Comprehensive Profiling of Amine-Containing Metabolite Isomers with Chiral Phosphorus Reagents.

Metabolite isomers play diverse and crucial roles in various metabolic processes. However, in untargeted metabolomics analysis, it remains a great challenge to distinguish between the constitutional isomers and enantiomers of amine-containing metabolites due to their similar chemical structures and physicochemical properties. In this work, the triplex stable isotope N-phosphoryl amino acids labeling (SIPAL) is developed to identify and relatively quantify the amine-containing metabolites and their isomers by using chiral phosphorus reagents coupled with high-resolution tandem mass spectroscopy. The constitutional isomers could be effectively distinguished with stereo isomers by using the diagnosis ions in MS/MS spectra. The in-house software MS-Isomerism has been parallelly developed for high-throughput screening and quantification. The proposed strategy enables the unbiased detection and relative quantification of isomers of amine-containing metabolites. Based on the characteristic triplet peaks with SIPAL tags, a total of 854 feature peaks with 154 isomer groups are successfully recognized as amine-containing metabolites in liver cells, in which 37 amine-containing metabolites, including amino acids, polyamines, and small peptides, are found to be significantly different between liver cancer cells and normal cells. Notably, it is the first time to identify S-acetyl-glutathione as an endogenous metabolite in liver cells. The SIPAL strategy could provide spectacular insight into the chemical structures and biological functions of the fascinating amine-containing metabolite isomers. The feasibility of SIPAL in isomeric metabolomics analysis may reach a deeper understanding of the mirror-chemistry in life and further advance the discovery of novel biomarkers for disease diagnosis.

Synthesis and Reactivity of an Anti-van't Hoff/Le Bel Compound with a Planar Tetracoordinate Silicon(II) Atom.

For a long time, planar tetracoordinate carbon (ptC) represented an exotic coordination mode in organic and organometallic chemistry, but it is now a useful synthetic building block. In contrast, realization of planar tetracoordinate silicon (ptSi), a heavier analogue of ptC, is still challenging. Herein we report the successful synthesis and unusual reactivity of the first ptSi species of divalent silicon present in 3, supported by the chelating bis(N-heterocyclic silylene)bipyridine ligand, 2,2'-{[(4-tBuPh)C(NtBu)]2SiNMe}2(C5N)2, 1]. The compound resulted from direct reaction of 1 with Idipp-SiI2 [Idipp = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]. Alternatively, it can also be synthesized by a two-electron reduction of the corresponding Si(IV) precursor 2 with 2 molar equiv of KC10H8. Density functional theory calculations show that the lone pair at the ptSi(II) resides almost completely in its 3pz orbital, very different from known four-coordinate silylenes. Oxidative addition of MeI to the ptSi(II) atom affords the corresponding pentacoordinate Si(IV) compound 4, with the methyl group located in an apical position. Remarkably, the reaction of 2 with [CuOtBu] leads to the regeneration of the bis(silylene) arms via Si-Si bond scission and induces the Si(II) → Si(IV) oxidation of the central Si(II) atom and concomitant two-electron reduction of the bipyridine moiety to form the neutral bis(silylene)silyl Cu(I) complex 5.

Where silylene-silicon centres matter in the activation of small molecules.

Small molecules such as H2, N2, CO, NH3, O2 are ubiquitous stable species and their activation and role in the formation of value-added products are of fundamental importance in nature and industry. The last few decades have witnessed significant advances in the chemistry of heavy low-coordinate main-group elements, with a plethora of newly synthesised functional compounds, behaving like transition-metal complexes with respect to facile activation of such small molecules. Among them, silylenes have received particular attention in this vivid area of research showing even metal-free bond activation and catalysis. Recent striking discoveries in the chemistry of silylenes take advantage of narrow HOMO-LUMO energy gap and Lewis acid-base bifunctionality of divalent Si centres. The review is devoted to recent advances of using isolable silylenes and corresponding silylene-metal complexes for the activation of fundamental but inert molecules such as H2, COx, N2O, O2, H2O, NH3, C2H4 and E4 (E = P, As).

