Product Stereoselectivity Research Articles

Exploring bulk and colloidal Mg/Al hydrotalcite–Au nanoparticles hybrid materials in aerobic olefin epoxidation

Au nanoparticles (AuNPs) were immobilized on S-containing amino acids (cysteine and methionine) Mg/Al hydrotalcite clay in both bulk and exfoliated (colloidal) forms. The Au nanoparticles were prepared by a biomimetic method using an anti-oxidant tea extract to reduce the Au salt solution. The performance of bulk and exfoliated clays with Au nanoparticles in aerobic olefin epoxidation was assessed with very interesting results. Both catalysts were very active towards the epoxide products; selectivity was found to be dependent on the catalyst form. The exfoliated catalysts yielded higher product stereoselectivity in the case of limonene epoxidation. These results can be explained by the existence of a confined environment around the AuNPs structures provided by the clay nanosheets wrapping the nanoparticles, modulating how substrates interact with the catalytic active centres. Based on experimental data mechanistic proposals were also rationalized for these catalysts showing how they assist the catalytic process.

Substrate Folding Modes in Trichodiene Synthase: A Determinant of Chemo- and Stereoselectivity

The folding mode of substrate FPP in sesquiterpene cyclases/synthases is key to the chemo- and stereoselectivity of the ultimate sesquiterpene products. However, the precise substrate folding modes in most sesquiterpene cyclases are still elusive, and it is challenging for theoretical simulations due to the high flexibility of FPP. Herein, by DFT/MM MD simulations, we obtain the optimal folding mode of FPP in the 1,6-closure trichodiene synthase and illuminate the whole catalytic mechanism for the biosynthesis of trichodiene. Furthermore, a simple and practical rule is proposed to decipher the relationship between the diverse FPP folding modes and chemical selectivity toward 1,6- and 1,10-ring closure, which are common pathways in all sesquiterpene cyclases.

Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki-Miyaura Coupling.

A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki-Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of a Pd(OAc)2/RuPhos catalytic system. Both the enol tosylation and Suzuki-Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either the E- or Z-olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki-Miyaura coupling. However, under the optimized cross-coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species.

Base-Mediated Hydroamination of Alkynes.

Inter- or intramolecular hydroamination reactions are a paradigmatic example of modern sustainable organic chemistry, as they are a catalytic, 100% atom-economical, and waste-free process of fundamental simplicity in which an amine is added to an alkyne substrate. Many enamines are found in many natural and synthetic compounds possessing interesting physiological and biological activities. The development of synthetic protocols for such molecules and their transformation is a persistent research topic in pharmaceutical and organic chemistry. Hydroamination is conspicuously superior to the other accessible methods, such as the imination of ketones or the aminomercuration/demercuration of alkynes, that involve the stoichiometric use of toxic reagents. Additionally, the hydroamination of alkyne substrates has been successfully employed as a key step in synthesizing target molecules through total syntheses containing substituted indoles, pyrroles, imidazoles, and other heterocycles as core moieties. Many research groups have explored inter- or intramolecular hydroamination of alkynes for the synthesis of diversely substituted nitrogen heterocycles using expensive metal catalysts. However, in contrast to metal-catalyzed hydroamination, the base-mediated hydroamination of alkynes has not been extensively studied. Various inorganic (such as hydroxides, phosphates, and carbonates) and organic bases have been proven to be valuable reagents for achieving the hydroamination process. This method represents an attractive strategy for the construction of a broad range of nitrogen-containing compounds that prevents the formation of byproducts in the creation of a C-N linkage. The presence of a base is thought to facilitate the attack of nitrogen nucleophiles, such as indoles, pyrroles, and imidazoles, on unsaturated carbon substrates through the activation of the triple bond and thus transforming the electron-rich alkyne into an electrophile. In the past few years, we have been involved in the development of methods for the nucleophilic addition of N-heterocycles onto terminal and internal alkynes using alkali base catalysts to achieve new carbon-nitrogen bond-forming reactions. During our study, we discovered the regioselective preferential nucleophilic addition of N-heterocycles onto the haloarylalkyne over N-arylation of the aryl halide. In this Account, we summarize our latest achievements in regio-, stereo-, and chemoselective hydroamination chemistry of N-nucleophiles with alkynes using a superbasic medium to produce a broad range of highly functionalized vinyl and styryl enamines, which are valuable and versatile synthetic intermediates for the synthesis of bioactive compounds. Interestingly, the stereoselectivity of the addition products (kinetically stable Z and thermodynamically stable E isomers) was found to be dependent upon time. It is worthwhile to note that hydroaminated products formed by the addition reaction can further be utilized for the synthesis of indolo-/pyrrolo[2,1-a]isoquinolines, naphthyridines, and bisindolo/pyrrolo[2,1-a]isoquinolinesvia tandem cyclization. This chemistry is expected to find application in organic synthesis for constructing a diverse variety of fused π-conjugated compounds, enaminones, and C-C coupled products.

