A rapid synthesis of harmicine was achieved through 1,3-dipolar cycloaddition and facile ring reconstruction, including mesylation, cleavage of the N-O bond, and subsequent cyclization. An enzymatic kinetic resolution was developed to obtain optically enriched tetrahydro-beta-carboline, which was further elaborated to prepare harmicine. Additionally, diastereomeric synthesis of harmicinic acid was also achieved, and stereochemical determination was enabled by chemical resolution and electronic circular dichroism calculations for the first time, providing an intriguing platform to access various derivatives for future medicinal research.

Catalytic asymmetric 1,4- and 1,6-conjugate addition between electron-deficient conjugated dienes and amine nucleophiles are one of the valuable basic transformations. In contrast, the corresponding N-1,5-conjugate addition reaction is electronically forbidden and considered unfeasible. We demonstrate that the N-1,5-addition can work efficiently via a palladium catalyst with a group of modified chiral PHOX ligands. The amine nucleophiles are introduced to the umpolung gamma-position of electron-deficient ester groups in moderate to good yield and with high stereoselectivity. Four types of cascade processes have been established to provide convenient routes for the synthesis of enantioenriched N-heterocycles, including 2-imidazolidones, tetrahydroquinoxalines, benzomorpholines, and 2-oxazolidones. Mechanistic studies suggest C-N bond formation as the rate-determining step.

Biocatalysis is an essential tool for asymmetric synthesis, significantly enhancing the production of chiral molecules. As advancements in protein screening and engineering rapidly evolve, the demand for efficient, rapid chiral analysis methods has intensified. Addressing this need, we introduce a high-throughput 19F NMR-based assay that provides comprehensive insights into the enantioselectivity, stereopreference, and yields of biocatalytic reactions. This assay has been successfully applied to screen imine reductases, showcasing its efficacy in the directed evolution for synthesizing an intermediate of the anti-Parkinson drug, rotigotine. Our method offers substantial promise for propelling forward the fields of biocatalysis and synthetic biology by accelerating the assessment of stereochemical outcomes in biocatalytic processes.

Propargylic substitution is a basic type of transformation in organic synthesis but relies on the existence of an alpha-leaving group. Thus, alkyne bearing an alkyl-linked remote leaving group is not considered as a suitable substrate for propargylation, and related remote substitution is unexplored. Here, we show that such a remote propargylation model can be established stereoselectively via copper catalysis. By combining the positive effects of d-orbital electron donation of alkynyl copper, ring strain release, and the cleaving tendency of the remote leaving group, propargylic cyclopropane fragmentation and functionalization is achieved in good yield and with high enantioselectivity. A set of modified chiral PPBOX ligands are developed to guarantee stereocontrol of the transformation. Both the amination and alkylation processes have been established to demonstrate the reliability of the design. Mechanistic studies show the necessity of Cu metal, ring strain, and remote leaving group in promoting C-C bond cleavage and that propargylic substitution might be the turnover-limiting step.

Polymethacrylate (PMMA) has held a long-standing interest in materials science due to its good processability, considerable optical and mechanical performance, and low price. However, the current challenge lies in maintaining high thermal stability across a wide temperature range for PMMA-based materials. Herein, a series of perfluorocyclobutyl (PFCB) aryl ether-containing PMMA copolymers were prepared to improve the heat resistance of PMMA-based materials via introducing PFCB moiety and forming crosslink network structures. First, a 4-(2-(4-methoxyphenoxy)perflurocyclobutoxy)-[1,1'-biphenyl]-4-ylmethyl methacrylate (PFBMA) monomer with PFCB moiety was copolymerized with methyl methacrylate (MMA) to provide PFCB-containing PMMA copolymers with exceptional thermal stability. Subsequently, a dimethacrylate monomer containing PFCB moiety was synthesized and copolymerized with MMA, resulting in crosslinked PMMA copolymers where PFCB served as a connection point. The resulting crosslinked PMMA copolymers showed higher glass transition temperature (Tg) and thermal decomposition temperature (Td) than those of PMMA, along with exceptional optical transparency. This study not only establishes an efficient synthetic route for the preparation of PFCB-containing PMMA copolymers but expands the structural diversity of functional polymers.

Swinhoeisterols A-C are 13(14 -> 8),14(8 -> 7)-diabeo-steroids possessing an intriguing 6/6/5/7 tetracyclic core framework and potent inhibitory activity against the histone acetyltransferase p300. Herein we report their divergent total syntheses from readily available (S)-Wieland-Miescher ketone. A tandem Negishi/Heck cross-coupling of a chloroenol triflate was developed to install the labile methylenecyclopentene motif using a silyl-tethered homoallylic zinc reagent that was carefully designed to suppress undesired [Pd]-H insertion. Furthermore, a Baran reductive olefin coupling of a diene, a rarely used radical donor, with a tethered acrylonitrile group allowed for the simultaneous construction of the seven-membered ring and two contiguous stereocenters, including a quaternary carbon center.

