Yuya Hu

Ring-opening copolymerization of epoxides and cyclic anhydrides by organoboron catalysts is presented. In view of their facile preparation and unprecedented performance (thermostability, reactivity, and productivity), the catalysts provided here hold promise in pushing ROCOP of epoxides with cyclic anhydrides to the industry line.

Abstract

Producing polyesters with high molecular weight (M_n) through ring-opening copolymerization (ROCOP) of epoxides with cyclic anhydrides remains a major challenge. Herein, we communicate a metal-free, highly active, and high thermoresistance system for the ROCOP of epoxides with cyclic anhydrides to prepare polyesters (13 examples). The organoboron catalysts can endure a reaction temperature as high as 180 °C for the ROCOP of cyclohexane oxide (CHO) with phthalic anhydride (PA) without the observation of any side reactions. The average M_n of the produced poly(CHO-alt-PA) climbed to 94.5 kDa with low polydispersity (Ð=1.19). Furthermore, an unprecedented turnover number of 9900, equivalent to an efficiency of 7.4 kg of polyester/g of catalyst, was achieved at a feed ratio of CHO/PA/catalyst=20000:10000:1 at 150 °C. Kinetic studies, crystal structure analysis, ¹¹B NMR spectra, and DFT calculations provided mechanistic justification for the effectiveness of the catalyst system.

Radical C−H Deuteration: A environmentally benign metal-free method for remote radical C−H deuteration at various unactivated sp³-C−H bonds including primary C−H bonds next to heteroatoms for the δ-deuteration of primary amines, γ-deuteration of aliphatic acids and α-deuteration of secondary amines has been developed.

Abstract

Site-selective incorporation of deuterium into biologically active compounds is of high interest in pharmaceutical industry. We present a mild and environmentally benign metal-free method for the remote selective radical C−H monodeuteration of aliphatic C−H bonds in various amides with inexpensive heavy water (D₂O) as the deuterium source. The method uses the easily installed N-allylsulfonyl moiety as an N-radical precursor that generates the remote C-radical via site-selective 1,5- or 1,6-hydrogen atom transfer (HAT). Methyl thioglycolate, that readily exchanges its proton with D₂O, serves as the radical deuteration reagent and as a chain-carrier. The highly site-selective monodeuteration has been applied to different types of unactivated sp ³ -C−H bonds and also to the deuteration of C−H bonds next to heteroatoms. The potential utility of this method is further demonstrated by the site-selective incorporation of deuterium into natural product derivatives and drugs.

A nickel-catalyzed alkenylarylation reaction of γ,δ-alkenylketones with alkenyl triflates and arylboronic esters is described. The reaction was made feasible by the use of 5-chloro-8-hydroxyquinoline as a ligand along with NiBr₂⋅DME as a catalyst and LiOtBu as base, and works with cyclic, acyclic, endocyclic and exocyclic alkenyl ketones. Control experiments indicate that carbonyl coordination is required for the reaction to proceed.

Abstract

We disclose a nickel-catalyzed reaction, which enabled us to difunctionalize unactivated γ,δ-alkenes in ketones with alkenyl triflates and arylboronic esters. The reaction was made feasible by the use of 5-chloro-8-hydroxyquinoline as a ligand along with NiBr₂⋅DME as a catalyst and LiOtBu as base. The reaction proceeded with a wide range of cyclic, acyclic, endocyclic and exocyclic alkenyl ketones, and electron-rich and electron-deficient arylboronate esters. The reaction also worked with both cyclic and acyclic alkenyl triflates. Control experiments indicate that carbonyl coordination is required for the reaction to proceed.

Make it a double: A strategy for the synthesis of novel double-allylation reagents based on the alkenylboration of alkenylboronates is presented. The ease and modularity with which the reagents can be prepared allows rapid access to a variety of complex diol motifs. In the context of these studies, we also demonstrate the first examples of the use of boronamides in allylation reactions.