Why different ligands can control stereochemistry selectivity of Ni-catalyzed Suzuki-Miyaura cross-coupling of benzylic carbamates with arylboronic esters: a mechanistic study.

Quantum chemistry calculations have been employed to study the mechanisms of nickel-catalyzed Suzuki-Miyaura cross-coupling reactions of benzylic carbamates with arylboronic esters, and the energy profiles have been computed to evaluate possible origins for the generation of different stereochemistry products. It has been demonstrated that the mechanism can be divided into three steps: oxidative addition, transmetallation and reduction elimination. Transmetallation is the rate-limiting step for the whole reaction cycle, and oxidative addition controls the stereoselectivity of the resulting products. Two possible pathways for the transmetallation step were proposed to consider the presence and absence of a base, and the results indicated that the former is energetically more favorable. Different ligands of nickel catalysts yield two kinds of stereochemistry products. For a phosphine ligand, an R product is afforded while for the N-heterocyclic carbene ligand, an S product is afforded. The distortion/interaction energy analysis and percent buried volume models have been performed to illustrate the origins of reaction stereoselectivity, and the interactions between catalysts and organic moieties control the stereoselectivity for both Ni(PMe3) and Ni(SIMes) catalysts.

β-Stereoselective Mannosylation Using 2,6-Lactones.

β-Stereoselective mannosylation using donors bearing the 2,6-lactone moiety is described. In general, glycosylation is a nucleophilic substitution reaction between an alcoholic nucleophile and a sugar moiety containing a leaving group at the anomeric position. Owing to stereoelectronic effects, the reaction tends to proceed via an SN1 mechanism to afford α-glycosides. We found that the introduction of a 2,6-lactone bridge can circumvent the competing SN1 reaction, affording β-glycosides with stereoinversion via SN2(-like) mechanisms. Glycosyl trichloroacetimidates are particularly efficient when activated by a combined catalyst of AuCl3 and 3,5-bis(trifluoromethyl)phenyl thiourea. In addition, the product stereoselectivity was highly dependent on the concentration of the reaction. Moreover, even when the reaction proceeds via an SN1 mechanism, the corresponding glycosyl cation appears to present sterically a β-directing nature. Overall, 2,6-lactones were promising structures for achieving β-mannosylations.

Effective Chirality Transfer in [3+2] Reaction between Allenyl-Rhodium and Enal: Mechanistic Study Based on DFT Calculations.

Theoretical calculation was performed to study the chirality transfer in a newly reported intramolecular [3+2] cycloaddition of enal and alleno rhodium species, generated in situ from an enynol precursor. [3.3.0] bicyclic system which contains two bridgehead quaternary carbons that can be achieved, the chirality of which are controlled by those of the starting material, and the product stereoselectivity is only determined by the α-position of the acetylene moiety. Density functional theory calculations predicted that only the cis [3.3.0] bicyclic product could be generated, regardless of either erythro or threo substrate, which was also confirmed by experimental observations.

Base- and acid-catalyzed intramolecular oxy-Michael reaction for the synthesis of tetrahydrofuran ring

Base- and acid-catalyzed intramolecular oxy-Michael reactions are reported. Three ε-hydroxy α,β-unsaturated ketones 1, 2, and 3 and one ester 4 were cyclized in 5-exo-trigonal fashion to afford 2,5-disubstituted tetrahydrofurans in good yields. The substituent at the γ-hydroxy group and its stereochemistry influenced the stereoselectivity of the THF products. The precursor 2 bearing an (R)-γ-hydroxy group gave 2,5-trans-6 exclusively. In contrast, 3, bearing an (S)-γ-hydroxy group, gave only 2,5-cis-7 under acidic conditions but gave a mixture of 2,5-trans and 2,5-cis isomers of 7 under basic conditions. On the other hand, in the absence of a hydroxyl group at the γ-position, the cyclization conducted under both basic and acidic reaction conditions provided a mixture of 2,5-trans- and 2,5-cis isomers of 5 and 8.

