Al(OTf)3-Catalyzed Regioselective N2-Arylation of Tetrazoles with Diazo Compounds.

Regioselective methods to access alkylated tetrazoles still remain a challenging goal. Herein, we describe a novel regioselective protocol for N2-arylation of tetrazoles with diazo compounds using inexpensive Al(OTf)3. This reaction could be conducted under mild conditions to access a diverse array of alkylated tetrazoles with 2-substituted tetrazoles as the major products, demonstrating a comprehensive range of substrate compatibility and excellent functional group compatibility. Mechanistic studies revealed a carbene-free process in this reaction procedure. Furthermore, the scale-up reaction and transformations of the N2-arylation of tetrazole products demonstrated the potential of this strategy.

Synthesis of 2,4-Disubstituted Oxazoles and Thiazoles via Brønsted Acid-Catalyzed Cyclization of α-diazoketones with Amides.

A novel method is described for the synthesis of 2,4-disubstituted oxazole and thiazole derivates via the coupling of α-diazoketones with (thio)amides or thioureas using trifluoromethanesulfonic acid (TfOH) as a catalyst. This protocol is characterized by mild reaction conditions, metal-free, and simplicity and also features good functional group tolerance, good to excellent yields, and a broad substrate scope with more than 40 examples. Experimental studies suggest a mechanism involving 2-oxo-2-phenylethyl trifluoromethanesulfonate as the key intermediate.

Copper-Catalyzed Asymmetric Remote C(sp3)-H Alkylation of N-Fluorocarboxamides with Glycine Derivatives and Peptides.

Saturated hydrocarbon bonds are ubiquitous in organic molecules; to date, the selective functionalization of C(sp3)-H bonds continues to pose a notorious difficulty, thereby garnering significant attention from the synthetic chemistry community. During the past several decades, a wide array of powerful new methodologies has been developed to enantioselectively modify C(sp3)-H bonds that is successfully applied in asymmetric formation of diverse bonds, including C-C, C-N, and C-O bonds; nevertheless, the asymmetric C(sp3)-H alkylation is elusive and, therefore, far less explored. In this work, we report a direct and robust strategy to construct highly valuable enantioenriched unnatural α-amino acid (α-AA) cognates and peptides by a copper-catalyzed enantioselective remote C(sp3)-H alkylation of N-fluorocarboxamides and readily accessible glycine esters under ambient conditions. The key to success lies in the optically active Cu catalyst generated through the coordination of glycine derivatives to enantiopure bisphosphine/Cu(I) species, which is beneficial to the single electronic reduction of N-fluorocarboxamides and the subsequent stereodetermining alkylation. More importantly, all types (primary, secondary, tertiary, and even α-oxy) of δ-C(sp3)-H bonds could be site- and stereospecifically activated by the kinetically favored 1,5-hydrogen atom transfer (1,5-HAT) step.

Visible-Light-Induced Defluorinative α-C(sp3)-H Alkylation for the Synthesis of gem-Difluoroallylated α-Trifluoromethylamines.

Herein, we describe a novel and efficient photoredox catalytic Cα radical addition/defluoroalkylation coupling reaction between α-trifluoromethyl alkenes and N-trifluoroethyl hydroxylamine. A series of gem-difluoroallylated α-trifluoromethylamines were synthesized by the Cα radical addition enabled by a 1,2-H shift of the in situ-generated N-trifluoroethyl radical. Notably, this protocol is distinguished by its mild conditions, easy operation, and excellent functional group tolerability.

Visible-Light-Driven C,N-Selective Heteroarylation of N-Fluoroalkyl Hydroxylamine Reagents with Quinoxalin-2(1H)-ones.

