Cu(I)-Catalyzed Chemo- and Enantioselective Desymmetrizing C-O Bond Coupling of Acyl Radicals.

Transition-metal-catalyzed enantioselective functionalization of acyl radicals has so far not been realized, probably due to their relatively high reactivity, which renders the chemo- and stereocontrol challenging. Herein, we describe Cu(I)-catalyzed enantioselective desymmetrizing C-O bond coupling of acyl radicals. This reaction is compatible with (hetero)aryl and alkyl aldehydes and, more importantly, displays a very broad scope of challenging alcohol substrates, such as 2,2-disubstituted 1,3-diols, 2-substituted-2-chloro-1,3-diols, 2-substituted 1,2,3-triols, 2-substituted serinols, and meso primary 1,4-diols, providing enantioenriched esters characterized by challenging acyclic tetrasubstituted carbon stereocenters. Partnered by one- or two-step follow-up transformations, this reaction provides a convenient and practical strategy for the rapid preparation of chiral C3 building blocks from readily available alcohols, particularly the industrially relevant glycerol. Mechanistic studies supported the proposed C-O bond coupling of acyl radicals.

Cu-catalysed enantioselective radical heteroatomic S-O cross-coupling.

The transition-metal-catalysed cross-coupling reaction has established itself as one of the most reliable and practical synthetic tools for the efficient construction of carbon-carbon/heteroatom (p-block elements other than carbon) bonds in both racemic and enantioselective manners. In contrast, development of the corresponding heteroatom-heteroatom cross-couplings has so far remained elusive, probably due to the under-investigated and often challenging heteroatom-heteroatom reductive elimination. Here we demonstrate the use of single-electron reductive elimination as a strategy for developing enantioselective S-O coupling under Cu catalysis, based on both experimental and theoretical results. The reaction manifests its synthetic potential by the ready preparation of challenging chiral alcohols featuring congested stereocentres, the expedient valorization of the biomass-derived feedstock glycerol, and the remarkable catalytic 4,6-desymmetrization of inositol. These results demonstrate the potential of enantioselective radical heteroatomic cross-coupling as a general chiral heteroatom-heteroatom formation strategy.

The Effect of Arthroscopic Extra-Articular Entire Coracohumeral Ligament Release for Patients with Recalcitrant Frozen Shoulder.

OBJECTIVE: The thickened coracohumeral ligament (CHL) is an important part of the typical manifestations and magnetic resonance imaging of frozen shoulder. However, only a few clinical studies with limited cases on arthroscopic extra-articular entire CHL release exist in the literature. This study was to evaluate the effect of arthroscopic extra-articular entire CHL release for patients with recalcitrant frozen shoulder. METHODS: From February 2014 to February 2020, 81 cases of recalcitrant frozen shoulder patients treated with surgery in a single-center shoulder department and followed for more than 2 years were analyzed. Arthroscopic 360° capsular release was performed with intra-articular partial release (IPR group) or additional extra-articular entire release (IPR + EER group) of CHL. The same rehabilitation program was performed after surgery in both groups. Visual analogue scale (VAS) for pain, range of motion (ROM), and the Constant-Murley scoring system was evaluated before operation, at 3 months after operation, 6 months after operation, and the final follow-up. T-test, Mann-Whitney U-test and chi-squared test were used to compared data. RESULTS: There were 39 patients in the IPR group, with an average follow-up of 29.2 months. A total of Forty-two patients in the IPR + EER group completed a mean follow-up of 25.7 months. All incisions healed in stages. There were significant differences in Constant-Murley shoulder score, VAS score, and ROM before operation and at the final follow-up in both groups (both P < 0.001). The VAS score of the IPR + EER group was lower than that of the IPR group at 3 months after surgery (P < 0.05), and 6 months after operation (P < 0.05). External rotation, internal rotation, and abduction of ROMs and Constant-Murley shoulder score were significantly greater in the IPR + EER group at 3 months (P < 0.001, P < 0.05, P < 0.001, P < 0.05, respectively) and 6 months after operation (P < 0.001, P < 0.05, P < 0.001, P < 0.05, respectively). At the last follow-up, there was no significant difference in forward flexion, internal rotation, and abduction of ROMs, VAS, and the Constant-Murley shoulder score between the IPR and IPR + EER groups. The external rotation of the IPR + EER group was still greater than that of the IPR group at the last follow-up (P < 0.001). CONCLUSION: Arthroscopic extra-articular entire coracohumeral ligament release could solve early pain of shoulder joint, recover shoulder joint functions effectively, and achieve a satisfactory efficacy in the treatment of recalcitrant frozen shoulder.

