Cerebral Palsy Heterogeneity: Clinical Characteristics and Diagnostic Significance from a Large-Sample Analysis.

INTRODUCTION: Cerebral palsy (CP) is a nonprogressive movement disorder resulting from a prenatal or perinatal brain injury that benefits from early diagnosis and intervention. The timing of early CP diagnosis remains controversial, necessitating analysis of clinical features in a substantial cohort. METHODS: We retrospectively reviewed medical records from a university hospital, focusing on children aged ≥24 months or followed up for ≥24 months and adhering to the International Classification of Diseases-10 for diagnosis and subtyping. RESULTS: Among the 2012 confirmed CP cases, 68.84% were male and 51.44% had spastic diplegia. Based on the Gross Motor Function Classification System (GMFCS), 62.38% were in levels I and II and 19.88% were in levels IV and V. Hemiplegic and diplegic subtypes predominantly fell into levels I and II, while quadriplegic and mixed types were mainly levels IV and V. White matter injuries appeared in 46.58% of cranial MRI findings, while maldevelopment was rare (7.05%). Intellectual disability co-occurred in 43.44% of the CP cases, with hemiplegia having the lowest co-occurrence (20.28%, 58/286) and mixed types having the highest co-occurrence (73.85%, 48/65). Additionally, 51.67% (697/1,349) of the children with CP aged ≥48 months had comorbidities. CONCLUSIONS: This study underscores white matter injury as the primary CP pathology and identifies intellectual disability as a common comorbidity. Although CP can be identified in infants under 1 year old, precision in diagnosis improves with development. These insights inform early detection and tailored interventions, emphasizing their crucial role in CP management.

Photoredox/Cu-Catalyzed Decarboxylative C(sp3)-C(sp3) Coupling to Access C(sp3)-Rich gem-Diborylalkanes.

gem-Diborylalkanes are highly valuable building blocks in organic synthesis and pharmaceutical chemistry due to their ability to participate in multi-step cross-coupling transformations, allowing for the rapid generation of molecular complexity. While progress has been made in their synthetic metholodology, the construction of ß-tertiary and C(sp3)-rich gem-diborylalkanes remains a synthetic challenge due to substrate limitations and steric hindrance issues. An approach is presented that utilizes synergistic photoredox and copper catalysis to achieve efficient C(sp3)-C(sp3) cross-coupling of alkyl N-hydroxyphthalimide esters, which can easily be obtained from alkyl carboxylic acids, with diborylmethyl species, providing a series of C(sp3)-rich gem-diborylalkanes with 1°, 2°, and even 3° ß positions. Furthermore, this approach can also be applied to complex medicinal compounds and natural products, offering rapid access to molecular complexity and late-stage functionalization of C(sp3)-rich drug candidates. Mechanistic experiments revealed that diborylmethyl Cu(I) species participated in both the photoredox process and the key C(sp3)-C(sp3) bond-forming step.

Photocatalyzed Borylcyclopropanation of Alkenes with a (Diborylmethyl)iodide Reagent.

Cyclopropane skeletons play a prominent role in the development of organic synthesis and pharmaceutical chemistry. Herein, we report the design and synthesis of a stable, multifunctional (diborylmethyl)iodide reagent (CHI(Bpin)2 ) for the photoinduced cyclopropanation of alkenes, providing an array of 1,2-substituted cyclopropylboronates in good yields. This α-haloboronic ester can be readily synthesized on a multigram scale from commercially available starting materials. Furthermore, the protocol displays high chemo- and diastereoselectivity, excellent functional-group tolerance, and allows for late-stage borylcyclopropanation of complex molecules. Mechanistic studies reveal that the borylcyclopropanation proceeds through a radical addition/polar cyclization pathway mediated by the photocatalyst fac-Ir(ppy)3 and visible light.

Base-Mediated Radical Borylation of Alkyl Sulfones.

A practical and direct method was developed for the production of versatile alkyl boronate esters via transition metal-free borylation of primary and secondary alkyl sulfones. The key to the success of the strategy is the use of bis(neopentyl glycolato) diboron (B2 neop2 ), with a stoichiometric amount of base as a promoter. The practicality and industrial potential of this protocol are highlighted by its wide functional group tolerance, the late-stage modification of complex compounds, no need for further transesterification, and operational simplicity. Radical clock, radical trap experiments, and EPR studies were conducted which show that the borylation process involves radical intermediates.

Selective, Transition Metal-free 1,2-Diboration of Alkyl Halides, Tosylates, and Alcohols.

Defunctionalization of readily available feedstocks to provide alkenes for the synthesis of multifunctional molecules represents an extremely useful process in organic synthesis. Herein, we describe a transition metal-free, simple and efficient strategy to access alkyl 1,2-bis(boronate esters) via regio- and diastereoselective diboration of secondary and tertiary alkyl halides (Br, Cl, I), tosylates, and alcohols. Control experiments demonstrated that the key to this high reactivity and selectivity is the addition of a combination of potassium iodide and N,N-dimethylacetamide (DMA). The practicality and industrial potential of this transformation are demonstrated by its operational simplicity, wide functional group tolerance, and the late-stage modification of complex molecules. From a drug discovery perspective, this synthetic method offers control of the position of diversification and diastereoselectivity in complex ring scaffolds, which would be especially useful in a lead optimization program.