Zn(OTf)2-Catalyzed Phosphinylation of Propargylic Alcohols: Access to γ-Ketophosphine Oxides.

The first facile and efficient Zn(OTf)2-catalyzed direct coupling of unprotected propargylic alcohols with arylphosphine oxides has been developed, affording a general, one-step approach to access structurally diverse γ-ketophosphine oxides via sequential Meyer-Schuster rearrangement/phospha-Michael reaction along with new C(sp3)-P and C═O bond formations, operational simplicity, and complete atom economy under ligand-free and base-free conditions.

Stable isotope N-phosphoryl amino acids labeling for quantitative profiling of amine-containing metabolites using liquid chromatography mass spectrometry.

Stable isotope chemical labeling liquid chromatography-mass spectrometry (LC-MS) is a powerful strategy for comprehensive metabolomics profiling, which can improve metabolites coverage and quantitative information for exploration of metabolic regulation in complex biological systems. In the current work, a novel stable isotope N-phosphoryl amino acids labeling strategy (SIPAL) has been successful developed for quantitative profiling of amine-containing metabolites in urine based on organic phosphorus chemistry. Two isotopic reagents, 16O2- and 18O2-N-diisopropyl phosphoryl l-alanine N-hydroxysuccinimide esters (16O/18O-DIPP-L-Ala-NHS), were firstly synthesized in high yields for labeling the amine-containing metabolites. The performance of SIPAL strategy was tested by analyzing standard samples including 20 l-amino acids, 10 d-amino acids and small peptides by using LC-MS. We observed highly efficient and selective labeling for SIPAL strategy within 15 min in a one-pot derivatization reaction under aqueous reaction conditions. The introduction of a neutral phosphate group at N-terminus can increase the proton affinity and overall hydrophobicity of targeted metabolites, leading to the better ionization efficiency in electrospray ionization processes and chromatographic separations of hydrophilic metabolites on reversed-phase column. Furthermore, the chiral metabolites, such as d-amino acids, could be converted to diastereomers after SIPAL and successfully separated on regular reversed-phase column. The chirality of labeled enantiomers can be determined by using different detection methods such as 31P NMR, UV, and MS, demonstrating the potential application of SIPAL strategy. In addition, absolute quantification of chiral metabolites in biological samples can be easily achieved by using SIPAL strategy. For this purpose, urine samples collected from a healthy volunteer were analyzed by using LC-ESI-Orbitrap MS. Over 300 pairs of different amine-containing metabolites have been manually identified with high relative abundance (signal-to-noise ratios greater than 10). Finally, a standard peptide could be relatively quantified by using SIPAL strategy in combination with MALDI-TOF MS, suggesting the potential application of this strategy for quantitative proteomics.

Copper-Catalyzed Direct Coupling of Unprotected Propargylic Alcohols with P(O)H Compounds: Access to Allenylphosphoryl Compounds under Ligand- and Base-Free Conditions.

The first facile and efficient copper-catalyzed direct C-P cross-coupling of unprotected propargylic alcohols with P(O)H compounds has been developed, providing a general, one-step approach to construct valuable allenylphosphoryl frameworks with operational simplicity and high step- and atom-economy under ligand-, base-, and additive-free conditions.

Main group metal-ligand cooperation of N-heterocyclic germylene: an efficient catalyst for hydroboration of carbonyl compounds.

N-heterocyclic ylide-like germylene effectively promotes the hydroboration of aldehydes and ketones under mild conditions with broad substrate tolerance, operational simplicity of procedure and excellent yields. A key intermediate in this catalytic system featuring a bicyclo[2,2,2]octane-like core has been successfully isolated and characterized, suggesting a new type of mechanism that involves the activation mode that mimics that of transition metal catalysts.