A humanized 4-1BB-targeting agonistic antibody exerts potent antitumor activity in colorectal cancer without systemic toxicity.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies and the patient survival rate remains unacceptably low. The anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody-based immune checkpoint inhibitors have been added to CRC treatment regimens, however, only a fraction of patients benefits. As an important co-stimulatory molecule, 4-1BB/CD137 is mainly expressed on the surface of immune cells including T and natural killer (NK) cells. Several agonistic molecules targeting 4-1BB have been clinically unsuccessful due to systemic toxicity or weak antitumor effects. We generated a humanized anti-4-1BB IgG4 antibody, HuB6, directed against a unique epitope and hypothesized that it would promote antitumor immunity with high safety. METHODS: The antigen binding specificity, affinity and activity of HuB6 were determined by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), biolayer interferometry (BLI) and flow cytometry. The antitumor effects were evaluated in humanized mice bearing syngeneic tumors, and possible toxicity was evaluated in humanized mice and cynomolgus monkeys. RESULTS: HuB6 showed high specificity and affinity for a binding epitope distinct from those of other known 4-1BB agonists, including utomilumab and urelumab, and induced CD8 + T, CD4 + T and NK cell stimulation dependent on Fcγ receptor (FcγR) crosslinking. HuB6 inhibited CRC tumor growth in a dose-dependent manner, and the antitumor effect was similar with urelumab and utomilumab in humanized mouse models of syngeneic CRC. Furthermore, HuB6 combined with an anti-PD-L1 antibody significantly inhibited CRC growth in vivo. Additionally, HuB6 induced antitumor immune memory in tumor model mice rechallenged with 4 × 106 tumor cells. Toxicology data for humanized 4-1BB mice and cynomolgus monkeys showed that HuB6 could be tolerated up to a 180 mg/kg dose without systemic toxicity. CONCLUSIONS: This study demonstrated that HuB6 should be a suitable candidate for further clinical development and a potential agent for CRC immunotherapy.

Copper-Catalyzed anti-Selective Radical 1,2-Alkylarylation of Terminal Alkynes.

A copper-catalyzed highly anti-selective radical 1,2-alkylarylation of terminal alkynes with aryl boronic acids and alkyl bromides has been established. The reaction exhibits high compatibility with a wide range of terminal alkynes and diverse aryl boronic acids, thus providing facile access to various stereodefined trisubstituted alkenes in high yield under mild reaction conditions. Preliminary mechanistic investigations support the formation of alkyl radicals and their subsequent addition to alkynes in the reaction.

Desymmetrization of unactivated bis-alkenes via chiral Brønsted acid-catalysed hydroamination.

Although great success has been achieved in catalytic asymmetric hydroamination of unactivated alkenes using transition metal catalysis and organocatalysis, the development of catalytic desymmetrising hydroamination of such alkenes remains a tough challenge in terms of attaining a high level of stereocontrol over both remote sites and reaction centers at the same time. To address this problem, here we report a highly efficient and practical desymmetrising hydroamination of unactivated alkenes catalysed by chiral Brønsted acids with both high diastereoselectivity and enantioselectivity. This method features a remarkably broad alkene scope, ranging from mono-substituted and gem-/1,2-disubstituted to the challenging tri- and tetra-substituted alkenes, to provide access to a variety of diversely functionalized chiral pyrrolidines bearing two congested tertiary or quaternary stereocenters with excellent efficiency under mild and user-friendly synthetic conditions. The key to success is indirect activation of unactivated alkenes by chiral Brønsted acids via a concerted hydroamination mechanism.

Recent Advances in First-Row Transition Metal/Chiral Phosphoric Acid Combined Catalysis.

Since the pioneering independent reports of Akiyama and Terada, the use of chiral phosphoric acids (CPAs) and derivatives as a versatile tool for asymmetric synthesis with good reactivity, regioselectivity, diastereoselectivity and enantioselectivity has emerged, forming an important part of the implementation of asymmetric counteranion-directed catalysis reported to date. In these achievements, the combination of metals with CPAs has enabled various catalytic modes beyond the scope of typical acid catalysis, such as relay catalysis, ion-pairing catalysis, and binary acid catalysis. The first-row transition metals (Sc-Zn) are considered to be sustainable transition metals and have received a great deal of attention. These naturally abundant metals display excellent Lewis acidity and function as powerful redox catalysts in synthesis involving both one and two-electron transfers. Hence, in this chapter, we summarize recent advances in the development of asymmetric reactions using a combination of first-row transition metals and CPAs. Furthermore, we provide a detailed discussion of the mechanisms involved in order to understand the interaction of the metal/phosphate and the origins of the asymmetric control of the transformations.

[Expression of the Fra-1 gene in the peripheral blood of children with Wilms tumor].