Recent advances in asymmetric borylation by transition metal catalysis.

Chiral organoboronates have played a critical role in organic chemistry and in the development of materials science and pharmaceuticals. Much effort has been devoted to exploring synthetic methodologies for the preparation of these compounds during the past few decades. Among the known methods, asymmetric catalysis has emerged as a practical and highly efficient strategy for their straightforward preparation, and recent years have witnessed remarkable advances in this respect. Approaches such as asymmetric borylative addition, asymmetric allylic borylation and stereospecific cross-coupling borylation, have been extensively explored and well established employing transition-metal catalysis with a chiral ligand. This review provides a comprehensive overview of transition metal-catalysed asymmetric borylation processes to construct carbon-boron, carbon-carbon, and other carbon-heteroatom bonds. It summarises a range of recent achievements in this area of research, with considerable attention devoted to the reaction modes and the mechanisms involved.

Selective C-N Borylation of Alkyl Amines Promoted by Lewis Base.

An efficient method for the metal-free deaminative borylation of alkylamines, using bis(catecholato)diboron as the boron source, to directly synthesize various alkyl potassium trifluoroborate salts is introduced. The key to this high reactivity is the utilization of pyridinium salt activated alkylamines, with a catalytic amount of a bipyridine-type Lewis base as a promoter. This transformation shows good functional-group compatibility (e.g., it is unimpeded by the presence of a ketone, indole, internal alkene, or unactivated alkyl chloride) and can serve as a powerful synthetic tool for borylation of amine groups in complex compounds. Mechanistic experiments and computations suggest a mechanism in which the Lewis base activated B2 cat2 unit intercepts an alkyl radical generated by single-electron transfer (SET) from a boron-based reductant.

Stereoselective Synthesis of Z Fluoroalkenes through Copper-Catalyzed Hydrodefluorination of gem-Difluoroalkenes with Water.

A copper catalytic system was established for the stereoselective hydrodefluorination of gem-difluoroalkenes through C-F activation to synthesize various Z fluoroalkenes. H2 O is used as the hydrogen source for the fluorine acceptor moiety. This mild catalytic system shows good-functional group compatibility, accepting a range of carbonyls as precursors to the gem-difluoroalkenes, including aliphatic, aromatic, and α,ß-unsaturated aldehydes and even ketones. It serves as a powerful synthetic method for the late-stage modification of complex compounds.

Nickel-Catalyzed Borylation of Aryl- and Benzyltrimethylammonium Salts via C-N Bond Cleavage.

By developing a mild Ni-catalyzed system, a method for direct borylation of sp(2) and sp(3) C-N bonds has been established. The key to this hightly efficient C-N bond borylative cleavage depends on the appropriate choice of the nickel catalyst Ni(COD)2, ICy·HCl as a ligand, and the use of 2-ethoxyethanol as the cosolvent. This transformation shows good functional group compatibility and can serve as a powerful synthetic tool for gram-scale synthesis and late-stage C-N borylation of complex compounds.

Nickel-Catalyzed Decarbonylative Borylation of Amides: Evidence for Acyl C-N Bond Activation.

A nickel/N-heterocyclic carbene catalytic system has been established for decarbonylative borylation of amides with B2 nep2 by C-N bond activation. This transformation shows good functional-group compatibility and can serve as a powerful synthetic tool for late-stage borylation of amide groups in complex compounds. More importantly, as a key intermediate, the structure of an acyl nickel complex was first confirmed by X-ray analysis. Furthermore, the decarbonylative process was also observed. These findings confirm the key mechanistic features of the acyl C-N bond activation process.

Direct Synthesis of Tertiary Phosphines via Alkoxide-Mediated Deborylative Phosphination of Organoboronates.

The direct transformation of alkylboron has emerged as a versatile and powerful methodology for creating carbon-carbon and carbon-heteroatom bonds. However, its potential application in the formation of carbon and phosphorus remains unexplored. In this study, we present an alkoxide base-promoted reaction system that enables deborylative phosphination of benzylic organoboronates and geminal bis(boronates) via selective C-B bond cleavage. This approach allows for the synthesis of valuable tertiary phosphines in good yields under mild conditions. The practicality and industrial potential of this approach are underscored by the operational simplicity, broad substrate scope, and easy scalability.

Facile preparation of organosilanes from benzylboronates and gem-diborylalkanes mediated by KOtBu.

