Product Stereoselectivity Research Articles

Catalytic Orthogonal Glycosylation Enabled by Enynal‐Derived Copper Carbenes

AbstractHerein, we present an approach for catalytic orthogonal glycosylation utilizing earth‐abundant copper carbenes. This method operates under mild conditions and employs readily accessible starting materials, including benchtop stable enynal‐derived glycosyl donors, synthesized at the gram scale. The reaction accommodates a variety of glycosyl acceptors, including primary, secondary, and tertiary alcohols. The enynal‐derived copper carbenes exhibit remarkable reactivity and selectivity, allowing for the formation of glycosidic linkages with different protecting groups and stereochemical patterns. This approach provides access to both 1,2‐cis‐ and ‐trans‐glycosidic linkages. The product stereoselectivity is independent of the anomeric configuration of the glycosyl donor, which also has orthogonal reactivity to widely used alkynes and thioglycoside donors. An iterative synthesis of a trisaccharide further demonstrates the application of this orthogonal reactivity.

DFT study on the Stereoselectivity of Asymmetric Synthesis of C, N‐Cyclic Azomethine Imines with Allyl Alkyl Ketones

AbstractBased on the density functional theory, the stereoselectivity of the asymmetric synthesis of tetrahydroisoquinolinopyrazole derivatives by the cycloaddition reaction of C, N‐cyclic azomethine imines with allyl alkyl ketones which was catalyzed using a chiral primary amine is studied theoretically. The results demonstrate that the four chiral transition states (TS‐1R2R, TS‐1R2S, TS‐1S2R and TS‐1S2S) are formed by the reaction of dienamine intermediate with C, N‐cyclic azomethine imine, and the reaction barrier of TS‐1R2S is in the lowest level (ΔG=6.98 kcal/mol). The consequence reveal that the 1R2S configuration product is formed by TS‐1R2S transition state. Non‐covalent interaction and electron density topology analysis show that the stereoselectivity of the chiral product is determined through van der Waals forces and hydrogen bond interaction of the transition state molecules.

Curcubit[8]uril-modulated asymmetric electroreductive hydrodimerization of coumarins with supramolecular encapsulation

The development of electrocatalytic methods for stereoselective reductive functionalization remains a challenge in organic synthesis. Herein, a novel strategy of supramolecule-modulated electrocatalytic stereoselectivity within the macrocyclic cavity is developed using a hybrid electrode prepared from the layer-by-layer assembly of Cu nanoparticles (CuNPs) and curcubit[8]uril (Q[8]). The hydrodimers with good yields of 71%-83% and superior stereoselectivity of up to 96% were afforded. The results of theoretical calculation and control experiments demonstrate that the hydrophobic cavity of Q[8] provides a microenvironment to accommodate two coumarin molecules via host–guest interactions. Q[8] plays a crucial role in modulating product stereoselectivity by controlling the assembly direction of coumarin toward “Head to Head” mode. The designed CuNPs-Q[8] electrode is remarkably stable, which can be reused five times at least without obvious loss of electrocatalytic activity.

Double-boron heterocyclic carbenes: a computational study of Diels-Alder reactions.

An aromatic boron-containing organic compound, C2B2H2, with an unusual CC bond was experimentally synthesized in 2017. Here we investigate the structure and bonding nature of C2B2H2 and its derivatives C2B2R2 using DFT and VB theory. Although the CC bond in C2B2R2 consists of a π bond and a charge-shift (CS) bond, C2B2F2 has the lowest LUMO energy and its LUMO is similar to that of ethylene, suggesting that C2B2F2 can be an ideal dienophile for the Diels-Alder reaction. Subsequently, the mechanism and stereoselectivity of the Diels-Alder reaction of C2B2F2 with 5-substituted cyclopentadienes are studied. Computations demonstrate that these Diels-Alder reactions are feasible thermodynamically and kinetically. The stereoselectivity and distortion angles of C2B2R2 exhibit linear correlations with the electronegativity difference between the two substituents bonded to the C(sp3) of cyclopentadiene, suggesting that the stereoselectivity of related Diels-Alder reaction products can be modulated by the substitution of cyclopentadiene. Considering the current interest in boron neutron capture therapy (BNCT), we design six BNCT drugs through the Diels-Alder reaction of C2B2F2 with dienes containing peptide fragments. Thus, we demonstrate a new method for designing three-in-one BNCT drugs via the facile Diels-Alder reaction.

Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry

AbstractMacrocyclic peptides have become increasingly important in the pharmaceutical industry. We present a detailed computational investigation of the reaction mechanism of the recently developed “CyClick” chemistry to selectively form imidazolidinone cyclic peptides from linear peptide aldehydes, without using catalysts or directing groups (Angew. Chem. Int. Ed. 2019, 58, 19073–19080). We conducted computational mechanistic to investigate the effects of intramolecular hydrogen bonds (IMHBs) in promoting a kinetically facile zwitterionic mechanism in “CyClick” of pentapeptide aldehyde AFGPA. Our DFT calculations highlighted the importance of IMHB in pre‐organization of the resting state, stabilization of the zwitterion intermediate, and the control of the product stereoselectivity. Furthermore, we have also identified that the low ring strain energy promotes the “CyClick” of hexapeptide aldehyde AAGPFA to form a thermodynamically more stable 15+5 imidazolidinone cyclic peptide product. In contrast, large ring strain energy suppresses “CyClick” reactivity of tetra peptide aldehyde AFPA from forming the 9+5 imidazolidinone cyclic peptide product.

Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry.

Macrocyclic peptides have become increasingly important in the pharmaceutical industry. We present a detailed computational investigation of the reaction mechanism of the recently developed "CyClick" chemistry to selectively form imidazolidinone cyclic peptides from linear peptide aldehydes, without using catalysts or directing groups (Angew. Chem. Int. Ed. 2019, 58, 19073-19080). We conducted computational mechanistic to investigate the effects of intramolecular hydrogen bonds (IMHBs) in promoting a kinetically facile zwitterionic mechanism in "CyClick" of pentapeptide aldehyde AFGPA. Our DFT calculations highlighted the importance of IMHB in pre-organization of the resting state, stabilization of the zwitterion intermediate, and the control of the product stereoselectivity. Furthermore, we have also identified that the low ring strain energy promotes the "CyClick" of hexapeptide aldehyde AAGPFA to form a thermodynamically more stable 15+5 imidazolidinone cyclic peptide product. In contrast, large ring strain energy suppresses "CyClick" reactivity of tetra peptide aldehyde AFPA from forming the 9+5 imidazolidinone cyclic peptide product.

Recent Advances of N-2,2,2-Trifluoroethylisatin Ketimines in Organic Synthesis

The special properties of fluorine atoms and fluorine-containing groups have led to an increasing number of applications for fluorine-containing organic compounds, which are also extremely widely used in the field of new drug development. Unfortunately, naturally fluorinated organics are rare in nature, so the selective introduction of fluorine atoms or fluorine-containing groups into organic molecules is very important for pharmaceutical/synthetic chemists. N-2,2,2-trifluoroethylisatin ketimines have received the attention of many chemists since they were first developed as fluorine-containing synthons in 2015. This paper reviews the organic synthesis reactions in which trifluoroethyl isatin ketimine has been involved in recent years, focusing on the types of reactions and the stereoselectivity of products, and also provides a prospect of its application in this field.

Visible light-catalyzed intermolecular [2+2] cycloaddition of 1,2-dihydropyridines: A combined experimental and DFT study

In this article, the intermolecular [2+2] cycloaddition of 1,2-dihydropyridines was achieved for the first time by visible light-catalyzed. A series of novel and complex cyclobutane derivatives, the dimers of diethyl 1,2-diaryl-1,2-dihydropyridine-3,5-dicarboxylate, were synthesized efficiently with visible light catalysts under the irradiation of blue LED lamps. The density functional theory and time-dependent density functional theory were used to elucidate the detailed reaction processes, such as the reaction mechanism and the stereoselectivity of cycloaddition products.

