Palladium-Catalyzed Asymmetric [3 + 2] Annulation of Vinylethylene Carbonates with Alkenes Installed on Cyclic N-Sulfonyl Imines: Highly Enantio- and Diastereoselective Construction of Chiral Tetrahydrofuran Scaffolds Bearing Three Vicinal and Quaternary Stereocenters.

A multisubstituted tetrahydrofuran building block bearing three vicinal chiral carbon centers widely exists in a broad spectrum of bioactive natural products, and the development of efficient and convenient methods to establish this skeleton remains a challenging task. Herein, we have developed an efficient method for the construction of significant tetrahydrofuran scaffolds bearing three vicinal and α-quaternary chiral carbon stereocenters through Pd-catalyzed asymmetric [3 + 2] annulation of vinylethylene carbonates with alkenes installed on cyclic N-sulfonyl imines. A series of multisubstituted tetrahydrofuran derivatives are obtained in high efficiencies with excellent enantioselectivities and diastereoselectivities. Density functional theory (DFT) studies are accomplished to rationalize the stereocontrol of the annulation process and disclose that methanol could be applied to stabilize the reactive zwitterionic π-allylpalladium via the H-bond interaction.

Highly diastereo- and enantioselective synthesis of multisubstituted allylic amino acid derivatives by allylic alkylation of a chiral glycine-based nickel complex and vinylethylene carbonates.

The asymmetric synthesis of multisubstituted allylic amino acid derivatives was accomplished by the allylic alkylation of a chiral glycine-based nickel complex with vinylethylene carbonates. High enantioselectivities and diastereoselectivities were obtained under mild reaction conditions. The gram-scale synthesis was carried out with a good yield and high enantioselectivity, indicating that the method is a highly efficient route to chiral multisubstituted allylic amino acid derivatives.

TfOH-Catalyzed [4 + 1] Annulation of p-Quinone Methides with α-Aryl Diazoacetates: Straightforward Access to Highly Functionalized 2,3-Dihydrobenzofurans.

We have developed a methodology for the greatly efficient construction of significant 2,3-dihydrobenzofuran scaffolds bearing a quaternary carbon center at the C2 position by means of [4 + 1] annulation reactions between p-quinone methides and α-aryl diazoacetates as C1 synthons through organocatalysis by readily accessible TfOH catalyst under mild and transition metal-free conditions. This metal-free protocol furnishes an operationally simple and swift process for the free assembly of diverse highly functionalized 2,3-dihydrobenzofurans and also features broad substrate scope, excellent functional group compatibility, and environmental friendliness. Mechanistic investigation suggested that the reaction undergoes a rapid cascade protonation/intermolecular Michael addition/intramolecular substitution process.

Specific Z-Selectivity in the Oxidative Isomerization of Allyl Ethers to Generate Geometrically Defined Z-Enol Ethers Using a Cobalt(II)(salen) Complex Catalyst.

Enol ether structural motifs exist in many highly oxygenated biologically active natural products and pharmaceuticals. The synthesis of the geometrically less stable Z-enol ethers is challenging. An efficient Z-selective oxidative isomerization process of allyl ethers catalyzed by a cobalt(II) (salen) complex using N-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (Me3NFPY•OTf) as an oxidant has been developed. Thermodynamically less stable Z-enol ethers were prepared in excellent yields with high geometric control. This methodology also demonstrates the effectiveness in controlling the Z-selective isomerization reaction of diallyl ethers at room temperature. This catalytic system provides an alternative pathway to extend the traditional reductive isomerization of allyl ethers.

Unified Strategy to Amphenicol Antibiotics: Asymmetric Synthesis of (-)-Chloramphenicol, (-)-Azidamphenicol, and (+)-Thiamphenicol and Its (+)-3-Floride.

The asymmetric synthesis of (-)-chloramphenicol, (-)-azidamphenicol, and (+)-thiamphenicol and its (+)-3-floride, (+)-florfenicol, is reported. This approach toward the amphenicol antibiotic family features two key steps: (1) a cinchona alkaloid derived urea-catalyzed aldol reaction allows highly enantioselective access to oxazolidinone gem-diesters and (2) a continuous flow diastereoselective decarboxylation of thermally stable oxazolidinone gem-diesters to form the desired trans-oxazolidinone monoesters with two adjacent stereocenters that provide the desired privileged scaffolds of syn-vicinal amino alcohols in the amphenicol family.

Copper-Catalyzed C(sp(2))-H Difluoroalkylation of Aldehyde Derived Hydrazones with Diboron as Reductant.

An efficient and general method for C(sp(2))-H difluoroalkylation of aldehyde derived hydrazones via a Cu(II)/B2pin2-catalyzed reaction between difluoroalkyl bromides and hydrazones was developed. In this reaction, both aromatic and aliphatic difluoroalkylated aldehyde derived hydrazones could be achieved in good to excellent yields. For some heteroaromatic aldehyde derived hydrazones, two fluoroacetates could be introduced onto the final products. A preliminary mechanism study manifested that a difluoroalkyl radical via SET pathway was involved in the reaction. In addition, the catalytic diboron reagent plays an indispensable role in this transformation.

Asymmetric Construction of Carbon-Fluorine Quaternary Stereogenic Centers via Synergistic Pd/Cu Catalysis.