Helical Polymers Showing Inverse Helicity and Synergistic Effect in Chiral Catalysis: Catalytic Functionality Determining Enantioconfiguration and Helical Frameworks Providing Asymmetric Microenvironment

This article reports optically active helical polymers showing inverse helicity, which is controlled by copolymer composition. L‐Proline‐derived monomer and an achiral monomer have been copolymerized, affording copolymers with optical activity and remarkable catalytic ability. By adjusting relative content of the two monomers, a series of copolymers with varied optical activity has been obtained. More notably, the handedness of the macromolecular helices inverses at specific monomer feed ratios. Copolymers with opposite helicity have been applied as chiral catalysts for asymmetric aldol reaction to investigate the exact role of helical structures in catalysis. The variation in the stereoselectivity of product has demonstrated an intriguing synergistic effect occurring between the helical macromolecular frameworks and pendent prolineamide groups. The macromolecular helices provide asymmetric microenvironment for the reaction while enantioconfiguration of the product is determined by the specific catalytic functionality. This study opens up new opportunities for manufacturing macromolecules as mimetic enzymes catalyzing asymmetric reactions. image

B(C6F5)3: A New Class of Strong and Bulky Lewis Acid for Exo-Selective Intermolecular Diels-Alder Reactions of Unreactive Acyclic Dienes with α,β-Enals.

Lewis acid B(C6F5)3 catalyzed the Diels-Alder reactions of multisubstituted open-chain dienes and α,β-enals to afford the desired products with high exo-selectivities are reported. The substituent effect of the dienes and dienophiles on the product's stereoselectivity was thoroughly investigated, and it was found that most of the desired exo-Diels-Alder products could be obtained in good yields and with high exo-stereoselectivities.

Assessing the stereoselectivity of carbonyl reductases toward the reduction of OPBE and docking analysis.

The asymmetric reduction of prochiral carbonyl compounds by NAD(P)H-dependent carbonyl reductases represents a powerful method for the production of optically active alcohols. The stereoselectivity of a series of carbonyl reductases were evaluated toward the reduction of ethyl 2-oxo-4-phenylbutyrate (OPBE). A majority of reductases produced the ethyl (R)-2-hydroxy-4-phenylbutyrate ((R)-HPBE) with low to excellent enantiomeric excess (e.e.), whereas about 30% reductases catalyzed OPBE to form (S)-HPBE. Among them, the carbonyl reductase from Saccharomyces cerevisiae (SeCR) and short-chain dehydrogenase from Gluconobacter oxydans (GoKR) exhibited 100% e.e., yielding the corresponding (R) and (S)-HPBE, respectively. However, the SeCR showed relative higher activity (29.0U/mg) and affinity (Km of 0.22mM) than those of GoKR. Docking analysis found that the interaction of OPBE with enzyme-NADPH complex determined the NADPH-provided hydrogen transfer and the configuration of reductive product. These results indicated that the three-dimensional (3D) structure of enzymes controlled the stereoselectivity of the reductive product based on the geometry of the substrate and cofactor.

Stereoselective Peterson olefinations from bench-stable reagents and N-phenyl imines.

The synthesis of bench-stable α,α-bis(trimethylsilyl)toluenes and tris(trimethylsilyl)methane is described and their use in stereoselective Peterson olefinations has been achieved with a wide substrate scope. Product stereoselectivity was poor with carbonyl electrophiles (E/Z ∼1:1 to 4:1) though this was significantly improved by employing the corresponding substituted N-benzylideneaniline (up to 99:1) as an alternative electrophile. The olefination byproduct was identified as N,N-bis(trimethylsilyl)aniline and could be easily separated from product by aqueous acid extraction. Evidence for an autocatalytic cycle has been obtained.

Structural insights into stereospecific reduction of α, β-unsaturated carbonyl substrates by old yellow enzyme from Gluconobacter oxydans.

We report the crystal structure of old yellow enzyme (OYE) family protein Gox0502 (a.a 1-315) in free form at 3.3 Å. Detailed structural analysis revealed the key residues involved in stereospecific determination of Gox0502, such as Trp66 and Trp100. Structure-based computational analysis suggested the bulky side chains of these tryptophan residues may play important roles in product stereoselectivity. The introduction of Ile or Phe or Tyr mutation significantly reduced the product diastereoselectivity. We hypothesized that less bulky side chains at these critical residues could create additional free space to accommodate intermediates with different conformations. Notably, the introduction of Phe mutation at residue Trp100 increased catalytic activity compared to wild-type Gox0502 toward a set of substrates tested, which suggests that a less bulky Phe side chain at residue W100F may facilitate product release. Therefore, Gox0502 structure could provide useful information to generate desirable OYEs suitable for biotechnological applications in industry.