T211K substitution in Pseudomonas putida phenylserine aldolase improves catalytic efficiency towards l-threo-4-nitrophenylserine with reversed stereoselectivity

Phenylserine aldolase from Pseudomonas putida (PSALD) catalyzes the conversion of glycine and 4-nitrobenzaldehyde to 4-nitrophenylserine with unsatisfactory enantioselectivity at the Cβ position. In this report, mutations adjacent to the substrate-binding pocket of PSALD were introduced using site-directed mutagenesis to improve product stereoselectivity. The activity of the variants towards native substrates l-threonine and l-allo-threonine decreased by 2- to 10-fold in the retro-aldol reaction when compared with that of wild-type (WT) PASLD. In particular, the T211K mutant biosynthesizes l-erythro-4-nitrophenylserine from glycine and 4-nitrobenzaldehyde as substrates with improved catalytic efficiency and reversed product stereoselectivity. This mutant synthesized l-erythro-4-nitrophenylserine with diastereoselectivity (de) of 84% and a conversion of 57%, whereas WT PSALD yielded a de of 5% and a conversion of 14%. In order to study the binding force between proteins and ligands, thermodynamic parameters were calculated by fluorescence spectroscopy. The determined thermodynamic parameters (ΔH = −76.52 kJ·mol–1, ΔS = −0.16 kJ·mol–1·K–1 and ΔG = −28.48 kJ·mol–1) indicate that the T211K mutation alters hydrogen bonds between PSALD and 4-nitrophenylserine. Molecular dynamics simulations elucidated the formation of a hydrogen bond between the amino group of T211K and the nitro group of 4-nitrophenylserine, which enhances the interaction between the mutant and product. This agent modifies the stereo-preference of threonine aldolases for the preparation of desired chiral β-hydroxy-α-amino acids by protein engineering.

Functional Characterization and Structural Insights Into Stereoselectivity of Pulegone Reductase in Menthol Biosynthesis.

Monoterpenoids are the main components of plant essential oils and the active components of some traditional Chinese medicinal herbs like Mentha haplocalyx Briq., Nepeta tenuifolia Briq., Perilla frutescens (L.) Britt and Pogostemin cablin (Blanco) Benth. Pulegone reductase is the key enzyme in the biosynthesis of menthol and is required for the stereoselective reduction of the Δ2,8 double bond of pulegone to produce the major intermediate menthone, thus determining the stereochemistry of menthol. However, the structural basis and mechanism underlying the stereoselectivity of pulegone reductase remain poorly understood. In this study, we characterized a novel (−)-pulegone reductase from Nepeta tenuifolia (NtPR), which can catalyze (−)-pulegone to (+)-menthone and (−)-isomenthone through our RNA-seq, bioinformatic analysis in combination with in vitro enzyme activity assay, and determined the structure of (+)-pulegone reductase from M. piperita (MpPR) by using X-ray crystallography, molecular modeling and docking, site-directed mutagenesis, molecular dynamics simulations, and biochemical analysis. We identified and validated the critical residues in the crystal structure of MpPR involved in the binding of the substrate pulegone. We also further identified that residues Leu56, Val282, and Val284 determine the stereoselectivity of the substrate pulegone, and mainly contributes to the product stereoselectivity. This work not only provides a starting point for the understanding of stereoselectivity of pulegone reductases, but also offers a basis for the engineering of menthone/menthol biosynthetic enzymes to achieve high-titer, industrial-scale production of enantiomerically pure products.

