Precision Synthesis of Polysarcosine via Controlled Ring-Opening Polymerization of N-Carboxyanhydride: Fast Kinetics, Ultrahigh Molecular Weight, and Mechanistic Insights.

The rapid and controlled synthesis of high-molecular-weight (HMW) polysarcosine (pSar), a potential polyethylene glycol (PEG) alternative, via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is rare and challenging. Here, we report the well-controlled ROP of sarcosine NCA (Sar-NCA) that is catalyzed by various carboxylic acids, which accelerate the polymerization rate up to 50 times, and enables the robust synthesis of pSar with an unprecedented ultrahigh molecular weight (UHMW) up to 586 kDa (DP ∼ 8200) and exceptionally narrow dispersity (D̵) below 1.05. Mechanistic experiments and density functional theory calculations together elucidate the role of carboxylic acid as a bifunctional catalyst that significantly facilitates proton transfer processes and avoids charge separation and suggest the ring opening of NCA, rather than decarboxylation, as the rate-determining step. UHMW pSar demonstrates improved thermal and mechanical properties over the low-molecular-weight counterparts. This work provides a simple yet highly efficient approach to UHMW pSar and generates a new fundamental understanding useful not only for the ROP of Sar-NCA but also for other NCAs.

Recyclable Polythioesters and Poly(thioester-co-peptoid)s via Ring-Opening Cascade Polymerization of Amino Acid N-Carboxyanhydrides.

Polythioesters (PTEs) are emerging sustainable polymers for their degradability and recyclability. However, low polymerizability of monomers and extensive side reactions often hampered the polymerization process. Moreover, copolymers containing both thioester and other types of functional groups in the backbone are highly desirable but rarely accomplished owing to several synthetic challenges. Here, we report the ring-opening cascade polymerization (ROCAP) of N-(2-(acetylthio)ethyl)-glycine N-carboxyanhydrides (TE-NCA) to afford recyclable PTEs and unprecedented poly(thioester-co-peptoid)s (P(TE-co-PP)s) in a controlled manner. By developing appropriated carboxylic acid-tertiary amine dual catalysts, intramolecular S-to-N acyl shift is coupled into the ROCAP process of TE-NCA to yield products with dispersity below 1.10, molecular weight (Mn) up to 84.5 kDa, and precisely controlled ratio of thioester to peptoids. Random copolymerization of sarcosine NCA (Sar-NCA) and TE-NCA gives thioester-embedded polysarcosine with facile backbone degradation while maintaining the water solubility. This work represents a paradigm shift for the ROP of NCAs, enriches the realm of cascade polymerizations, and provides a powerful synthetic approach to functional PTEs and P(TE-co-PP)s that are otherwise difficult or impossible to make.

Why [4 + 2 + 1] but Not [2 + 2 + 1]? Why Allenes? A Mechanistic Study of the Rhodium-Catalyzed [4 + 2 + 1] Cycloaddition of In Situ Generated Ene-Ene-Allenes and Carbon Monoxide.

Transition metal-catalyzed [4 + 2 + 1] cycloaddition of in situ generated ene/yne-ene-allenes (from ene/yne-ene propargyl esters) and carbon monoxide (CO) gives the [4 + 2 + 1] cycloadducts rather than [2 + 2 + 1] cycloadducts. Investigating the mechanism of this [4 + 2 + 1] reaction and understanding why the [2 + 2 + 1] reaction does not compete and the role of the allene moiety in the substrates are important. This is also helpful to guide the future design of new [4 + 2 + 1] cycloadditions. Reported here are the kinetic and computed studies of the [4 + 2 + 1] reactions of ene-ene propargyl esters and CO. A quantum chemical study (at the DLPNO-CCSD(T)//BMK level) revealed that the [4 + 2 + 1] reaction includes four key steps, which are 1,3-acyloxy migration (rate-determining step), oxidative cyclization, CO migratory insertion, and reductive elimination. The allene moiety in the substrates is critical for providing additional coordination to the rhodium center in the final step of the catalytic cycle, which in turn favors the reductive elimination transition state in the [4 + 2 + 1] rather than in the [2 + 2 + 1] pathway. The CO insertion step in the [4 + 2 + 1] reaction, which could occur through either the UP (favored here) or DOWN CO insertion pathway, has also been deeply scrutinized, and some guidance from this analysis has been provided to help the future design of new [4 + 2 + 1] reactions. Quantum chemical calculations have also been applied to explain why [4 + 2] and [4 + 1] cycloadditions do not happen and how trienes as side products for some substrates are generated.