Abstract

Double-allylation reagents allow for the construction of highly complex molecules in an expedient fashion. We have developed an efficient, modular, and enantioselective approach towards accessing novel variants of these reagents through Cu/Pd-catalyzed alkenylboration of alkenylboron derivatives. Importantly, we demonstrate novel use of an allylBdan reagent directly in a stereocontrolled allylation without initial deprotection to the boronic ester. These allylation products are employed in a second intermolecular allylation to access complex diol motifs, which has yet to be shown with these types of double-allylation reagents. Overall, the modularity of this approach and the ease in which complex structural motifs can be accessed in a rapid manner signify the importance and utility of this method.

The reaction of Ph₃GePCO with the ylide Ph₃PCH₂ and subsequent reactions are used to access Ph₃PCHC(O)P(GePh₃)₂ and Ph₃PCHC(O)PH₂. The zwitterionic nature of these species illustrates this new strategy to stabilization of acylphosphines. Indeed the latter species is a rare example of an air stable primary acyl-phosphine, devoid of a stabilizing heteroatom adjacent to the carbonyl fragment.

Abstract

Primary acyl-phosphines are scarce in the literature. Here we show that the reaction of Ph₃GePCO with the ylide Ph₃PCH₂ proceeds to give the species Ph₃PCHC(O)PH(GePh₃) 1. Deprotonation of 1 with Na[N(SiMe₃)₂] generates the salt [Na(THF)₂][Ph₃PCHC(O)P(GePh₃)] 2 which provides subsequent access to the bis-germanylated acylphosphine, Ph₃PCHC(O)P(GePh₃)₂ 3. Alternatively, treatment of 1 with HCl in dioxane affords the primary acylphosphine Ph₃PCHC(O)PH₂ 4. Compound 4 is a rare example of an air stable primary acyl-phosphines and the first devoid of a stabilizing heteroatom adjacent to the carbonyl fragment.

Efficient demethylation of methyl phenyl ethers was achieved by biocatalytic O₂-free methyl transfer to thiols forming thio ethers. Since the methyl group is not cleaved from the sulfur under these conditions, the thiol compound acts like a trap driving the reaction towards completion.

Abstract

Demethylating methyl phenyl ethers is challenging, especially when the products are catechol derivatives prone to follow-up reactions. For biocatalytic demethylation, monooxygenases have previously been described requiring molecular oxygen which may cause oxidative side reactions. Here we show that such compounds can be demethylated anaerobically by using cobalamin-dependent methyltransferases exploiting thiols like ethyl 3-mercaptopropionate as a methyl trap. Using just two equivalents of this reagent, a broad spectrum of substituted guaiacol derivatives were demethylated, with conversions mostly above 90 %. This strategy was used to prepare the highly valuable antioxidant hydroxytyrosol on a one-gram scale in 97 % isolated yield.

A ligand-controlled regioselective thiocarbonylation of alkynes is reported. Various linear and branched α,β-unsaturated thioesters are produced in a straightforward manner. This protocol is characterized by its ligand-controlled regioselectivity pattern, wide substrate scope, and unprecedented functional group compatibility. This is the first example on thiocarbonylation of internal alkynes.

Abstract

Thiocarbonylation of alkynes offers an ideal procedure for the synthesis of unsaturated thioesters. A robust ligand-controlled regioselective thiocarbonylation of alkynes is developed. Utilizing boronic acid and 5-chlorosalicylic acid as the acid additive to in situ form 5-chloroborosalicylic acid (5-Cl-BSA), and bis(2-diphenylphosphinophenyl)ether (DPEphos) as the ligand, linear α,β-unsaturated thioesters were produced in a straightforward manner. Switching the ligand to tri(2-furyl)phosphine can turn the reaction selectivity to give branched products. Remarkably, this approach also represents the first example on thiocarbonylation of internal alkynes.

