcased how the stereochemical arrangement of these chromophores distinctly influences their redox behavior.This methodology paves the way for previously inaccessible borazines to serve asprivileged precursorsto transcend the conventional bidimensionality associated with graphenoid systems and pioneer the construction of new forms of three-dimensional C(sp2)-based architectures.

Tropone Hydrazides in [10+2]‐Hetero‐Higher‐Order Cycloaddition for the Synthesis of Tetrahydropyridazine Derivatives

Abstract[10+2]‐Hetero‐higher‐order cycloaddition between tropone hydrazides (acting as 10π‐components) and 3‐alkylidene oxindoles (acting as 2π‐components) has been established. Under Brønsted base catalysis the reaction proceeded in a fully peri‐ and diastereoselective manner with the stereochemical outcome governed mainly by electronic interactions. Following such a strategy, a series of structurally diverse tetrahydropyridazines were prepared in 30–70% yields. Furthermore, the potential of the obtained cycloadducts has been confirmed in selected chemoselective transformations.

2-Halomethyleneoxetanes from 2-Methyleneoxetanes by Reaction with N-Halosuccinimides: Reactant Influences on Stereochemical Outcomes and Reaction Pathways.

The first general synthesis of 2-halomethyleneoxetanes, realized by the reaction of 2-methyleneoxetanes with N-halosuccinimides (NXS), is reported. The relative diastereoselectivities of the transformations were dependent on the halogen of NXS, while alternative reaction outcomes were influenced by substituents on the oxetane. Quantum mechanical calculations and molecular dynamics simulations exploring the basis of the observed diastereoselectivities are described. These highly strained heterocycles underwent standard cross-coupling reactions, demonstrating their utility as synthetic intermediates.

Controlling (E/Z)-Stereoselectivity of -NHC=O Chlorination: Mechanism Principles for Wide Scope Applications.

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.

Asymmetric Organocatalytic Diels-Alder Reaction of Olefinic Azlactones with Unsaturated Thiazolones: Access to Spirocyclohexenone Thiazolone Skeletons.

Chiral bifunctional thiourea-catalyzed Diels-Alder reaction between olefinic azlactones and alkylidene thiazolone derivatives is reported here for the first time. The asymmetric Diels-Alder reaction delivers vicinal tertiary-quaternary stereocenters in spirocyclohexenone thiazolones in moderate to high yields and good stereochemical outcomes. The protocol can be adapted to a broad array of substrates. Moreover, the reaction is scaled up, and the chiral spirocyclohexenone thiazolone was converted into valuable spirocyclic-1,2-amidoalcohol highlighting the synthetic utility of our methodology.