Pairwise Stereoselective Hydrogenation of Propyne on Supported Pd–Ag Catalysts Investigated by Parahydrogen-Induced Polarization

Alkyne semihydrogenation offers a key approach for the synthesis of stereodefined molecules. The stereoselective hydrogenation of propyne to propene over Al2O3-supported Pd–Ag bimetallic catalysts is studied by using parahydrogen-induced polarization (PHIP) NMR technique. The supported catalysts were prepared by an incipient-wetness impregnation method, and their properties were systemically tuned by altering Pd and Ag components. Structural characterization by X-ray diffraction, infrared spectra, and transmission electron microscope shows the formation of highly dispersed bimetallic Pd–Ag nanoparticles with random alloy structures on Al2O3 support. For the hydrogenation of propyne over Pd–Ag catalysts with higher Ag concentration, the adsorbed protons are mostly restricted on the active Pd ensembles, which favors a higher pairwise hydrogen addition to propyne, leading to a stronger PHIP effect. The product stereoselectivity measurements show that the pairwise syn-addition to propyne increases with Ag content in the Pd–Ag alloy. The reaction conditions impact the pairwise hydrogenation stereoselectivity. A lower H2/propyne ratio of reactant flow or a higher total reactant flow rate enhances the apparent pairwise syn-addition stereoselectivity, which can be accounted for by the suppressed cis–trans isomerization process and/or a higher intrinsic pairwise syn-addition selectivity.

Flyby reaction trajectories: Chemical dynamics under extrinsic force.

Dynamic effects are an important determinant of chemical reactivity and selectivity, but the deliberate manipulation of atomic motions during a chemical transformation is not straightforward. Here, we demonstrate that extrinsic force exerted upon cyclobutanes by stretching pendant polymer chains influences product selectivity through force-imparted nonstatistical dynamic effects on the stepwise ring-opening reaction. The high product stereoselectivity is quantified by carbon-13 labeling and shown to depend on external force, reactant stereochemistry, and intermediate stability. Computational modeling and simulations show that, besides altering energy barriers, the mechanical force activates reactive intramolecular motions nonstatistically, setting up "flyby trajectories" that advance directly to product without isomerization excursions. A mechanistic model incorporating nonstatistical dynamic effects accounts for isomer-dependent mechanochemical stereoselectivity.

Organo-Cobalt Complexes in Reversible-Deactivation Radical Polymerization.

Cobalt complexes have played an essential role in different chemical reactions. One of them that has attracted substantial attention in polymer science is cobalt mediated radical polymerization (CMRP), which is famous for its remarkable efficiency in controlling the radical polymerization of vinyl acetate (VAc) and other less active monomers (LAMs). Two pathways, reversible termination (RT) and degenerative transfer (DT), were recognized to control the polymerization in CMRP and could be further used to rationalize the mechanism of other RDRP methods. These control mechanisms were then found to be correlated to the redox potential of cobalt complexes and thus could be judged more quantitatively. The control of polymer composition and tacticity could also be achieved by using CMRP. The hybridization of CMRP and atom transfer radical polymerization (ATRP) could directly synthesize the vinyl acetate/methyl methacrylate and vinyl acetate/styrene block copolymers in one pot. The copolymer of acrylates and 1-octene could be obtained by visible-light-induced CMRP. With the addition of bulky Lewis acid, CMRP of N,N-dimethylacrylamide (DMA) showed high isotacticities with the contents of meso dyads (m) and meso triads (mm) up to 94 % and 87 %, respectively, and generated the crystalline PDMA with Tm as high as 276 °C. This personal account reviewed the development of CMRP with the mechanistic understanding, the control of composition and stereoselectivity of the polymeric products, and its perspective.