We developed an asymmetric decarboxylative allylic alkylation of vinylethylene carbonates with α-fluoro pyridinyl acetates through a synergistic palladium/copper catalysis. This protocol provides chiral allylic alcohol with carbon-fluorine quaternary stereogenic centers in good yield with good enantioselectivities and excellent regioselectivities. The utility of this approach was further demonstrated via a gram-scale experiment and derivatizations of the product.

Regio- and stereoselective syntheses of chiral α-quaternary (Z)-trisubstituted allylic amino acids via synergistic Pd/Cu catalysis.

Synergistic palladium/copper catalysis for asymmetric allylic alkylation of vinylethylene carbonates with aldimine esters has been developed for the synthesis of α-quaternary (Z)-trisubstituted allylic amino acids under mild conditions. This methodology features broad substrate compatibilities in yields of up to 87% and up to 94% ee. A facile scale-up and straightforward conversion to 1,2,3,5-tetrasubstituted pyrrole and 1,2,5,6-tetrahydropyridine bearing chiral quaternary carbon centers verifies the synthetic utility of this method.

Ligand-enabled palladium-catalyzed hydroesterification of vinyl arenes with high linear selectivity to access 3-arylpropanoate esters.

Palladium-catalyzed linear-selective hydroesterification of vinyl arenes with alcohols enabled by diphosphine ligands derived from bis[2-(diphenylphosphino)ethyl]amides has been developed. A variety of 3-arylpropanoate esters were obtained in high yields and regioselectivity. The robustness of this methodology was further demonstrated by the efficient gram-scale synthesis of the ethyl 3-phenylpropanoate as a precursor to hydrocinnamic acid.

Room-temperature Pd-catalyzed methoxycarbonylation of terminal alkynes with high branched selectivity enabled by bisphosphine-picolinamide ligand.

We report the room-temperature Pd-catalyzed methoxy-carbonylation with high branched selectivity using a new class of bisphosphine-picolinamide ligands. Systematic optimization of ligand structures and reaction conditions revealed the significance of both the picolinamide and bisphosphine groups in the ligand backbone. This strategic design of ligand was leveraged to deliver various α-substituted acrylates in good to excellent yields.

Robust, scalable construction of an electrophilic deuterated methylthiolating reagent: facile access to SCD3-containing scaffolds.

We have established a practical and concise method for the straightforward access of a universal deuterated methylthiolating reagent through a one-pot gram-scale operation under mild conditions. This odourless electrophilic SCD3 reagent was widely applied to react with numerous representative nucleophiles and approached various valuable SCD3 analogues with excellent levels of deuterium content (>99% D). The divergent further transformations were smoothly carried out to obtain the significant derivatives with different oxidative states in high efficiency.

Palladium-Catalyzed Regio- and Stereoselective Cross-Coupling of Vinylethylene Carbonates with Ketimine Esters to Generate (Z)-Tri- and Tetra-substituted Allylic Amino Acid Derivatives.

Herein we report the palladium-catalyzed regio- and stereoselective cross-coupling of vinylethylene carbonates with ketimine esters to construct allylic amino acid scaffolds. This operationally simple protocol furnished (Z)-tri- and tetra-substituted allylic amino acid derivatives in good to excellent yields with distinguished geometric control under mild reaction conditions and proved to be sufficient in large-scale synthesis while retaining excellent reactivity and stereoselectivity, highlighting the practical value of this transformation.

The Chapman rearrangement in a continuous-flow microreactor.

The Chapman rearrangement is of practical significance in pharmaceutical and fine chemical industries. It is a high temperature reaction with an exothermic nature in numerous cases. The conventional batch-wise synthesis is limited by its operational complexities, temperature control difficulties and scale-up hurdles. In this work, a microreactor-based continuous-flow approach was developed to perform the rearrangement in a highly controlled and safer manner. High conversions were obtained within short residence times (≤20 minutes). The detailed kinetics of this reaction, using 2,6-dichloro-phenyl N-phenyl benzimidate and 2-carbomethoxy-phenyl N-phenyl benzimidate as the representative reactants, was explored at varying temperatures to understand the intensified reaction behavior, and was modelled based on the obtained experimental data. The continuous process was scaled up to a 16-fold larger reactor volume by increasing the diameter of the microreactor while maintaining the residence time without further optimization. A very slight variation was observed in the conversion for the larger-sized flow system. Upscaling the batch reaction to a 10 times larger volume, by contrast, resulted in a dramatic decrease in the conversion. The simplicity of scaling up continuous-flow system was clearly demonstrated. A CFD model coupled with the obtained rearrangement kinetics was developed and well validated against the experimental data, which provided a robust platform for guiding the relevant process design and optimization of the continuous-flow processes. The results presented shed new light on the developments and applications of continuous-flow method for the classical Chapman rearrangement that require harsh high temperatures.

Copper/B2pin2-catalyzed C-H difluoroacetylation-cycloamidation of anilines leading to the formation of 3,3-difluoro-2-oxindoles.

An original and efficient synthesis of 3,3-difluoro-2-oxindole derivatives has been developed via copper/B2pin2-catalyzed difluoroacetylation of aniline via C-H activation followed by intramolecular amidation. In this method, amino groups in primary, secondary or tertiary anilines act as directing groups, providing ortho-difluoroacetylated products regioselectively. And in the first two cases, further intramolecular amidation affords 3,3-difluoro-2-oxindole derivatives via a one-pot strategy. This method facilitates the synthesis of compound A as a potent and selective EP3 receptor antagonist in only five steps in 13% yield instead of the previously reported nine steps in overall 4% yield.