Rhodium(I)-Catalyzed Three-Component [4+2+1] Cycloaddition of Two Vinylallenes and CO.

Transition metal-catalyzed [4+2+1] reactions of dienes (or diene derivatives such as vinylallenes), alkynes/alkenes, and CO (or carbenes) are expected to be the most straightforward approach to synthesize challenging seven-membered ring compounds, but so far only limited successes have been realized. Here, an unexpected three-component [4+2+1] reaction between two vinylallenes and CO was discovered to give highly functionalized tropone derivatives under mild conditions, where one vinylallene acts as a C4 synthon, the other vinylallene as a C2 synthon, and CO as a C1 synthon. It was proposed that this reaction occurred via oxidative cyclization of the diene part of one vinylallene molecule, followed by insertion of the terminal alkene part of the allene moiety in another vinylallene, into the Rh-C bond of five-membered rhodacycle. Then, CO insertion and reductive elimination gave the [4+2+1] cycloadduct. Further experimental exploration of why ene/yne-vinylallenes and CO gave monocyclic tropone derivatives instead of 6/7-bicyclic ring products were reported here.

Rhodium-Catalyzed [4+2+1] Cycloaddition of In Situ Generated Ene/Yne-Ene-Allenes and CO.

Reported herein is the first rhodium-catalyzed [4+2+1] cycloaddition of in situ generated ene/yne-ene-allenes and CO to synthesize challenging seven-membered carbocycles fused with five-membered rings. This reaction is designed based on the 1,3-acyloxy migration of ene/yne-ene-propargyl esters to ene/yne-ene-allenes, followed by oxidative cyclization, CO insertion, and reductive elimination to form the final [4+2+1] cycloadducts. The possible competing [4+1], [4+2], and [2+2+1] cycloadditions were disfavored, making the present reaction an efficient way to access functionalized 5/7 rings.

Asymmetric Hydrogenation of In†Situ Generated Isochromenylium Intermediates by Copper/Ruthenium Tandem Catalysis.

The first asymmetric hydrogenation of in situ generated isochromenylium derivatives is enabled by tandem catalysis with a binary system consisting of Cu(OTf)2 and a chiral cationic ruthenium-diamine complex. A range of chiral 1H-isochromenes were obtained in high yields with good to excellent enantioselectivity. These chiral 1H-isochromenes could be easily transformed into isochromanes, which represent an important structural motif in natural products and biologically active compounds. The chiral induction was rationalized by density functional theory calculations.

Cycloaddition Reaction of Vinylphenylfurans and Dimethyl Acetylenedicarboxylate to [8 + 2] Isomers via Tandem [4 + 2]/Diradical Alkene-Alkene Coupling/[1,3]-H Shift Reactions: Experimental Exploration and DFT Understanding of Reaction Mechanisms.

An experimental test of designed [8 + 2] reaction of vinylphenylfuran and dimethyl acetylenedicarboxylate (DMAD) has been carried out, showing that the reaction gave unexpected addition products under different conditions. When the reaction was conducted under thermal conditions in toluene, expoxyphenanthrene, which was named as a [8 + 2] isomer, was generated. The scope of this reaction has been investigated in the present study. In addition, experiments and DFT calculations have been conducted to investigate how the reaction between vinylphenylfuran and DMAD took place. Surprisingly, the reaction did not involve the expected [8 + 2] intermediate, o-quinodimethane. Instead, the reaction starts from intermolecular Diels-Alder reactions between DMAD and the furan moiety of vinylphenylfuran, followed by unexpected intramolecular alkene-alkene coupling. This step generates a diradical species, which then undergoes [1,3]-H shift to give the experimentally observed expoxyphenanthrene. DFT calculations revealed that, the [8 + 2] cycloadduct cannot be obtained because the [1,5]-H shift process from the [1,5]-vinyl shift intermediate is disfavored kinetically compared to the [1,3]-H shift to the [8 + 2] isomer.

Intramolecular CH⋯π attraction mediated conformational polymorphism of constrained helical peptides.