Herein, we disclose a direct and powerful strategy for the synthesis of highly valuable α-trifluoromethylamine and N-trifluoroethylamine derivatives from a visible-light-promoted C,N-selective heteroarylation of N-trifluoroethyl hydroxylamine reagents with quinoxalin-2(1H)-ones under ambient conditions. The chemoselectivity of the process (trifluoroalkylation or N-trifluoroethylamination) can easily be dictated and modulated by a selection of N-trifluoroethyl hydroxylamine substrates. The key to success is the protecting group on the N atom of hydroxylamine reagents, which can control the process of 1,2-H shift of the in situ-generated N-trifluoroethyl radical. Remarkable features of this method include mild conditions, easy operation, high selectivity, and excellent functional group tolerability. More importantly, the trifluoroalkylated products can be readily derivatized into other interesting imidazo-fused heterocycles that would be of great potential for the exploitation of pharmaceutically relevant molecules.

Chemodivergent Synthesis of Sulfonamide and Sulfones from N-Tosylhydrazones by Switching Catalyst and Temperature.

A catalyst- and temperature-controlled selective synthesis of sulfonamide and sulfones from N-tosylhydrazones and MBH carbonates has been developed. The use of palladium catalysts exclusively leads to sulfonamide products at room temperature, whereas the selective synthesis of sulfones is dominant for a temperature-controlled coupling reaction without palladium catalysis. Importantly, the catalyst- or temperature-controlled reaction exhibits high nucleophilicity rather than carbene reactivity in these transformations.

TfOH-Catalyzed Regioselective S-H Insertion of Cyclic Thioamide Derivatives with Diazo Compounds at Room Temperature.

We have developed a method for highly regioselective S-H bond insertion reactions of various diazo compounds and cyclic thioamide derivatives at room temperature. These reactions provide straightforward access to alkylated benzimidazoles, benzothiazoles, and benzoxazoles. This mild method uses readily available TfOH as a catalyst and features a broad substrate scope, good functional group tolerance, good to excellent yields, and high regioselectivities.

Correction: Regioselective O-alkylation of 2-pyridones by TfOH-catalyzed carbenoid insertion.

Correction for 'Regioselective O-alkylation of 2-pyridones by TfOH-catalyzed carbenoid insertion' by Zhewei Yan et al., Chem. Commun., 2023, 59, 106-109, https://doi.org/10.1039/d2cc05676c.

Regioselective O-alkylation of 2-pyridones by TfOH-catalyzed carbenoid insertion.

Selective alkylation of 2-pyridone could solve a challenge in chemistry and streamline the synthesis of important molecules. Here we report the regioselective O-alkylation of 2-pyridones by TfOH-catalyzed carbenoid insertion. In the catalytic system, alkylation of 2-pyridone was achieved with unprecedented regioselectiviy (>99 : 1). This protocol is characterized by mild reaction conditions, metal-free, and simplicity. Moreover, this method provides the desired products in good yield and demonstrates a broad substrate scope in this transformation.

Visible-Light-Promoted Xanthate-Transfer Cyclization Reactions of Unactivated Olefins under Photocatalyst- and Additive-Free Conditions.

A general visible-light-induced photocatalyst-/additive-free strategy was developed for the construction of various nitrogen-heterocycles (42 examples, up to 97% yield) such as γ-lactams, δ-lactams, pyrrolidines, indolones, quinolinones, and fused polycyclic structures at room temperature. The prominent features of this protocol are mild and environmentally friendly conditions, broad substrate scope, and good functional group tolerance. Importantly, the reaction can be performed under natural sunlight, the most sustainable energy source imaginable. Furthermore, this strategy provides straightforward access to a range of derivatives through subsequent elaboration of the xanthate group.

TfOH-catalyzed regioselective N2-alkylation of indazoles with diazo compounds.

Selective alkylation of indazoles is still a highly challenging topic in chemistry and the synthesis of important molecules. Herein, a novel highly selective N2-alkylation of indazoles with diazo compounds is described in the presence of TfOH. Unlike the traditional metal- and base-catalysed version, this protocol highlights the regioselectivity of alkylation of indazoles and a metal-free catalysis system, affording N2-alkylated products in good to excellent yields with high regioselectivity (N2/N1 up to 100/0) and excellent functional group tolerance. Furthermore, a gram scale synthesis was conducted successfully to give rise to the corresponding products. Mechanistic studies through control experiments provide plausible mechanistic proposals.

Painful Terminal Neuroma Prevention by Capping PRGD/PDLLA Conduit in Rat Sciatic Nerves.

