High Stereoselectivity Research Articles

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.

Proline-Functionalized Magnetic Nanoparticles as Highly Performing Asymmetric Catalysts.

Amino acids have a crucial role in the field of asymmetric organocatalysis for the production of chiral compounds with high added value and specific biological activity. In particular, proline offers high activity and stereoselectivity for catalyzing aldol reactions in organic solvents. However, proline-based catalysts often lack water-solubility, accessibility, catalytic performance, or recovery in aqueous media. This work reports the design of proline-functionalized poly(methyl methacrylate) (PMMA) nanoparticles with a magnetic core that offer high availability of chiral units in water and high recyclability. A proline-based copolymerizable surfactant is designed and integrated onto the surface of PMMA nanoparticles through a miniemulsion polymerization process without using additional surfactants. The miniemulsion technique allows the incorporation of magnetite to the system to create a magnetically separable catalyst. The chiral nanocatalyst presents a high diastereoselective catalytic activity for the intermolecular aldol reaction between p-nitrobenzaldehyde and cyclohexanone in water.

Stereoselective Synthesis of Oxetanes Catalyzed by an Engineered Halohydrin Dehalogenase.

Although biocatalysis has garnered widespread attention in both industrial and academic realms, the enzymatic synthesis of chiral oxetanes remains an underdeveloped field. Halohydrin dehalogenases (HHDHs) are industrially relevant enzymes that have been engineered to accomplish the reversible transformation of epoxides. In our work, a biocatalytic platform was constructed for the stereoselective kinetic resolution of chiral oxetanes and formation of 1,3-disubstituted alcohols. HheC from Agrobacterium radiobacter AD1 was engineered to identify key variants capable of catalyzing the dehalogenation of γ-haloalcohols (via HheC M1-M3) and ring opening of oxetanes (via HheC M4-M5) to access both (R)- and (S)-configured products with high stereoselectivity and remarkable catalytic activity, yielding up to 49% with enantioselectivities exceeding 99% ee and E>200. The current strategy is broadly applicable as demonstrated by expansion of substrate scope to include up to 18 examples for dehalogenations and 16 examples for ring opening. Additionally, the functionalized products are versatile building blocks for pharmaceutical applications. To shed light on the molecular recognition mechanisms for the relevant variants, molecular dynamic (MD) simulations were performed. The current strategy expands the scope of HHDH-catalyzed chiral oxetane ring constructions, offering efficient access to both enantiomers of chiral oxetanes and 1,3-disubstituted alcohols.

Stereoselective Synthesis of Oxetanes Catalyzed by an Engineered Halohydrin Dehalogenase

Although biocatalysis has garnered widespread attention in both industrial and academic realms, the enzymatic synthesis of chiral oxetanes remains an underdeveloped field. Halohydrin dehalogenases (HHDHs) are industrially relevant enzymes that have been engineered to accomplish the reversible transformation of epoxides. In our work, a biocatalytic platform was constructed for the stereoselective kinetic resolution of chiral oxetanes and formation of 1,3‐disubstituted alcohols. HheC from Agrobacterium radiobacter AD1 was engineered to identify key variants capable of catalyzing the dehalogenation of γ‐haloalcohols (via HheC M1‐M3) and ring opening of oxetanes (via HheC M4‐M5) to access both (R)‐ and (S)‐configured products with high stereoselectivity and remarkable catalytic activity, yielding up to 49% with enantioselectivities exceeding 99% ee and E>200. The current strategy is broadly applicable as demonstrated by expansion of substrate scope to include up to 18 examples for dehalogenations and 16 examples for ring opening. Additionally, the functionalized products are versatile building blocks for pharmaceutical applications. To shed light on the molecular recognition mechanisms for the relevant variants, molecular dynamic (MD) simulations were performed. The current strategy expands the scope of HHDH‐catalyzed chiral oxetane ring constructions, offering efficient access to both enantiomers of chiral oxetanes and 1,3‐disubstituted alcohols.

Remote C─H Bond Activation via Enantioselective Carbopalladation and 1,4-Pd Migration Cascade Process.

Carbopalladation-initiated cascade reaction involving 1,4-Pd migration is a straightforward and powerful approach to activate remote C─H bond, forging versatile fused polycyclic compounds containing fluorene fragment which are highly valuable synthetic targets. However, its asymmetric variants pose considerable challenges and have not been explored. Here the first asymmetric palladium-catalyzed tandem carbopalladation is reported, 1,4-Pd migration reaction of ortho-iodophenol-derived allyl ether under mild conditions, allowing the transformation of a wide range of substrates in good to excellent enantioselectivities, and providing a facile and straight forward access to tetracyclic dihydroindeno[1,2,3-de]chromene bearing a chiral fluorene skeleton. A good functional group tolerance, high stereoselectivity, as well as the good chiroptical properties (high fluorescence quantum yields, circular dichroism) of the products make this approach highly attractive. Moreover, density functional theory (DFT) calculations indicate that the protonation of five-membered palladacycle intermediate is more favorable rather than its direct reductive elimination process.