OBJECTIVE: To study the expression of the Fra-1 gene in the peripheral blood of children with Wilms tumor and its clinical significance. METHODS: Fifty children pathologically diagnosed with Wilms tumor between December 2012 and January 2018 were enrolled as the case group, and 40 healthy children for physical examination were selected as the control group. Among the 45 children with Wilms tumor who were followed up, the children with continuous remission were included in the ideal efficacy group (n=33), and those with recurrence, metastasis or death were included in the poor efficacy group (n=12). Peripheral blood samples were collected from all subjects. Quantitative real-time PCR was used to measure the mRNA expression of Fra-1. RESULTS: The case group had significantly higher mRNA expression of Fra-1 in peripheral blood than the control group (P<0.05). In the case group, Fra-1 mRNA expression was significantly different between the individuals with and without distant metastasis and those with different TNM stages (P<0.05), but was not significantly different between the individuals with different sexes, ages, tumor diabetes, tumor locations and alpha-fetoprotein levels (P>0.05). The mRNA expression of Fra-1 was significantly lower in the ideal efficacy group than in the poor efficacy group (P<0.05). CONCLUSIONS: Fra-1 may be involved in the development of Wilms tumor and plays a certain role in its development, invasion and metastasis, but the mechanism remains to be further studied.

Redox-Neutral α-C-H Functionalization of Pyrrolidin-3-ol.

A redox-neutral α-C-H oxygenation of commercially available pyrrolidin-3-ol with a monoprotected p-quinone generated an N-aryliminium ion intermediate, which reacted in situ with boronic acid nucleophiles to produce a series of cis-2-substituted pyrrolidin-3-ols. With this strategy, 8-epi-(-)-lentiginosine was synthesized from (3R,4R)-pyrrolidine-3,4-diol in three steps.

Achiral Pyridine Ligand-Enabled Enantioselective Radical Oxytrifluoromethylation of Alkenes with Alcohols.

A conceptually novel strategy with achiral pyridine as the ancillary ligand to stabilize high-valent copper species for the first asymmetric radical oxytrifluoromethylation of alkenes with alcohols under CuI /phosphoric acid dual-catalysis has been developed. The transformation features mild reaction conditions, a remarkably broad substrate scope and excellent functional group tolerance, offering an efficient approach to a wide range of trifluoromethyl-substituted tetrahydrofurans bearing an α-tertiary stereocenter with excellent enantioselectivity. Mechanistic studies support the presumed role of the achiral pyridine as a coordinative ligand on copper metal to stabilize the key transient reaction species involved in the asymmetric induction process.

Synthesis of γ-Lactams by Mild, o-Benzoquinone-Induced Oxidation of Pyrrolidines Containing Oxidation-Sensitive Functional Groups.

The late-stage oxidation of substituted pyrrolidines offers good flexibility for the construction of γ-lactam libraries, and especially in recent years the methods for functionalization of pyrrolidine have been available. We reported a new strategy for oxidation of pyrrolidines to γ-lactams: reaction of pyrrolidine with an o-benzoquinone gives an N,O-acetal by direct oxidation of the α-C-H bond of the pyrrolidine ring, and then the N,O-acetal is further oxidized by the o-benzoquinone to the γ-lactam. Because the first oxidation occurs selectively at the α-C-H of the pyrrolidine ring, oxidation-sensitive functional groups (allyl-, vinyl-, hydroxyl-, and amino groups) on pyrrolidine ring are unaffected. The synthetic utility of this novel method was demonstrated by the facile syntheses of (S)-vigabatrin and two analogues.

Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings.

Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavourable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. To address this problem, we herein disclose a radical-based approach for diversity-oriented synthesis of various benzannulated carbon- and heteroatom-containing 8-11(14)-membered ketone libraries. This strategy involves 1,4- or 1,5-aryl migration triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation, or perfluoroalkylation of unactivated alkenes followed by intramolecular ring expansion. Demonstration of this method as a highly flexible tool for the construction of 37 synthetically challenging medium-sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Some of these products showed potent inhibitory activity against the cancer cell or derivative of human embryonic kidney line in preliminary biological studies. The mechanism of this novel strategy is investigated by control experiments and DFT calculations.

Redox-Triggered α-C-H Functionalization of Pyrrolidines: Synthesis of Unsymmetrically 2,5-Disubstituted Pyrrolidines.

By using o-benzoquinone as an internal oxidant, the regio- and diastereoselective functionalization of the secondary over the tertiary α-C-H bond of 2-substituted pyrrolidines is first realized. Subsequent intermolecular addition of a nucleophile to the generated N,O-acetal and cleavage of the aromatic substituent leads to 2,5-disubstituted pyrrolidines.