In nature, biochemical processes depend on polymorphism, a phenomenon by which discrete biomolecules can adopt specific conformations based on their environment. However, it is often difficult to explore the generation mechanism and achieve polymorphic control in artificial supramolecular assembly systems. In this work, we propose a feasible thought for exploring the transformation mechanism of polymorphism in peptide assembly from the perspective of thermodynamic regulation, which enables polymorphic composition to be limited by switchable intramolecular CH⋯π attraction within a certain temperature range. Combined with the density functional theory calculations, we obtained thermodynamic theoretical data supporting the conformation transition and the underlying polymorphism formation principle. Afterward, we properly designed the peptide to alter the probability of CH⋯π attraction occurring. Then, we selectively obtained a homogeneous morphological form with corresponding molecular conformation, which further demonstrated the important role of molecular conformational manipulation in polymorphism selection. This unique template-based strategy developed in this study may provide scientists with an additional line of thought to guide assembly paths in other polymorphic systems.

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride.

The production of polypeptides via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is usually conducted under stringent anhydrous conditions. The ROP of proline NCA (ProNCA) for the synthesis of poly-L-proline (PLP) is particularly challenging due to the premature product precipitation as polyproline type I helices, leading to slow reactions for up to one week, poor control of the molar mass and laborious workup. Here, we report the unexpected water-assisted controlled ROP of ProNCA, which affords well-defined PLP as polyproline II helices in 2-5 minutes and almost-quantitative yields. Experimental and theoretical studies together suggest the as-yet-unreported role of water in facilitating proton shift, which significantly lowers the energy barrier of the chain propagation. The scope of initiators can be expanded from hydrophobic amines to encompass hydrophilic amines and thiol-bearing nucleophiles, including complex biomacromolecules such as proteins. Protein-mediated ROP of ProNCA conveniently affords various protein-PLP conjugates via a grafting-from approach. PLP modification not only preserves the biological activities of the native proteins, but also enhances their resistance to extreme conditions. Moreover, PLP modification extends the elimination half-life of asparaginase (ASNase) 18-fold and mitigates the immunogenicity of wt ASNase >250-fold (ASNase is a first-line anticancer drug for lymphoma treatment). This work provides a simple solution to a long-standing problem in PLP synthesis, and offers valuable guidance for the development of water-resistant ROP of other proline-like NCAs. The facile access to PLP can greatly boost the application potential of PLP-based functional materials for engineering industry enzymes and therapeutic proteins.

A moisture-tolerant route to unprotected α/ß-amino acid N-carboxyanhydrides and facile synthesis of hyperbranched polypeptides.

A great hurdle in the production of synthetic polypeptides lies in the access of N-carboxyanhydrides (NCA) monomers, which requires dry solvents, Schlenk line/gloveboxe, and protection of side-chain functional groups. Here we report a robust method for preparing unprotected NCA monomers in air and under moisture. The method employs epoxy compounds as ultra-fast scavengers of hydrogen chloride to allow assisted ring-closure and prevent NCA from acid-catalyzed decomposition under moist conditions. The broad scope and functional group tolerance of the method are demonstrated by the facile synthesis of over 30 different α/ß-amino acid NCAs, including many otherwise inaccessible compounds with reactive functional groups, at high yield, high purity, and up to decagram scales. The utility of the method and the unprotected NCAs is demonstrated by the facile synthesis of two water-soluble polypeptides that are promising candidates for drug delivery and protein modification. Overall, our strategy holds great potential for facilitating the synthesis of NCA and expanding the industrial application of synthetic polypeptides.

Rh-Catalyzed Cycloisomerization of 1,7-Ene-Dienes to Synthesize trans-Divinylpiperidines: A Formal Intramolecular Addition Reaction of Allylic C-H Bond into Dienes.

An originally designed Rh-catalyzed [4 + 2] cycloaddition reaction of nitrogen-tethered 1,7-ene-dienes turned out to be a cycloisomerization reaction, which involves allylic C-H activation/alkene insertion into Rh-H bond/reductive elimination processes. Deuterium labeling experiments gave support to the proposed mechanism. This unexpected cycloisomerization reaction provides an efficient way to synthesize trans-divinylpiperidines from easily accessed linear 1,7-ene-dienes.