Nature Communications, Published online: 31 May 2021; doi:10.1038/s41467-021-23504-2

Synthesis of fluorinated organic molecules is of high interest for agrochemistry and pharmaceutics, but efficient and general reagents for introducing -CF2- groups are lacking. Here, the authors report the synthesis of 3,3-difluoropropen-1-yl ammonium salts as stable and scalable gem-difluoromethylation reagents, which react with a range of nucleophiles under mild conditions and high regioselectivity.

A transaminase-based dynamic kinetic resolution was developed for the preparation of β-branched aromatic α-amino acids with high diastereo- and enantioselectivity. The reaction was facilitated by the use of a thermophilic enzyme that tolerates elevated temperatures and pH values and exhibits broad substrate promiscuity. The utility of the process was demonstrated in the total synthesis of jomthonic acid A (see scheme).

Abstract

β-Branched noncanonical amino acids are valuable molecules in modern drug development efforts. However, they are still challenging to prepare due to the need to set multiple stereocenters in a stereoselective fashion, and contemporary methods for the synthesis of such compounds often rely on the use of rare-transition-metal catalysts with designer ligands. Herein, we report a highly diastereo- and enantioselective biocatalytic transamination method to prepare a broad range of aromatic β-branched α-amino acids. Mechanistic studies show that the transformation proceeds through dynamic kinetic resolution that is unique to the optimal enzyme. To highlight its utility and practicality, the biocatalytic reaction was applied to the synthesis of several sp³-rich cyclic fragments and the first total synthesis of jomthonic acid A.

Nature Chemistry, Published online: 24 May 2021; doi:10.1038/s41557-021-00698-y

Many C–C bond activation methods involve strain-releasing cleavage of small rings to compensate for unfavourable kinetics and thermodynamics. Now, the 1,2-positional interchange of vicinal C–C and C–Pd bonds has been reported, giving access to quaternary carbon–palladium bonds. This dyotropic rearrangement has been used for the enantioselective synthesis of functionalized fluorinated cyclopentanes.

An efficient and broadly applicable palladium-catalyzed iodination of inexpensive and abundant aryl and vinyl carboxylic acids via in situ activation to the acid chloride and formation of a phosphonium salt was developed. The use of 1-iodobutane as iodide source in combination with a base and a deoxychlorinating reagent gives access to a wide range of aryl and vinyl iodides under Pd/Xantphos catalysis.

Abstract

We report an efficient and broadly applicable palladium-catalyzed iodination of inexpensive and abundant aryl and vinyl carboxylic acids via in situ activation to the acid chloride and formation of a phosphonium salt. The use of 1-iodobutane as iodide source in combination with a base and a deoxychlorinating reagent gives access to a wide range of aryl and vinyl iodides under Pd/Xantphos catalysis, including complex drug-like scaffolds. Stoichiometric experiments and kinetic analysis suggest a unique mechanism involving C−P reductive elimination to form the Xantphos phosphonium chloride, which subsequently initiates an unusual halogen exchange by outer sphere nucleophilic substitution.

Phosphine-catalyzed tandem Michael addition/intramolecular Wittig reactions have been developed for the synthesis of chiral 2,5-dihydro-1 H -pyrrole and tetrahydropyridine derivatives. These processes have been rendered catalytic in phosphine, thanks to the in situ reduction of phosphine oxide by phenylsilane. Furthermore, catalytic and asymmetric P(III)/P(V) processes were implemented using enantiopure chiral phosphines.

Synthesis
DOI: 10.1055/a-1394-7511

The formation of the C=N bond in recent studies on heterocyclic compounds via the aza-Wittig reaction is reviewed. Furthermore, two different strategies for the formation of heterocyclic compounds, including intermolecular and intramolecular aza-Wittig reactions are described. The primary aim of this review is to provide up-to-date information on the application of the aza-Wittig reaction in the synthesis of a wide range of N-containing heterocyclic compounds in the chemical literature since 2010.1 Introduction2 Mechanism of the Staudinger and Aza-Wittig Reactions3 Intramolecular Aza-Wittig Reaction4 Intermolecular Aza-Wittig Reaction5 Conclusion
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