ChemInform Abstract: Highly Stereoselective anti‐Markovnikov Hydrothiolation of Alkynes and Electron‐Deficient Alkenes by a Supported Cu‐NHC Complex.

AbstractThe recyclable and efficient heterogeneous catalyst tolerates a broad substrate scope and exhibits higher activity and product stereoselectivity to Z‐vinyl sulfides than its homogeneous analog.

ChemInform Abstract: Base‐Catalyzed Stereoselective Intermolecular Addition of Imidazoles onto Alkynes: An Easy Access to Imidazolyl Enamines.

Abstract An efficient transition metal-free approach for the regio- and stereoselective addition of imidazoles 1a – f onto alkynes 2a – l to provide the Z - and E isomers of imidazolyl enamines 3a – q and 4a – d using catalytic amount of KOH is described. Stereoselectivity of the addition products ( Z and E isomer) was found to be dependent upon time. Competitive experiments show that imidazole is less reactive than pyrrole and more reactive than aniline towards hydroamination.

Base-catalyzed stereoselective intermolecular addition of imidazoles onto alkynes: an easy access to imidazolyl enamines

An efficient transition metal-free approach for the regio- and stereoselective addition of imidazoles 1a–f onto alkynes 2a–l to provide the Z- and E isomers of imidazolyl enamines 3a–q and 4a–d using catalytic amount of KOH is described. Stereoselectivity of the addition products (Z and E isomer) was found to be dependent upon time. Competitive experiments show that imidazole is less reactive than pyrrole and more reactive than aniline towards hydroamination.

Enhancement of (stereo)selectivity in dynamic kinetic resolution using a core-shell nanozeolite@enzyme as a bi-functional catalyst.

A core-shell nanozeolite@enzyme bi-functional catalyst is constructed, which greatly improves selectivity and stereoselectivity of products in dynamic kinetic resolution of aromatic secondary alcohols compared with mixed catalysts, especially those involving small acyl donors.

DFT study on the organocatalytic carbonyl–olefin metathesis

Organocatalytic carbonyl–olefin metathesis has been given a systematic theoretical study with density functional theory (DFT) method. The catalytic cycle includes three key steps: (a) (3+2) cycloaddition of (E/Z)-hydrazonium ion I (from the reaction of aldehyde with the hydrazine catalyst) with olefin to produce pyrazolidinium ion II; (b) proton transfer between two nitrogen atoms in II to give pyrazolidinium ion III; (c) cycloreversion of III to produce hydrazonium ion IV, whose hydrolysis leads to the metathesis product. It is found that the stereo-selectivity of product is determined by the first step. The catalyst with high steric effect can effectively improve the stereo-selectivity. The second step, namely the proton transfer, is the rate-determining step in the whole catalytic cycle. Water molecule can effectively facilitate this step. In the third step, olefins with high strain, such as cyclopropene substrate, favor the cycloreversion.

ChemInform Abstract: Organic Stereochemistry. Part 8. Prostereoisomerism and the Concept of Product Stereoselectivity in Biochemistry and Xenobiotic Metabolism

AbstractReview: 114 refs.

Organic Stereochemistry. Part 8

AbstractThis review terminates our general presentation of the principles of stereochemistry with special reference to the biomedicinal sciences. Here, we discuss and illustrate the principles of prostereoisomerism, and apply these to product and substrateproduct stereoselectivity in drug metabolism. The review begins with an overview of the concept of prostereoisomerism, discussing such aspects as homotopic, enantiotopic, and diastereotopic groups and faces. The main part of this review is dedicated to drug and xenobiotic metabolism. Here, the concept of prostereoisomerism proves particularly helpful to avoid confusing metabolic reactions in which an existing stereogenic element (e.g., a stereogenic center) influences the course of the reaction (substrate stereoselectivity), with metabolic reactions which create a stereogenic element (almost always a stereogenic center; product stereoselectivity). Specifically, examples of product stereoselectivity will be taken from functionalization reactions (so‐called phase‐I reactions) and conjugation (so‐called phase‐II reactions). Cases where stereoisomeric substrates show distinct product stereoselectivities (substrateproduct stereoselectivity) will also be presented.