Neuroma formation after amputation as a long-term deficiency leads to spontaneous neuropathic pain that reduces quality of life of patients. To prevent neuroma formation, capping techniques are implemented as effective treatments. However, an ideal, biocompatible material covering the nerves is an unmet clinical need. In this study, biocompatible characteristics presented by the poly(D,L-lactic acid)/arginylglycylaspartic acid (RGD peptide) modification of poly{(lactic acid)-co- [(glycolic acid)-alt-(L-lysine)]} (PRGD/PDLLA) are evaluated as a nerve conduit. After being capped on the rat sciatic nerve stump in vivo, rodent behaviors and tissue structures are compared via autotomy scoring and histological analyses. The PRGD/PDLLA capped group gains lower autotomy score and improves the recovery, where inflammatory infiltrations and excessive collagen deposition are defeated. Transmission electron microscopy images of the regeneration of myelin sheath in both groups show that abnormal myelination is only present in the uncapped rats. Changes in related genes (MPZ, MBP, MAG, and Krox20) are monitored quantitative real-time polymerase chain reaction (qRT-PCR) for mechanism investigation. The PRGD/PDLLA capping conduits not only act as physical barriers to inhibit the invasion of inflammatory infiltration in the scar tissue but also provide a suitable microenvironment for promoting nerve repairing and avoiding neuroma formation during nerve recovery.

Construction and in vitro evaluation of enzyme nanoreactors based on carboxymethyl chitosan for arginine deprivation in cancer therapy.

In this study, a pH-induced morphological transition from micelles to vesicles for an amphiphilic photo cross-linkable biocopolymer (Az-NaCMCS), synthesized by mixing azidobenzaldehyde (Az) and an aqueous solution of carboxymethyl chitosan sodium salt (NaCMCS), was used for encapsulation of l-arginine deiminase (ADI). The aqueous solution of enzyme-loaded vesicles obtained was followed by UV-irradiation to result in shell cross-linked enzyme nanoreactors. The nanoreactors were characterized by TEM and DLS. Its encapsulation efficiency and loading capacity were determined. The encapsulation process showed no effect on the activity of ADI. The cross-linked shell of nanovesicles exhibited permeability to the substrate and product. The nanoreactors are enzymatically active and stable in blood plasma at 37°C. The in vitro growth inhibitory activity against MH134 cells showed almost the same dose-response profile as that of the native ADI. The nanoreactors exhibit the potential for arginine deprivation in cancer therapy.

A novel bioactive nerve conduit for the repair of peripheral nerve injury.

The use of a nerve conduit provides an opportunity to regulate cytokines, growth factors and neurotrophins in peripheral nerve regeneration and avoid autograft defects. We constructed a poly-D-L-lactide (PDLLA)-based nerve conduit that was modified using poly{(lactic acid)-co-[(glycolic acid)-alt-(L-lysine)]} and ß-tricalcium phosphate. The effectiveness of this bioactive PDLLA-based nerve conduit was compared to that of PDLLA-only conduit in the nerve regeneration following a 10-mm sciatic nerve injury in rats. We observed the nerve morphology in the early period of regeneration, 35 days post injury, using hematoxylin-eosin and methylene blue staining. Compared with the PDLLA conduit, the nerve fibers in the PDLLA-based bioactive nerve conduit were thicker and more regular in size. Muscle fibers in the soleus muscle had greater diameters in the PDLLA bioactive group than in the PDLLA only group. The PDLLA-based bioactive nerve conduit is a promising strategy for repair after sciatic nerve injury.

PRGD/PDLLA conduit potentiates rat sciatic nerve regeneration and the underlying molecular mechanism.