Methods to efficiently synthesize organosilanes are valuable in the fields of synthetic chemistry and materials science. During the past decades, boron conversion has become a generic and powerful approach for constructing carbon-carbon and other carbon-heteroatom bonds, but its potential application in forming carbon-silicon remains unexplored. Herein, we describe an alkoxide base-promoted deborylative silylation of benzylic organoboronates, geminal bis(boronates) or alkyltriboronates, allowing for straightforward access to synthetically valuable organosilanes. This selective deborylative methodology exhibits operational simplicity, broad substrate scope, excellent functional group compatibility and convenient scalability, providing an effective and complementary platform for the generation of diversified benzyl silanes and silylboronates. Detailed experimental results and calculated studies revealed an unusual mechanistic feature of this C-Si bond formation.

Cu-mediated vs. Cu-free selective borylation of aryl alkyl sulfones.

A Cu-catalysed borylation of aryl alkyl sulfones was developed for the high yield synthesis of versatile arylboronic esters using a readily prepared NHC-Cu catalyst. In addition, the selective cleavage of either alkyl(C)-sulfonyl or aryl(C)-sulfonyl bonds of a cyclic sulfone via Cu-free or Cu-mediated processes generates the corresponding sulfinate salts, which can be further derivatised to provide sulfonyl-containing boronate esters, such as sulfones and sulfonyl fluorides.

Direct Synthesis of α-Amino Nitriles from Sulfonamides via Base-Mediated C-H Cyanation.

Herein, we disclose a transition-metal-free reaction system that enables α-cyanation of sulfonamides through C-H bond cleavage for the preparation of α-amino nitriles, including difficult-to-access all-alkyl α-tertiary scaffolds. More than 50 substrate examples prove a wide functional group tolerance. Additionally, its synthetic practicality is highlighted by gram-scalability and the late-stage modification of natural compounds. Mechanistic experiments suggest that this process involves in situ formation of an imine intermediate via base-promoted elimination of HF.

Metal-free C(sp3)-H functionalization of sulfonamides via strain-release rearrangement.

With the increasing awareness of sustainable chemistry principles, the development of an efficient and mild strategy for C(sp3)-H bond activation of nitrogen-containing compounds without the utilization of any oxidant and metal is still highly desired and challenging. Herein, we present a metal-free reaction system that enables C-H bond functionalization of aliphatic sulfonamides using DABCO as a promoter under mild conditions, affording a series of α,ß-unsaturated imines in good yields with high selectivities. This protocol tolerates a broad range of functionalities and can serve as a powerful synthetic tool for the late-stage modification of complex compounds. More importantly, control experiments and detailed DFT calculations suggest that this process involves [2 + 2] cyclization/ring-cleavage reorganization, which opens up a new platform for the establishment of other related reorganization reactions.

Copper-catalysed, diboron-mediated cis-dideuterated semihydrogenation of alkynes with heavy water.

Methods to incorporate deuterium atoms into organic molecules are valuable for the pharmaceutical industry. Here, we found that diboron reagents can efficiently mediate the transfer of two D atoms from heavy water directly onto alkynes through copper-catalysed cis-selective semihydrogenation. Avoiding the use of costly and flammable D2 gas, this safe and practical process can proceed with excellent chemoselectivity and stereoselectivity. Utilizing the present method as the key step, the formal asymmetric total synthesis of d2-deuterium-labeled cis-combretastatin A4 is demonstrated. Mechanistic studies suggest that monoborylation of alkynes is the key step for this semihydrogenation process.

Nickel-catalysed retro-hydroamidocarbonylation of aliphatic amides to olefins.

Amide and olefins are important synthetic intermediates with complementary reactivity which play a key role in the construction of natural products, pharmaceuticals and manmade materials. Converting the normally highly stable aliphatic amides into olefins directly is a challenging task. Here we show that a Ni/NHC-catalytic system has been established for decarbonylative elimination of aliphatic amides to generate various olefins via C-N and C-C bond cleavage. This study not only overcomes the acyl C-N bond activation in aliphatic amides, but also encompasses distinct chemical advances on a new type of elimination reaction called retro-hydroamidocarbonylation. This transformation shows good functional group compatibility and can serve as a powerful synthetic tool for late-stage olefination of amide groups in complex compounds.

Generation of high-affinity fully human anti-interleukin-8 antibodies from its cDNA by two-hybrid screening and affinity maturation in yeast.

We have developed a technology for rapidly generating novel and fully human antibodies by simply using the antigen DNA. A human single-chain variable fragment (scFv) antibody library was constructed in a yeast two-hybrid vector with high complexity. After cloning cDNA encoding the mature sequence of human interleukin-8 (hIL8) into the yeast two-hybrid system vector, we have screened the human scFv antibody library and obtained three distinct scFv clones that could specifically bind to hIL8. One clone was chosen for further improvement by a novel affinity maturation process using the error-prone PCR of the scFv sequence followed by additional rounds of yeast two-hybrid screening. The scFv antibodies of both primary and affinity-matured scFv clones were expressed in E. coli. All purified scFvs showed specific binding to hIL8 in reciprocal coimmunoprecipitation and ELISA assays. All scFvs, as well as a fully human IgG antibody converted from one of the scFv clones and expressed in the mammalian cells, were able to effectively inhibit hIL8 in neutrophil chemotaxis assays. The technology described can generate fully human antibodies with high efficiency and low cost.