Some like it weak: different activity of Raney® nickel in transfer hydrogenation under air and inert atmosphere

Transfer hydrogenation (TH) of six substrates catalyzed by Raney® nickel and conducted at 150 °C for 5 h under air or argon was studied. Significant decrease of conversion was observed under air as compared with TH under argon: 57% vs. 98% for menthone and 39% vs. 54% for camphor, respectively. Regardless of different reaction atmosphere used, aluminum segregated on the catalyst surface to form micron-sized alumina crystallites to modify the adsorption capacity, to inhibit the catalyst activity and to change the products selectivity of TH. Moreover, the changes of the catalyst structure under air entailed the change of reaction rates of both hydrodeoxygenation and dearomatization of acylbenzenes (ketones), as well as benzylic alcohols. Thus, manipulating by reaction atmosphere of TH catalyzed by Raney® nickel can be considered as an efficient tool to govern a chemo-, regio- and stereo-selectivity of products.

Ring Expansion and 1,2-Migration Cascade of Benzisoxazoles with Ynamides: Experimental and Theoretical Studies.

Demonstrated herein is an AuI -catalyzed annulation of sulfonyl-protected ynamides with substituted 1,2-benzisoxazoles for the synthesis of E-benzo[e][1,3]oxazine derivatives. The transformation involves the addition of benzisoxazole to the gold-activated ynamide, ring expansion of the benzisoxazole fragment to provide an α-imino vinylic gold intermediate, and 1,2-migration of the sulfonamide motif to the masked carbene center to deliver the respective ring-expanded benzo[e][1,3]oxazine of predominant E configuration. A trapping experiment justifies the participation of the α-imino masked gold carbene. DFT computations also support the hypothesized mechanism and rationalize the product stereoselectivity.

DNA G-Quadruplexes Activate Heme for Robust Catalysis of Carbene Transfer Reactions.

Guanine-rich single-stranded DNAs and RNAs that fold into G-quadruplexes (GQs) are known to complex tightly with FeII-heme and FeIII-heme (hemin), ubiquitous cellular cofactors. Heme–GQ (DNA) complexes, known as heme·DNAzymes, are able to utilize hydrogen peroxide as an oxidant to vigorously catalyze a variety of one-electron (peroxidase) and two-electron (peroxygenase) oxidation reactions. Herein, we show that complexes of FeII-heme with GQs also robustly catalyze a mechanistically distinct reaction, carbene transfer to an alkene substrate. Significant enhancements were seen in both reaction kinetics and product turnover (∼180) relative to disaggregated FeII-heme in the absence of DNA or in the presence of other DNA folds, such as single-stranded or double-stranded DNA. Heme binds to GQs by end-stacking. Simple, intramolecularly folded GQs are unable to provide a complexly structured “distal side” environment to the bound heme; therefore, such DNAzymes do not display significant product stereoselectivity. However, intermolecular GQs with multiple pendant nucleotides show increasing stereoselectivity in addition to their enhanced catalytic rates. These results recapitulate the unique functional synergy and highlight the surprising catalytic versatility of complexes formed between heme and DNA/RNA GQs. Our findings suggest that heme·DNAzymes and heme·ribozymes may prove to be useful reagents for carbon–carbon bond forming “green” reactions carried out in vitro and likely within living cells.

Catalytic performance of bulk and colloidal Co/Al layered double hydroxide with Au nanoparticles in aerobic olefin oxidation

A Co/Al layered double hydroxide material was synthesized in both bulk and exfoliated (colloidal) forms. Anion exchange with methionine allowed immobilization of Au nanoparticles previously prepared by a biomimetic method using an anti-oxidant tea aqueous extract to reduce the Au salt solution. The catalytic performance of bulk and exfoliated clays Au-hybrid materials was assessed in aerobic olefin epoxidation. Both catalysts were very active towards the epoxide products and with very interesting substrate conversion levels after 80 h reaction time. The Au-exfoliated material, where the nanosheets work as large ligands, yielded higher product stereoselectivity in the case of limonene epoxidation. This arises from a confined environment around the Au nanoparticles wrapped by the clay nanosheets modulating access to the catalytic active centres by reagents. Mechanistic assessment was also accomplished for styrene oxidation by DFT methods.