Peripheral nerve injury requires optimal conditions in both macro-environment and micro-environment for reestablishment. Though various strategies have been carried out to improve the macro-environment, the underlying molecular mechanism of axon regeneration in the micro-environment provided by nerve conduit remains unclear. In this study, the rat sciatic nerve of 10 mm defect was made and bridged by PRGD/PDLLA nerve conduit. We investigated the process of nerve regeneration using histological, functional and real time PCR analyses after implantation from 7 to 35 days. Our data demonstrated that the ciliary neurotrophic factor highly expressed and up-regulated the downstream signaling pathways, in the case of activated signals, the expressions of axon sprout relative proteins, such as tubulin and growth-associated protein-43, were strongly augmented. Taken together, these data suggest a possible mechanism of axon regeneration promoted by PRGD/PDLLA conduit, which created a micro-environment for enhancement of diffusion of neurotrophic factors secreted by the injured nerve stumps, and activation of molecular signal transduction involved in growth cone, to potentiate the nerve recovery.

Promotion of peripheral nerve regeneration and prevention of neuroma formation by PRGD/PDLLA/ß-TCP conduit: report of two cases.

In the field of nerve repair, one major challenge is the formation of neuroma. However, reports on both the promotion of nerve regeneration and prevention of traumatic neuroma in the clinical settings are rare in the field of nerve repair. One of the reasons could be the insufficiency in the follow-up system. We have conducted 33 cases of nerve repair using PRGD/PDLLA/ß-TCP conduit without any sign of adverse reaction, especially no neuroma formation. Among them, we have selected two cases as representatives to report in this article. The first case was a patient with an upper limb nerve wound was bridged by PRGD/PDLLA/ß-TCP conduit and a plate fixation was given. After nearly 3-years' follow-up, the examination results demonstrated that nerve regeneration effect was very good. When the reoperation was performed to remove the steel plate we observed a uniform structure of the regenerated nerve without the formation of neuroma, and to our delight, the implanted conduit was completely degraded 23 months after the implantation. The second case had an obsolete nerve injury with neuroma formation. After removal of the neuroma, the nerve was bridged by PRGD/PDLLA/ß-TCP conduit. Follow-up examinations showed that the structure and functional recovery were improved gradually in the 10-month follow-up; no end-enlargement and any other abnormal reaction associated with the characteristic of neuroma were found. Based on our 33-case studies, we have concluded that PRGD/PDLLA/ß-TCP nerve conduit could both promote nerve regeneration and prevent neuroma formation; therefore, it is a good alternative for peripheral nerve repair.

PDLLA/PRGD/ß-TCP conduits build the neurotrophin-rich microenvironment suppressing the oxidative stress and promoting the sciatic nerve regeneration.

A novel nerve guidance conduit comprising poly{(lactic acid)-co-[(glycolic acid)-alt-(l-lysine)]} (PRGD), poly (d,l-lactic acid) (PDLLA) and ß-tricalcium phosphate (ß-TCP) was constructed to facilitate the peripheral nerve regeneration. From the comparative study, PDLLA/PRGD/ß-TCP conduit achieved the best recovery in regard of the ultrastructure observation and the SFI evaluation. At the first stage of the injury (7 days), the maximum expression augments in ZnSOD (6.4 folds) and GPX4 (6.8 folds) were observed in PDLLA/PRGD/ß-TCP group; while striking rise in actin (6.8 folds), tubulin (5.6 folds), and ERM components expressions were observed later (35 days). Meanwhile, compared with PDLLA and PDLLA/PRGD conduits, PDLLA/PRGD/ß-TCP conduits achieved the highest local nerve growth factor (NGF) content and an accumulating BDNF content. We speculated that addition of RGD and ß-TCP in the composites were the main positive factors to build the microenvironment rich in NGF and BDNF, which help to counteract with the oxidative stress and to boost the cytoskeletal protein expressions. Therefore, PDLLA/PRGD/ß-TCP could be promising composites used in peripheral nerve regeneration.

Dog tibial nerve regeneration across a 30-mm defect bridged by a PRGD/PDLLA/ß-TCP/NGF sustained-release conduit.