Rh‐catalyzed Hydroamination of Allenes: Asymmetric N‐Allylation of Amino Acids and Peptides

AbstractIn the growing field of peptidomimetics, there is a constant need for new synthetic methods to generate new bioactive compounds. Herein, we present an atom‐economic approach for the branched‐selective allylation of aliphatic amine moieties of α‐amino acids and small oligopeptides. This Rh‐catalyzed hydroamination of allenes with a commercially available ligand forms a new stereocenter, often chemoselectively, in a catalyst‐controlled manner, providing high yields and stereoselectivities without the need for an additive. The method is shown to be effective in gram scale without the need for column chromatography for purification, and ready‐to‐use allylated substrates for solid‐phase peptide synthesis can be synthesized in two steps from the products of the catalysis.

Enantioselective SN1-type reaction via electrochemically generated chiral α-Imino carbocation intermediate

Electrochemical reactions via carbocation intermediates remain fundamental transformations that build up molecular functionality and complexity in a sustainable manner. Enantioselective control of such processes is a great challenge in a highly ionic electrolyte solution. Here, we report an anodic generation of chiral α-imino carbocation intermediates by enamine catalysis. The chiral carbocation intermediates can be intercepted by a variety of nucleophiles such as alcohols, water and thiols with high stereoselectivity. The key SN1 step proceeds via a tertiary amine-mediated proton shuttle that facilitates facial selection in reacting with carbocation.

Cobalt-Catalyzed Chemo- and Stereoselective Transfer Semihydrogenation of 1,3-Dienes with Water as a Hydrogen Source.

(Z)-1,2-Disubstituted, trisubstituted, and tetrasubstituted alkenes are not only important units in medicinal chemistry, natural product synthesis, and material science but also useful intermediates in organic synthesis. Development of catalytic stereoselective transformations to access multisubstituted alkenes with various substitution patterns from easily accessible modular starting materials and readily available catalysts is a crucial goal in the field of catalysis. Water is an ideal hydrogen source for catalytic transfer hydrogenation despite of the high difficulty to activate water. Here, we report a cobalt-catalyzed protocol for regio- and stereoselective transfer semihydrogenation of 1,3-dienes to construct a broad scope of (Z)-1,2-disubstituted, (Z)-, (E)-trisubstituted, and tetrasubstituted alkenes in high stereoselectivity with H2O as the hydrogen source. Mechanistic studies revealed that the reactions proceeded through a unique Co(I)/Co(III) cycle and involved a 1,4-cobalt shift process, which is an unprecedented reaction pathway, providing a new platform for modular synthesis of multisubstituted alkenes as well as opportunities for designing novel reaction modes and pushing forward the advancement in organocobalt chemistry.

A Single Enzyme in Enantiocomplementary Synthesis of β-Nitroalcohols: Bidirectional Catalysis by Hydroxynitrile Lyase.

A single enzyme, Baliospermum montanum hydroxynitrile lyase (BmHNL), without alteration, enabled bidirectional catalysis in enantiocomplementary synthesis of chiral β-nitroalcohols. BmHNL catalyzed promiscuous Henry (24 examples) and retro-Henry reaction (22 examples) provided up to >99% and 50% conversion to (S)- and (R)-β-nitroalcohols respectively, while both cases displayed up to >99% ee. The broad substrate scope and high stereoselectivity of BmHNL represents its synthetic applications in sustainable production of diverse chiral β-nitroalcohols. Kinetic parameters of BmHNL was determined for Henry and retro-Henry reaction, which reveals poor catalytic efficiency for both the promiscuous transformations, however, the former has better efficiency than the latter. Practical applicability of the biocatalyst and transformation was illustrated by preparative scale synthesis of chiral intermediates of (S)-Tembamide, and (S)-Micanozole.

Rh-Catalyzed Carbonylative Cyclization of Propargylic Alcohols with Aryl Boronic Acids.

2(3H)-Furanones are tremendously important not only because of their wide occurrence in bioactive compounds but also due to their versatility in organic synthesis. Here, a straightforward approach to 2(3H)-furanones from readily available tertiary propargylic alcohols with arylboronic acids in the presence of CO using rhodium as a catalyst has been established. The method exhibits a broad substrate scope tolerating useful functional groups with a moderate to high stereoselectivity.