Diterpene Synthase-Catalyzed Biosynthesis of Distinct Clerodane Stereoisomers.

The diterpene synthase clerodienyl diphosphate synthase 1 (PvCPS1) from the crop plant switchgrass (Panicum virgatum) stereoselectively converts (E,E,E)-geranylgeranyl diphosphate (GGPP) into the clerodane natural product, cis-trans-clerodienyl diphosphate (CLPP, 1). Structure-guided point mutations of PvCPS1 redirected product stereoselectivity toward the formation of a rare cis-clerodane diastereomer, cis-cis-CLPP (2). Additionally, an alternative cis-clerodane diastereomer, (5S,8S,9R,10R)-13Z-CLPP (3), was produced when treating PvCPS1 and select variants thereof with the cis-prenyl substrate (Z,Z,Z)-nerylneryl diphosphate (NNPP). These results support the hypothesis that substrate configuration and minor active-site alterations impact precatalysis substrate folding in the stereoselective biosynthesis of clerodane diterpenoid scaffolds, and can be employed to provide enzymatic access to a broader range of bioactive clerodane natural products.

Influence of Stereochemistry on the Bioactivation and Glucuronidation of 4-Ipomeanol.

A potential CYP4B1 suicide gene application in engineered T-cell treatment of blood cancers has revived interest in the use of 4-ipomeanol (IPO) in gene-directed enzyme prodrug therapy, in which disposition of the administered compound may be critical. IPO contains one chiral center at the carbon bearing a secondary alcohol group; it was of interest to determine the effect of stereochemistry on 1) CYP4B1-mediated bioactivation and 2) (UGT)-mediated glucuronidation. First, (R)-IPO and (S)-IPO were synthesized and used to assess cytotoxicity in HepG2 cells expressing rabbit CYP4B1 and re-engineered human CYP4B1, where the enantiomers were found to be equipotent. Next, a sensitive UPLC-MS/MS assay was developed to measure the IPO-glucuronide diastereomers and product stereoselectivity in human tissue microsomes. Human liver and kidney microsomes generated (R)- and (S)-IPO-glucuronide diastereomers in ratios of 57:43 and 79:21, respectively. In a panel of 13 recombinantly expressed UGTs, UGT1A9 and UGT2B7 were the major isoforms responsible for IPO glucuronidation. (R)-IPO-glucuronide diastereoselectivity was apparent with each recombinant UGT, except UGT2B15 and UGT2B17, which favored the formation of (S)-IPO-glucuronide. Incubations with IPO and the UGT1A9-specific chemical inhibitor niflumic acid significantly decreased glucuronidation in human kidney, but only marginally in human liver microsomes, consistent with known tissue expression patterns of UGTs. We conclude that IPO glucuronidation in human kidney is mediated by UGT1A9 and UGT2B7. In human liver, it is mediated primarily by UGT2B7 and, to a lesser extent, UGT1A9 and UGT2B15. Overall, the lack of pronounced stereoselectivity for IPO's bioactivation in CYP4B1-transfected HepG2 cells, or for hepatic glucuronidation, suggests the racemate is an appropriate choice for use in suicide gene therapies.

Stereoconvergent 1,4-Addition Reaction of 5H-Oxazol-4-ones with E,Z Isomeric Mixture of Alkylidene β-Ketoesters Catalyzed by Chiral Guanidines.

A 1,4-addition reaction of 5H-oxazol-4-ones to alkylidene β-ketoesters, which was catalyzed by using chiral guanidines via a dynamic kinetic resolution process that involved geometric isomerization of the alkylidene β-ketoesters, was developed. This method allowed using E,Z isomeric mixture of various acyclic alkylidene β-ketoesters to obtain the products stereoselectively. The relation between the geometry and the stereoselectivity of products was investigated, and the derivatization of the products to the corresponding α-acyl-γ-lactone was performed.