Biosynthesis of free fatty acids (FFAs) in mammals is pivotal for metabolic homeostasis, yet a comprehensive understanding of tissue-specific biosynthesis and inter-tissue crosstalk of FFAs remains incomplete. In vivo stable-isotope tracing metabolomics is utilized to comprehensively measure FFA biosynthesis and inter-tissue crosstalk in mice. Systematically assessing tissue-specific biosynthesis of 13 FFAs across 15 tissues unveils dynamic spatial and temporal accumulation and redistribution of FFAs throughout the body. Employing an analytical framework to deconvolve mass isotopologue patterns, inter-tissue crosstalk is explored for saturated, polyunsaturated, and monounsaturated FFAs, and quantify communications of FFA (16:0) and FFA (18:0) between the liver and other tissues. Then, a decline in fatty acid biosynthesis in peripheral tissues but not in the brain of aged mice is observed, particularly evident in palmitic acid and monounsaturated fatty acids. These findings illuminate the complex interplay between tissue-specific fatty acid biosynthesis and the maintenance of metabolic homeostasis.

Metabolic reactions play important roles in organisms such as providing energy, transmitting signals, and synthesizing biomacromolecules. Charting unknown metabolic reactions in cells is hindered by limited technologies, restricting the holistic understanding of cellular metabolism. Using mass spectrometry-resolved stable-isotope tracing metabolomics, we develop an isotopologue similarity networking strategy, namely IsoNet, to effectively deduce previously unknown metabolic reactions. The strategy uncovers similar to 300 previously unknown metabolic reactions in living cells and mice. Specifically, we elaborately chart the metabolic reaction network related to glutathione, unveiling three previously unreported reactions nestled within glutathione metabolism. Among these, a transsulfuration reaction, synthesizing gamma-glutamyl-seryl-glycine directly from glutathione, underscores the role of glutathione as a sulfur donor. Functional metabolomics studies systematically characterize biochemical effects of previously unknown reactions in glutathione metabolism, showcasing their diverse functions in regulating cellular metabolism. Overall, these newly uncovered metabolic reactions fill gaps in the metabolic network maps, facilitating exploration of uncharted territories in cellular biochemistry.

An efficient C-N cross-coupling between readily available aryl chlorides and diaryl amines has been established by using Pd/TXPhos as catalyst, leading to a diversity of triarylamines in high yields. Detailed experimentation revealed that terphenyl phosphine ligand TXPhos exhibited premier catalytic performance in comparison with common ligands and the choice of base and solvent was crucial to reactivity. Strong bases, such as NaOtBu and LHMDS, were the preferred ones for electron-rich diarylamines, while bases including alkali metal carbonates and phosphates were the suitable choice for diarylamines possessing electron-withdrawing substituents. Notably, the use of TXPhos as supporting ligand enabled the extension to weak base such as NaOPh with electron-rich diarylamine substrates. Mechanistic studies indicated that a Pd phenolate species initially formed after the oxidative addition step when NaOPh was employed as the base, which would facilitate the generation of Pdamide complex after amine coordination. The synthetic utility of this coupling protocol was exemplified by the efficient synthesis of several carbazole-based OLED molecules and the practicality was demonstrated by the achievement of up to 3300 TON.

Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8(+) T cells. Instead, cancer cells outcompete CD8(+) T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8(+) T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.

A KOtBu-mediated C2-benzylation of quinoline N-oxides with benzylboronates under mild reaction conditions has been developed. The reaction shows broad scope for both of the quinoline N-oxides and benzylboronates, especially, secondary and tertiary benzylboronates are also compatible with this reaction. DFT calculations indicate that the reaction is promoted by the nucleophilic addition of KOtBu to boronate rather than the deprotonation of benzylic C-H bond with KOtBu.

Glycosaminoglycans (GAGs) are essential polysaccharides crucial for various cellular functions, such as cell proliferation, migration, and differentiation. However, their complex structure and variability from natural sources pose challenges for functional studies and therapeutic applications. In this study, we engineered a glycopeptide that assembles into fibrils, emulating the functional attributes of GAGs. Utilizing cryo-EM, we elucidated the atomic structure of the designed glycopeptide fibril, which is composed of three identical protofilaments intertwined into a left-handed helix and held together by a variety of intermolecular interactions. Remarkably, the functional sugar units, glucuronic acids, are orderly positioned on the fibril surface, making them readily accessible to the solvent. This distinctive spatial configuration allows the designed glycopeptide fibril to effectively mimic key GAG functionalities, including the promotion of cell proliferation, cell migration, and osteogenic differentiation. Our findings offer a structural framework for designing glycan functionalities on glycopeptide fibrils and open avenues for developing glycopeptide-based materials with versatile biological activities. This work further enhances the potential of these materials for applications in therapeutic and regenerative medicine.