Light-promoted stereoselective late-stage difunctionalization and anti-tumor activity of oridonin

The late-stage difunctionalization of diterpene oridonin by light-promoted direct oxyamination with various O-benzoylhydroxylamines was carried out to afford C16α-N-C17-OBz-oridonin derivatives (1–25) for the first time. Though as a radical reaction, it features high stereoselectivity to only produce C16α-N-C17-OBz-oridonins. The in vitro antiproliferative activity of these C16α-N-C17-OBz-oridonins against the human breast cancer cell lines (MCF-7) was evaluated by MTT assay, showing that most of the synthesized compounds possessed moderate anticancer activity against MCF-7 cell lines superior or similar to the parent compound oridonin. The derivative 25 with a N-methyl-N-(naphthalen-1-ylmethyl) substitution showed better cytotoxicity against MCF-7 cells (IC50 value of 11.75 μM) than oridonin (IC50 value of 17.95 μM).

Gold(I)−Catalyzed Synthesis of Cyclic Sulfamides via an Intramolecular Dehydrative Amination of Allylic Alcohols: A Strategy for 1,3‐Diamine Synthesis

AbstractA gold(I)‐catalyzed intramolecular dehydrative amination method has been developed to synthesize diverse cyclic sulfamides efficiently. Reactions proceed smoothly at room temperature using a combination of (IPr)AuCl (5 mol%) and AgBF4 (5 mol%). This method showcases a broad substrate scope, encompassing challenging seven‐membered ring structures, and exhibits functional group compatibility. Moreover, the reaction demonstrates high stereoselectivity, allowing the synthesis of enantiomerically enriched cyclic sulfamides from chiral secondary allylic alcohols. The synthesized cyclic sulfamides serve as valuable intermediates for generating 1,3‐diamines. This approach provides an improved route for cyclic sulfamide synthesis and a strategic entry point for obtaining essential 1,3‐diamine derivatives.

Bio-electrocatalytic Alkene Reduction Using Ene-Reductases with Methyl Viologen as Electron Mediator.

Asymmetric hydrogenation of alkene moieties is important for the synthesis of chiral molecules, but achieving high stereoselectivity remains a challenge. Biocatalysis using ene-reductases (EReds) offers a viable solution. However, the need for NAD(P)H cofactors limits large-scale applications. Here, we explored an electrochemical alternative for recycling flavin-containing EReds using methyl viologen as a mediator. For this, we built a bio-electrocatalytic setup with an H-type glass reactor cell, proton exchange membrane, and carbon cloth electrode. Experimental results confirm the mediator's electrochemical reduction and enzymatic consumption. Optimization showed increased product concentration at longer reaction times with better reproducibility within 4-6 h. We tested two enzymes, Pentaerythritol Tetranitrate Reductase (PETNR) and the Thermostable Old Yellow Enzyme (TOYE), using different alkene substrates. TOYE showed higher productivity for the reduction of 2-cyclohexen-1-one (1.20 mM h-1), 2-methyl-2-cyclohexen-1-one (1.40 mM h-1) and 2-methyl-2-pentanal (0.40 mM h-1), with enantiomeric excesses ranging from 11 % to 99 %. PETNR outperformed TOYE in terms of enantioselectivity for the reduction of 2-methyl-2-pentanal (ee 59 % ± 7 % (S)). Notably, TOYE achieved promising results also in reducing ketoisophorone, a challenging substrate, with similar enantiomeric excess compared to published values using NADH.

Highly Stereoselective Synthesis of 2-Acyl-3-sulfonamidobut-2-enoates Using Solid Calcium Carbide as a Substitute for Gaseous Acetylene.

Multifunctional group compounds, 2-acyl-3-sulfonamidobut-2-enoates, are efficiently constructed using solid calcium carbide as an alkyne source through the simultaneous formation of two bonds in one step. The salient features of this protocol are the use of an inexpensive, abundant, and easy-to-use alkyne source as a substitute for flammable and explosive gaseous acetylene, low-cost catalyst, mild conditions, wide substrate scope, high stereoselectivity, satisfactory yield, and simple manipulation. This method can also be extended to the gram scale.

Modular Synthesis of Tetrasubstituted Vinyl Sulfides via One-Pot Sequential Carbene Transfer Reaction from Thiols with α-Diazo Carbonyl Compounds.

We present a one-pot reaction that offers an efficient approach to synthesizing tetrasubstituted vinyl sulfides with high stereoselectivity. This method involves the sequential Wolff rearrangement, ylide formation, and [1,4]-aryl transfer by utilizing aryl and alkyl thiols and α-diazo carbonyl compounds as substrates. Notably, this reaction features commercially available materials, straightforward operation, atom economy, and broad substrate scope. Moreover, the primary photophysical properties (aggregation-induced emission effect) of the products were also investigated, which might be useful in functional materials via structural modification.

Stereodivergent Synthesis of Pyridyl Cyclopropanes via Enzymatic Activation of Pyridotriazoles.