Nerve conduits have emerged as alternatives to autologous nerve grafts, but their use in large-diameter, critical nerve repairs is limited. In the previous study, we prepared a PRGD/PDLLA/ß-TCP/NGF sustained-release nerve conduit, which was made of RGD peptide modified poly{(lactic acid)-co-[(glycolic acid)-alt-(L-lysine)]} (PRGD), poly(d,l-lactic acid) (PDLLA), ß-tricalcium phosphate (ß-TCP) and nerve growth factor (NGF). Here we attempted to use the PRGD/PDLLA/ß-TCP/NGF sustained-release nerve conduit to bridge a 30-mm dog tibial nerve defect in six beagles. The other beagles were divided into group autograft (n = 6) as positive control and group PDLLA (n = 6) as negative control. After 9 months of implantation, nerve conduction velocities, the density of myelinated fibers, the mean diameter of axon, and the average thickness of myelin sheath in tibial nerves bridged with PRGD/PDLLA/ß-TCP/NGF sustained-release nerve conduits were similar to those treated with autologous nerve (p > 0.05). Neither electrophysiological nor histological restoration was obtained in group PDLLA. Evidence is thus provided in support of the use of PRGD/PDLLA/ß-TCP/NGF sustained-release nerve conduits as alternatives to autologous nerve grafts for treatment of large-diameter, critical defects in peripheral nerves.

Use new PLGL-RGD-NGF nerve conduits for promoting peripheral nerve regeneration.

BACKGROUND: Nerve conduits provide a promising strategy for peripheral nerve injury repair. However, the efficiency of nerve conduits to enhance nerve regeneration and functional recovery is often inferior to that of autografts. Nerve conduits require additional factors such as cell adhesion molecules and neurotrophic factors to provide a more conducive microenvironment for nerve regeneration. METHODS: In the present study, poly{(lactic acid)-co-[(glycolic acid)-alt-(L-lysine)]} (PLGL) was modified by grafting Gly-Arg-Gly-Asp-Gly (RGD peptide) and nerve growth factor (NGF) for fabricating new PLGL-RGD-NGF nerve conduits to promote nerve regeneration and functional recovery. PLGL-RGD-NGF nerve conduits were tested in the rat sciatic nerve transection model. Rat sciatic nerves were cut off to form a 10 mm defect and repaired with the nerve conduits. All of the 32 Wistar rats were randomly divided into 4 groups: group PLGL-RGD-NGF, group PLGL-RGD, group PLGL and group autograft. At 3 months after surgery, the regenerated rat sciatic nerve was evaluated by footprint analysis, electrophysiology, and histologic assessment. Experimental data were processed using the statistical software SPSS 10.0. RESULTS: The sciatic function index value of groups PLGL-RGD-NGF and autograft was significantly higher than those of groups PLGL-RGD and PLGL. The nerve conduction velocities of groups PLGL-RGD-NGF and autograft were significantly faster than those of groups PLGL-RGD and PLGL. The regenerated nerves of groups PLGL-RGD-NGF and autograft were more mature than those of groups PLGL-RGD and PLGL. There was no significant difference between groups PLGL-RGD-NGF and autograft. CONCLUSIONS: PLGL-RGD-NGF nerve conduits are more effective in regenerating nerves than both PLGL-RGD nerve conduits and PLGL nerve conduits. The effect is as good as that of an autograft. This work established the platform for further development of the use of PLGL-RGD-NGF nerve conduits for clinical nerve repair.

Interaction of olfactory ensheathing cells with nerve repairing scaffolds.

OBJECTIVE: To investigate a new way to yield plenty of high purity olfactory ensheathing cells (OECs) and its biocompatibility with appropriate scaffolds. METHODS: OECs were prepared from neonatal Wister rats and co-cultured with poly [LA-co-(Glc-alt-Lys)] (PLGL). Its contact angle, adherent rate, and activity rate were tested. RESULTS: The contact angle of poly (D, L-lactic acid) (PDLLA) (84.5 degree+/-1.5 degree) was significantly higher than that of PLGL (52.6 degree+/-0.8 degree), the adherent rate of PLGL (80%) was significantly higher than that of the PDLLA (57%), and the activity rate of PLGL (88%) was much higher than that of the PDLLA (76%). CONCLUSION: PLGL possesses better hydrophilicity and biocompatibility than PDLLA, and it can provide a better cell growth circumstance which is helpful for the effective treatment of nerve injury.