Hemoproteins have recently emerged as powerful biocatalysts for new-to-nature carbene transfer reactions. Despite this progress, these strategies have remained largely limited to diazo-based carbene precursor reagents. Here, we report the development of a biocatalytic strategy for the stereoselective construction of pyridine-functionalized cyclopropanes via the hemoprotein-mediated activation of pyridotriazoles (PyTz) as stable and readily accessible carbene sources. This method enables the asymmetric cyclopropanation of a variety of olefins, including electron-rich and electrodeficient ones, with high activity, high stereoselectivity, and enantiodivergent selectivity, providing access to mono- and diarylcyclopropanes that incorporate a pyridine moiety and thus two structural motifs of high value in medicinal chemistry. Mechanistic studies reveal a multifaceted role of 7-halogen substitution in the pyridotriazole reagent toward favoring multiple catalytic steps in the transformation. This work provides the first example of asymmetric olefin cyclopropanation with pyridotriazoles, paving the way to the exploitation of these attractive and versatile reagents for enzyme-catalyzed carbene-mediated reactions.

Highly Regio-/Stereoselective Synthesis of Carbohydrates with Unsaturated Glycosyl Donors under Mild Conditions

AbstractCarbohydrates and their conjugates play important roles in life activities and drug development. Our group was committed to the general and effective glycosylation methods and their application in chemical biology using unsaturated glycosyl donors. In the past five years, we have reported several synthetic strategies with high stereoselectivity and milder conditions compared with previous works. In particular, high chemo-/regio- and stereoselective O-glycosylation, C-glycosylation and S-glycosylation could be achieved via palladium catalysis under open-air conditions at room temperature. In this Account, we will introduce our research progress in constructing four types of glycosides.1 Introduction2 Stereoselective Synthesis of O-Glycosides3 Stereoselective Synthesis of C-Glycosides4 Stereoselective Synthesis of N-Glycosides5 Stereoselective Synthesis of S-Glycosides6 Conclusion

A green Heck reaction protocol towards trisubstituted alkenes, versatile pharmaceutical intermediates.

The Heck reaction is widely employed to build a variety of biologically relevant scaffolds and has been successfully implemented in the production of active pharmaceutical ingredients (APIs). Typically, the reaction with terminal alkenes gives high yields and stereoselectivity toward the trans-substituted alkenes product, and many green variants of the original protocol have been developed for such substrates. However, these methodologies may not be applied with the same efficiency to reactions with challenging substrates, such as internal olefins, providing trisubstituted alkenes. In the present work, we have implemented a Heck reaction protocol under green conditions to access trisubstituted alkenes as final products or key intermediates of pharmaceutical interest. A set of preliminary experiments performed on a model reaction led to selecting a simple and green setup based on a design of experiments (DoE) study. In such a way, the best experimental conditions (catalyst loading, equivalents of alkene, base and tetraalkylammonium salt, composition, and amount of solvent) have been identified. Then, a second set of experiments were performed, bringing the reaction to completion and considering additional factors. The protocol thus defined involves using EtOH as the solvent, microwave (mw) irradiation to achieve short reaction times, and the supported catalyst Pd EnCat®40, which affords an easier recovery and reuse. These conditions were tested on different aryl bromides and internal olefines to evaluate the substrate scope. Furthermore, with the aim to limit as much as possible the production of waste, a simple isomerization procedure was developed to convert the isomeric byproducts into the desired conjugated E alkene, which is also the thermodynamically favoured product. The approach herein disclosed represents a green, efficient, and easy-to-use handle towards different trisubstituted alkenes via the Heck reaction.

Kinetic Resolution of β-Branched Aldehydes through Peptide-Catalyzed Conjugate Addition Reactions.

The catalytic kinetic resolution of racemic β-branched aldehydes offers a straightforward stereoselective entry to aldehydes and addition products. Yet, control over stereoselectivity is difficult due to the conformational flexibility of β-branched aldehydes. Here, we show that the peptide catalyst H-dPro-αMePro-Glu-NH2 resolves β-branched aldehydes through reaction with nitroolefins and provides γ-nitroaldehydes with three consecutive stereogenic centers in high yields and stereoselectivities. Kinetic, NMR spectroscopic, and computational studies provided insights into the selectivity-determining step and origins of the kinetic resolution.

Superelectrophilic Nonclassical Carbocations.

The chemistry of dicationic and tricationic 2-norbornyl cations has been studied. A series of N-heterocyclic functionalized norborneol substrates were prepared and ionization of these compounds in superacid provided superelectrophilic species. These highly charged 2-norbornyl cations were found to react with arene nucleophiles in high yields and stereoselectivity. Density functional theory computational studies suggest that increasing positive charge on the structures tends to enhance the degree of nonclassical (or 3-center-2-electron) bonding through separation of the cationic charges.